volume 26 supplement 2 october 2003

USP Veterinary Pharmaceutical Information Monographs Antibiotics

USP VETERINARY PHARMACEUTICAL INFORMATION MONOGRAPHS ANTIBIOTICS

CONTENTS v 1 33 36 46 51 71 74 79 81 87 109 119 144 149 151 161 164 185 191 202 207 225 253 257 262 269 Introduction Aminoglycosides (VeterinarySystemic) Aminopenicillins (VeterinaryIntramammary-Local) Aminopenicillins (VeterinarySystemic) Amoxicillin and Clavulanate (VeterinarySystemic) Cephalosporins (VeterinarySystemic) Cephapirin (VeterinaryIntramammary-Local) Chloramphenicol (VeterinarySystemic) Erythromycin (VeterinaryIntramammary-Local) Florfenicol (VeterinarySystemic) Fluoroquinolones (VeterinarySystemic) Lincosamides (VeterinarySystemic) Macrolides (VeterinarySystemic) Metronidazole (VeterinarySystemic) Penicillin G (VeterinaryIntramammary-Local) Penicillin G (VeterinarySystemic) Pirlimycin (VeterinaryIntramammary-Local) Potentiated Sulfonamides (VeterinarySystemic) Pyrimethamine (VeterinarySystemic) Rifampin (VeterinarySystemic) Spectinomycin (VeterinarySystemic) Sulfonamides (VeterinarySystemic) Tetracyclines (VeterinarySystemic) Indications Index Dosing Index Veterinary Brand and Generic Name Index Human Brand and Generic Name Index

Introduction v

Introduction
WHATS DIFFERENT ABOUT A USP DRUG INFORMATION MONOGRAPH
The Veterinary Medicine Expert Committee on Drug Information gratefully acknowledges the nancial support of its parent organization, the United States Pharmacopeia, to publish these monographs. It also is appreciative to the Food Animal Residue Avoidance Databank (FARAD) for supplying slaughter and milk withdrawal information where extra-label drug use in food animals is noted. This information is provided in cooperation with MICROMEDEX, a Thomson Healthcare Company. included where it may be helpful. Each draft chapter or monograph is then put through a review process that includes USP Veterinary Medicine Committee members, regulatory representatives, pharmaceutical manufacturers, ad hoc specialists, and public review. At present, USP monographs are the only drug information source in veterinary medicine undergoing such extensive expert review, a process through which the credibility of the information is maintained. USP drug information is a work-in-progress. The information is in constant revision and is a continuous collection of the current judgments of experts in the use of medications. The following chapters have been developed over 7 years, with information added and revised, as necessary.

USP history, organizational structure, and publications

In pursuit of its mission to promote public health, the United States Pharmacopeia (USP) develops authoritative information about the appropriate use of medicines, including those used in animals. This non-government, not-for-prot organization draws on a long-standing dedication to public involvement in the establishment of scientic standards. USP achieves its goals through the contributions of volunteers representing health care professions, as well as science, academia, the U.S. government, the pharmaceutical industry, and consumer organizations. USP was established in 1820 with the primary goal of setting standards for the identity, strength, and quality of medicinal compounds and this remains at the core of the organization. Currently, USP provides standards for more than 3,800 prescription and non-prescription drugs, nutritional and dietary supplements, veterinary drugs, and health care products. These standards are published in the United States Pharmacopeia (USP) and the National Formulary (NF), which are ofcially recognized in the Federal Food, Drug, and Cosmetic Act (21 U.S.C. 321 et seq.). USP also produces Reference Standards, which are an integral part of USPs standards program. The development of USP information on the best use of medications was begun in 1970, growing out of the public process of developing quality standards. USP information advisory panels were created to assure that the information under development is evidence-based, consensusestablished, practical, and clinically relevant. This work was expanded into a separate public health program and in 1980, the rst USP DI was published. Today, in association with MICROMEDEX, USP continues to provide oversight and approval of drug information content in the USP DI database, which covers nearly all medicines in the U.S. and Canada.

Unique features
This special issue of the Journal of Veterinary Pharmacology and Therapeutics contains a series of drug information monographs on antimicrobials used in veterinary medicine. What makes this information different from other sources of veterinary drug information? A succinct listing would include: The incorporation of extra-label and label indications and dosages for all domestic species. See the section below, Finding the specic drug information you need; Label and extra-label uses, for details on how this information is differentiated. The inclusion of slaughter and milk withdrawals when extra-label drug use in food animals is considered an acceptable option for therapy. Withdrawal times have been provided by FARAD for the specied conditions noted. The inclusion of information about both U.S. and Canadian veterinary drug products. The grouping of indications into three categories. The Accepted category indicates that clear evidence exists to support use of the drug for a particular purpose. Acceptance not established (potentially useful) indicates that use of the drug for an indication may be worthy of consideration if superior therapies do not exist, but the evidence is either scant or subject to concern based on experimental design. If a use is viewed as ineffective or has been replaced by clearly superior therapies, the indication is deemed Unaccepted. These categorizations are applied to label and extralabel uses. The use of tables of scientic evidence to address controversial issues during the review process, particularly relative to extra-label drug use. Review of the information by a Food and Drug Administration (FDA) liaison to the committee. Although comments made by the FDA are taken quite seriously, those opinions are nonbinding on the USP. The information contained in these monographs should not be considered an endorsement or acceptance by the FDA as to a given use or dosage. The review of each monograph by the USP Veterinary Medicine Committee. This committee consists of 10 to 15 volunteers recognized as experts in pharmacology, internal medicine, or species discipline(s).

The veterinary drug information monograph creation process

Very soon after the USP DI was rst published, an advisory panel on veterinary medicine was created. Since 1982, veterinary pharmacologists, veterinary pharmacists, and other specialists have contributed their time and expertise in creating and revising drug information through USPs unique process. This drug information is developed by exhaustive compilation of approved product label information and also collection and analysis of publicly available data on each drug from research studies and clinical reports. Careful attention is paid to differentiating species-specic information. With the agreement of MICROMEDEX, information from the human USP DI database is

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vi Introduction

Finding the specic drug information you need Label and extra-label uses
The Indications section of each drug monograph is designed to provide information about indications in drug product labeling in the U.S. and Canada. Extra-label indications for which clinical and research data have been evaluated are also included. Indications found in product labeling are listed rst. Brackets around an indication signify that it is not found in any product labeling in the U.S. at the time of last major revision. Some indications are followed by a superscript 1, meaning they are not included in Canadian product labeling. Examples of bracket and superscript 1 placement in the monographs: [Pneumonia, bacterial (treatment)] An extra-label use in the U.S. An indication is included in Canadian product labeling. An indication found in U.S. Pneumonia, bacterial (treatment)1 product labeling but not in Canadian product labeling. [Pneumonia, bacterial (treatment)]1 An extra-label use in both the U.S. and Canada.

ACKNOWLEDGEMENTS
The following individuals are recognized for their contributions and support towards the production of this body of work:

USP Staff
Roger Williams, MD (CEO and Executive Vice President, USP) Ian DeVeau, PhD (Senior Scientist, Veterinary Drugs, Information and Standards Development, USP) Amy S. Neal, DVM (USP consultant, writer and editor) Jerome A. Halperin, BS, MPH, MS (former CEO and Executive Vice President, USP) Keith Johnson (former Director, Drug Information Division, USP) David Nash, DVM (former Director, Veterinary Medicine, Information and Standards Development, USP) E. Kathryn Meyer, VMD (former Drug Information Specialist and Coordinator, Veterinary Practitioners Reporting Program, USP)

2000 to 2005 Veterinary Medicine Committee

Cory Langston, DVM, PhD, DACVCP, Chair Michael D. Apley, DVM, PhD, BS, DACVCP Dawn M. Boothe, BS, MS, DVM, PhD, DACVCP, DACVIM Terrence P. Clark, DVM, PhD, DACVCP Gigi F. Davidson, BS, RPh, DICVP Patricia Dowling, DVM, MS, DACVIM, DACVCP Douglas T. Kemp, PharmD, DICVP Mark G. Papich, DVM, MS, BS, DACVCP M. Gatz Riddell, DVM, MS Jim E. Riviere, DVM, PhD, MS, BS Roderick C. Tubbs, DVM, PhD Jeff R. Wilcke, DVM, MS, DACVCP

Species and dosage forms

Within each category of the Indications section the information is arranged in a hierarchy as follows: indication, followed by the species to which that indication applies, and nally the dosage forms used in that species for that indication. You will see that some species and dosage forms are also given bracket and superscript 1 designations; these have the same meaning for species and dosage forms as described above for indications. To decrease clutter and confusion, only the highest level of the hierarchy is given a bracket or superscript 1 (indication > species > dosage form). That is, if the indication is not found on any label in the U.S. (a bracketed, extralabel use) then the species under it will not be bracketed because it is obvious that no species are on the label of any product in the United States for this indication.

1995 to 2000 Veterinary Medicine Advisory Panel

Cory Langston, DVM, PhD, DACVCP, Chair Michael D. Apley, DVM, PhD, BS, DACVCP Gordon Brumbaugh, DVM, PhD, DACVCP Thomas Burkgren, DVM, MBA Cynthia T. Culmo, RPh Lloyd E. Davis, PhD, DVM Patricia Dowling, DVM, MS, DACVIM, DACVCP Stuart Forney, RPh, MS Antoinette D. Jernigan, DVM, PhD, DACVCP Mark G. Papich, DVM, MS, DACVCP Thomas E. Powers, DVM, PhD Jim E. Riviere, DVM, PhD Charles R. Short, DVM, PhD, DACVCP Hector Sumano Lopez, DVM, PhD Jeff R. Wilcke, DVM, MS, DACVCP

Dosing
In the USP veterinary drug information monographs, dosage forms are always listed separately to provide an opportunity to list specic information for each type of product. In the Dosage Forms section, indications and species are bracketed or given a superscript 1 following the same rules applied in the Indications section, except that they reect the labeling of the specic dosage form. Dosages listed are not always label dosages even if the species is in the product labeling.

Label and extra-label withdrawal times

Established withdrawal times from product labeling are listed in the Withdrawal times tables for each dosage form labeled for use in food-producing animals. But be sure to consult the approved labeling on the product you are using for the specic government established dose and withdrawal time. Extra-label withdrawal times are listed in the Withdrawal times section for each extra-label use and/or dose recommended for food-producing animals. As always, veterinarians will use their own clinical judgment, following the guidelines of the Animal Medicinal Drug Use Clarication Act, to determine a safe extra-label withdrawal time. Cory Langston, DVM, PhD, DACVCP Chair, USP Veterinary Medicine Expert Committee on Drug Information 2003 Thomson MICROMEDEX

1990 to 1995 Veterinary Medicine Advisory Panel

Lloyd E. Davis, DVM, PhD, Chair Arthur L. Aronson, DVM, PhD Gordon Brumbaugh, DVM, PhD, DACVCP Gordon L Coppoc, DVM, PhD Sidney A. Ewing, DVM, PhD Stuart D. Forney, RPh, MS William G. Huber, DVM, PhD William L. Jenkins, DVM, PhD, DACVCP All rights reserved

Introduction vii Cory Langston, DVM, PhD, DACVCP Mark G. Papich, DVM, MS, DACVCP John W. Paul, DVM, PhD Thomas E. Powers, DVM, PhD, DACVCP Charles R. Short, DVM, PhD, DACVCP Richard H. Teske, DVM, PhD Jeff R. Wilcke, DVM, MS, DACVCP Arthur L. Aronson, DVM, PhD Nicholas H. Booth, DVM, PhD Gordon L Coppoc, DVM, PhD George T. Edds, DVM, PhD Sidney A. Ewing, DVM, PhD Peter A. Eyre, BVMS, PhD Stuart D. Forney, RPh, MS William G. Huber, DVM, PhD Robert W. Phillips, DVM, PhD Thomas E. Powers, DVM, PhD I.A. Schipper, DVM, PhD Richard H. Teske, DVM, PhD

1985 to 1990 Panel on Veterinary Medicine

Lloyd E. Davis, PhD, DVM, Chair Arthur L. Aronson, DVM, PhD Nicholas H. Booth, DVM, PhD Gordon L Coppoc, DVM, PhD Sidney A. Ewing, DVM, PhD Stuart D. Forney, RPh, MS Diane K. Gerken, DVM, PhD William G. Huber, DVM, PhD William L. Jenkins, DVM, PhD Robert W. Phillips, DVM, PhD Thomas E. Powers, DVM, PhD Charles R. Short, DVM, PhD Richard H. Teske, DVM, PhD Jeff R. Wilcke, DVM, MS

For more information about USP Veterinary Pharmaceutical Information monographs you may contact:
Ian F. DeVeau, PhD United States Pharmacopeia 12601 Twinbrook Parkway Rockville, Maryland 20852 United States Telephone number: 1-301-881-0666 E-mail: ifd@usp.org www.usp.org

1983 to 1985 Panel on Veterinary Medicine

Lloyd E. Davis, PhD, DVM, Chair H. Richard Adams, DVM, PhD

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AMINOGLYCOSIDES VeterinarySystemic 1

AMINOGLYCOSIDES VeterinarySystemic
This monograph includes information on the following aminoglycoside aminocyclitols: Amikacin; Dihydrostreptomycin*; Gentamicin; Kanamycin; Neomycin; Streptomycin. It also contains information on the following aminocyclitol: Apramycin. Some commonly used brand names are:
Amifuse E [Amikacin] Amiglyde-V [Amikacin] Amiglyde-V Injection [Amikacin] Amiglyde-V Intrauterine Solution [Amikacin] Amiject D [Amikacin] Amikacin C Injection [Amikacin] Amikacin E Solution [Amikacin] AmTech AmiMax C Injection [Amikacin] AmTech AmiMax E Solution [Amikacin] AmTech GentaMax 100 [Gentamicin] AmTech Gentamicin Sulfate Pig Pump Oral Solution [Gentamicin] AmTech Gentapoult [Gentamicin] AmTech Neomycin Oral Solution [Neomycin] Apralan [Apramycin] Apralan Soluble [Apramycin] Biosol Liquid [Neomycin] CaniGlide [Amikacin] Equi-Phar EquiGlide [Amikacin] Ethamycin [Dihydrostreptomycin] Garacin Pig Pump [Gentamicin] Garacin Piglet Injection [Gentamicin] Garacin Soluble Powder [Gentamicin] Garasol Injection [Gentamicin] Garasol Pig Pump Oral Solution [Gentamicin] Garasol Solution Injectable [Gentamicin] Gen-Gard [Gentamicin] Genta-fuse [Gentamicin] GentaMax 100 [Gentamicin] GentaVed 50 [Gentamicin] GentaVed 100 [Gentamicin] Gentocin [Gentamicin] Gentocin Solution [Gentamicin] Gentocin Solution Injectable [Gentamicin] Gentozen [Gentamicin] Kantrim [Kanamycin] Legacy [Gentamicin] Neo-325 [Neomycin] Neomed 325 [Neomycin] Neomix 325 [Neomycin] Neomix AG 325 [Neomycin] Neomix AG 325 Medicated Premix [Neomycin] Neomix Soluble Powder [Neomycin] Neomycin 200 [Neomycin] Neomycin 325 [Neomycin] Neo-Sol 50 [Neomycin] Neosol-Oral [Neomycin] Neosol Soluble Powder [Neomycin] Neoved 200 [Neomycin] Neovet 325/100 [Neomycin] Neovet Neomycin Oral Solution [Neomycin]

Note: For a listing of dosage forms and brand names by country availability, see the Dosage Forms section(s).

CATEGORY:
Antibacterial (systemic).

INDICATIONS
Note: Bracketed information in the Indications section refers to uses that either are not included in U.S. product labeling or are for products not commercially available in the U.S.

GENERAL CONSIDERATIONS
Aminoglycosides are utilized primarily in the treatment of infections caused by aerobic gram-negative organisms{R-107; 108; 116}. They are not active against anaerobic organisms. In addition to their strength in the treatment of gram-negative pathogens, aminoglycosides can be effective against some gram-positive organisms, such as Staphylococcus aureus{R-107; 108}, some mycobacteria{R-116; 124}, some mycoplasma strains{R-116}, and some spirochetes{R-263}. They are sometimes administered concurrently with other antibacterials for a possible

*Not commercially available in the U.S. as a single entity. Not commercially available in Canada as a single entity. 2003 Thomson MICROMEDEX

synergistic effect. However, the use of aminoglycosides in the treatment of infection in animals has been tempered by toxicity considerations in the animal treated{R-116}. Often, systemic use is limited to the treatment of serious gram-negative infections resistant to less toxic medications. Also, local environment at the therapeutic site can affect the efcacy of these drugs, acidic or purulent conditions can hamper their effect{R-5; 7; 20; 116; 160}, and the presence of cations (calcium or magnesium ions, for example) can decrease antibacterial effect{R-266}. Streptomycin was the earliest aminoglycoside introduced{R-116}. It is active against mycobacteria, Leptospira{R-243; 244}, Francisella tularensis, and Yersinia pestis, but only some mycoplasma, gram-negative organisms, and Staphylococcus species{R-116}. Dihydrostreptomycin is chemically very similar to streptomycin{R-116}. The introduction of newer aminoglycosides has eclipsed the signicance of dihydrostreptomycin and streptomycin in the face of increasing bacterial resistance{R-122; 235; 239}, although some dosage forms of these medications are still available. Neomycin became available for use a few years after streptomycin. Neomycin has been effective against many gram-negative organisms and Staphylococcus aureus{R-116}. However, the use of neomycin is limited by a relatively high risk of toxicity with systemic use{R-116}; it is not available for parenteral administration. Kanamycin was introduced as a less toxic alternative to older aminoglycosides and was soon followed by gentamicin and later by amikacin{R-116}. The spectrum of activity of kanamycin primarily focuses on gram-negative organisms and a few gram-positive organisms{R-93}. The prevalence of resistance of some pathogens, including Escherichia coli and Salmonella species, to kanamycin is higher than to gentamicin{R-108; 109113; 144}, and this has limited the use of kanamycin. The use of kanamycin has also been eclipsed by the derivation of amikacin, a drug with a very similar pharmacokinetic prole{R-178} but superior activity against pathogens such as Pseudomonas species and kanamycin-resistant Enterobacteriaceae{R-178}. Gentamicin has been widely used in the treatment of gram-negative organisms and some gram-positive organisms{R-5}. As with other aminoglycosides, use is limited by risk of toxicity. In vitro tests have shown gentamicin to be active against Salmonella arizonae (Arizona hinshawii){R-7}, Enterobacter aerogenes{R-7; 125}, E. coli{R-1; 5; 7; 125}, Klebsiella species{R-1; 5; 7; 125}, Neisseria{R-1; 5; 7; 125}, most indolepositive and some indole-negative Proteus species{R-1; 5; 7; 125}, some Pasteurella multocida{R-122; 127}, Pseudomonas aeruginosa{R-1; 5; 7; 125}, Salmonella{R-1; 5; 7; 125}, Serratia marcescens{R-1; 5; 7; 125}, Shigella{R-1; 5; 7; 125} , Staphylococcus species{R-1; 5; 7; 109111; 123; 125}, including Staphylococcus intermedius{R-109111}, and some Streptococcus species{R-1; 5; 7; 125} . Amikacin was developed from kanamycin and has the broadest spectrum of activity of the aminoglycosides{R-37}. It is considered effective against strains not susceptible to other aminoglycosides because it resists some aminoglycoside inactivating enzymes{R-91; 137; 178}. In addition to those organisms listed above for gentamicin, in vitro tests have shown amikacin to be effective against E. coli, Klebsiella and Pseudomonas species resistant to gentamicin{R-143; 266}, Citrobacter freundii, Listeria monocytogenes, and Providencia species{R-91; 92}. There are reports in the U.S. and abroad of some in vitro resistance to

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2 AMINOGLYCOSIDES VeterinarySystemic gentamicin and other aminoglycosides by Salmonella species{R-113; 117119} , but the strains tested are still susceptible to amikacin{R-118; 199; 250} . Apramycin is an aminocyclitol antibiotic with a chemical structure very similar to that of the aminoglycosides but different enough to leave it unaffected by many aminoglycoside inactivating enzymes{R-245}. At low concentrations, apramycin is more effective in inhibiting bacterial protein synthesis than kanamycin A, streptomycin, amikacin, or gentamicin{R-96}. Apramycin is active against Staphylococcus aureus, many gram-negative organisms, and some mycoplasma strains{R-163}. Apramycin has been reported to be effective in vitro against E. coli and Salmonella species{R-96; 164} that are resistant to streptomycin and neomycin{R-167; 173}. Resistance to aminoglycosides is produced primarily by enzymes encoded by genes located on bacterial plasmids{R-116; 168}. The enzymes act inside the bacterium to modify the aminoglycoside, thereby preventing it from binding to ribosomes{R-116; 168}. This type of plasmidassociated resistance is transferable between bacteria. A single type of plasmid may confer cross-resistance to multiple aminoglycosides{R-116; 117; 120; 145} and also resistance to other unrelated antimicrobials{R-7; 114; 115; 120; 145; 168}. In some cases, a single plasmid gene encoding for one enzyme, an acetyltransferase, may confer resistance to several aminoglycosides{R-171}. For example, the enzyme aminoglycoside 3-N-acetyltransferase IV allows the bacterium to be resistant to apramycin, gentamicin, netilmicin, and tobramycin{R-171}. A single bacterial isolate may have any one of a variety of combinations of resistance to different antibiotics conferred by the particular plasmid it carries{R-168}. As an example, an E. coli strain may be resistant to ampicillin, apramycin, chloramphenicol, gentamicin, kanamycin, sulfonamide, streptomycin, tetracycline, and trimethoprim{R-168}. Other E. coli isolates cultured from the same geographic region may carry resistance to a few or many of the same antibiotics in different combinations{R-168}. The nature of resistance in organisms such as E. coli and Salmonella species has been a focus of international research because of concerns about potential transferance of antimicrobial resistance from animal to human pathogens{R-168172}. Bacteria may also utilize other methods of reducing the efcacy of aminoglycosides. Some strains of bacteria are less permeable to aminoglycosides, requiring much higher concentrations of aminoglycosides to kill them and, therefore, can be selected during treatment{R-116}. Resistance developed by chromosomal resistance is minimal and develops slowly for most of the aminoglycosides, with the exception of streptomycin or dihydrostreptomycin; resistance to streptomycin can occur from a single-step mutation{R-116}. antimicrobials should rely on a specic diagnosis and knowledge of pathogen susceptibility. Calves1: Neomycin sulfate for medicated feed is indicated in the control and treatment of enteritis caused by susceptible Escherichia coli{R-94}. Streptomycin oral solution{R-181; 182} is indicated in the treatment of bacterial enteritis caused by susceptible organisms. Cattle and sheep: Neomycin sulfate for medicated feed1, neomycin sulfate powder for oral solution{R-97; 104} and neomycin sulfate oral solution{R-98; 103} are indicated in the control and treatment of bacterial enteritis caused by susceptible Escherichia coli. If systemic signs develop, medications that are well absorbed systemically should be considered for addition to or substitution for therapy with this medication{R-98}. Chickens: [Neomycin oral powder]{R-104}, [neomycin oral solution]{R-103}, and streptomycin1 {R-181; 182} are indicated in the control and treatment of bacterial enteritis in chickens. Goats1: Neomycin sulfate for medicated feed, neomycin sulfate powder for oral solution{R-97; 104} and neomycin sulfate oral solution{R-98; 103} are indicated in the control and treatment of bacterial enteritis caused by susceptible Escherichia coli. If systemic signs develop, medications that are well absorbed systemically should be considered for addition to or substitution for therapy with this medication{R-98}. Kids1 and lambs1: Neomycin sulfate for medicated feed{R-94} is indicated in the control and treatment of bacterial enteritis caused by susceptible Escherichia coli. Piglets: Apramycin sulfate powder for oral solution1{R-95}, gentamicin injection{R-7; 9; 125}, gentamicin powder for oral solution1 {R-15}, gentamicin oral solution{R-11; 14}, neomycin sulfate for medicated feed1{R-94}, neomycin sulfate oral solution{R-98; 103}, neomycin sulfate powder for oral solution{R-97; 104}, [dihydrostreptomycin]{R-106}, and streptomycin{R-181; 182} are indicated in the control and treatment of enteritis (weanling pig scours) in piglets caused by susceptible E. coli. If systemic signs develop, medications that are well absorbed systemically should be considered{R-98}. Pigs1: Neomycin sulfate for medicated feed is indicated in the control and treatment of enteritis (weanling pig scours) in piglets caused by susceptible E. coli{R-94}. [Horses]: Neomycin sulfate powder for oral solution{R-97; 104} and neomycin sulfate oral solution{R-103} are indicated in the control and treatment of bacterial enteritis caused by susceptible Escherichia coli. If systemic signs develop, medications that are well absorbed systemically should be considered for addition to or substitution for therapy with this medication. [Turkeys]: Neomycin sulfate powder for oral solution{R-104} and neomycin oral solution{R-103} are indicated in the control and treatment of bacterial enteritis in turkeys. E. coli infection (treatment) Chicks, 1-day-old: Gentamicin injection{R-7; 8} is indicated in the prevention of early mortality in chicks caused by susceptible E. coli. Turkeys, growing1: Neomycin sulfate powder for oral solution is indicated in the control of mortality associated with susceptible E. coli in growing turkeys{R-2}. Paracolon (treatment)Turkey poults, 1- to 3-day-old: Gentamicin injection{R-7; 8} is indicated in the treatment of infections in turkeys caused by susceptible Salmonella arizonae. Pseudomonas aeruginosa infection (treatment); or Salmonella typhimurium infection (treatment)Chicks, 1-day-old: Gentamicin injection{R-7; 8} is indicated in the prevention of early mortality

ACCEPTED
Bacteremia (treatment); or Septicemia (treatment)Cats and dogs: Kanamycin sulfate injection1{R-93}, [amikacin injection]1{R-264}, and [gentamicin injection]1{R-7} are indicated in the treatment of bacteremia or septicemia caused by susceptible organisms. Bone and joint infections (treatment)1Cats and dogs: Kanamycin sulfate injection{R-93}, [amikacin injection]1{R-264}, and [gentamicin injection]{R-264} are indicated in the treatment of bone and joint infections caused by susceptible organisms{R-93}. Enteritis (treatment)The primary treatment for enteritis in many cases is aggressive uid replacement. Treatment of enteritis with

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AMINOGLYCOSIDES VeterinarySystemic 3 in chicks caused by suceptible Pseudomonas aeruginosa, and Salmonella typhimurium. Respiratory tract infections, bacterial (treatment)Cats and dogs: Gentamicin injection{R-4; 7}, kanamycin injection1{R-93}, and [amikacin injection]1{R-264} are indicated in the treatment of susceptible respiratory tract infections, including pneumonia and upper respiratory tract infections. Skin and soft tissue infections, bacterial (treatment) Cats: Gentamicin injection{R-4; 7; 123}, kanamycin injection1{R-93}, and [amikacin injection{R-139; 140; 264}]1 are indicated in the treatment of susceptible skin and soft tissue infections. Dogs: Amikacin injection1{R-91}, gentamicin injection{R-4; 7}, and kanamycin injection1{R-93} are indicated in the treatment of susceptible skin and soft tissue infections. In the case of staphyloccocal dermatitis, although the in vitro susceptibility of canine Staphylococcus intermedius to gentamicin is persistently high{R-109111}, practical administration and toxicity considerations with long-term therapy have limited the usefulness of aminoglycosides{R-109}. Swine dysentery (treatment)1Pigs: Gentamicin powder for oral solution{R-15} and gentamicin oral solution{R-11} are indicated in the treatment of swine dysentery caused by susceptible Treponema hyodysenteriae. Urinary tract infections, bacterial (treatment) Cats: Gentamicin injection{R-4; 7}, kanamycin injection1 {R-93}, and [amikacin injection{R-139; 140; 264}]1 are indicated in the treatment of urinary tract infections, such as cystitis, caused by susceptible organisms. Dogs: Amikacin injection1{R-4; 7}, gentamicin injection{R-4; 7}, and kanamycin injection1{R-93} are indicated in the treatment of urinary tract infections caused by susceptible organisms. Uterine infections, bacterial (treatment) Cats: Kanamycin injection1{R-93}, [amikacin injection{R-139; 140; 264}]1, and [gentamicin injection{R-264}]1 are indicated in the treatment of endometritis in cats{R-93}. Dogs: Kanamycin injection1{R-93}, [gentamicin injection{R-7}], and [amikacin injection{R-264}]1 are indicated in the treatment of uterine infections (metritis) in dogs caused by susceptible organisms. Horses: Amikacin uterine solution{R-92}, gentamicin uterine infusion{R-1}, and gentamicin injection{R-4; 7} are indicated in the control of bacterial infections of the uterus caused by susceptible organisms. Infections, bacterial (treatment) [Calves]1 and [cattle]1: The extralabel use of aminoglycosides in cattle has been strongly discouraged because of the long duration of drug residues in some tissues (see the Regulatory Considerations section). However, in the case of bacterial infections susceptible to gentamicin in cattle that will not be used for food production, there are pharmacokinetic data available to estimate dosing for amikacin in calves{R-141; 144} and gentamicin in calves and cattle{R-21; 22; 25}. Use of aminoglycosides should be restricted to susceptible bacterial infections caused by pathogens resistant to antimicrobials that are less likely to produce prolonged residues. [Donkeys]1, [foals]1, [horses]1, and [ponies]1: Although the safety and efcacy have not been established, amikacin has been recommended in the treatment of susceptible bacterial infections in donkeys, foals, horses (systemic administration), and ponies, based on pharmacokinetic studies{R-130132; 136; 137} and in vitro antimicrobial susceptibility of common pathogens{R-159; 253}. Although the safety and efcacy have not been established, gentamicin has been recommended in the treatment of susceptible bacterial infections in foals and horses, based on pharmacokinetic studies{R-4652; 53; 55} and in vitro antimicrobial susceptibility of common pathogens{R-159; 253}. [Minor species]1: Although the safety and efcacy have not been established, amikacin has been suggested for the treatment of susceptible bacterial infections in African gray parrots{R-150}, ball pythons{R-155}, goats that will not be used for food production{R-151}, gopher snakes{R-154}, gopher tortoises{R-156}, guinea pigs{R-152}, and red-tailed hawks{R-147}, based on pharmacokinetic studies. Although the safety and efcacy have not been established, gentamicin has been suggested for the treatment of susceptible bacterial infections in the following species, if not used for food production: baboons{R-76}, budgerigars{R-86}, buffalo calves{R-78}, eagles{R-88}, goats{R-40}, hawks{R-88}, llamas{R-82}, owls{R-88}, and pythons{R-89}, based on pharmacokinetic studies. Panleukopenia (treatment)1; or Pneumonitis (treatment)1Cats: U.S. product labeling includes the use of gentamicin in the treatment of secondary bacterial infections associated with panleukopenia in cats{R-4} and the use of kanamycin in the treatment of bacterial complications of feline pneumonitis{R-93}. These uses may be appropriate for bacterial infections that are susceptible to these medications; however, they are not considered more appropriate or more generally accepted than other antimicrobials in the treatment of bacterial infections associated with viral infections. [Leptospirosis (treatment)]Cattle, dogs, and pigs: Canadian product labeling includes the use of dihydrostreptomycin in the treatment of leptospirosis in cattle, dogs, and pigs{R-106}. Studies have shown that, while shedding of leptospires in the urine of cattle can be halted for at least 2 months by the administration of a single dose of dihydrostreptomycin, carriers are not necessarily eliminated{R-243; 244}. Equally effective alternative medicines exist.

ACCEPTANCE NOT ESTABLISHED

Distemper, canine (treatment)1Dogs: U.S. product labeling includes the use of kanamycin in the treatment of bacterial complications of canine distemper{R-93}. This use may be appropriate for bacterial infections that are susceptible to kanamycin; however, it is not considered more appropriate or more generally accepted than other antimicrobials in the treatment of bacterial infections associated with viral infections. Gastrointestinal infections (treatment)1; Mastitis (treatment)1; Otitis media (treatment)1; or Pancreatitis (treatment)1Cats and dogs: U.S. product labeling for kanamycin includes use in the treatment of gastrointestinal infections, mastitis, otitis media, and pancreatitis in cats and dogs{R-93}; however, based on current knowledge about tissue penetration and pathogen susceptibility, there are more appropriate antibiotics for use in the treatment of these infections. 2003 Thomson MICROMEDEX

UNACCEPTED
[Mastitis (treatment)]Cattle and pigs: Although some Canadian product labeling has listed the use of dihydrostreptomycin in the treatment of mastitis in cows and sows, there is no published evidence that this treatment is effective. Dihydrostreptomycin is irregularly distributed into milk when administered at the labeled dose{R-247}. Another member of this drug family, gentamicin, has All rights reserved

4 AMINOGLYCOSIDES VeterinarySystemic been shown in some studies to be ineffective in the treatment of coliform mastitis{R-259260}. [Pneumonia (treatment)]Calves and cattle: Although Canadian product labeling includes the use of dihydrostreptomycin in the treatment of bacterial pneumonia in calves{R-106}, there is no published evidence available pertaining to efcacy of this therapy. Such use is not recommended by the USP Veterinary Medicine Advisory Panel{R-258} due to the lack of efcacy data and the potential for extended tissue withdrawal times. [Uterine infections (treatment)] Cattle: Although Canadian product labeling has included the use of gentamicin uterine solution or gentamicin injection administered by the intrauterine route in the treatment of uterine infections in cattle{R-7}, this use is not recommended. Intrauterine gentamicin dosage regimens necessary to produce therapeutic concentrations in uterine tissue other than the endometrium can lead to signicant systemic drug distribution and a risk of long-term tissue residues of gentamicin{R-2830}. Dogs: Although Canadian product labeling includes the use of gentamicin injection administered by the intrauterine route in the treatment of uterine infections in dogs, such use is not recommended{R-258}.
1

gentamicin injection in chickens, cows, piglets, and turkey poults; and neomycin sulfate oral solution and neomycin sulfate powder for oral solution in cattle, chickens, pigs, sheep, and turkeys. See the Dosage Forms section.

CHEMISTRY
Source: AmikacinSemi-synthetic; derived from kanamycin{R-91}. ApramycinProduced by fermentation of Streptomyces tenebrarius{R-18; 96} . GentamicinCreated from fermentation of Micromonospora purpurea{R-1; 5; 18} . KanamycinProduced through fermentation by Streptomyces kanamyceticus{R-93}. NeomycinThe sulfate of an antibacterial substance produced by Streptomyces fradiae{R-256}. StreptomycinPrepared from fermentation of Streptomyces griseus, an actinomycete organism isolated from soil{R-256}. Chemical group: Amikacin, dihydrostreptomycin, gentamicin, kanamycin, neomycin, and streptomycinAminoglycoside antibiotics. ApramycinAminocyclitol. Note: The aminoglycosides are dened by their mechanism of action, binding with the 30S ribosomal subunit{R-251}. The term aminocyclitol describes the structure of both the aminoglycosides and apramycin; however, the structure of apramycin differs just enough from other aminoglycosides that it may be listed as an aminocyclitol rather than specically an aminoglycoside. It is very similar physicochemically to other aminoglycosides{R-164}. Chemical name: Amikacin sulfated-Streptamine, O-3-amino-3-deoxy-alpha-d-glucopyranosyl-(1 6)-O-[6-amino-6-deoxy-alpha-d-glucopyranosyl-(1 4)]N1-(4-amino-2-hydroxy-1-oxobutyl)-2-deoxy, (S)-, sulfate (1:2) (salt){R-18}. Apramycind-Streptamine, 4-O-[(8R)-2-amino-8-O-(4-amino-4-deoxyalpha-d-glucopyranosyl)-2,3,7-trideoxy-7-(methylamino)-d-glyceroalpha-d-allo-octodialdo-1,5:8,4-dipyranos-1-yl]-2-deoxy-{R-18}. Dihydrostreptomycin sulfateDihydrostreptomycin sulfate (2:3) (salt){R18} . Gentamicin sulfateA complex antibiotic substance formulated as sulfate salts, including aminosugars{R-24}; three major components, sulfates of gentamicin C1, gentamicin C2, and gentamicin C1A{R-18} and minor components that are sometimes present, called A, B, B1, and X. Kanamycin sulfated-Streptamine, O-3-amino-3-deoxy-alpha-d-glucopyranosyl(1 6)-O-[6-amino-6-deoxy-alpha-d-glucopyranosyl(1 4)]2-deoxy-, sulfate (1:1) (salt){R-18}. Neomycin sulfateNeomycin sulfate{R-18}. Streptomycin sulfated-Streptamine, O-2-deoxy-2-(methylamino)-alphal-glucopyranosyl-(1 2)-O-5-deoxy-3-C-formyl-alpha-l-lyxofuranosyl-(1 4)-N,N-bis(aminoiminomethyl)-, sulfate (2:3) (salt){R-18}. Molecular formula: Amikacin sulfateC22H43N5O132H2SO4{R-18}. ApramycinC21H41N5O11{R-18}. Dihydrostreptomycin sulfate(C21H41N7O12)23H2SO4{R-18}. Gentamicin Gentamicin C1: C21H43N5O7{R-17}. Gentamicin C2: C20H41N5O7{R-17}. Gentamicin C1A: C19H39N5O7{R-17}. All rights reserved

Not included in Canadian product labeling or product not commercially available in Canada.

REGULATORY CONSIDERATIONS
U.S. Because drug residues can persist in some tissues for many months, the extralabel use of aminoglycosides in food-producing animals should be avoided when there are no established scientic data on residue depletion. A voluntary resolution against the administration of aminoglycosides to cattle has been instituted by the Academy of Veterinary Consultants, the American Association of Bovine Practitioners, the National Cattlemens Beef Association, and the American Veterinary Medical Association (AVMA){R-257}. The AMVA resolution states that, Until further scientic information becomes available, aminoglycoside antibiotics should not be used in cattle, except as specically approved by the FDA{R-257}. At issue is the need for a clearer understanding of the complexity of aminoglycoside residue depletion for food-producing animals{R-25; 32; 34; 36}. Drug residues can persist in some tissues for many months. Gentamicin is not labeled for use in horses intended for food production. Neomycin is not labeled for use in veal calves. Withdrawal times have been established for the use of apramycin sulfate powder for oral solution, gentamicin sulfate oral solution, and gentamicin sulfate powder for oral solution in pigs; gentamicin injection in chicks, piglets, and turkey poults; neomycin sulfate for medicated feed, neomycin sulfate oral solution or neomycin sulfate powder for oral solution in cattle, goats, pigs, and sheep; and streptomycin sulfate oral solution in calves, chickens, and pigs. See the Dosage Forms section. Canada Gentamicin is not labeled for use in horses intended for food production. Withdrawal times have been established for the use of apramycin sulfate powder for oral solution or gentamicin sulfate oral solution in pigs; dihydrostreptomycin injection in cattle and pigs; 2003 Thomson MICROMEDEX

AMINOGLYCOSIDES VeterinarySystemic 5 Kanamycin sulfateC18H36N4O11H2SO4{R-18}. Streptomycin sulfate(C21H39N7O12)23H2SO4{R-18}. Molecular weight: Amikacin sulfate781.76{R-18}. Apramycin539.58{R-19}. Dihydrostreptomycin sulfate1461.42{R-18}. Gentamicin Gentamicin C1: 477.61{R-17}. Gentamicin C2: 463.59{R-17}. Gentamicin C1A: 449.56{R-17}. Kanamycin sulfate582.58{R-18}. Streptomycin sulfate1457.39{R-18}. Description: Amikacin Sulfate USPWhite, crystalline powder{R-19}. Dihydrostreptomycin Sulfate USPWhite or almost white, amorphous or crystalline powder. Amorphous form is hygroscopic{R-19}. Gentamicin Sulfate USPWhite to buff powder{R-19}. Kanamycin Sulfate USPWhite, odorless, crystalline powder{R-19}. Neomycin Sulfate USPWhite to slightly yellow powder, or cryodesiccated solid. Is odorless or practically so and is hygroscopic{R-19}. Streptomycin Sulfate USPWhite or practically white powder. Is odorless or has not more than a faint odor. Is hygroscopic, but is stable in air and on exposure to light. Its solutions are acid to practically neutral to litmus{R-19}. pKa: Amikacin8.1{R-256}. Dihydrostreptomycin8.8{R-254}. Gentamicin sulfate8.2{R-254}. Kanamycin7.2{R-256}. Neomycin sulfate8.3{R-254}. Solubility: Amikacin Sulfate USPFreely soluble in water{R-19}. Apramycin sulfateHighly soluble in water and slightly soluble in the lower alcohols{R-96}. Dihydrostreptomycin Sulfate USPFreely soluble in water; practically insoluble in acetone, in chloroform, and in methanol{R-19}. Gentamicin Sulfate USPFreely soluble in water; insoluble in alcohol, in acetone, in chloroform, and in ether{R-19}. Kanamycin Sulfate USPFreely soluble in water; insoluble in acetone and in ethyl acetate{R-19}. Neomycin Sulfate USPIts solutions are dextrorotatary. Freely soluble in water; very slightly soluble in alcohol; insoluble in acetone, in chloroform, and in ether{R-19}. Streptomycin Sulfate USPFreely soluble in water, very slightly soluble in alcohol; practically insoluble in chloroform{R-19}. synthesis by disruption of polysomes and may prevent the initiation of DNA replication{R-107}. AminocyclitolsApramycin is bactericidal. It also acts against bacteria by inhibiting protein synthesis at the ribosome level{R-96}. Like the aminoglycosides, it inhibits the translocation step of protein synthesis and induces translation errors{R-96}. Absorption: Intramammary administrationIn cows with mastitis, gentamicin is well absorbed systemically following intramammary administration. With a single dose (1.1 mg per kg of body weight), concentrations of antibiotic in the serum (measured in one study up to 1.09 0.15 mcg per mL) could result in prolonged tissue residues{R-26}. Intramuscular or subcutaneous administrationAmikacin, dihydrostreptomycin, gentamicin, and kanamycin generally are rapidly and well absorbed from intramuscular and subcutaneous routes of administration{R-177; 230; 247}. Intrauterine administrationCows: In healthy cows, 39% of a total intrauterine dose of 2500 mg, administered once a day for 3 days, was absorbed systemically and produced serum concentrations of up to 6.6 mcg/mL{R-28}. In cows with endometritis, absorption was similar, with 36% of an intrauterine dose of 4 mg/kg of body weight administered once a day for 3 days absorbed systemically, producing peak serum concentrations of 6 to 11 mcg/mL{R-29}. A smaller total intrauterine dose of 225 to 275 mg produced plasma concentrations of 0 to 2.5 mcg/mL{R-30}, while 70% of the dose administered remained in the lumen of the uterus{R-17; 30}. Because of the demonstrated intrauterine absorption of aminoglycosides, some clinicians have warned that intrauterine administration is likely to result in residues above regulatory limits in food-producing animals{R-60}. Oral administrationIn general, aminoglycosides and apramycin are very poorly absorbed from oral administration in adult animals, including cattle, chickens, and pigs{R-46; 96; 166; 230}. However, 11% of an oral neomycin dose of 30 mg per kg of body weight (mg/kg) was absorbed in 3-day-old calves and 1 to 2% of the dose was absorbed by 2-month-old calves, regardless of ruminant status{R-238}. In very young calves, this absorption can be signicant. When neomycin was administered orally to 2- to 4-day-old calves at a dose of 33 mg/kg for 14 days, absorption was signicant enough to produce relatively high concentrations of drug in the kidneys (approximately 300 mcg per gram of tissue){R-240}. Some absorption of apramycin has also been shown to occur in neonatal pigs{R-296}. Damage to the gastrointestinal mucosa can also lead to increased aminoglycoside absorption{R-166; 230} . Moderate enteritis from induction of coccidial infection in chickens caused a signicant increase in absorption of a 43 mg/kg dose of apramycin for 5 days{R-166}. Serum concentrations were increased from 0.04 to 0.06 mcg/mL and tissue concentrations were also increased{R-166}. Distribution: Aminoglycosides are distributed primarily into the extracellular space{R-46} and over time accumulate in tissues{R-25}. The amount of antibiotic in most tissues appears to be dependent on the total dose administered over time rather than the size of each individual dose{R-25; 34}. Aminoglycosides do not distribute well across membrane barriers and, therefore, are not found at high concentrations in brain tissue, cerebrospinal uid, ocular uid, or respiratory secretions{R-20; 153; 230}.

PHARMACOLOGY/PHARMACOKINETICS
Note: See also Tables I and II for this monograph. Mechanism of action/effect: AminoglycosidesBactericidal{R-107; 116}. Aminoglycosides enter susceptible bacteria by oxygen-dependent active transport (making anaerobes impervious to them){R-107} and by passive diffusion{R-37}. Once the antibiotic has gained access, it binds irreversibly to a receptor protein on the 30S ribosomal subunit{R-5; 107} and blocks the formation of a complex that includes mRNA, formylmethionine, and tRNA{R-107}. As a result, the tRNA is translated incorrectly, producing a nonfunctional protein{R-107}. Aminoglycosides also disrupt protein

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All rights reserved

6 AMINOGLYCOSIDES VeterinarySystemic Systemic administration Otic tissue: Aminoglycosides concentrate in the perilymph of the inner ear. The damage to the ciliated cells can result in deafness; vestibular nerve injury may result as well{R-263}. Renal tissue: When aminoglycosides are administered systemically, the predominant site of drug accumulation is the renal cortex in most species tested, including cats, cattle, pigs, and sheep{R-20; 25; 34; 42; 67; 230} . Therapeutic concentrations are also reached in other tissues and slow depletion from some tissues may prolong the presence of residues{R-25; 230}. For cats, cattle, pigs, and sheep, the following general relative gentamicin concentrations are reached over time with repeated doses, from highest to lowest concentrations: renal cortex; renal medulla; liver/lung/spleen; skeletal muscle{R-25; 34; 42; 67; 230} . Renal proximal tissues actively take up and accumulate aminoglycosides by pinocytosis{R-265}. Once within the tubular cells, the drug may cause dysfunction in lysosomes, mitochondria, proximal tubule cell plasma membrane phospholipids and enzymes, and glomerular ltration{R-37}. Other tissues: Cats: Amikacin is distributed into uterine tissue so that tissue concentrations are about 25% of the current serum concentration{R-140}. Horses: AmikacinAmikacin is distributed into peritoneal uid and synovial uid in the horse with a peak of 13.7 3.2 mcg/mL and 16.8 8.8 mcg/mL, respectively, at the rst sample, 1 hour after an intravenous dose of 6.6 mg per kg of body weight{R-137}. GentamicinGentamicin is distributed into endometrial tissue so that tissue concentration is higher than plasma concentrations reached after 7 days of intramuscular therapy with a dose of 5 mg/ kg every 8 hours{R-53}. Gentamicin is distributed into synovial uid in normal horses to produce a peak of 6.4 mcg/mL at 2 hours with a single 4.4 mg/kg intravenous dose{R-58}. However, local inammation may increase drug concentrations in the joint and concentrations may increase with repeated doses. Gentamicin is distributed into jejunal and colonic tissue with a maximum gentamicin concentration of 4.13 1.8 mcg/mL measured in the large colon at 0.5 hour after administration and 2.26 1.35 mcg/mL measured in jejunum at 0.33 hour{R-59}. Intra-articular administrationHorses: Intra-articular administration of 150 mg of gentamicin resulted in a peak synovial concentration of 1828 240 mcg/mL 15 minutes after administration{R-61}. The intra-articular administration of buffered gentamicin produced more synovitis and higher gentamicin concentrations (2680 1069 mcg/mL) than unbuffered gentamicin{R-61}; however, synovial concentrations 12 hours later were very similar for buffered and unbuffered gentamicin. Synovial concentrations remained >10 mcg/mL for at least 24 hours{R-61}. A peak plasma concentration of 0.69 mcg/mL at 15 minutes after intra-articular administration was measured{R-61}; gentamicin was no longer detectable in plasma at 6 hours. Intrauterine administrationHorses: AmikacinIntrauterine administration of a total dose of 2 grams produces a peak of greater than 40 mcg per gram of endometrial tissue within 1 hour after infusion{R-92}. Twenty-four hours after infusion, 2 to 4 mcg of amikacin per gram of endometrial tissue is still present{R-92}. GentamicinIntrauterine administration of 2.5 grams of gentamicin once daily for 5 days resulted in endometrial tissue concentrations of 41.65 17 mcg/gram 24 hours after the last dose{R-60}. The addition of progesterone, administered concurrently, increased the sample to 100.33 19.27 and the administration of estradiol concurrently with gentamicin increased the sample to 74.09 8.6 mcg/gram{R-60}. At the same time, measured serum concentrations of gentamicin peaked at 0.64 0.06 for gentamicin administered alone; the concurrent administration of progesterone or estradiol increased gentamicin serum concentrations to a peak of 8.34 1.34{R-60}. Regional limb perfusionHorses: AmikacinRegional intravenous perfusion of amikacin (125 mg diluted in 60 mL of electrolyte solution) into the distal limb of horses produced sufciently high concentrations of antibiotic in local joint uid, bone, and serum in the limb to be effective in the treatment of most susceptible organisms{R-267}. Protein binding: AmikacinCalves: 6% at a concentration of 5 to 150 mcg per mL of serum (mcg/mL){R-141}. Dihydrostreptomycin Cows: 8%, at a concentration of 2.5 to 5 mcg/mL{R-129}. Ewes: 12%, at a concentration of 2.5 to 5 mcg/mL{R-129}. GentamicinHorses and foals: < 30%{R-1; 47}. KanamycinEwes: 0 to 4%, at a concentration of 2.5 to 5 mcg/mL{R129} . Neomycin Cows: 45%, at a concentration of 5 to 10 mcg/mL{R-129}. Ewes: 50%, at a concentration of 5 to 10 mcg/mL{R-129}. SpectinomycinCows: 6%, at a concentration of 12.5 to 25 mcg/mL{R129} . Biotransformation: In many species, aminoglycosides are eliminated in the form of the administered drug{R-96; 143; 150; 177; 180; 238}; that is, they are not biotransformed. Elimination: Parenterally administered aminoglycosides are predominantly excreted unchanged in the urine{R-96; 164; 177; 180}. Only a small amount is excreted in the bile in some species, such as cattle{R-1}. For amikacin in dogs and gray parrots, gentamicin in calves, cows, horses, and sheep, and kanamycin in dogs, 75 to 100% of the dose is eliminated unchanged in the urine in the rst 8 to 24 hours{R-1; 7; 20; 22; 32; 143; 150; 178; 204} . Because the kidney is the site of predominant accumulation and elimination of drug, the analysis of elimination seems straightforward. However, researchers have described a dose-dependent slow elimination phase (gamma phase) many times longer than the initial elimination phase{R-32}. It is postulated that gentamicin is bound to tissues by one of at least two different processes so that some gentamicin is released quickly and gentamicin bound by another process is released more slowly{R-25; 32; 34; 36}. It is not known if these processes are tissue-specic.

PRECAUTIONS TO CONSIDER PREGNANCY/REPRODUCTION

Amikacin Dogs: Reproductive studies have not been performed in dogs{R-91}. All rights reserved

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AMINOGLYCOSIDES VeterinarySystemic 7 Horses: No evidence was found of impaired fertility in mares given an intrauterine dose of 2 grams of amikacin 8 hours before natural breeding{R-92}. In in vitro studies, equine sperm exposed to 0.1 mg of benzethonium chloride per mL of solution, present in some amikacin products, showed impaired viability{R-92}. Product labeling recommends that mares not be bred for 8 hours after intrauterine treatment with amikacin{R-92}. ApramycinNo adverse effects have been observed in laboratory animals pertaining to mutagenicity, teratology, or reproduction{R-96}. DihydrostreptomycinBulls: No effect was noted on spermatogenesis, seminal pH, ejaculate volume, percentage of motile spermatozoa, rate of spermatozoal motility, or concentration of spermatozoa from nine beef bulls on the third or seventh days after the second dose of 22 mg of dihydrostreptomycin per kg of body weight every 12 hours for two doses{R-242}. Gentamicin Cats and dogs: Reproductive studies have not been performed with gentamicin in cats and dogs{R-4}. Horses: Intrauterine treatment of mares with gentamicin is not recommended the day of breeding{R-4}. Rats: Ototoxicity has been shown to be a risk even before the auditory organs have begun to function in developing rats{R-188}. adults. Higher doses may be necessary in animals less than 6 weeks old compared with adults{R-266}. Very young animals may absorb signicant amounts of orally administered apramycin or neomycin. See Absorption, above in this monograph.

GERIATRICS
In a case report study of dogs, advanced age of more than 8 years appeared to be a risk factor in susceptibility to gentamicin nephrotoxicity{R-215}. However, it is not known if these dogs had subclinical renal compromise, which is known to increase the nephrotoxicity of gentamicin{R-217}, or some other dysfunction associated with aging.

DRUG INTERACTIONS AND/OR RELATED PROBLEMS

The following drug interactions and/or related problems have been selected on the basis of their potential clinical signicance (possible mechanism in parentheses where appropriate)not necessarily inclusive ( = major clinical signicance): Note: Combinations containing any of the following medications, depending on the amount present, may also interact with this medication. Aminoglycosides, two or more concurrently{R-4; 91} (concurrent administration may increase the risk of ototoxicity, nephrotoxicity, or neuromuscular blockade{R-4}) Calcium (intravenous calcium supplementation may decrease nephrotoxicity associated with aminoglycosides; in horses, 20 mg of intravenous calcium gluconate per kg of body weight administered every 12 hours decreased nephrotoxicity of high dose gentamicin [20 mg/kg every 8 hours for 14 days] administered to adult ponies{R-223}) Calcium channel blocker{R-232} (an increased risk of neuromuscular blockade may occur with concomitant administration with an aminoglycoside{R-232}) Halothane anesthesia (horses administered gentamicin, 4 mg/kg, while under halothane anesthesia have signicant changes in the pharmacokinetics of gentamicin; total body clearance and volume of distribution decrease while half-life of elimination increases; a longer gentamicin dosing interval after anesthesia may help correct for the changes, but serious consideration should be given to choice of another antimicrobial{R-204}) Iron, supplemental (the risk of auditory and renal toxicity might be increased when aminoglycosides are administered with iron supplements; guinea pigs administered gentamicin at 100 mg/kg a day for 30 days showed a more rapid and profound hearing loss within the treatment period with concurrent administration of supplemental iron at a dose of 2 to 6 mg/ kg a day; the effect was iron dosedependent{R-198}; a study in rats showed increased renal tubular damage when gentamicin was administered at a dose of 100 mg/kg a day to rats given iron supplementation{R-202}) Ketorolac{R-224}, Phenylbutazone{R-203}, or Nonsteroidal anti-inammatory drugs (NSAIDs), other (in the horse, concurrent administration of phenylbutazone with gentamicin affects the pharmacokinetics of gentamicin by decreasing the half-life of elimination by 23% and decreasing the volume of All rights reserved

LACTATION
Because of poor lipid solubility, aminoglycosides have relatively poor penetration from plasma into milk{R-22; 26}. In general, parenteral administration of gentamicin has not been shown to produce therapeutic milk concentrations (greater than 3 to 5 mcg/mL) for the treatment of most gram-negative mammary pathogens{R-22; 23; 25} . At any one time, approximately 10 to 15% of plasma gentamicin levels may appear in milk{R-22; 26}. Intramammary administration of gentamicin to cows with experimental mastitis results in signicant systemic absorption (88%), leading to long persistence of drug residues in some tissues, such as renal tissue{R-23; 26}. ApramycinCows, goats, and sheep: Apramycin has limited distribution from parenteral administration into milk in healthy glands{R-163}. It is distributed into bovine milk at higher concentrations during acute clinical mastitis, but it is not known if concentrations would be high enough to have clinical effect without signicant residue and toxicity considerations{R-163}. DihydrostreptomycinCows: When administered at an intramusuclar dose of 11 mg/kg, dihydrostreptomycin is irregularly distributed into the milk for at least 18 hours{R-247}. GentamicinCows: With an intramuscular dose of 5 mg/kg, a peak concentration of 1.5 to 1.8 mcg/mL is measured 2 to 6 hours after administration{R-22; 26}.

PEDIATRICS
The susceptibility of young animals to toxicity from aminoglycosides may be species-specic and drug-specic. Young dogs, rabbits, and rats have shown resistance to gentamicin nephrotoxicity in some studies{R219; 268} , while 2- to 3-month-old foals may be more susceptible than adults to toxicity{R-208; 219}. The renal function of young rats, 21-days old, was more strongly affected by the administraton of amikacin than was the renal function of adults given the same dose{R-192}. Young animals typically have a higher percentage of extracellular water and, therefore, have a higher volume of distribution compared with 2003 Thomson MICROMEDEX

8 AMINOGLYCOSIDES VeterinarySystemic distribution [area] by 26%; the pharmacokinetics of phenylbutazone do not appear to be affected{R-203}; also, the nephrotoxic potential of NSAIDs can increase the risk of renal toxicity, as ketorolac does when administered to rats concurrently with gentamicin{R-224}; however, unixin was shown to have no effect on the pharmacokinetics of gentamicin when administered concurrently to adult horses{R-265}) Loop diuretics, including{R-143} Ethacrynic acid{R-143; 197; 229} or Furosemide{R-4; 91; 185; 207} (because these medications can cause ototoxicity in patients with renal compromise, the risk of potentiating toxicity during concurrent use with aminoglycosides should be considered{R-143}; also, there is evidence that the combination of kanamycin and ethacrynic acid can cause permanent auditory ototoxicity in healthy cats without subsequent signs of renal compromise{R-197}; concurrently administered systemic gentamicin and ethacrynic acid also causes more profound ototoxicity in guinea pigs than either drug administered alone{R-229}) Nephrotoxic medications, other{R-4} or Ototoxic medications, other{R-4} (concurrent use may increase the risk of ototoxicity or nephrotoxicity) Neuromuscular blocking agents or drugs with neuromuscular blocking activity{R-4; 186; 187; 199201}, other (concurrent use with aminoglycosides can increase the risk of neuromuscular blockade, particularly during anesthesia{R-186} but there may be little clinical signicance; administration of gentamicin [2 to 6 mg/kg dose] does potentiate the neuromuscular blocking effect of atracurium in inhalant-anesthetized cats, dogs, and horses; however, minimal to no effect on recovery from anesthesia was noted{R-199201}; edrophonium reversed any remaining neuromuscular block during recovery{R-199201}; calcium supplementation can also help reverse neuromuscular blockade [see Treatment of overdose]) measurement of plasma concentrations and/or evidence of toxicity may also be required) Methoxyurane or Polymyxins, parenteral (concurrent and/or sequential use of these medications with aminoglycosides should be avoided since the potential for nephrotoxicity and/or neuromuscular blockade may be increased; neuromuscular blockade may result in skeletal muscle weakness and respiratory depression or paralysis [apnea]; caution is also recommended when methoxyurane or polymyxins are used concurrently with aminoglycosides during surgery or in the postoperative period)

LABORATORY VALUE ALTERATIONS

The following have been selected on the basis of their potential clinical signicance (possible effect in parentheses where appropriate)not necessarily inclusive ( = major clinical signicance): With physiology/laboratory test values Aspartamine aminotransferase (AST [SGOT]), serum and Lactate dehydrogenase (LDH), serum (in galahs [cockatoos] and macaws, values are reported to increase with therapeutic gentamicin administration of 5 mg/kg every 12 hours{R-205})

HUMAN LABORATORY VALUE ALTERATIONS{R-255}

In addition to the above laboratory value alterations, the following alterations have been reported in humans, and are included in the human monograph Aminoglycosides (Systemic) in the USP DI Volume I; these laboratory value alterations are intended for informational purposes only and may or may not be applicable to the use of aminoglycosides in animals: With physiology/laboratory test values Alanine aminotransferase (ALT [SGPT]), serum and Alkaline phosphatase, serum and Aspartate aminotransferase (AST [SGOT]), serum and Bilirubin, serum and Lactate dehydrogenase (LDH), serum (values may be increased) Blood urea nitrogen (BUN) and Creatinine, serum (concentrations may be increased) Calcium, serum and Magnesium, serum and Potassium, serum and Sodium, serum (concentrations may be decreased)

HUMAN DRUG INTERACTIONS{R-255}

In addition to the above drug interactions reported in animals, the following drug interactions have been reported in humans, and are included in the human monograph, Aminoglycosides (Systemic) in USP DI Volume I; these drug interactions are intended for informational purposes only and may or may not be applicable to the use of aminoglycosides in the treatment of animals: Antimyasthenics (concurrent use of medications with neuromuscular blocking action may antagonize the effect of antimyasthenics on skeletal muscle; temporary dosage adjustments of antimyasthenics may be necessary to control symptoms of myasthenia gravis during and following use of medications with neuromuscular blocking action) Beta-lactam antibiotics (aminoglycosides can be inactivated by many beta-lactam antibiotics [cephalosporins, penicillins] in vitro and in vivo in patients with signicant renal failure; degradation depends on the concentration of the beta-lactam agent, storage time, and temperature) Indomethacin, intravenous (when aminoglycosides are administered concurrently with intravenous indomethacin in the premature neonate, renal clearance of aminoglycosides may be decreased, leading to increased plasma concentrations, increased elimination half-lives, and risk of aminoglycoside toxicity; dosage adjustment of aminoglycosides based on 2003 Thomson MICROMEDEX

MEDICAL CONSIDERATIONS/CONTRAINDICATIONS
The medical considerations/contraindications included have been selected on the basis of their potential clinical signicance (reasons given in parentheses where appropriate)not necessarily inclusive ( = major clinical signicance). Except under special circumstances, this medication should not be used when the following medical problems exist: Dehydration, hypovolemic{R-4; 5; 91} (hypovolemic animals can have increased susceptibility to renal toxicity and should be rehydrated prior to treatment with aminoglycosides{R-91}; however, clinicians may administer the rst dose of All rights reserved

AMINOGLYCOSIDES VeterinarySystemic 9 aminoglycoside to treat life-threatening infections while rehydration is in progress{R-262}) Hypersensitivity to aminoglycosides{R-7; 92; 93} (a previous reaction to one aminoglycoside may contraindicate use of the same or other aminoglycosides due to cross-sensitivity) Renal dysfunction{R-4; 91} (alternative antimicrobials should be considered in animals with severe renal compromise and/or renal azotemia{R-4; 5}; because they lack the ability to compensate, even dogs with subclinical renal dysfunction can develop nonreversible acute renal failure from a dose that produces only mild polyuria in dogs with healthy kidneys{R-213; 214} ; if an aminoglycoside must be given, increasing the dosing interval is more effective in preventing toxicity than decreasing the dose{R-217}) Risk-benet should be considered when the following medical problems exist: Cardiac dysfunction{R-5} (gentamicin may exacerbate a decreasing heart rate or depression of blood pressure{R-5}) Endotoxemia (even a low serum concentration of endotoxin may increase the toxicity of the aminoglycosides by increasing their concentration in the kidneys{R-184}; the administration of an aminoglycoside to treat gram-negative bacterial infections may also increase the amount of endotoxin released{R-184}; see the Veterinary Dosing Information section) Hypocalcemia (although the clinical impact is not clear, aminoglycosides, including dihydrostreptomycin and neomycin, have been shown to decrease the total blood calcium concentration in cattle through decreasing the protein-bound calcium{R-187}; this effect caused signs of hypocalcemia in 77% of lactating cows treated with 4.5 mg of intravenous neomycin per kg of body weight{R-187}) Potential risk factors for acute renal failure{R-185; 215}, other, including Acidosis Advanced age Diabetes mellitus Dirolarial infection{R-91} Electrolyte imbalances Fever Sepsis Hepatic dysfunction Hyperviscosity syndromes Hypoalbuminemia Hypotension Septicemia Trauma, severe (level of risk of nephrotoxicity with administration of aminoglycosides can be difcult to assess, but caution is indicated in animals with one or several factors associated with increased risk, such as those affecting renal perfusion) Pyelonephritis{R-226} (rats with infected kidneys are more susceptible to gentamicin toxicity than healthy rats{R-226}) Aminoglycoside, serum concentration (because of the risk of nephrotoxicity and the wide variability in drug disposition, it is recommended that, whenever possible, serum aminoglycoside concentration should be monitored in animals receiving repeated doses, and dosage adjustments made{R-55; 56}; when multiple dosing is done in a 24-hour period, peak and trough concentrations have been considered the most helpful with the least number of tests{R-57}. With once-daily dosing, serum concentrations are more typically measured at 1 and 2 hours or 2 and 4 hours after the daily dose{R-266}. Many sources recommend serum concentrations be allowed to drop below 1 mcg/mL for gentamicin and below 2.5 to 5 mcg/mL for amikacin or kanamycin for an extended period within a dosing interval to reduce the risk of toxicity{R-47; 51; 63; 148; 185; 209; 230}.) Renal function tests{R-4; 91} (serial urinalyses may be the most sensitive tests for renal toxicosis in spite of the fact that no early urinary test has been developed that can consistently warn clinicians when serious renal toxicity occurs; serial urinalyses may be monitored for decreased specic gravity in the absence of uid therapy or appearance of casts, protein, albumin, glucose, or blood in the absence of leukocytes and bacteria{R-4; 208}; proteinuria may be seen within 24 hours with extremely high toxic doses{R-206}; early indication of nephrotoxicity may be possible with the ratio of urinary gamma glutamyltranspeptidase to urinary creatinine excretion [UGGT/UCr] ]; this enzyme concentraton ratio is increased to three times the baseline within 2 to 3 days of a nephrotoxic gentamicin dose of 30 mg/kg{R-206; 209; 210; 211}; however, because even a single dose of gentamicin can cause some renal tubule changes, elevations in the UGGT/UCr ratio may occur without subsequent severe kidney damage; therefore, some clinicians believe that other tests may be needed to decide if gentamicin therapy must be discontinued{R-210; 220; 221}; serum creatinine, creatinine clearance tests, specic gravity, blood urea nitrogen and/or clinical signs of nephrotoxicity may not be diagnostic of severe kidney damage for at least 7 days{R-4; 206; 210; 216})

SIDE/ADVERSE EFFECTS
The following side/adverse effects have been selected on the basis of their potential clinical signicance (possible signs and, for humans, symptoms in parentheses where appropriate)not necessarily inclusive:

THOSE INDICATING NEED FOR MEDICAL ATTENTION

Incidence more frequent All species Nephrotoxicity{R-7; 212}; ototoxicity, auditory; ototoxicity, vestibular Note: Evidence of physiological effects on the kidneys has been demonstrated with a single dose of gentamicin at 15 mg per kg of body weight (mg/kg) in 5-month-old beagles, although clinical disease is not necessarily produced{R-209; 212}. It is assumed that renal damage associated with aminoglycoside administration runs a range from mild, subclinical changes to more severe nephrotoxicity, to acute renal failure{R-4; 209; 212}. The animals ability to recover most likely depends on the type of medication exposure and the amount of healthy renal tissue remaining to compensate{R-213}. Neomycin is considered the most nephrotoxic aminoglycoside, dihydrostreptomycin and streptomycin the least nephrotoxic, and the other common aminoglycosides included in this monograph are considered somewhere between those three drugs in their toxicity{R-254}. Aminoglycoside All rights reserved

PATIENT MONITORING
The following may be especially important in patient monitoring (other tests may be warranted in some patients, depending on condition; = major clinical signicance): 2003 Thomson MICROMEDEX

10 AMINOGLYCOSIDES VeterinarySystemic administration is, as a rule, immediately withdrawn when evidence of renal damage is found; however, many signs of toxicity may be delayed for some time after signicant damage has occurred. Although renal toxicity is dependent on the concentration of aminoglycoside in the renal cortex, many variables can affect how much of the medication reaches the cortex and how serious the effects will be, making it difcult to consistently predict which animal is likely to develop clinical toxicity with a particular therapeutic dosage regimen. Aminoglycosides cause nephrotoxicity by accumulating in the proximal tubular cells and, once there, interfering with cellular metabolism and transport processes{R-218; 225}. The tubular changes can progress to proximal tubular necrosis with increasing exposure to the drug. Fairly late in the process, glomerular ltration rate is affected and azotemia appears{R-225}. These changes may simultaneously occur at different rates in different parts of the renal cortex, making it possible to have both reabsorption defects and glomerular ltration rate reduction at the same time{R-225}. The toxic renal changes caused by gentamicin and other aminoglycosides will decrease elimination of the antibiotic and increase serum antibiotic concentrations, thereby increasing the potential toxicity{R-57; 209}. Elimination half-lives of 24 to 45 hours have been reported in the horse with renal toxicity, prolonging the toxic exposure to the drug{R-57}. While peritoneal dialysis is useful in lowering creatinine and blood urea nitrates, it may not be effective in signicantly speeding the elimination of the accumulating aminoglycoside{R-57}. If there is enough healthy tissue remaining in the kidneys, acute renal failure may be reversible by regeneration and hypertrophy of remaining tissue{R-193; 213}. Dogs with subclinical renal dysfunction are more sensitive to the toxicity of gentamicin; they develop oliguria and acute renal failure that may not be reversible from a high gentamicin dose that produces only mild polyuria in dogs with healthy kidneys{R-213; 214}. Therefore, merely adjusting dosage regimens to compensate for renal dysfunction may not be sufcient to avoid toxicity. Careful selection of candidates for aminoglycoside therapy and a dosage regimen designed to minimize risk of nephrotoxicity is recommended. Some aminoglycosides are more likely to cause auditory ototoxicity and others are more likely to cause vestibular ototoxicity{R-4; 7}. This may be due to the distribution characteristics of each drug and its ability to concentrate in each sensory organ{R-183}. As demonstrated in studies on guinea pigs,{R-183; 190} amikacin, kanamycin, and dihydrostreptomycin are more toxic to the cochlea than to vestibular organs{R-183; 190; 191; 233}. Neomycin causes severe cochlear toxicity{R-233}. Studies in guinea pigs have shown that auditory toxicity is often delayed{R-189}, requiring at least 4 days after administration of a toxic dose for hearing loss to be measurable{R-189}. This period of delay may shorten with higher doses{R-189}. Vestibular toxicity is more often seen than auditory toxicity with streptomycin{R-233}. Incidence less frequent or rare All species Neuromuscular blockade{R-7} Note: Neuromuscular paralysis{R-7} is considered rare compared with the nephrotoxic and ototoxic effects of aminoglycosides{R-232}. The neuromuscular blocking effects of dihydrostreptomycin, gentamicin, kanamycin, neomycin, and streptomycin at a dose of 14 to 43 mg per kg of body weight have been demonstrated during pentobarbital anesthesia (28 to 32 mg per kg of body weight [mg/kg]) in nonhuman primates{R-186}. However, respiratory depression and apnea occurred only at the highest antibiotic dosages{R-186}. Neuromuscular blockade and respiratory paralysis have been reported in response to high doses of gentamicin (40 mg/kg) in the cat{R-7}. The postsynaptic blocking component of this effect can be reversed by a cholinesterase inhibitor, such as neostigmine, and the apparent presynapic effect can be antagonized by the administration of calcium{R-186}.

THOSE INDICATING NEED FOR MEDICAL ATTENTION ONLY IF THEY CONTINUE OR ARE BOTHERSOME
Incidence more frequent Birds Local tissue trauma, mildat site of injection{R-86} Incidence rare Dogs Diarrhea{R-91}with amikacin; vomiting{R-91}with amikacin Incidence unknown Calves and pigs Diarrheaseen in animals given oral doses of apramycin or neomycin that are higher than the label dose{R-96; 241}. Cats Local tissue trauma, mildat site of intramuscular injection with amikacin{R-93; 139} Dogs Local tissue trauma, mildat site of injection, with amikacin or gentamicin{R-5; 91; 93}

HUMAN SIDE/ADVERSE EFFECTS{R-255}

In addition to the above side/adverse effects reported in animals, the following side/adverse effects have been reported in humans, and are included in the human monograph Aminoglycosides (Systemic) in USP DI Volume I; these side/adverse effects are intended for informational purposes only and may or may not be applicable to the use of aminoglycosides in the treatment of animals: Incidence more frequent Nephrotoxicity; neurotoxicity; ototoxicity, auditory; ototoxicity, vestibular; peripheral neuritisonly with streptomycin Incidence less frequent Hypersensitivity; optic neuritisonly with streptomycin Incidence rare Endotoxin-like reactiongentamicin only; neuromuscular blockade Note: Neuromuscular blockade, respiratory paralysis, ototoxicity, and nephrotoxicity may occur following local irrigation or topical application of aminoglycosides during surgery. Because of its potential toxicity, use of parenteral neomycin is not recommended.

OVERDOSE
For more information on the management of overdose or unintentional ingestion, contact the American Society for the Prevention of Cruelty to Animals (ASPCA) National Animal Poison Control Center (8884264435 or 9004430000; a fee may be required for consultation) and/or the drug manufacturer.

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AMINOGLYCOSIDES VeterinarySystemic 11

GENERAL CONSIDERATIONS
When systemically absorbed, the aminoglycosides have the potential to cause nephrotoxicity, neurotoxicity, or ototoxicity{R-91}. This includes absorption through irrigation of tissues in surgery and sometimes from topical application{R-91}. Because of the narrow therapeutic index, the margin between therapeutic concentrations and toxic concentrations, for aminoglycosides used in animals, toxicity is a potential risk in the best of circumstances. The minimum gentamicin dose required to produce nephrotoxicity is variable between species and between animals{R-212} and the data listed in this section cannot clearly dene the dose that will produce serious toxicity in a particular animal. Toxic doseInformation about toxicity of the aminoglycosides has been drawn primarily from human therapeutic literature. It has been reported that minimum serum concentrations within a dosing interval of greater than 2 mcg/mL for gentamicin and greater than 2.5 to 5 mcg/mL for amikacin or kanamycin signicantly increase the risk of toxicity{R-148; 185; 209}. Persistant peak serum concentrations of gentamicin greater than 10 to 12 mcg/mL and of amikacin or kanamycin greater than 30 to 40 mcg/mL are also considered to increase the risk of toxicity{R-230}. Amikacin: DogsRenal toxicity: Minimal to mild renal changes are seen with a dose of 45 mg per kg of body weight (mg/kg) a day for 2 weeks{R-91} or 30 mg/kg a day for 90 days{R-91}. Guinea pigs: Auditory and vestibular ototoxicity Marked hearing loss150 to 225 mg/kg a day in divided doses every 8 hours for 1 week{R-190; 191}. Hearing loss, less pronouncedWhen the 150 mg/kg dose was administered every 24 hours for 7 to 21 days, there was a signicant decrease in vestibular and auditory damage{R-190; 191} . Apramycin: Chickens No effect: With a dose of 50 mg per kg of feed, fed as the only ration, no toxic signs are noted{R-195}. With a dose of 150 to 250 mg per kg of feed, a reduction in serum hemoglobin and erythrocytes may be noted, as well as dystrophic changes in the internal organs{R-195}. DogsNo effect: Chronic administration yielded no toxicity with 50 parts per million (ppm) fed to dogs for 1 year{R-96}. Pigs No effect: With a dose of up to 300 mg per liter of drinking water for 15 days, no signs of toxicity were noted. With a dose of 500 to 1000 mg per liter of drinking water (5 to 10 times the label dose) for more than 15 days, some animals developed a drop in the percentage of neutrophils and an increase in lymphocyte percentage in the complete blood count{R-194}. RatsNo effect: Chronic administration yielded no toxicity with 10,000 ppm fed to rats for 2 years{R-96}. Gentamicin: Renal Cats: No signicant effectA dose of 4.4 mg/kg every 12 hours for 12 days produced no signicant effects{R-228}. Toxic effectOnly mild nephritis was produced by 20 mg/kg a day administered subcutaneously for 70 days{R-227}.

Dogs: Toxic effectA parenteral dose of 30 mg/kg a day for 10 days (or 10 mg/kg every 8 hours for 8 days) produced evidence of renal toxicity, including elevated serum urea nitrogen concentration, elevated serum creatinine, proteinuria, decreased urine specic gravity, decreased exogenous creatinine clearance, decreased glomerular ltration rate, and histological evidence of renal toxicity{R-269; 270}. Foals: Toxic effectNephrotoxicity occurred in one of twelve foals given 17.6 mg/kg every 12 hours and one of twelve given 8.8 mg/ kg every 12 hours for 15 days{R-218}. Hawks, red tailed: Toxic effectAn intravenous dose of 10 mg/kg every 12 hours for 4 days caused signicantly increased serum uric acid concentrations{R-87}. Lambs: Toxic effectAn intravenous dose of 80 mg/kg a day for up to 20 days produced renal tubular necrosis and dilation{R-206}. Serum creatinine concentrations of up to 132 micromoles per liter were measured beginning 14 days, on average, after initiation of therapy{R-206}. Kanamycin: DogsToxic effect: A single dose of 100 mg/kg administered to three dogs caused a transient decrease in auditory perception in one dog as measured by auditory brain stem response{R-196}. Administration of 100 mg/kg daily for 9 weeks caused a complete loss of hearing for high-frequency tone, although changes did not begin until about 2 weeks after the beginning of therapy{R-196}. Streptomycin: Cats No effect: A dose of 25 mg/kg a day, administered for 9 to 28 days, did not cause signs of toxicity{R-246}. Toxic effect: An intramuscular dose of 50 mg/kg a day, divided into doses administered every 8 hours for 9 to 28 days, produced nonreversible hearing loss in most cats{R-246}. A dose of 200 mg/kg produced both permanent hearing loss and vestibular impairment{R-246}. Lethal dose Note: These doses have been reported as lethal but are not necessarily the minimum lethal dose in a particular animal. No effect is listed if the research was intended to dene a lethal dose. Amikacin: LD50Dogs: Intramuscular or intravenous, >250 mg/kg{R91} . Apramycin: Chickens and dogsNo effect: No mortality was observed with 520 mg/kg as a single dose in chickens and dogs{R-96}. MiceIn mice, greater than 5200 mg/kg as a single dose produced no mortality{R-96}. Gentamicin: Cats40 to 70 mg/kg a day administered subcutaneously caused renal necrosis and death within 10 days{R-227}. Hawks, red-tailedAn intravenous dose of 20 mg/kg every 12 hours was lethal for all ve birds in 2 to 6 days; predominant signs were indicative of neuromuscular blockade{R-87}.

CLINICAL EFFECTS OF OVERDOSE

The following effects have been selected on the basis of their potential clinical signicance (possible signs in parentheses where appropriate)not necessarily inclusive: Note: The following overdose effects mirror the side/adverse effects listed in this monograph because of the small therapeutic index for

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12 AMINOGLYCOSIDES VeterinarySystemic aminoglycosides. These effects may occur in some animals with therapeutic doses so that most animals treated should be monitored for adverse effects. These are also dose-related effects, however, with risk increasing as the dose rises above recommended levels{R-7}. All species Nephrotoxicity{R-7; 212}; neuromuscular blockade; ototoxicity, auditory; ototoxicity, vestibular which pathogen growth is inhibited after the serum concentration falls below minimum inhibitory concentrations{R-80}. The PAE has been shown to occur when amikacin or gentamicin is administered to treat gram-negative infections{R-174}. Postantibiotic effect may be evidence that exposure to a high concentration of antimicrobial causes cellular changes in the pathogen that will inevitably cause death after drug concentrations have dropped below the MIC{R-158}. The PAE may be shortened in neutropenic animals but prolonged in animals with renal impairment{R-174}. 3) An extended period of serum drug concentrations below a minimum amount is expected to decrease the risk of aminoglycoside toxicity. Dosing is usually designed to produce peaks above the MIC and troughs below a minimum concentration to prevent adverse effects, regardless of the frequency of dosing within a 24-hour period. Many sources recommend serum concentrations be allowed to drop below 2 mcg/mL for gentamicin and to less than 2.5 to 5 mcg/mL for amikacin or kanamycin for an extended period within a dosing interval to reduce the risk of toxicity{R-47; 51; 63; 148; 185; 209; 230}. A plasma or serum concentration of at least 8 to 10 times the MIC of the organism has been recommended for the aminoglycoside antibiotics to be effective{R-155}. Individualized dosing/Patient monitoring: Even within the same species, individual animals can differ widely in the serum concentrations produced from the same dosage regimen{R-83; 89; 213; 230}. When this relative unpredictability is combined with the often small difference between therapeutic and toxic serum concentrations of aminoglycosides, the determination of serum concentrations in a particular animal becomes very valuable. When it is economically possible to measure plasma or serum concentrations during aminoglycoside therapy, the information can be used to maximize efcacy and minimize toxicity{R-130132}. Note: There can be up to a fourfold difference between avian species in the elimination of gentamicin{R-85}. It is recommended that speciesspecic pharmacokinetic data be used to develop dosing for birds, if at all possible{R-148}. Once daily dosing: The continuing effort to maximize therapeutic effect and minimize toxic effect of aminoglycosides has led to ongoing research on the efcacy of a 24-hour dosing interval{R-160; 232; 252}. Dosing once a day is considered by some clinicians to be a rational use of aminoglycosides in specic situations{R-232}. The supporting arguments include that use of the highest safe single dose has been linked to increased efcacy in human studies, greater bacterial killing and a longer postantibiotic effect are expected with a higher peak concentration, and once-a-day dosing allows for the longest period of low serum concentration to minimize toxicity{R-160; 232; 252}. Concern has been expressed that dosing once every 24 hours may be less effective than repeated daily dosing in some situations, such as in immunocompromised patients{R-158}. Studies with guinea pigs have demonstrated no signicant difference in bacterial killing between gentamicin administered subcutaneously at 6 mg/kg every 24 hours versus 2 mg/kg every 8 hours{R-80}. However, once-a-day dosing has been less effective in treating some infections in neutropenic animals{R-158; 232}. Some researchers have demonstrated a potential for development of resistance with dosing once a day{R-232}; but others have described an adaptive resistance to aminoglycosides in Pseudomonas species that occurs with doses repeated within 16 hours in animal models but that is reduced by longer dosing intervals in the rst 3 days{R-160}. Some clinicians have expressed reservations about oncedaily dosing when intestinal damage allows continued exposure to

TREATMENT OF OVERDOSE
Recommended treatment consists of the following: Note: Some experts suggest that administration of a beta-lactam antibiotic that binds an aminoglycoside (ticarcillin, for example) will decrease the toxicity after accidental overdose of aminoglycosides{R266} . For neuromuscular blockade Administration of edrophonium, 0.5 mg/kg, will reverse neuromuscular blocking effects{R-200; 201}. Administration of calcium chloride at 10 to 20 mg/kg, calcium gluconate at 30 to 60 mg/kg, or neostigmine at a dose of 100 to 200 mcg per kg of body weight can also reverse muscle response depression and associated dyspnea{R-186}. For renal toxicity Aminoglycoside administration should be immediately discontinued{R-208}. Polyionic electrolyte uid therapy should be initiated to stimulate diuresis{R-208}. Note: Three or more weeks of therapy may be required for recovery in animals with sufcient remaining renal tissue to compensate{R-215}. Oliguria may be a poor prognostic sign{R-215}.

CLIENT CONSULTATION
There are reports that aminoglycosides, such as neomycin or streptomycin, can cause contact dermatitis in human beings{R-236}. Direct contact with skin should be avoided by people handling these products{R-236}.

VETERINARY DOSING INFORMATION

Resistance: Reports of antimicrobial resistance support recommendations to culture pathogens to be sure the use of an aminoglycoside is warranted. There is also some evidence that limiting the use of aminglycosides and, in particular, limiting administration at subtherapeutic concentrations to a population of animals may limit the increase in E. coli resistance that is seen with more intense antimicrobial use{R-234}.

FOR PARENTERAL DOSAGE FORMS ONLY

Systemic aminoglycosides are generally dosed to achieve a high peak serum concentration followed by a period of subtherapeutic serum concentration. This strategy is built on several factors: 1) Aminoglycosides kill bacteria by a concentration-dependent mechanism{R-80} rather than dependence on the length of time the organism is exposed to the antibiotic{R-160}. A spike in concentration{R-80; 232} or, in some situations, a plateau{R-155; 157} above the minimum inhibitory concentration is neccessary for effective bacterial killing. 2) A high peak of antibiotic will cause the most killing of bacteria and will also cause the most prolonged postantibiotic effect (PAE), in

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AMINOGLYCOSIDES VeterinarySystemic 13 bacteria that may replicate during the prolonged periods of subtherapeutic aminoglycoside concentration{R-263}. Desired benets include reduction of toxicity. If the total daily dose of aminoglycoside is kept constant, less frequent dosing per day is associated with decreasing renal toxicity{R-232}. The same is true for gentamicin ototoxicity in guinea pigs but, while the single daily dose has not been shown to be more toxic for amikacin or kanamycin, the benet in reducing ototoxicity is less clear for amikacin or kanamycin in guinea pigs{R-190; 191; 232}. Renal dysfunction: Treatment with gentamicin every 8 hours is not recommended in patients with subclinical renal disease{R-72}. Because drug clearance may be slowed with gentamicin treatment, the risk of nephrotoxicity may be increased. Trough serum concentrations can be reduced by increasing the dosing interval and decreasing the dose{R185} . Some clinicians have developed methods to calculate an increased dosing interval based on the creatinine clearance concentration; however, the most prudent course may be to avoid use of aminoglycosides if it is necessary to signicantly reduce the aminoglycoside dose because of poor renal function{R-72}. Endotoxemia: Producing high serum and tissue concentrations of aminoglycoside as early as possible in animals with gram-negative sepsis is important{R-72}. The release of endotoxin by gram-negative organisms may be enhanced by administration of the antibiotic{R-184}. The systemic effects of endotoxemia will also increase the risk of concentrating aminoglycosides in the renal tissue and causing acute renal failure{R-185}. Diabetes mellitus: It appears that diabetic dogs may have increased clearance of gentamicin and reduced volume of distribution (VolDss) of gentamicin, which make them less susceptible to nephrotoxicity at therapeutic doses of the medication{R-71}; however, the possibility of subclinical renal disease should also be considered. Concurrent uid administration: In horses, the administration of therapeutic uids, similar to those that are used in the treatment of colic, does not signicantly change the pharmacokinetics of concurrently administered gentamicin{R-45}. Gastointestinal microora: Parenterally administered amikacin appears to have minimal effect on gastrointestinal microora in horses{R-136}. Gastrointestinal surgery: When gentamicin administration (4 to 6.6 mg/ kg every 24 hours) is begun immediately after abdominal surgery for naturally occurring colic, the pharmacokinetics of the gentamicin has been measured to be within the reference range for normal healthy horses{R-265}. from gentamicin overdose compared with horses not receiving calcium{R-223}. Sheep: Sheep fed a low protein diet (straw and barley) have a signicantly lower total clearance and volume of distribution at steady state than sheep fed a high protein diet (alfalfa and barley). This results in an increased serum concentration of gentamicin in the group fed a low protein diet{R-38}.

AMIKACIN SUMMARY OF DIFFERENCES

Category: Aminoglycoside Indications: General considerationsHas the broadest spectrum of activity of the aminoglycosides and is considered effective against strains not susceptible to other aminoglycosides. Side/adverse effects: Intermediate renal toxicity. More toxic to the cochlea than to vestibular organs. Diarrhea and vomiting in dogs. Mild local tissue trauma in cats and dogs.

MUCOSAL DOSAGE FORMS AMIKACIN SULFATE UTERINE SOLUTION

Usual dose: Uterine infectionsHorses: Intrauterine, 2 grams, administered every twenty-four hours for three days{R-92; 105; 138}. The medication should be mixed with 200 mL of 0.9% sodium chloride injection before administration{R-92}. Note: Product labeling recommends that mares not be bred for eight hours after intrauterine treatment with amikacin{R-92}. Strength(s) usually available{R-231}: U.S. Veterinary-labeled product(s): 250 mg per mL (Rx) [Amifuse E; Amiglyde-V Intrauterine Solution{R-92}; Amikacin E Solution; AmTech AmiMax E Solution; EquiPhar EquiGlide; generic]. Note: These products contain 0.1 mg benzethonium chloride per mL as a preservative{R-92}. Canada Veterinary-labeled product(s): 250 mg per mL (Rx) [Amiglyde-V]. Withdrawal times: U.S. and CanadaProduct is not labeled for use in horses to be used for food production{R-92}. Stability: A change from a colorless solution to pale yellow in color does not indicate a decrease in potency of the antimicrobial{R-92}. Packaging and storage: Store below 40 C (104 F), preferably between 15 and 30 C (59 and 86 F), unless otherwise specied by manufacturer. USP requirements: Not in USP{R-19}.

FOR ORAL DOSAGE FORMS ONLY

Chickens: Because poultry litter may contain bacteria with multiple antibiotic resistance, treatment of litter to prevent contamination before reutilization in soil or bedding is recommended{R-121}.

DIET/NUTRITION
Dogs: Dogs with normal renal function consuming a higher protein diet (26%) for 3 weeks before treatment have a faster gentamicin clearance and a larger volume of distribution than dogs fed a medium (13%) or low (9%) protein diet{R-73}. Horses: Horses fed an alfalfa diet rather than oats alone have a smaller degree of nephrotoxicosis from administration of gentamicin{R-222}. Likewise, horses administered supplemental calcium gluconate, 20 mg/kg every 12 hours, have a decreased risk of acute renal failure

PARENTERAL DOSAGE FORMS

Note: Bracketed information in the Dosage Forms section refers to uses that either are not included in U.S. product labeling or are for products not commercially available in the U.S.

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14 AMINOGLYCOSIDES VeterinarySystemic

AMIKACIN SULFATE INJECTION USP

Note: Intravenous administrationWhen amikacin is administered by the intramuscular or subcutaneous route, it is rapidly and completely absorbed. Although not always listed on product labeling, this medication is also commonly administered intravenously. An indwelling catheter is used for convenience and to minimize the discomfort of repeated dosing{R-263}. To further decrease the risk of neuromuscular blockade, it is recommended that the drug be diluted in saline or administered slowly{R-263}. Usual dose: [Bacteremia]1; [Bone and joint infections]1; [Respiratory tract infections]1; [Septicemia]1; Skin and soft tissue infections1; Urinary tract infections1; or [Uterine infections]1Dogs: Intramuscular or subcutaneous, 10 mg per kg of body weight every eight to twelve hours{R-91; 143}. Once-daily dosingIntramuscular or subcutaneous, 15 to 30 mg per kg of body weight every twenty-four hours{R-266}. [Bacteremia]1; [Bone and joint infections]1; [Respiratory tract infections]1; [Septicemia]1; [Skin and soft tissue infections]1; [Urinary tract infections]1; or [Uterine infections]1Cats: Intramuscular or subcutaneous, 10 mg per kg of body weight every eight hours{R-139; 140; 264}. Once-daily dosingIntramuscular or subcutaneous, 10 to 15 mg per kg of body weight every twenty-four hours{R-266}. Note: [Calves]1Animal Medicinal Drug Use Clarication Act (AMDUCA) regulations should be considered before the extra-label use of aminoglycosides in food-producing animals: Although the safety and efcacy of amikacin have not been established, a dose of 12 mg per kg of body weight every twelve hours has been suggested for use in the treatment of susceptible bacterial infections{R-141; 144}. [Donkeys]1 and [ponies]1Although the safety and efcacy of amikacin have not been established, a dose of 6 mg per kg of body weight every six hours, administered intravenously, has been recommended in the treatment of bacterial infections in donkeys and ponies{R-136}. [Foals, less than 30 days of age]1Although the safety and efcacy of amikacin have not been established, a dose of 20 to 25 mg per kg of body weight every twenty-four hours, administered by the intramuscular or intravenous route, has been recommended in the treatment of susceptible bacterial infections in foals{R-6; 130132; 134; 266; 271}. [Goats]1AMDUCA regulations should be considered before the extra label use of aminoglycosides in food-producing animalsAlthough the safety and efcacy of amikacin have not been established, a subcutaneous dose of 8 mg per kg of body weight every twelve hours has been suggested in the treatment of susceptible bacterial infections in goats{R-151}. In one study, this was predicted to provide peak serum concentrations of 32.3 mcg/mL{R-151}. [Guinea pigs]1Although the safety and efcacy of amikacin have not been established, an intramuscular dose of 15 mg per kg of body

weight every twelve hours has been suggested for the treatment of susceptible bacterial infections in guinea pigs{R-152}. [Hawks, red-tailed]1Although the safety and efcacy of amikacin have not been established, a dose of 15 to 20 mg per kg of body weight every twenty-four hours or 7 to 10 mg per kg of body weight every twelve hours, administered intramuscularly, has been suggested for the treatment of susceptible bacterial infections in red-tailed hawks{R-147}. This recommendation is based on pharmacokinetic data. In this study, it was also noted that larger birds tended to develop lower peak serum drug concentrations than smaller birds in response to the same dose{R-147}. [Horses]1 and [foals, more than 30 days of age]1Although the safety and efcacy have not been established, an intramuscular or intravenous dose of 10 mg per kg of body weight every twenty-four hours has been recommended in the treatment of susceptible bacterial infections, based on pharmacokinetic data{R-6}. For some infections in horses, dosing more than once a day may still be necessary and, in those cases, an intravenous dose of 6 mg per kg of body weight every eight hours has been recommended{R-136}. [Parrots, African gray]1Although the safety and efcacy of amikacin have not been established, an intravenous or intramuscular dose of 10 to 20 mg per kg of body weight every eight to twelve hours has been recommended in the treatment of susceptible bacterial infections, based on pharmacokinetic data{R-150}. [Pythons, ball]1Although the safety and efcacy of amikacin have not been established, an intramuscular dose of 3.48 mg per kg of body weight as a single dose has been recommended in the treatment of susceptible bacterial infections in ball pythons{R-155}. [Snakes, gopher]1Although the safety and efcacy of amikacin have not been established, an intramuscular loading dose of 5 mg per kg of body weight, followed by 2.5 mg per kg of body weight every seventy-two hours has been suggested in the treatment of susceptible bacterial infections in gopher snakes{R-154}. It has also been recommended that snakes be kept at the high end of their preferred temperature range (37 C) to maximize distribution of drug in the body{R-154}. [Tortoises, gopher]1Although the safety and efcacy of amikacin have not been established, an intramuscular dose of 5 mg per kg of body weight (including shell), administered every forty-eight hours, has been suggested for the treatment of susceptible bacterial infections in gopher tortoises{R-156}.

Strength(s) usually available{R-231}: U.S. Veterinary-labeled product(s): 50 mg per mL (Rx) [Amiglyde-V Injection{R-91}; Amiject D; Amikacin C Injection; AmTech AmiMax C Injection; CaniGlide; GENERIC]. Note: These products contain 0.1 mg benzethonium chloride per mL{R92} . Canada Veterinary-labeled product(s): Not commercially available. Withdrawal times: U.S.This product is not labeled for use in food-producing animals and should not be administered to such animals because of the risk of longterm antibiotic residues{R-258}.

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AMINOGLYCOSIDES VeterinarySystemic 15 Packaging and storage: Store below 40 C (104 F), preferably between 15 and 30 C (59 and 86 F), unless otherwise specied by manufacturer. USP requirements: Preserve in single-dose or in multiple-dose containers, preferably of Type I or Type III glass. A sterile solution of Amikacin Sulfate in Water for Injection, or of Amikacin in Water for Injection prepared with the aid of Sulfuric Acid. Contains an amount of amikacin sulfate equivalent to the labeled amount of amikacin, within 10% to +20%. Meets the requirements for Identication, Bacterial endotoxins, pH (3.55.5), and Particulate matter, and for Injections{R-19}.
1

Packaging and storage: Store below 40 C (104 F), preferably between 15 and 30 C (59 and 86 F), unless otherwise specied by manufacturer. Protect from moisture and excessive heat{R-96}. Preparation of dosage form: Prepare fresh solution daily according to manufacturers labeling{R-96}. Incompatibilities: Activity of the medication may be reduced if water delivery system contains rust{R-96}. USP requirements: Not in USP{R-19}.

Not included in Canadian product labeling or product not commercially available in Canada

DIHYDROSTREPTOMYCIN APRAMYCIN SUMMARY OF DIFFERENCES

Category: Aminocyclitol. Indications: General considerationsApramycin is active against Staphylococcus aureus, many gram-negative organisms, and some mycoplasma. It has been reported to be effective in vitro against Escherichia coli and Salmonella species{R-96; 164} that are resistant to streptomycin and neomycin{R-167; 173}. Side/adverse effects: This medication produces minimal side/adverse effects and toxicity when administered by the oral route.

SUMMARY OF DIFFERENCES
Category: Aminoglycoside. Indications: General considerationsActive against mycobacteria, Leptospira{R-243; 244}, Francisella tularensis, and Yersinia pestis, but only some mycoplasma, gram-negative organisms, and Staphylococcus species{R-116}. The introduction of newer aminoglycosides has eclipsed the signicance of dihydrostreptomycin in the face of increasing bacterial resistance. Lactation: Irregularly distributed into the milk of cows for 18 hours or more. Side/adverse effects: Less nephrotoxic than other aminoglycosides. Unlike streptomycin, dihydrostreptomycin is associated with more auditory than vestibular toxicity{R-233}.

ORAL DOSAGE FORMS APRAMYCIN SULFATE POWDER FOR ORAL SOLUTION

Usual dose: Enteritis, E. coliPiglets: Oral, 12.5 mg per kg of body weight a day for seven days (375 mg per gallon or 100 mg per liter), administered in the only source of water{R-95; 96}. Note: Water consumption should be monitored closely and adjusted to avoid overdose. Strength(s) usually available{R-231}: U.S. Veterinary-labeled product(s): 48 grams per packet (OTC) [Apralan Soluble]. Canada Veterinary-labeled product(s): 48 grams per packet (OTC) [Apralan]. Withdrawal times: U.S.{R-95}
Withdrawal time Species Pigs Meat (days) 28

ORAL DOSAGE FORMS

Note: Bracketed information in the Dosage Forms section refers to uses that either are not included in U.S. product labeling or are for products not commercially available in the U.S.

DIHYDROSTREPTOMYCIN INJECTION USP

Usual dose: Note: [Cattle], [dogs], and [pigs]Although Canadian product labeling includes a dose of 25 mg per kg of body weight for three to ve days in the treatment of leptospirosis in cattle, dogs, and pigs, studies have shown that while shedding of leptospires will be halted for at least 2 months, carriers are not necessarily eliminated{R-243; 244}. Although Canadian product labeling includes the use of dihydrostreptomycin in the treatment of bacterial pneumonia in calves, there is no published evidence available pertaining to efcacy of this therapy. Such use is not recommended by the USP Veterinary Medicine Advisory Panel{R-258} due to the lack of efcacy data and the potential for extended tissue withdrawal times. Strength(s) usually available{R-231}: U.S. Veterinary-labeled product(s): Not commercially available. Canada Veterinary-labeled product(s): 500 mg per mL (OTC) [Ethamycin{R-106}].

Canada{R-96}
Withdrawal time Species Pigs Meat (days) 28

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16 AMINOGLYCOSIDES VeterinarySystemic Withdrawal times: Canada

Withdrawal time Species Calves, pigs Cattle Meat(days) 30 30 Milk (hours)

96

USP requirements: Preserve in single-dose or in multiple-dose containers, preferably of Type I glass. A sterile solution of Gentamicin Sulfate in Water for Injection. Label Uterine Infusion to indicate that it is for veterinary use only. The label states that it must be diluted with 0.9% Sodium Chloride Irrigation before aseptic uterine infusion. May contain suitable buffers, preservatives, and sequestering agents. Contains the labeled amount, within 10 to +25%. Meets the requirements for Identication, Sterility, and pH (3.05.5).{R-19}

Packaging and storage: Store below 40 C (104 F), preferably between 15 and 30 C (59 and 86 F), unless otherwise specied by manufacturer. USP requirements: Preserve in single-dose or in multiple-dose containers. Label it to indicate that it is intended for veterinary use only. Contains an amount of Dihydrostreptomycin Sulfate equivalent to the labeled amount of dihydrostreptomycin, within 10% to +20%. Contains one or more suitable preservatives. Meets the requirements for Identication, Bacterial endotoxins, Sterility, and pH (5.08.0){R-19}.

ORAL DOSAGE FORMS GENTAMICIN ORAL SOLUTION

Usual dose: Enteritis, E. coli Piglets, 1 to 3 days of age: Oral, 5 mg as a total dose, administered once at the onset of signs{R-13; 14}. Note: The above dose is for pig pump solutions, administered at the strength provided in metered dose packaging{R-13; 14}; see manufacturers product labeling. Piglets, weanling1: Oral, 25 mg per gallon of water (approximately 1.1 mg per kg of body weight), administered as the sole source of drinking water for three consecutive days{R-11}. Swine dysentery1Pigs: Oral, 50 mg per gallon of water (approximately 2.2 mg per kg of body weight), administered as the sole source of drinking water for three consecutive days{R-11}. Strength(s) usually available{R-231}: U.S. Veterinary-labeled product(s): 4.35 mg per mL (OTC) [Garacin Pig Pump{R-13}]. 5 mg per mL (OTC) [AmTech Gentamicin Sulfate Pig Pump Oral Solution]. Canada Veterinary-labeled product(s): 4.35 mg per mL (OTC) [Garasol Pig Pump Oral Solution{R-14}]. Withdrawal times: U.S.{R-13}
Withdrawal time Species Piglets Meat (days) 14

GENTAMICIN SUMMARY OF DIFFERENCES

Category: Aminoglycoside. Indications: General considerationsGentamicin has been widely used in the treatment of gram-negative organisms and some gram-positive organisms. As with other aminoglycosides, use is limited by risk of toxicity. Side/adverse effects: Intermediate nephrotoxicity. It is considered to be equally toxic to the cochlea and to vestibular organs.

MUCOSAL DOSAGE FORMS GENTAMICIN UTERINE INFUSION USP

Usual dose: Uterine infections, bacterialHorses: Intrauterine, 2 to 2.5 grams as a total dose a day for three to ve days during estrus{R-1}. Before administration, the dose should be diluted with 200 to 500 mL of sterile physiological saline{R-1}. Strength(s) usually available{R-231}: U.S. Veterinary-labeled product(s): 50 mg per mL (Rx) [Gentocin Solution{R-1}]. 100 mg per mL (Rx) [AmTech GentaMax 100; GentaMax 100; GentaVed 100; Gentocin Solution; Gentozen; Legacy; GENERIC{R-3}]. Canada Veterinary-labeled product(s): Not commercially available. Withdrawal times: U.S.This product is not labeled for use in food-producing animals in the U.S., including horses intended for food production{R-1}. Packaging and storage: Store between 2 and 30 C (36 and 86 F){R-1}, unless otherwise specied by manufacturer. 2003 Thomson MICROMEDEX

Canada{R-14}
Withdrawal time Species Piglets Meat (days) 11

Packaging and storage: Store below 40 C (104 F), preferably between 15 and 30 C (59 and 86 F), unless otherwise specied by manufacturer. Protect from freezing{R-13}. Preparation of dosage form: This medication is dispensed in a pig pump. Medication is administered by one plunger depression to deliver 5 mg into each pigs mouth{R-12}. All rights reserved

AMINOGLYCOSIDES VeterinarySystemic 17 Stability: Contents of pig pump medication bottle should be destroyed 90 days after opening, if unused{R-12}. Medicated drinking water should be prepared daily{R-11}. Incompatibilities: To prevent inactivation of the drug, medicated drinking water should not be stored in rusty containers{R-11}. USP requirements: Not in USP{R-19}. absorbed. Although not always listed on product labeling, this medication is also commonly administered intravenously. An indwelling catheter is used for convenience and to minimize the discomfort of repeated dosing{R-263}. To further decrease the risk of neuromuscular blockade, it is recommended that the drug be diluted in saline or administered slowly{R-263}.

GENTAMICIN POWDER FOR ORAL SOLUTION

Usual dose: Enteritis, E. coli1Piglets: Oral, 25 mg per gallon of water (approximately 1.1 mg per kg of body weight), administered as the sole source of drinking water for three consecutive days{R-15}. Swine dysentery1Pigs: Oral, 50 mg per gallon of water (approximately 2.2 mg per kg of body weight), administered as the sole source of drinking water for three consecutive days{R-15}. Note: Under extreme hot or cold weather conditions, product labeling recommends that the concentration of medication be adjusted, based on expected changes in water consumption{R-15}. Strength(s) usually available{R-231}: U.S. Veterinary-labeled product(s): 66.7 mg of gentamicin per gram of powder (OTC) [Garacin Soluble Powder]. 333.3 mg of gentamicin per gram of powder (OTC) [Gen-Gard]. Canada Not commercially available. Withdrawal times: U.S.{R-15}
Withdrawal time Species Pigs, piglets Meat (days) 10

Packaging and storage: Store below 40 C (104 F), preferably between 15 and 30 C (59 and 86 F), unless otherwise specied by manufacturer. To avoid degradation of medication, this product should not be stored in rusty containers{R-15}. Preparation of dosage form: Prepare daily according to manufacturers recommendation{R-15}. USP requirements: Not in USP{R-19}.
1

Not included on Canadian product labeling or product not commercially available in Canada.

PARENTERAL DOSAGE FORMS

Note: Bracketed information in the Dosage Forms section refers to uses that either are not included in U.S. product labeling or are not commercially available in the U.S.

GENTAMICIN INJECTION USP

Note: Intravenous administrationWhen gentamicin is administered by the intramuscular or subcutaneous route, it is rapidly and completely 2003 Thomson MICROMEDEX

Usual dose: [Bacteremia]; [Bone and joint infections]1; Respiratory tract infections; [Septicemia]; Skin and soft tissue infections; Urinary tract infections; or [Uterine infections]1 Cats: Intramuscular, intravenous, or subcutaneous, 3 mg per kg of body weight every eight hours{R-63; 64}. Once-daily dosingIntramuscular, intravenous, or subcutaneous, 5 to 8 mg per kg of body weight every twenty-four hours{R-266}. Dogs: Intramuscular or subcutaneous, 4.4 mg per kg of body weight every eight hours{R-4; 7}. Once-daily dosingIntramuscular or subcutaneous, 10 to 15 mg per kg of body weight every twenty-four hours{R-266}. Note: Authors of a study of obese cats considered to be approximately 45% overweight (4.6 to 6.6 kg body weight) recommended an intramuscular, intravenous, or subcutaneous dose of 2.5 mg per kg of body weight every eight hours to compensate for pharmacokinetic differences from normal-weight cats{R-68}. Treatment of urinary tract infections with aminoglycosides should be reserved for those cases in which resistance exists to safer alternative antimicrobials. Despite label directions to limit treatment duration to 7 days{R-4}, most urinary tract infections will require extended therapy. This is possible with the aminoglycosides, provided careful monitoring is performed (see Patient monitoring). According to product labeling, treatment with gentamicin injection should not exceed 7 days{R-4}. Enteritis, Escherichia coliPiglets, 1- to 3-day-old: Intramuscular, 5 mg as a single total dose{R-7; 9}. E. coli infection; Pseudomonas aeruginosa infection; or Salmonella typhimurium infectionChicks, 1-day-old: Subcutaneous, 0.2 mg as a total single dose{R-7; 8}. ParacolonTurkey poults, 1- to 3-day-old: Subcutaneous, 1 mg as a total single dose{R-7; 8}. Uterine infections, bacterialHorses: Intrauterine, 2 to 2.5 grams a day for three to ve days during estrus{R-4; 7}. Before administration, the dose should be diluted with 200 to 500 mL of sterile physiological saline{R-4; 7}. Note: The following recommendations have been suggested based on pharmacokinetic studies: [Baboons]1Although the safety and efcacy of gentamicin have not been established, an intramuscular dose of 3 mg per kg of body weight every six to eight hours has been suggested in the treatment of Pseudomonas aeruginosa infections in baboons{R-76}. [Buffalo calves]1Animal Medicinal Drug Use Clarication Act (AMDUCA) regulations should be considered before the extra label All rights reserved

18 AMINOGLYCOSIDES VeterinarySystemic use of aminoglycosides in food-producing animals: Although the safety and efcacy of gentamicin have not been established, an intramuscular dose of 3.25 mg per kg of body weight as an initial dose, followed by 2 to 3 mg per kg of body weight every twelve hours has been recommended in the treatment of susceptible bacterial infections in buffalo calves{R-77; 78}. [Budgerigars]1Although the safety and efcacy of gentamicin have not been established, an intramuscular dose of 5 mg per kg of body weight every eight hours for three days has been suggested in the treatment of susceptible bacterial infections in budgerigars{R-86}. [Calves, less than 2 weeks of age]1AMDUCA regulations should be considered before the extra label use of aminoglycosides in foodproducing animals: Although the safety and efcacy have not been established, an intravenous dose of 12 to 15 mg per kg of body weight every twenty-four hours has been recommended in the treatment of susceptible bacterial infections, based on pharmacokinetic data{R-21; 266}. [Cattle]1AMDUCA regulations should be considered before the extra label use of aminoglycosides in food-producing animals: Although the safety and efcacy have not been established, an intramuscular dose of 5 to 6 mg per kg of body weight every twenty-four hours has been recommended in the treatment of susceptible bacterial infections, based on pharmacokinetic data{R-22; 25; 261; 266}. [Eagles]1, [hawks]1, or [owls]1Although the safety and efcacy of gentamicin have not been established, an intramuscular or intravenous dose of 2.5 mg per kg of body weight every eight hours has been recommended in the treatment of susceptible bacterial infections in eagles, hawks, and owls{R-88}. Caution is advised in extrapolating dosage recommendations from one avian species to another, as pharmacokinetics can vary widely. [Goats]1AMDUCA regulations should be considered before the extra label use of aminoglycosides in food-producing animals: Although the safety and efcacy of gentamicin have not been established, an intravenous dose of 4 mg per kg of body weight every eight hours has been recommended for use in the treatment of susceptible bacterial infections in goats{R-40}. [Horse foals]1 and [pony foals]1, less than 30 days of ageAlthough the safety and efcacy have not been established, some researchers suggest that dosing of gentamicin for horse and pony foals less than 30 days of age should be an intramuscular or intravenous dose of 10 to 14 mg per kg of body weight every twenty-four hours{R-6; 266}. [Horses]1 and [foals, more than 30 days of age]1Although the safety and efcacy of gentamicin have not been established, an intramuscular or intravenous dose of 4 to 6.8 mg per kg of body weight every twenty-four hours has been suggested for the treatment of susceptible bacterial infections in horses and foals more than 30 days of age{R-6; 46; 50; 52; 53; 55; 252; 265; 266}. [Llamas]1AMDUCA regulations should be considered before the extra label use of aminoglycosides in food-producing animals: Although the safety and efcacy of gentamicin have not been established, a dose of 2.5 mg per kg of body weight every eight hours for six days has been suggested in the treatment of bacterial infections in llamas{R-82}. [Pythons]1Although the safety and efcacy of gentamicin have not been established, an intramuscular dose of 2.5 mg per kg of body weight as an initial dose, followed by 1.5 mg per kg of body weight at ninety-sixhour intervals has been suggested in the treatment of susceptible bacterial infections in pythons{R-89}. Strength(s) usually available{R-231}: U.S. Veterinary-labeled products: 5 mg per mL (Rx) [Garacin Piglet Injection{R-9}]. 50 mg per mL (Rx) [GentaVed 50; Gentocin{R-4}]. 100 mg per mL (OTC) [AmTech Gentapoult; Garasol Injection{R-8}; Genta-fuse; generic]. Canada Veterinary-labeled products: 5 mg per mL (Rx) [Garasol Solution Injectable{R-10}]. 50 mg per mL (Rx) [Gentocin Solution Injectable{R-7}]. 100 mg per mL (Rx [Gentocin Solution Injectable]. Withdrawal times: U.S.This product is not labeled for use in horses to be used in food production{R-4}.
Withdrawal time Species Chicks Piglets Turkey poults Meat (days) 35 40 63

CanadaThis product is not labeled for use in horses to be used in food production{R-7}.
Withdrawal time Species Chicks Piglets Turkey poults Meat (days) 35 42 63

Note: The administration of gentamicin to cattle in the treatment of uterine infections is included in Canadian product labeling. However, gentamicin is not labeled for use in food-producing animals in the U.S. and the USP Veterinary Medicine Advisory Panel does not recommend use in the treatment of uterine infections in cattle. Therefore, the labeled intrauterine dose and withdrawal time for cattle are not listed in this monograph. Packaging and storage: Store between 15 and 30 C (59 and 86 F){R-4}, unless otherwise specied by manufacturer. Keep from freezing{R-4}. USP requirements: Preserve in single-dose or in multiple-dose containers, preferably of Type I glass. May contain suitable buffers, preservatives, and sequestering agents, unless it is intended for intrathecal use, in which case it contains only suitable tonicity agents. Contains an amount of gentamicin sulfate equivalent to the labeled amount of gentamicin, within 10% to +25%. Meets the requirements for Identication, Bacterial endotoxins, pH (3.05.5), and Particulate matter, and for Injections{R-19}.
1

Not included on Canadian product labeling or product not commercially available in Canada.

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AMINOGLYCOSIDES VeterinarySystemic 19

KANAMYCIN SUMMARY OF DIFFERENCES

Category: Aminoglycoside. Indications: General considerationsSpectrum of activity focuses primarily on gram-negative organisms and a few gram-positive organisms. Side/adverse effects: Intermediate nephrotoxicity. More toxic to the cochlea than to vestibular organs.

Side/adverse effects: High risk of nephrotoxicity and severe cochlear toxicity when parenterally administered.

ORAL DOSAGE FORMS

Note: Bracketed information in the Dosage Forms section refers to uses that either are not included in U.S. product labeling or are not commercially available in the U.S.

PARENTERAL DOSAGE FORMS KANAMYCIN INJECTION USP

Usual dose: Bacteremia or septicemia1; Bone and joint infections1; Otitis media1; Pancreatitis1; Respiratory tract infections1; Skin and soft tissue infections1; Urinary tract infections1; or Uterine infections1Cats and dogs: Subcutaneous, 5.5 mg per kg of body weight every twelve hours{R-93}. According to product labeling, this medication may also be given by intramuscular injection, if necessary{R-93}. Note: Another source recommends a dose of 10 mg per kg of body weight every six hours in the dog, based on pharmacokinetic data{R-177}. Strength(s) usually available{R-231}: U.S. Veterinary-labeled product(s): 200 mg per mL (Rx) [Kantrim]. Canada Veterinary-labeled product(s): Not commercially available. Packaging and storage: Store below 40 C (104 F), preferably between 15 and 30 C (59 and 86 F), unless otherwise specied by manufacturer. Stability: Unopened vials may darken in color during storage, but potency is unaffected{R-93}. USP requirements: Preserve in single-dose or in multiple-dose containers, preferably of Type I or Type III glass. Contains suitable buffers and preservatives. Contains an amount of Kanamycin Sulfate equivalent to the labeled amount of kanamycin, within 10% to +15%. Meets the requirements for Identication, Bacterial endotoxins, Sterility, pH (3.55.0), and Particulate matter and for Injections{R-19}.
1

NEOMYCIN SULFATE FOR MEDICATED FEED

Usual dose: Enteritis, Escherichia coli (treatment)1Cattle, goats, pigs, and sheep: Oral, 22 mg per kg of body weight a day for up to a maximum of fourteen days{R-16; 94}. Note: This product is labeled for use in the preparation of Type B or Type C medicated feeds; Type C medicated feeds may be either medicated solid feeds or milk replacers. To administer the recommended dosage, adjustments must be made in the concentration of neomycin in feed or milk replacer, based on factors altering consumption, such as age and weight of the animal, disease signs, and environmental factors{R-94}. Strength(s) usually available{R-231}: U.S. Veterinary-labeled product(s): 715 grams per kg (OTC) [Neomix AG 325 Medicated Premix]. Canada Veterinary-labeled product(s): Not commerically available. Withdrawal times: U.S.
Withdrawal time Species Cattle and ruminating calves Goats and kids, pigs and piglets Sheep and lambs Meat (days) 1 3 2

Note: Products are not labeled for use in preruminating calves to be processed for veal or for lactating dairy cattle or goats producing milk for human consumption. Packaging and storage: Store below 40 C (104 F), preferably between 15 and 30 C (59 and 86 F), in a tightly closed container, unless otherwise specied by manufacturer. Store in a dry place, securely closing packaging to prevent caking of contents{R-231}. Preparation of dosage form: Prepare solutions daily according to manufacturers instructions. USP requirements: Not in USP{R-19}.

Not included on Canadian product labeling or product not commercially available in Canada.

NEOMYCIN SULFATE ORAL SOLUTION USP

Usual dose: Enteritis, E. coliCattle, goats1, [horses], pigs, and sheep: Oral, 22 mg per kg of body weight a day, administered in the only source of drinking water for fourteen days{R-98100}. Note: For many of these products, individual animal treatment is also possible by dividing the daily dose and administering as a drench with milk or water or by mixing in an individual animals only water supply{R-98100}. Consult the manufacturers product labeling. All rights reserved

NEOMYCIN SUMMARY OF DIFFERENCES

Category: Aminoglycoside. Indications: General considerationsEffective against many gramnegative organisms and Staphylococcus aureus. 2003 Thomson MICROMEDEX

20 AMINOGLYCOSIDES VeterinarySystemic Canadian product labeling lists the dose of neomycin in terms of mL per liter of drinking water and an incrementally increasing dose from 2 weeks to adult, or 2 weeks to 26 weeks of age, for chickens and turkeys, respectively{R-103}. See product labeling for specic dosing directions. Strength(s) usually available{R-231}: U.S. Veterinary-labeled product(s): 200 mg per mL (OTC) [AmTech Neomycin Oral Solution; Biosol Liquid{R-98}; Neomycin 200{R-100}; Neosol-Oral; Neoved 200; Neovet Neomycin Oral Solution; generic{R-99}]. Canada Veterinary-labeled product(s): 200 mg per mL (OTC) [Biosol Liquid{R-103}]. Withdrawal times: U.S.
Withdrawal time Species Cattle Goats, pigs Sheep Meat (days) 1 3 2

USP requirements: Preserve in tight, light-resistant containers, preferably at controlled room temperature. Contains an amount of neomycin sulfate equivalent to the labeled amount of neomycin, within 10 to +25%. Meets the requirements for Identication and pH (5.07.5){R-19}.

NEOMYCIN SULFATE POWDER FOR ORAL SOLUTION

Usual dose: E. coli infection1Turkeys, growing: Oral, 22 mg per kg of body weight a day, administered in the only source of drinking water for ve days{R-2; 97}. Enteritis, E. coliCattle, goats1, [horses], pigs, and sheep: Oral, 22 mg per kg of body weight a day for fourteen days, administered in the only source of drinking water{R-97; 104}. Note: For many of these products, individual animal treatment is also possible by dividing the daily dose and administering as a drench with milk or water or by mixing in an individual animals only water supply{R-97}. Consult manufacturers product labeling for specic dosing directions. Canadian product labeling lists the dose of neomycin in terms of mL per liter of drinking water and an incrementally increasing dose from 2 weeks to adult, or 2 weeks to 26 weeks of age, for chickens and turkeys, respectively{R-104}. Consult manufacturers product labeling for specic dosing directions. Strength(s) usually available{R-231}: U.S. Veterinary-labeled product(s): 715 mg per gram of powder (OTC) [Neo-325; Neomix 325{R-97}; Neomix AG 325; Neomycin 325{R-101}; Neo-Sol 50; Neosol Soluble Powder; Neovet 325/100]. Canada Veterinary-labeled product(s): 715 mg per gram of powder (OTC) [Neomix Soluble Powder{R-104}]. 813 mg per gram of powder (OTC) [Neomed 325; Neomycin 325]. Withdrawal times: U.S.
Withdrawal time

Note: Products are not labeled for use in preruminating calves to be processed for veal or for lactating dairy cattle or goats producing milk for human consumption.
Withdrawal time Species Cattle, goats Pigs, sheep Meat (days) 30 20

Note: Products are not labeled for use in preruminating calves to be processed for veal or for lactating dairy cattle or goats producing milk for human consumption. Canada
Withdrawal time

Species Species Cattle Chickens, broiler Chickens, laying, pigs, sheep, turkeys Meat (days) 30 7 14 Cattle Goats, pigs Sheep Turkeys, growing

Meat (days) 1 3 2 0

Note: This product is not labeled for use in lactating dairy cattle or horses to be slaughtered for human consumption.

Note: Products are not labeled for use in preruminating calves to be processed for veal or for lactating dairy cattle or goats producing milk for human consumption.{R-97; 101}
Withdrawal time Species Meat (days) 30 20

Packaging and storage: Store below 40 C (104 F), preferably between 15 and 30 C (59 and 86 F), unless otherwise specied by manufacturer.
Cattle, goats Pigs, sheep

Preparation of dosage form: Prepare solutions daily according to manufacturers instructions. When administered in the drinking water, adjustments must be made in concentration, based on factors altering water consumption, such as age, disease signs, and environmental factors{R-98}. 2003 Thomson MICROMEDEX

Note: Products are not labeled for use in preruminating calves to be processed for veal or for lactating dairy cattle or goats producing milk for human consumption{R-97}. All rights reserved

AMINOGLYCOSIDES VeterinarySystemic 21 Canada

Withdrawal time Species Cattle Chickens, broiler Chickens, laying, pigs, sheep, turkeys Meat (days) 30 7 14

Note: Strength of administered solution may be adjusted to compensate for variations in age or weight, the severity of disease signs, and environmental factors that may affect water consumption{R-182}.

Packaging and storage: Store below 40 C (104 F), preferably between 15 and 30 C (59 and 86 F), unless otherwise specied by manufacturer. Preparation of dosage form: Prepare solutions daily according to manufacturers instructions. When administered in the drinking water, adjustments must be made in concentration, based on factors altering water consumption, such as age, disease signs, and environmental factors{R-98}. USP requirements: Not in USP{R-19}.
1

Strength(s) usually available{R-231}: U.S. Veterinary-labeled product(s): 250 mg per mL (OTC) [GENERIC]. Canada Veterinary-labeled product(s): Not commercially available. Withdrawal times: U.S.
Withdrawal time Species Calves Chickens Pigs Meat (days) 2 4 0

Not included in Canadian product labeling or product not commercially available in Canada.

STREPTOMYCIN SUMMARY OF DIFFERENCES

Category: Aminoglycoside. Indications: General considerationsFirst aminoglycoside introduced. Active against mycobacteria, Leptospira{R-243; 244}, Francisella tularensis, and Yersinia pestis, but only some mycoplasma, gram-negative organisms, and Staphylococcus species{R-116}. The introduction of newer aminoglycosides has eclipsed the signicance of streptomycin in the face of increasing bacterial resistance. Side/adverse effects: Less nephrotoxic than other aminoglycosides. Vestibular toxicity is more often seen than auditory toxicity.

Note: Product labeling listing the above withdrawal times states that they are not labeled for use in chickens producing eggs for human consumption. Packaging and storage: Store below 40 C (104 F), preferably between 15 and 30 C (59 and 86 F), unless otherwise specied by manufacturer. Preparation of dosage form: Prepare according to manufacturers instruction.

USP requirements: Not in USP{R-19}.

1

ORAL DOSAGE FORMS STREPTOMYCIN SULFATE ORAL SOLUTION

Usual dose: Enteritis, bacterial1Calves, chickens, and pigs: Oral, 22 to 33 mg per kg of body weight, administered in the only source of drinking water{R-181; 182}.

Not included in Canadian product labeling or product not commercially available in Canada.

Developed: 05/1/00 Revised: 09/30/02 Interim revision: 04/04/03

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22 AMINOGLYCOSIDES VeterinarySystemic

Table 1. Pharmacology/pharmacokineticsintravenous administration.

Dose (mg/kg) Number of doses VolD area (L/kg) VolD steady state (L/kg) Clearance (mL/min/kg) Elimination half-life, initial phase (hour) Elimination half-life, gamma phase* (hour)

Species AMIKACIN Birds Chickens{R-146} Emus{R-149} Parrots, African grey{R-150}

10 7.2 5 10 20 7.5 10 5 5 10 20 5 10 20 6 7 7 7 7 7 4.4 6 6.6 11 6 3.48; IC 3.48; IC 7.5

Single Single Single Single Single Single Single Single Single Single Single Single Single Single Single Single Single Every 8 hours for 2 days Every 8 hours for 2 d/6 days Every 8 hours for 6 days Single Single Single Single Single Single Single Single

0.229 0.08 0.18 0.03 0.289 0.184 0.444 0.35 0.01 0.4 0.03 0.134 0.008 0.141 0.08 0.184 0.22 0.258 0.227 0.361 0.157 0.473 0.067 0.60 0.09 0.56 0.11 0.43 0.05 0.198 0.052 0.215 0.174 0.028 0.138 0.018 0.173 0.46 0.17 0.41 0.11 0.2 0.03

0.193 0.06 0.17 0.07 0.233 0.122 0.308 0.27 0.02 0.17 0.02

1.82 0.28 0.5 0.16 3.1 2.4 3.8 1.5 0.2 1.5 0.03 1.46 0.26 1.83 0.26 2.02 0.38 2.3 0.04 2.82 2.66 3.57

0.87 1.06 0.9 1.34 2.51 0.58 3.09 0.27 1.31 0.32 0.8 to 1.3 0.8 to 1.3 0.8 to 1.3 1.07 0.98 1.03 1.9 2.69 5.39 3.46 2.86 0.89 4 1.11 1.44 2.8 1.57 1.14 1.3 126 110 1.93 0.27

6.06

Calves{R-142}
{R-141}

Cats{R-139}
{R-140}

Dogs{R-143}

Donkeys{R-136} Foals, 3 days of age{R-130} 5 days of age{R-130} Premature, hypoxic{R-131} Neonatal, critically ill
{R-131; 132}

0.15 0.422 0.051

0.97 1.92 0.37 2.22 0.35 1.9 1.13 2.44 0.73 1.3 0.3 1.49 0.39 0.75 1.28 0.19 1.41 0.22 1.5 0.04 0.01 0.04 0.01 0.7 0.06

Neonatal, critically ill, azotemic, and hypoxemic{R-132} Horses{R-137}

{R-136} {R-137} {R-137}

0.207

Ponies{R-136} Pythons, ball{R-155} 25 C 37 C Sheep{R-142} APRAMYCIN Birds Chicks, 18-day-old{R-62} Chickens{R-162} Chickens{R-165} Pigeons{R-162} Quail, Japanese{R-167} Calves, 3- to 5-week old{R-164} Cows, lactating{R-163} Goats, lactating{R-163} Rabbits{R-162} Sheep{R-162} Ewes, lactating{R-163} GENTAMICIN Birds Eagles{R-88} Hawks, red-tailed{R-88} Owls{R-88} Roosters{R-84} Buffalo calves, 3 to 4 months of age (Murrah){R-77} Camels{R-79} Cats,{R-65} with induced endotoxemia without endotoxemia

0.15

10 10 75 10 10 20 20 20 10 10 20

Single Single Single Single Single Single Single Single Single Single Single

0.245 0.01 0.182 0.021 5.62 0.14 0.077 0.001 0.133 0.007 1.26 0.18

4.82 0.08

3.63 0.23 1.3 0.17 31.3 0.83 3.5 0.03 3.1 0.01 3.22 0.44 12.16 1.69 11.69 2.31 4.3 0.68 1.3 0.07 14.14 1.75

0.8 0.01 1.68 0.07 2.1 0.01 0.25 0 0.5 0.02 4.4 1.21 2.10 0.24 0.47 0.16 0.80 0.14 1.51 0.14 1.84 0.19

0.708 0.012 1.36 0.11 0.284 0.035 0.167 0.08 1.45 0.10

10 10 10 5 5 2 3 3

Single Single Single Single Single Single Single Single

0.21 0.24 0.23 0.23

0.01 0.03 0.02 0.02

0.21 0.01

1.01 2.09 1.41 0.78

0.09 0.16 0.1 0.13

2.46 1.35 1.93 3.38

0.32 0.18 0.24 0.62

0.43 0.03 0.32 0.02 0.19 0.02 0.2 0.03

0.91 0.12 1.35 0.11 2.6 0.7 2 0. 2

5.69 0.54 2.93 0.24 1.1 0.2 1.28 0.21

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AMINOGLYCOSIDES VeterinarySystemic 23

Table 1. (Contd.)
VolD area (L/kg) VolD steady state (L/kg) 0.12 0.02 Elimination half-life, initial phase (hour) 1.37 0.24 1.79 0.21 1.25 0.3 2.5 0.6 2 0.3 2 0.2 1.9 0.1 3.9 1.7 2.16 0.25 1.3 0.2 1.9 1.83 0.18 Elimination half-life, gamma phase* (hour)

Species Cats, obese{R-68} Cats{R-64}

{R-63}

Dose (mg/kg) 3 3 5 4 4 4 4 3 5 4 4.4 5 10 3 4.4 4.4 2.2 5 5 4 4 4 4 4 4 2.2 2.2 2.2 2.2

Number of doses Single Every 8 hours for 5 days Single Single Single Single Single Single Single Single Single Single Single Single Single Single Single Single Single Single Single Single Single Single Single Single Single Every 8 hours for 24 hours Every 8 hours for 10 days Single Single Single Every 12 hours for 2.5 days Single Single Single Single Every 8 hours for 24 hours Every 8 hours for 10 days Single Single Single Single Single Every 8 hours for 7 days Single Single Single Single

Clearance (mL/min/kg) 1.07 0.25

0.14 0.02 0.4 0.04 0.4 0.05 0.34 0.02 0.33 0.04 1.95 1.24 0.3 0.08 0.14 0.02 0.25 0.19 0.04 0.35 0.04 0.17 0.03 0.32 0.13 0.23 0.08 0.26 0.04 0.24 0.32 0.03 0.38 0.08 0.4 0.13 0.36 0.05 0.32 0.05 0.17 0.03 0.3 0.05 0.18 0.02 0.46 0.05 0.18 0.02 0.2 0.05 0.18 0.03 0.2 0.06 0.2 0.3 0.03 0.35 0.06 0.34 0.1 0.33 0.05 0.28 0.03 0.16 0.22 0.15 0.01 0.37 0.38 0.32 0.31 0.75 0.04 0.04 0.02 0.03 0.2

1.38 0.35 1.92 0.43 2.44 0.34 2.02 0.27 2.10 0.32 4.9 1.9 1.68 0.4 1.29 0.26 1.12 1.32 0.17 4.08 0.62 2.29 0.48 2.84 0.95 2.27 0.41 1.67 0.48 3.10 0.27 1.7 1.75 0.47 2.98 1.48 2.60 0.96 2.4 0.87 3.66 1.93 1.69 0.65 2.18 0.5 1.04 0.13

Calves,{R-21} 1 day of age 5 days of age 10 days of age 15 days of age Calves,{R-20} 4 to 5 weeks of age Calves,{R-180} 6 weeks of age Cows, adult{R-21}
{R-26}

0.13 0.02 0.16 0.03

Cows, lactating

{R-22}

Puppies, 5 months of age (beagles){R-70} Dogs (mixed breed){R-69} Dogs,{R-71} with diabetes mellitus without diabetes Donkeys{R-43} Goats{R-39}
{R-40}

0.91 0.26 1.1 1.08 1.87 0.96 0.09 1.73 2.12 1.51 1.69 1.77 1.01 1.09 1.52 1.96 0.83 1.06 0.39 0.53 0.55 0.55 0.52 0.92 0.32

Horse foals,{R-47} 1 day of age 5 days of age 10 days of age 15 days of age 30 days of age Horses{R-47}
{R-61} {R-45} {R-50}

Horses,{R-54} with induced endotoxemia without endotoxemia Horses{R-46}

3 3 3.3 3.3

0.15 0.04 0.2 0.03

0.14 0.17 0.12 0.18

0.04 0.01 0.02 0.01

1.17 0.35 1.41 0.19 1.4 0.2 1.4 0.2

1.54 0.15 1.66 0.06 1.2 0.3 1.2 0.2

Horses,{R-204} without halothane with halothane anesthesia Horses{R-44}

{R-252} {R-50}

4 4 5 6.6 6.6 6.6

0.26 0.02 0.26 0.03 0.25 0.03 0.12 0.04 0.21 0.01

0.24 0.03 0.14 0.06

1.54 0.81 1.15 3.44

0.27 0.32 0.12 0.44

2.01 0.35 4.03 1.69 2.54 0.33 3 2.8 0.78 1.08

Llamas{R-82}
{R-81}

2.5 5 4 5 5 2 3 3 3 3.5

0.22 0.06 0.25 0.03 0.12 0.59 0.11 0.43 0.06 0.32 0.32 0.14 0.01 0.79 0.04 0.47 0.03 0.24 0.03

0.97 0.13 1.1 0.14 0.51 2 0.17 2.8 0.17 1.66 0.12 1.69 0.07

2.75 0.67 2.77 0.34 3.03 5.19 0.3 3.5 0.23 1. 9 0.94 0.04 0.77 0.08 1.5 0.029 0.74 0.25

Piglets,{R-41} newborn 42 days of age Pigs{R-42} Rabbits{R-75} Rabbits,{R-76} with induced endotoxemia without endotoxemia Rabbits{R-74}

20.2

0.11 0.02

2.82 0.97

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24 AMINOGLYCOSIDES VeterinarySystemic

Table 1. (Contd.)
VolD area (L/kg) 0.19 0.06 0.16 0.01 VolD steady state (L/kg) Elimination half-life, initial phase (hour) 1.4 0.08 1.68 0.28 41.9 18.5 57.5 26.2 1.75 2.4 0.5 Elimination half-life, gamma phase* (hour)

Species Sheep{R-31}
{R-35} {R-36; 37} {R-36}

Dose (mg/kg) 2.2 3 3 3 4 10 10 20

Number of doses Single Single Single Every 8 hours for 7 days Single Single Single Single

Clearance (mL/min/kg) 1.56 0.40 1.15 0.08 0.66 0.26

0.15 0.01 0.41 0.2

{R-33} {R-32} {R-36; 37} {R-36; 37}

0.16 0.24 0.03 0.38 0.2 0.71 0.75

1.03 1.03 0.15 0.81 0.32 0.88 0.34

30.4 18.9 88.9 19.8 167.2 42.7

KANAMYCIN Birds Chicks, 18-day-old{R-162} Chickens{R-162} Pigeons{R-162} Dogs{R-177}

10 10 10 10 10 10 10 10 10

Single Single Single Single Every 8 hours for 7 doses Single Single Single Single

0.671 0.045 0.294 0.004 0.292 0.034 0.255 0.030 0.252 0.018 0.263 0.022 0.228 0.025 0.254 0.017 0.262 0.027

4.78 0.26 1.4 0.1 3.55 0.08 3.21 .72 3.04 0.55 1.5 0.18 1.48 0.19 2.95 0.20 1.67 0.15

1.6 2.4 0.9 0.97 0.31 0.98 0.18 1.9 1.8 0.17 1 1.8

Goats{R-162} Horses{R-176} Rabbits{R-162} Sheep{R-162} NEOMYCIN Calves,{R-180} 2 days of age 1 week of age 2 weeks of age 4 weeks of age >8 months of age Calves, 3 months of age{R-237} Horses{R-176} Sheep{R-248} STREPTOMYCIN Horses{R-176}

10 10 10 10 10 12 10 10 10

Single Single Single Single Single Single Single Single Single

0.356 0.472 0.322 0.462 0.355

0.042 0.085 0.056 0.065 0.075 1.17 0.23

2.26 3.62 2.31 2.63 2.03 4.16

0.61 0.58 0.31 0.24 0.54 0.67

2.12 0.39 1.5 0.03 1.59 0.08 1.9 0.01 2.04 0.19 1.4 0.47 2.1 0.97 1.98 0.5 3.40 0.42

7.48 2.02

0.232 0.06 0.304 0.08 0.231 0.04

1.38 0.39 1.52 0.33 0.79 0.13

*Researchers have described a dose-dependent slow elimination phase (gamma) many times longer than the initial elimination phase{R-32}. It is postulated that gentamicin is bound to tissues by one of at least two different processes so that some gentamicin is released quickly and gentamicin bound to tissue by another process is more gradually eliminated{R-25; 32; 34; 36}. Clearance was the only pharmacokinetic value that differed with statistical signicance for amikacin between 3 and 5 days of age{R-130}. Another study showed no pharmacokinetic differences for amikacin between foals of 1 and 7 days of age{R-133}. IC = Intracardiac

Table 2. Pharmacology/pharmacokineticsother systemic data.

Dose (mg/kg); Number of Route doses Absorption half-life (hour) Peak serum concentration (mcg/mL) Time to peak concentration (hour) Terminal half-life, initial phase (hours) Terminal half-life, gamma phase* (hours)

Species AMIKACIN Birds Chickens{R-157}

{R-146}

Bioavailability (%)

10; 20; 20; 20;

IM IM IM IM

Cockatiels

{R-148}

15; IM 20; IM 5; IM 10; IM 20; IM

Hawks, red tailed{R-147} Parrots, African gray{R-150}

Single Single Single 0.48 0.158 Every 8 hours for 10 doses Every 12 hours for 3 days Single 0.16 0.05 Single Single Single

19.9 30.8 50.79 4.05 38.58 6.96 27.3 6.89 56 8.8 10.8 0.63 21.1 1.77 32.7 1.23

0.25 0.25 0.5 0.258 0.79 0.37 1 0.64 0.16 1 0.75 0.75

91

2.3 2.9 1.43 0.34 1.86 0.42 1.29 2.02 0.63 1.08 1.04 0.97

98 61 106

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AMINOGLYCOSIDES VeterinarySystemic 25

Table 2. (Contd.)
Terminal half-life, initial phase (hours) 1.94 0.34 2.2

Species Calves{R-142}
{R-144}

Dose (mg/kg); Number of Route doses 7.5; IM 10; IM 25; IM 5; IM 5; SC 5; IM 5; SC 10; IM 10; SC 20; IM 20; SC 10; IM 10; SC 10; IM 10; SC Single Single Single Single Single Single Single Single Single Single Single Single Single Single Single

Absorption half-life (hour)

Peak serum concentration (mcg/mL) 23.5 2.4 30 3.7 57.7 3.6 16.41 1.98 22.61 4.29 18.45 23.17 38.51 39.55 65.57 67.88 14 (from graph)

Time to peak concentration (hour) 0.83 0.14 0.05 0.05 0.75 0.2 0.67 0.12 0.5 0.75 0.5 0.75 0.5 0.75 1 1 0.75 0.5 0.14 0.03 0.3 0.09 0.4 0.07 0.05 1 1 1 0.5

Bioavailability (%) 99

Terminal half-life, gamma phase* (hours)

Cats{R-139}
{R-140}

95 123 94 100 94 100 94 100 1 1.5 102 107 0.98 0.07 1.25 0.07 1.17 0.75 98

Dogs{R-143} Goats{R-151} Guinea pigs{R-152}

0.24 0.21 0.03 0 0.11 0.06 0.14 0.05

27.63 1.61 38.93 3.06 12.2 0.4 20.5 1.1 41.6 1.5 34.17 3.54 13.3 1.6 23 0.6 29.8 3.2 14.7 1.14

3.75; IM Single 7.5; IM Single 15; IM Single 7; IO 4.4; IM 6.6; IM 11; IM 7; IM Single Single Single Single Single

Horse foals, 3- to 5-day old{R-130} Horses{R-137}

Pony foals, 2- to 11-day old{R-135} Pythons, ball{R-155} 25 C 37 C Sheep{R-139} Snakes, gopher{R-154} 25 C 37 C Tortoises, gopher{R-156} APRAMYCIN Calves, 3- to 5-week old{R-164}

3 0.29

3.48; IM Single 3.48; IM Single 7.5; IM 5; IM 5; IM 5; IM 10; IM 20; 30; 40; 20; IM IM IM IM Single Single Single Single Single Single Single Single Single Single Single Single Single

1.31 2.27

11.94 1.67 13.87 2.61 34.4 6.5

1.47 0.72 1.27 0.6 1.26 0.34

109 109 87 1.96 0.38 71.9 10 75.4 30.1

5.58 2.77 5.69 1.11 25 (from graph) 18.6 40.8 1.49 1.84 42.52 4.79 0.19 0 0.1 0 11.06 0.31 0.79 0.02 0.84 0.24 31.04 3.67 44.7 25.6 65 78 87 0.5 0.5 1 1 1 0.5 0 0.76 0.03 0.2 0.01 0.53 0.09 0.5 0 1 1.5 2.5

Cows, lactating{R-163} Birds Chickens{R-165} Quail, Japanese{R-167} Ewes, lactating{R-163} DIHYDROSTREPTOMYCIN Cattle{R-247}
{R-249}

60 58 2 56 70

4.42 0.63 2.31 0.02 1.22 0.01 2.31 0.38 2.42 0.29

75; IM 75; PO 50; PO 10; IM

11; IM Single 16.5; IM Single 25; IM Single 25; IM 3; IM 5; IM 10; IM 5; IM 5 to 20; IM 5; IM Single Single Single Single Every 12 hours for 3 days Single Single

Pigs{R-249} GENTAMICIN Baboons{R-76} Birds Budgerigars{R-86} Cockatiels{R-148} Cranes{R-85} Galahs{R-205} (cockatoos)

1.58 17.3 37 4.66 1.45 0.25 0.25 1 0.53 0.53 1.29 2.75 0.62 20.55 1.3 0.5 1.23

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26 AMINOGLYCOSIDES VeterinarySystemic

Table 2. (Contd.)
Terminal half-life, initial phase (hours)

Species Eagles{R-88} Hawks{R-88} Macaws{R-205}

Dose (mg/kg); Number of Route doses 10; IM 10; IM 5; IM 5; IM 10; IM 5 to 20; IM 5 to 20; IM 10; IM Single Single Single Every 12 hours for 7 days Single Single Single Single

Absorption half-life (hour)

Peak serum concentration (mcg/mL)

Time to peak concentration (hour)

Bioavailability (%) 70 95

Terminal half-life, gamma phase* (hours)

20.62 2.45 14.15 1.75

0.5 0.5 95

1.17

Owls{R-88} Quail{R-85} Pheasants

{R-85}

0.7 0.2 1.25 0.25 0.43 0.08 39.4 9.6 0.75 3.79 0.23

Buffalo calves, 3 to 4 months of age{R-78} Camels,{R-79} normal hydration dehydrated Cats{R-62} Cats,{R-65} with endotoxemia without endotoxemia Cats{R-68}
{R-63}

2; IM 2; IM 2.5; IM 5; IM 3; 3; 3; 3; 3; 5; 5; IM SC IM SC SC IM SC

Single Single Single Single Single Single Single Single Single Single Single Single Every 8 hours for 3 days Single Every 8 hours For 10 days Single Single Single Single Single Single Single Single Single Single Every 12 hours for 2.5 days Single Single Single Every 8 hours for 7 days Single Single Single Single Every 8 hours for 7 days Single Single Single Single Single Single Single 0.4 0.15 0.02 0.19 0.22 0.21 0.15 0.08 0.09 0.11 0.03

5.4 0.4 3 0.36 9.1 0.8 23.1 2.1 12.53 3.57 12.43 2.05 13.79 3.15 15.25 1.49 17 2 21.6 1.96 23.5 3.57 40.46 1.05 32.56 2.39 15.39 6.19

1.09 0.21 1.83 0.48 0.5 0.5 0.54 0.42 0.43 0.54 0.58 0.67 0.25 0.16 0.12 0.11 0.17 0.13 0.12

135 54

0.11 0.16

84 68 76 70 92

1.0 0.23 1.08 0.23 1.0 0.17 1.24 0.1 1.24 0.22 1.27 0.27 1.14 0.11 2.52 0.1 2.65 0.27

Cows{R-29}
{R-29}

5; IM 5; IM 5; IM 5; IM 5; IM 3; IM 3; SC 5; IM 5; SC 2; IM 4; IM 2; IM 4; IM 3.3; IM 3.3; IM 4.4; IM 6.6; IM 2; IM 5; IM 2.5; IM 3.5; IM 3.5; SC 4; IM 3; IM

0.28 0.02 0.23 0.01 0.63 0.28

0.98 0.05 0.98 0.09 0.75

Cows, lactating{R-22} Cows, lactating{R-22} Cows, with endometritis{R-29} Dogs, (mixed-breed){R-69} Goats{R-39}
{R-39}

44.91 9.38 0.21 0.02 0.16 0.26 19.36 1.56 10.7 10.2 33.9 4.37 28 3.84 18.2 52 18.2 66 11.7 12.2 5.3 5.3 1.7 2.8 0.84 0.06 0.52 0.69 0.67 0 0.66 0 0.5 0.5 0.5 0.5 0.8 0.3 0.8 0.1 0.5 1.3 0.5 0.25 1 96 94 96 77 2.37 0.47 3.56 0.39 4.28 2.23 3.07 0.68 3.68 0.71 2.87 0.82 2.5 0.9 3.5 0.6 2.71 0.35

Horse foals{R-48} 1 month of age 1 month of age 3 months of age 3 months of age Horses{R-46}

{R-57} {R-252}

16.8 22 4.9 0.25 0.06 6.85 12.74 1.94 5.76 14.5 1.7 11.5 13.7

100 2.81 0.28 2.13 0.48 50.9

Pony foals{R-49} Ponies{R-53} Pythons, blood{R-89} Rabbits{R-74} Sheep{R-32}

{R-33}

0.48 0.25 0.57 0.16

132 113 99

0.83 0.14 0.78 0.15 1.82 82.1 17.8

KANAMYCIN Calves{R-144; 179} Cattle

{R-179}

10; IM 25; IM 10; IM 10; IM 25; IM 7.5; IM 10; IM

31 3.1 57.3 4.9 30.7 6.54 19.28 3.7 58.98 4.58 25.8 27.6 7.5

0.5 0.5 1 0.5 0.5 0.49 0.53 0.37 89

2.2 2.2

Chickens{R-179} Dogs{R-178}
{R-177}

1.03 0.77 0.094

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AMINOGLYCOSIDES VeterinarySystemic 27

Table 2. (Contd.)
Terminal half-life, initial phase (hours)

Species Dogs{R-179}
{R-178} {R-179}

Dose (mg/kg); Number of Route doses 15; IM 25; IM 39; IM 5; IM 10; IM 10; IM 10; IM 20; IM 15; IM 20; IM 30; IM 24; IM 96; PO 10; IM 10; IM 10; IM 10; SC 10; IM 10; IM Single Single Single

Absorption half-life (hour)

Peak serum concentration (mcg/mL) 37.75 1.32 55.6 84.56 24.81 12.55 1.89 35.8 5.7 36.8 12.5 32.2 9.01 55.62 8.12 36.9 8.97 54.74 18.53 58.5 27.11 31.7 11.8 0.26 0.37 2.43 9.9 25.6 8.8 17.63 2.27 18.66 3.05 43.4 21.4 44.5 2.7

Time to peak concentration (hour) 0.5 0.68 0.5 1 1 1 0.5 1 1 0.5 0.5 1.38 0.95 2.6 2.9

Bioavailability (%)

Terminal half-life, gamma phase* (hours)

0.5

0.93

Horses{R-175}
{R-176}

Single Single 0.32 0.04 Every 12 hours 0.38 0.13 for 7 doses Single Single Single Single Single Single Every 12 hours for 15.5 days Single 0.16 0.05 Every 12 hours 0.21 0.08 for 7 doses Single Single 0.31 0.13 0.35 0.14

100 96

2.66 0.51 2.34 0.45

Pigs{R-179} Sheep{R-179}

NEOMYCIN Calves, 3 months of age{R-237}

127 0.45 74 66

11.5 3.8

Horses{R-176}

2.58 0.69 2.67 0.69 2.68 0.29 2.82 0.51 3.83 0.3 3.84 1.18

Sheep{R-248} STREPTOMYCIN Horses{R-176}

1.33 0.41 1 0.32 1 1

75 85 83 98

Single 0.34 0.15 Every 12 hours 0.32 0.14 for 7 doses

*Researchers have described a slow elimination phase (gamma) many times longer than the initial elimination phase{R-32}. It is postulated that gentamicin is bound to tissues by one of at least two different processes so that some gentamicin is released quickly and gentamicin bound to tissue by another process is more gradually eliminated{R-25; 32; 34; 36} . The major pharmacokinetic values for intraosseus administration of amikacin did not signicantly differ from those measured for intravenous administration{R-130}. Although the half-lives of absorption and elimination were similar at different temperatures, the estimated volume of distribution and clearance were signicantly higher at the warmer temperature{R-154}. IM = intramuscular, IO = intraosseous, SC = subcutaneous

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AMINOGLYCOSIDES VeterinarySystemic 29
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Mader DR, Conzelman GM, Baggot JD. Effects of ambient temperature on the half-life and dosage regimen of amikacin in the gopher snake. J Am Vet Med Assoc 1985 Dec 1; 187(11): 11346. 155. Johnson JH, Jensen JM, Brumbaugh GW, et al. Amikacin pharmacokinetics and the effects of ambient temperature on the dosage regimen in ball pythons (Python regius). J Zoo Wildl Med 1997 Mar; 28(1): 808. 156. Caligiuri R, Kollias GV, Jacobson E, et al. The effects of ambient temperature on amikacin pharmacokinetics in gopher tortoises. J Vet Pharmacol Ther 1990; 13: 28791. 157. Itoh N, Kikuchi N, Hiramune T. Antimicrobial effects of amikacin therapy on experimentally induced Salmonella typhimurium infection in fowls. J Vet Med Sci 1996 May; 58(5): 4259. 158. Staneva M, Markova B, Atanasova I, et al. Pharmacokinetic and pharmacodynamic approach for comparing two therapeutic regimens using amikacin. Antimicrob Agents Chemother 1994 May; 38(5): 9815. 159. Moore RM, Schneider RK, Kowalski J, et al. Antimicrobial susceptibility of bacterial isolates from 233 horses with musculoskeletal infection during 19791989. Equine Vet J 1992; 24(6): 4506. 160. Xiong Y, Caillon J, Kergueris MF, et al. Adaptive resistance of Pseudomonas aeruginosa induced by aminoglycosides and killing kinetics in a rabbit endocarditis model. Antimicrob Agents Chemother 1997 Apr; 41(4): 8236. 161. Orsini JA, Benson CE, Spencer PA, et al. Resistance to gentamicin and amikacin of gram-negative organisms isolated from horses. Am J Vet Res 1989 Jun; 50(6): 9235. 162. Lashev LD, Pashov DA, Marinkov TN. Interspecies differences in the pharmacokinetics of kanamycin and apramycin. Vet Res Commun 1992; 16(4): 293300. 163. Ziv G, Kurtz B, Risenberg R, et al. Serum and milk concentrations of apramycin in lactating cows, ewes, and goats. J Vet Pharmacol Ther 1995; 18: 34651. 164. Ziv G, Bor A, Soback S, et al. Clinical pharmacology of apramycin in calves. J Vet Pharmacol Ther 1985; 8: 95104. 165. A NA, Ramadan A. Kinetic disposition, systemic bioavailability and tissue distribution of apramycin in broiler chickens. Res Vet Sci 1997 May-Jun; 62(3): 24952. 166. Thomson TD, Watkins KL, Novilla MN, et al. Effects of intestinal pathology due to coccidial infection on the oral absorption of apramycin in 4-week-old broiler chickens. Acta Vet Scand Suppl 1991; 87: 2757. 167. Lashev LD, Mihailov R. Pharmacokinetics of apramycin in Japanese quail. J Vet Pharmacol Ther 1994 Oct; 17(5): 3945. 168. Pohl P, Glupczynski Y, Marin M, et al. Replicon typing characterization of plasmids encoding resistance to gentamicin and apramycin in Escherichia coli and Salmonella typhimurium isolated from human and animal sources in Belgium. Epidemiol Infect 1993 Oct; 111(2): 22938. 169. Low JC, Angus M, Hopkins G, et al. Antimicrobial resistance of Salmonella enterica Typhimurium DT104 isolates and investigation of strains with transferable apramycin resistance. Epidemiol Infect 1997; 118(2): 97103. 170. Hunter JEB, Bennett M, Hart CA, et al. Apramycin resistant Escherichia coli isolated from pigs and a stockman. Epidemiol Infect 1994 Jun; 112(3): 473 80. 171. Hunter JEB, Shelley JC, Walton JR, et al. Apramycin resistant plasmids in Escherichia coli: possible transfer to Salmonella typhimurium in calves. Epidemiol Infect 1992 Apr; 108(2): 2718. 172. Chaslus-Dancla E, Pohl P, Meurisse M, et al. High genetic homology between plasmids of human and animal origins conferring resistance to the aminoglycosides gentamicin and apramycin. Antimicrob Agents Chemother 1991 Mar; 35(3): 5903. 173. Ryden R, Moore BJ. The in vitro activity of apramycin, a new aminocyclitol antibiotic. J Antimicrob Chemother 1977; 3: 60913. 174. Fantin B, Ebert S, Leggett J, et al. Factors affecting duration of in vivo postantibiotic effect for aminoglycosides against gram-negative bacilli. J Antimicrob Chemother 1991 Jun; 27(6): 82936. 175. Brown MP, Stover SM, Kelly RH, et al. Kanamycin sulfate in the horse: serum, synovial uid, peritoneal uid, and urine concentrations after single-dose intramuscular administration. Am J Vet Res 1981 Oct; 42(10): 18235. 176. Baggot JD, Love DN, Rose RJ, et al. The pharmacokinetics of some aminoglycoside antibiotics in the horse. J Vet Pharmacol Ther 1981 Dec; 4(4): 27784. 177. Baggot JD. Pharmacokinetics of kanamycin in dogs. J Vet Pharmacol Ther 1978; 1: 16370. 178. Cabana BE, Taggart JG. Comparative pharmacokinetics of BB-K8 and kanamycin in dogs and humans. Antimicrob Agents Chemother 1973 Apr; 3(4): 47883. 179. Andreini G, Pignattelli P. Kanamycin blood levels and residues in domestic animals. Veterinaria 1972; 21: 5172. 180. Burrows GE, Barto PB, Martin B. Comparative pharmacokinetics of gentamicin, neomycin, and oxytetracycline in newborn calves. J Vet Pharmacol Ther 1987; 10: 5463. 181. Strep-Sol Freedom of Information Summary, NADA 065252. Sponsor: Veterinary Services, Inc. Supplemental September 5, 1993. 182. Streptomycin Oral Solution Freedom of Information Summary, ANADA: 200197. Sponsor: Contemporary Products, Inc. 183. Kitasato I, Yokota M, Inouye S, et al. Comparative ototoxicity of ribostamycin, dactimicin, dibekacin, kanamycin, amikacin, tobramycin, gentamicin, sisomicin and netilmicin in the inner ear of guinea pigs. Chemotherapy 1990; 36(2): 15568. 184. Bergeron MG, Bergeron Y. Inuence of endotoxin on the intrarenal distribution of gentamicin, netilmicin, tobramycin, amikacin, and cephalothin. Antimicrob Agents Chemother 1986 Jan; 29(1): 712. 185. Grauer GF. Prevention of acute renal failure. Vet Clin North Am Small Anim Pract 1996 Nov; 26(6): 144759. 186. Adams HR. Neuromuscular blocking effect of aminoglycoside antibiotics in nonhuman primates. J Am Vet Med Assoc 1973 Sep 15; 163(6): 6136. 187. Crawford LM, Harvey T, Campbell DL. Hypocalcemic effect of aminoglycoside antibiotics in the dairy cow. Can J Comp Med 1977 Jul; 41(3): 2516. 188. OLeary SJ, Moore DR. Development of cochlear sensitivity to aminoglycoside antibiotics. Ann Otol Rhinol Laryngol 1998 Mar; 107(3): 2206.

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AMINOGLYCOSIDES VeterinarySystemic 31
189. Beaubien AR, Desjardins S, Ormsby E, et al. Delay in hearing loss following drug administration. Acta Otolaryngol (Stockh) 1990; 109: 34552. 190. Bamonte F, Dionsotti S, Gamba M, et al. Relation of dosing regimen to aminoglycoside ototoxicity: evaluation of auditory damage in the guinea pig. Chemotherapy 1990; 36(1): 4150. 191. Pettorossi VE, Ferraresi A, Errico P, et al. The impact of different dosing regimens of the aminoglycosides netilmicin and amikacin on vestibulotoxicity in the guinea pig. Eur Arch Otorhinolaryngol 1990; 247: 277 82. 192. Melendez E, Lopez M, Lopez C, et al. Age-related differences in the glomerular and renal tubular effects of amikacin in the rat. Biol Neonate 1996; 70: 22934. 193. Scherberich JE, Mondorf WA. Nephrotoxic potential of antiinfective drugs as assessed by tissue-specic proteinuria of renal antigens. Int J Clin Pharmacol Ther 1998 Mar; 36(3): 1528. 194. Pashov D, Diakov L, Lashev L. Subchronic toxicity of apramycin in pigs. Vet Med Nauki 1987; 24(7): 3742. 195. Pashov D, Diakov L, Vangelov S. Chronic 90-day toxicity of apramycin in chickens. Vet Med Nauki 1987; 24(9): 416. 196. Uzuka Y, Furuta T, Yamaoka M, et al. Threshold changes in auditory brainstem response (ABR) due to the administration of kanamycin in dogs. Exp Anim 1996 Oct; 45(4): 32531. 197. Xu S, Shepherd RK, Chen Y, et al. Profound hearing loss in the cat following the single co-administration of kanamycin and ethacrynic acid. Hear Res 1993 Nov; 70(2): 20515. 198. Conlon BJ, Smith DW. Supplemental iron exacerbates aminoglycoside ototoxicity in vivo. Hear Res 1998 Jan; 115(12): 15. 199. Hildebrand SV, Hill T. Interaction of gentamycin and atracurium in anaesthetised horses. Equine Vet J 1994; 26(3): 20911. 200. Forsyth SF, Ilkiw JE, Hildebrand SV. Effect of gentamicin administration on the neuromuscular blockade induced by atracurium in cats. Am J Vet Res 1990 Oct; 51(10): 16758. 201. Martinez EA, Mealey KL, Wooldridge AA, et al. Pharmacokinetics, effects on renal function, and potentiation of atracurium-induced neuromuscular blockade after administration of a high dose of gentamicin in isouraneanesthetized dogs. Am J Vet Res 1996 Nov; 57(11): 16236. 202. Kays SE, Crowell WA, Johnson MA. Iron supplementation increases gentamicin nephrotoxicity in rats. J Nutr 1991 Nov; 121(11): 186975. 203. Whittem T, Firth EC, Hodge H, et al. Pharmacokinetic interactions between repeated dose phenylbutazone and gentamicin in the horse. J Vet Pharmacol Ther 1996; 19: 4549. 204. Smith CM, Steffey EP, Baggot JD, et al. Effects of halothane anesthesia on the clearance of gentamicin sulfate in horses. Am J Vet Res 1988 Jan; 49(1): 1922. 205. Flammer K, Fiorello-Barrett J, Wilson RC, et al. Adverse effects of gentamicin in scarlet macaws and galahs. Am J Vet Res 1990 Mar; 51(3): 4047. 206. Fadel AA, Larkin HA. Gentamicin-induced nephrotoxicosis in lambs. Res Vet Sci 1996; 61: 18792. 207. Raisbeck MF, McIntyre WB. Fatal nephrotoxicosis associated with furosemide and gentamicin therapy in a dog. J Am Vet Med Assoc 1983 Oct 15; 183(8): 8923. 208. Riviere JE, Traver DS, Coppoc GL. Gentamicin toxic nephropathy in horses with disseminated bacterial infection. J Am Vet Med Assoc 1982 Mar 15; 180(6): 64851. 209. Brown SA, Garry FB. Comparison of serum and renal gentamicin concentrations with fractional urinary excretion tests as indicators of nephrotoxicity. J Vet Pharmacol Ther 1988 Dec; 11(4): 3307. 210. Rivers BJ, Walter PA, OBrien TD, et al. Evaluation of urine gamma-glutamyl transpeptidase-to-creatinine ratio as a diagnostic tool in an experimental model of aminoglycoside-induced acute renal failure in the dog. J Am Anim Hosp Assoc 1996 Jul-Aug; 32(4): 32336. 211. Grauer GF, Creco DS, Behrend EN, et al. Estimation of quantitative enzymuria in dogs with gentamicin-induced nephrotoxicosis using urine enzyme/creatinine rations from spot urine samples. J Vet Intern Med 1995 Sep/Oct; 9(5): 3247. 212. Riviere JE, Hinsman EJ, Coppoc GL, et al. Single dose gentamicin nephrotoxicity in the dog: early functional and ultrastructural changes. Res Commun Chem Pathol Pharmacol 1981 Sep; 33(3): 40318. 213. Frazier DL, Aucoin DP, Riviere JE. Gentamicin pharmacokinetics and nephrotoxicity in naturally acquired and experimentally induced disease in dogs. J Am Vet Med Assoc 1988 Jan 1; 192(1): 5763. 214. Frazier DL, Dix LP, Bowman KF, et al. Increased gentamicin nephrotoxicity in normal and diseased dogs administered identical serum drug concentration proles: increased sensitivity in subclinical renal dysfunction. J Pharmacol Exp Ther 1986; 239(3): 94651. 215. Brown SA, Barsanti JA, Crowell WA. Gentamicin-associated acute renal failure in the dog. J Am Vet Med Assoc 1985 Apr 1; 186(7): 68690. 216. Greco DS, Turnwald GH, Adams R, et al. Urinary gamma-glutamyl transpeptidase activity in dogs with gentamicin-induced nephrotoxicity. Am J Vet Res 1985 Nov; 46(11): 23325. 217. Riviere JE, Carver MP, Coppoc GL. Pharmacokinetics and comparative nephrotoxicity of xed-dose versus xed-interval reduction of gentamicin dosage in subtotal nephrectomized dogs. Toxicol Appl Pharmacol 1984; 75: 496509. 218. Riviere JE, Hinsman EJ, Coppoc GL, et al. Morphological and functional aspects of experimental gentamicin nephrotoxicity in young beagles and foals. Vet Res Commun 1983 Dec; 7(1/4): 2113. 219. Riviere JE, Coppoc GL, Hinsman EJ, et al. Species dependent gentamicin pharmacokinetics and nephrotoxicity in the young horse. Fundam Appl Toxicol 1983; 3: 44857. 220. Garry F, Chew DJ, Hoffsis GF. Enzymuria as an index of renal damage in sheep with induced aminoglycoside nephrotoxicosis. Am J Vet Res 1990 Mar; 51(3): 42832. 221. Rossier Y, Divers TJ, Sweeney RW. Variations in urinary gamma glutamyl transferase/urinary creatinine ratio in horses with or without pleuropneumonia treated with gentamicin. Equine Vet J 1995; 27(3): 21720. 222. Schumacher J, Wilson RC, Spano JS, et al. Effect of diet on gentamicininduced nephrotoxicosis in horses. Am J Vet Res 1991 Aug; 52(8): 12748. 223. Brasheir MK, Geor RJ, Ames TR, et al. Effect of intravenous administration on gentamicin-induced nephrotoxicosis in ponies. Am J Vet Res 1998 Aug; 59(8): 105562. 224. Jaquenod M, Ronnhedth C, Cousins MJ, et al. Factors inuencing ketorolacassociated perioperative renal dysfunction. Anesth Analg 1998 May; 86(5): 10907. 225. Brown SA, Rakich PM, Barsanti JA, et al. Fanconi syndrome and acute renal failure associated with gentamicin therapy in a dog. J Am Anim Hosp Assoc 1986 Sep/Oct; 22(5): 63540. 226. Beauchamp K, Poirier A, Bergeron MG. Increased nephrotoxicity of gentamicin in pyelonephritic rats. Kidney Int 1985; 28: 10613. 227. Waitz JA, Moss EL, Weinstein MJ. Aspects of the chronic toxicity of gentamicin sulfate in cats. J Infect Dis 1971 Dec; 124 (Suppl): S125-S129. 228. Short CR, Hardy ML, Clarke CR, et al. The nephrotoxic potential of gentamicin in the cat: a pharmacokinetic and histopathologic investigation. J Vet Pharmacol Ther 1986; 9(3): 3259. 229. Conlon BJ, McSwain SD, Smith DW. Topical gentamicin and ethacrynic acid: effects on cochlear function. Laryngoscope 1998 Jul; 108(7): 10879. 230. Brown SA, Riviere JE. Comparative pharmacokinetics of aminoglycoside antibiotics. J Vet Pharmacol Ther 1991; 14: 135. 231. Arrioja-Dechert A, editor. Compendium of veterinary products, CD ed. Port Huron, MI: North American Compendiums, Inc. 2002. 232. Gilbert DN. Once-daily aminoglycoside therapy. Antimicrob Agents Chemother 1991 Mar; 35(3): 399405. 233. Wersall J. Ototoxic antibiotics: a review. Acta Otolaryngol Suppl (Stockh) 1995; 519: 269. 234. Mathew AG, Upchurch WG, Chattin SE. Incidence of antibiotic resistance in fecal Escherichia coli isolated from commercial swine farms. J Anim Sci 1998 Feb; 76(2): 42934. 235. Cote S, Harel J, Higgins, et al. Resistance to antimicrobial agents and prevalence of R plasmids in Pasteurella multocida from swine. Am J Vet Res 1991 Oct; 52(10): 16537. 236. Gauchia R, Rodriguez-Serna M, Silvestre JF, et al. Allergic contact dermatitis from streptomycin in a cattle breed. Contact Dermatitis 1996 Dec; 35(6): 3745. 237. Pedersoli WM, Ravis WR, Jackson J. Disposition and bioavailability of neomycin in Holstein calves. J Vet Pharmacol Ther 1994; 17: 511. 238. Aschbacher PW, Feil VJ. Neomycin metabolism in calves. J Anim Sci 1994 Mar; 22(3): 6839. 239. Cid D, Piriz S, Ruiz-Santa-Quiteria JA, et al. In vitro susceptibility of Escherichia coli strains isolated from diarrhoeic lambs and goat kids to 14 antimicrobial agents. J Vet Pharmacol Ther 1996; 19: 397401. 240. Shaikh B, Jackson J, Thaker NH. Neomycin residues in kidneys of orally dosed non-ruminating calves determined by high-performance liquid chromatographic and microbiological assay methods. J Vet Pharmacol Ther 1995; 18: 1502. 241. Rollin RE, Mero KN, Kozisek PB, et al. Diarrhea and malabsorption in calves associated with therapeutic doses of antibiotics: absorptive and clinical changes. Am J Vet Res 1986 May; 47(5): 98791.

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32 AMINOGLYCOSIDES VeterinarySystemic
242. Abbitt B, Berndtson WE, Seidel GE. Effect of dihydrostreptomycin or oxytetracycline on reproductive capacity of bulls. Am J Vet Res 1984 Nov; 45(11): 22436. 243. Gerritsen MJ, Koopmans MJ, Dekker TCEM, et al. Effective treatment with dihydrostreptomycin of naturally infected cows shedding Leptospira interrigans serovar hardjo subtype hardjobovis. Am J Vet Res 1994 Mar; 55(3): 33943. 244. Ellis WE, Montgomery J, Cassells JA. Dihydrostreptomycin treatment of bovine carriers of Leptospira interrogans serovar hardjo. Res Vet Sci 1985; 39: 2925. 245. Barragry TB. Veterinary Drug Therapy. Philadelphia: Lea & Febiger; 1994. p. 2489. 246. Christiansen G. The toxicity of selected therapeutic agents used in cats. Vet Med Small Anim Clin 1980 Jul; 75(7): 11337. 247. Hammond PB. Dihydrostreptomycin dose-serum level relationships in cattle. J Am Vet Med Assoc 1953; 122: 2036. 248. Errecalde JO, Lanusse CE, Landoni MF. Pharmacokinetics of neomycin in sheep after intravenous, intramuscular, subcutaneous, and intratracheal administration. Zentralbl Veterinarmed [A] 1990 Apr; 37(3): 1639. 249. Stalheim OHV. Absorption and excretion of tritiated dihydrostreptomycin in cattle and swine. Am J Vet Res 1970 Mar; 31(3): 497500. 250. National Antimicrobial susceptibility Monitoring Program-Veterinary Isolates. FDA/USDA/CDC. Center for Veterinary Medicine. April 1998. p. 127. 251. Dorlands illustrated medical dictionary. 28th ed. Philadelphia: W.B. Saunders Company; 1994. p. 58. 252. Magdesian KG, Hogan PM, Cohen ND, et al. Pharmacokinetics of a high dose of gentamicin administered intravenously or intramuscularly to horses. J Am Vet Med Assoc 1998 Oct 1; 213(7): 100711. 253. Snyder JR, Pascoe JR, Hirsh DC. Antimicrobial susceptibility of microorganisms isolated from equine orthopedic patients. Vet Surg 1987 May-Jun; 16(3): 197201. 254. Riviere JE, Craigmill AL, Sundlof SF. Handbook of comparative pharmacokinetics and residues of veterinary antimicrobials. Boca Raton, FL: CRC Press, Inc; 1991. p. 26375. 255. Klasco RK, editor. USP DI Drug information for the healthcare professional. Volume I. Greenwood Village, CO: MICROMEDEX, Inc.; 2003. 256. Gennaro AR, editor. Remington: the science and practice of pharmacy. 19th ed. Easton, PA: Mack Publishing Company; 1995. p. 1299303. 257. Resolutions submitted for HOD actions. J Am Vet Med Assoc 1998 Jun 15; 212(12): 18523. 258. Panel comment, Rec 6/99. 259. Erskine RJ, Davis BS, Spears HJ. Intramammary administration of gentamicin as treatment for experimentally induced Escherichia coli mastitis in cows. Am J Vet Res 1992 Mar; 53(3): 37581. 260. Jones GF, Ward GE. Evaluation of systemic administration of gentamicin for treatment of coliform mastitis in cows. J Am Vet Med Assoc 1990 Sep 15; 197(6): 7315. 261. Panel comment, Rec 6/1/99. 262. Panel comment, Rec 6/1/99. 263. Panel comment, Rec 6/1/99. 264. Panel consensus, 9/10/99. 265. Tudor RA, Papich MG, Redding WR. Drug disposition and dosage determination of once daily administration of gentamicin sulfate in horses after abdominal surgery. J Am Vet Med Assoc 1999 Aug 15; 215(4): 5036. 266. Panel comment, Rec 8/7/99. 267. Murphey ED, Santschi EM, Papich MG. Regional intravenous perfusion of the distal limb of horses with amikacin sulfate. J Vet Pharmacol Ther 1999; 22: 6871. 268. Cowan RH, Jukkola AF, Avant BS. Pathophysiologic evidence of gentamicin nephrotoxicity in neonatal puppies. Pediatr Res 1980; 14: 120411. 269. Cronin RE, Bulger RE, Southern P, et al. Natural history of aminoglycoside nephrotoxicity in the dog. J Lab Clin Med 1980; 95(3): 46374. 270. Davies C, Forrester SD, Troy GC, et al. Effects of a prostaglandin E1 analogue, misoprostol, on renal function in dogs receiving nephrotoxic doses of gentamicin. Am J Vet Res 1998; 59(8): 104854. 271. McFarlane D, Papich M, Breuhaus B, et al. Pharmacokinetics of amikacin sulfate in sick and healthy foals. International Veterinary Emergency and Critical Care Society. Proceedings of the 5th Conference. San Antonio, Texas.

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AMINOPENICILLINS VeterinaryIntramammary-Local 33

AMINOPENICILLINS VeterinaryIntramammary-Local
This monograph includes information on the following: Amoxicillin; Hetacillin. Some commonly used brand names for veterinary-labeled products are: Amoxi-Mast and Hetacin-K Intramammary Infusion. Note: For a listing of dosage forms and brand names by country availability, see the Dosage Forms section(s). Not commercially available in Canada. Hetacillin potassiumC19H22KN3O4S.{R-9} Molecular weight: Amoxicillin419.45.{R-9} Hetacillin potassium427.56.{R-9} Description: Amoxicillin USPWhite, practically odorless, crystalline powder.{R-10} Hetacillin potassiumWhite to light buff, crystalline powder. Solubility: Amoxicillin USPSlightly soluble in water and in methanol; insoluble in carbon tetrachloride and in chloroform.{R-10} Hetacillin potassiumFreely soluble in water; soluble in alcohol.

CATEGORY:
Antibacterial (intramammary-local).

PHARMACOLOGY/PHARMACOKINETICS INDICATIONS GENERAL CONSIDERATIONS

Aminopenicillins have activity against penicillin-sensitive gram-positive bacteria as well as some gram-negative bacteria. Aminopenicillins are susceptible to destruction by beta-lactamases and therefore are not effective against bacteria that produce these enzymes.{R-1-3} Most strains of Klebsiella, Proteus, Pseudomonas, and Staphylococcus{R-17} are resistant.{R-1; 4} Mechanism of action/effect: Like other penicillins, the aminopenicillins produce their bactericidal effect by inhibiting bacterial cell wall synthesis.{R-11} These antibiotics must penetrate the cell wall to attach to specic proteins on the inner surface of the bacterial cell membrane. In actively growing cells, the binding of ampicillin or amoxicillin within the cell wall leads to interference with production of cell wall peptidoglycans and subsequent lysis of the cell in an isoosmotic environment.{R-1113}

ACCEPTED
Mastitis (treatment)1Cows, lactating: Amoxicillin and hetacillin are indicated in the treatment of mastitis caused by susceptible organisms such as Streptococcus agalactiae.{R-5; 6} Intramammary therapy alone is indicated only in the treatment of subacute or subclinical mastitis manifested by mild changes in the milk or udder. Acute or peracute mastitis, in which gross inammatory changes in the milk or udder or systemic signs appear, requires administration of other medications also, which may include systemic antibiotics and/or supportive therapy.{R-7}
1

Distribution: Medications infused into a teat are considered to be fairly evenly distributed in that quarter of the healthy mammary gland; however, in an udder affected by moderate to severe mastitis, the presence of edema, blockage of milk ducts, and reduced blood circulation causes uneven distribution.{R-14}

PRECAUTIONS TO CONSIDER PATIENT MONITORING

The following may be especially important in patient monitoring (other tests may be warranted in some patients, depending on condition; = major clinical signicance): Bacteriologic pathogens in milk (milk samples should be tested 3 weeks after treatment is discontinued; mastitis is not considered bacteriologically cured until samples show an absence of the mastitis-causing organisms) Clinical signs of mastitis (although a resolution of clinical signs of mastitis is not an indication that a bacteriologic cure has been achieved{R-15}, monitoring of the clinical condition of the mammary gland, teat, and milk produced can aid in diagnosis of a recurrence of mastitis or initial diagnosis of mastitis in another cow in the herd) Somatic cell count (somatic cell counts performed on milk to monitor the dairy herd are used primarily to maintain milk quality, but they are also used to assess the approximate overall effectiveness of mastitis control programs, which may include antibiotic treatment of cows).{R-7}

Not included in Canadian product labeling or product not commercially available in Canada.

REGULATORY CONSIDERATIONS
U.S. Withdrawal times have been established. See the Dosage Forms section.

CHEMISTRY
Source: AmoxicillinSemisynthetic derivative of ampicillin.{R-8} HetacillinDerived from the penicillin nucleus, 6-aminopenicillanic acid and chemically related to ampicillin.{R-6} Chemical group: Beta-lactam antibiotics. Chemical name: Amoxicillin4-Thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid, 6[[amino(4-hydroxyphenyl)acetyl]amino]-3,3-dimethyl-7-oxo-, trihydrate [2S-[2alpha,5alpha,6beta(S*)]]-.{R-9} Hetacillin potassium4-Thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid, 6-(2,2-dimethyl-5-oxo-4-phenyl-1-imidazolidinyl)-3,3-dimethyl7-oxo-, monopotassium salt, [2S-[2alpha,5alpha,6beta(S*)]]-.{R-9} Molecular formula: AmoxicillinC16H19N3O5S3H2O.{R-9} 2003 Thomson MICROMEDEX

SIDE/ADVERSE EFFECTS
The following side/adverse effects have been selected on the basis of their potential clinical signicance (possible signs in parentheses where appropriate)not necessarily inclusive: All rights reserved

34 AMINOPENICILLINS VeterinaryIntramammary-Local

THOSE INDICATING NEED FOR MEDICAL ATTENTION

Incidence unknown Cows Allergic reactions{R-6}local or systemic

Withdrawal times: U.S.{R-5}

Withdrawal time Species Meat (days) 12 Milk (hours) 60

OVERDOSE
For information in cases of overdose or unintentional ingestion, contact the American Society for the Prevention of Cruelty to Animals (ASPCA) National Animal Poison Control Center (888-426-4435 or 900-443-0000; a fee may be required for consultation) and/or the drug manufacturer.

Cows, lactating

Packaging and storage: Store below 24 C (75 F){R-5}, unless otherwise specied by manufacturer. USP requirements: Preserve in well-closed disposable syringes. A suspension of Amoxicillin in a suitable vegetable oil vehicle. Label it to indicate that it is intended for veterinary use only. Contains the labeled amount, within )10% to +20%. Contains a suitable dispersing agent and preservative. Meets the requirements for Identication and Water (not more than 1.0%).{R-10}
1

CLIENT CONSULTATION
Treatment of mastitis in dairy cattle is best achieved by a comprehensive mastitis control program in which herd management is the primary focus. The program should include good maintenance of milking equipment and constant evaluation of milking procedures and teat health as well as strategic treatment of clinical cases of mastitis.

Not included in Canadian product labeling or product not commercially available.

VETERINARY DOSING INFORMATION

The choice of antibiotic for the treatment of mastitis should be based on knowledge of culture and sensitivity of pathogens causing mastitis in the cow and the dairy herd. The available intramammary aminopenicillin products are formulated for use in the lactating cow only.{R-15; 16} Before administration of intramammary amoxicillin or hetacillin, the following steps should be performed:{R-5; 6} The udder should be milked out completely and the teats and udder washed with warm water and a disinfectant. Care should be taken to avoid washing excess dirt down from the udder onto the teat ends. The area should be dried thoroughly and each teat wiped with a separate cotton ball soaked with an antiseptic such as 70% isopropyl alcohol. Persons performing the treatment should wash and dry their hands before each treatment. The tip of the syringe should be inserted into the teat end as little as possible and the contents of the syringe should be injected into each streak canal while the teat is held rmly. The medication should then be gently massaged up the teat canal into the udder. A teat dip is recommended on all teats following treatment.

HETACILLIN SUMMARY OF DIFFERENCES

Pharmacology/pharmacokinetics: Hetacillin must undergo a rapid and spontaneous local hydrolysis to ampicillin to be therapeutically active. Hydrolysis is believed to occur in aqueous solution with high efciency; however, hydrolysis is slower in strongly acidic environments.{R-1719}

INTRAMAMMARY DOSAGE FORMS HETACILLIN POTASSIUM INTRAMAMMARY INFUSION

Note: The dosing and strength of the dosage form available are expressed in terms of ampicillin activity.{R-6} Usual dose: Mastitis1Cows, lactating: Intramammary, 62.5 mg (ampicillin activity) into each affected quarter of the udder every twenty-four hours for a maximum of three doses.{R-6}

AMOXICILLIN INTRAMAMMARY DOSAGE FORMS AMOXICILLIN INTRAMAMMARY INFUSION USP

Usual dose: Mastitis1Cows, lactating: Intramammary, 62.5 mg into each affected quarter of the udder every twelve hours for a maximum of three doses.{R-5} Strength(s) usually available: U.S.{R-5} Veterinary-labeled product(s): 62.5 mg per 10 mL (Rx) [Amoxi-Mast]. Canada Veterinary-labeled product(s): Not commercially available. 2003 Thomson MICROMEDEX

Strength(s) usually available: U.S. Veterinary-labeled product(s): 62.5 mg (ampicillin activity) per 10 mL (Rx) [Hetacin-K Intramammary Infusion]. Canada Veterinary-labeled product(s): Not commercially available. Withdrawal times: U.S.
Withdrawal time Species Cows, lactating Meat (days) 10 Milk (hours) 72

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AMINOPENICILLINS VeterinaryIntramammary-Local 35 Packaging and storage: Store below 40 C (104 F), preferably between 15 and 30 C (59 and 86 F), unless otherwise specied by manufacturer. USP requirements: Not in USP.{R-10}
1

Not included in Canadian product labeling or product not commercially available in Canada.

Developed: 06/05/95 Interim revision: 04/24/96; 05/14/97; 5/26/98; 10/12/99; 09/30/02; 02/28/03

REFERENCES
1. Ampicillin package insert (Amp-equine, SmithKline BeechamUS), Rev 5/1991, Rec 10/18/94. 2. Amoxicillin package insert (Moxilean, M.T.C. PharmaceuticalsCanada), Rec 9/27/94. 3. Ampicillin package insert (Polyex, Fort Dodge Laboratories, Inc.US), Rev 1/94, Rec 10/24/94. 4. Sarasola P, McKellar QA. Pharmacokinetics and applications of ampicillin sodium as an intravenous infusion in the horse. J Vet Pharmacol Ther 1993; 16: 639. 5. Amoxicillin intramammary infusion package insert (Amoxi-Mast, Pzer Animal HealthUS), Rev 9/97. Downloaded from www.pzer.com/ah on 8/26/02.

6. Hetacillin intramammary infusion package insert (Hetacin-K, Fort Dodge Laboratories, Inc.US), Rec 10/24/94. 7. Heath SE. Bovine mastitis. In: Howard JL. Current veterinary therapy 3: food animal practice. Philadelphia: W. B. Saunders; 1993. p. 7629. 8. Amoxicillin package insert (Amoxi-Tabs, SmithKline BeechamUS), Rev 7/93, Rec 10/18/94. 9. USP dictionary of USAN and international drug names, 2002 ed. Rockville, MD: The United States Pharmacopeial Convention, Inc. 2002. 10. The United States pharmacopeia. The national formulary. USP 26th revision (January 1, 2003). NF 21st ed (January 1, 2003). Rockville, MD: The United States Pharmacopeial Convention, Inc. 2002. p. 141, 2548. 11. Donowitz GR, Mandell GL. Beta-lactam antibiotics. N Engl J Med 1988; 318: 41926. 12. Papich MG. The beta-lactam antibiotics: clinical pharmacology and recent developments. Compend Contin Educ Pract Vet 1987; 9(1): 6874. 13. Wright AJ, Wilkowski CJ. The penicillins. Mayo Clin Proc 1983; 58: 2132. 14. Jarp J, Bugge JP, Larsen S. Clinical trial of three therapeutic regimens for bovine mastitis. 1989; 124: 6304. 15. Craven N. Efcacy and nancial value of antibiotic treatment of bovine clinical mastitis during lactationa review. Br Vet J 1987; 143: 41022. 16. Hady PJ, Lloyd JW, Kaneene JB. Antibacterial use in lactating dairy cattle. J Am Vet Med Assoc 1993 Jul; 203(2): 21020. 17. Panel comment, 2/20/95. 18. Manufacturer comment, 2/28/95. 19. Sutherland R, Robinson OP. Laboratory and pharmacological studies in man with hetacillin and ampicillin. Br Med J 1967 Jun 24; 2(555): 8048.

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36 AMINOPENICILLINS VeterinarySystemic

AMINOPENICILLINS VeterinarySystemic
This monograph includes information on the following: Amoxicillin; Ampicillin. Some commonly used brand names are: For veterinary-labeled products
Amoxi-Drop [Amoxicillin] Amoxi-Inject [Amoxicillin] Amoxil Tablets [Amoxicillin] Amoxi-Tabs [Amoxicillin] Biomox Oral Suspension [Amoxicillin] Biomox Tablets [Amoxicillin] Moxilean-50 Suspension [Amoxicillin] Polyex [Ampicillin] Robamox-V Oral Suspension [Amoxicillin] Robamox-V Tablets [Amoxicillin] Penbritin [Ampicillin] Polycillin-N [Ampicillin] Principen [Ampicillin] Totacillin [Ampicillin] Totacillin-N [Ampicillin]

Pneumonia, bacterial (treatment) Calves, nonruminating1: Parenteral ampicillin is indicated for the treatment of respiratory tract infections caused by susceptible organisms, including some bacterial pneumonias associated with shipping fever complex.{R-3} Cats and dogs: Parenteral ampicillin and [amoxicillin] are indicated in the treatment of pneumonia caused by susceptible organisms.{R-12} Cattle: Parenteral amoxicillin and parenteral ampicillin are indicated for the treatment of respiratory tract infections caused by susceptible organisms, including some bacterial pneumonias associated with shipping fever complex.{R-3; 5; 11} [Horses]1: Parenteral ampicillin is used for the treatment of pneumonia caused by susceptible organisms.{R-1} Pododermatitis, necrotic, acute (treatment)1Cattle: Parenteral amoxicillin is indicated in the treatment of acute necrotic pododermatitis caused by susceptible Fusobacterium necrophorum{R-11}; if administered early in the course of the disease, amoxicillin may reduce the severity of lesions.{R-62} Skin and soft tissue infections (treatment) Cats and dogs: Amoxicillin and parenteral ampicillin are indicated in the treatment of soft tissue infections and wounds caused by susceptible organisms.{R-3; 5; 6; 13} [Horses]1: Parenteral ampicillin is used in the treatment of skin and soft tissue infections, including abscesses and wounds, caused by susceptible organisms.{R-1} [Strangles (treatment)]1Horses: Parenteral ampicillin may be used in the treatment of strangles caused by susceptible Streptococcus equi.{R-1} Tonsillitis, bacterial (treatment); or Tracheobronchitis, bacterial (treatment); or Upper respiratory tract infections (treatment)Cats and dogs: Amoxicillin and parenteral ampicillin are indicated in the treatment of tonsillitis, tracheobronchitis, and upper respiratory tract infections caused by susceptible organisms{R-3; 5; 6}.

For human-labeled products

Ampicin [Ampicillin] Apo-Ampi [Ampicillin] Novo-Ampicillin [Ampicillin] Nu-Ampi [Ampicillin] Omnipen [Ampicillin] Omnipen-N [Ampicillin]

CATEGORY:
Antibacterial (systemic).

INDICATIONS
Note: Bracketed information in the Indications section refers to uses that either are not included in U.S. product labeling or are for products not commercially available in the U.S.

GENERAL CONSIDERATIONS
The aminopenicillins have activity against penicillin-sensitive grampositive bacteria as well as some gram-negative bacteria. Ampicillin is effective against alpha- and beta-hemolytic streptococci, including Streptococcus equi{R-1}, nonpenicillinase-producing Staphylococcus species, some Bacillus anthracis, and most strains of Clostridia.{R-3} Ampicillin is also effective against gram-negative bacteria, including many strains of Escherichia coli (E. coli), Salmonella, and Pasteurella multocida.{R-3} Amoxicillin has the same spectrum of activity as ampicillin, but has slightly better activity against some gram-negative bacteria, including E. coli, and Salmonella species.{R-4} Most anaerobic bacteria, except beta-lactamaseproducing strains of Bacteroides, are sensitive to amoxicillin{R-78}. The aminopenicillins are subject to destruction by beta-lactamases and therefore are not effective against some bacteria that produce these enzymes.{R-1; 3} Most strains of Klebsiella, Proteus, and Pseudomonas are resistant.{R-1; 23}

ACCEPTANCE NOT ESTABLISHED

[Bacterial infections (treatment)]1Calves, nonruminating: Until recently, amoxicillin tablets were labeled in the United States for use in the treatment of infections in calves caused by susceptible E. coli{R-8}. Although the labeled product is no longer available, oral amoxicillin may be used in the treatment of susceptible infections in calves. [Leptospirosis (treatment)]1Dogs: Although the efcacy has not been established, amoxicillin is used in therapy of leptospirosis in dogs. Penicillin and penicillin derivatives (including amoxicillin) are considered to be effective for eliminating leptospiremia, but it is not known if they are effective in terminating the carrier state{R-30; 31; 91}.
1

ACCEPTED
Dermatitis, bacterial (treatment)Dogs: Amoxicillin is indicated in the treatment of bacterial dermatitis caused by susceptible organisms; however, amoxicillin is not the treatment of choice because bacteria that cause dermatitis are often resistant to this medication{R-7; 14; 6870}. Gastroenteritis, bacterial (treatment)Cats and dogs: Amoxicillin and parenteral ampicillin are indicated in the treatment of bacterial gastrointestinal tract infections caused by susceptible organisms.{R-3; 6} Genitourinary tract infections, bacterial (treatment)Cats and dogs: Amoxicillin and parenteral ampicillin are indicated and [oral] ampicillin is used in the treatment of genitourinary tract infections, including cystitis and urethritis, caused by susceptible organisms.{R-3;
5; 6; 15; 24}

Not included in Canadian product labeling or product not commercially available in Canada.

REGULATORY CONSIDERATIONS
U.S. Ampicillin is not labeled for use in horses to be used for food production.{R-1} Withdrawal times have been established for amoxicillin and ampicillin. See the Dosage Forms section.{R-3; 8}

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AMINOPENICILLINS VeterinarySystemic 37 Canada Withdrawal times have been established for ampicillin. See the Dosage Forms section.{R-5} The aminopenicillins penetrate gram-negative bacterial cell walls more rapidly than do the natural penicillins such as penicillin G and therefore are more efcient in destroying those organisms. Amoxicillin enters the gram-negative cell more easily than does ampicillin; this is considered to be the basis for the greater activity of amoxicillin against some gramnegative bacteria.{R-19} Absorption: The aminopenicillins are stable in gastric uid.{R-8} One of the primary differences between ampicillin and amoxicillin is the difference in absorption after oral administration. A higher percentage of amoxicillin than of ampicillin is absorbed after oral administration to cats, dogs, pigs, and preruminant calves.{R-2528; 46} In people, the more complete oral absorption of amoxicillin leaves less drug remaining in the intestinal tract than does ampicillin; therefore amoxicillin is associated with a lower incidence of diarrhea as a side effect; however, amoxicillin is also less effective than ampicillin in the treatment of some intestinal bacterial infections in people.{R-20} In horses, ampicillin sodium is well absorbed following intramuscular or subcutaneous administration; however, oral dosage forms are poorly absorbed by adult horses{R-84}. Oral absorption of amoxicillin has been reported to be between 5.3 and 10.4%{R-42; 86}. Ampicillin trihydrate administered intramuscularly produces lower ampicillin blood concentrations that extend over a longer period of time than does ampicillin sodium{R-27; 49}. Note: There is evidence that giving amoxicillin and clavulanate concurrently has little effect on the pharmacokinetics of either medication{R-82}; therefore, the following information based on dosing with amoxicillin and clavulanate combination may be useful in predicting the absorption of amoxicillin alone. Calves{R-82} Preruminant calves (2 weeks old): Absorption of amoxicillin when administered orally in combination with clavulanate at doses of 10 to 20 mg per kg of body weight (mg/kg) is 34 to 36%. Early ruminant calves (6 weeks old): Absorption of amoxicillin and clavulanate combination is much poorer than in preruminant calves given the same oral dose; therapeutic serum amoxicillin concentrations are not achieved in early ruminant calves. Distribution: The aminopenicillins are rapidly and widely distributed into most body uids{R-6; 8; 23; 39} with the exception of uids of the eye and the prostate gland{R-69}; also, distribution into cerebrospinal uid is low unless the meninges are inamed{R-8}. Penetration into synovial uid is high{R-87; 89}. Volume of distribution Amoxicillin: Horses Adult: Area325 mL per kg of body weight (mL/kg){R-42}. Steady state192 mL/kg{R-86}. Foal (6 to 7 days of age): Area369 mL/kg{R-41}. Steady state265 mL/kg{R-41}. Ampicillin: CatsArea: 116 mL/kg{R-40}. HorsesSteady state: 180 mL/kg{R-23; 86}; 263 mL/kg{R-85}. Protein binding: AmoxicillinHorses: Moderate (37 to 38%){R-45}.

CHEMISTRY
Source: AmoxicillinSemisynthetic derivative of ampicillin{R-14}. AmpicillinSemisynthetic penicillin{R-1}. Chemical name: Amoxicillin4-Thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid, 6-[[amino(4-hydroxyphenyl)acetyl]amino]-3,3-dimethyl-7-oxo-, trihydrate[2S-[2 alpha,5 alpha,6 beta(S*)]]-{R-16}. Ampicillin4-Thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid, 6-[(aminophenylacetyl)amino]-3,3-dimethyl-7-oxo-, [2S-[2 alpha,5 alpha,6 beta(S*)]]-{R-16}. Ampicillin sodium4-Thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid, 6-[(aminophenylacetyl)amino]-3,3-dimethyl-7-oxo-, monosodium salt, [2S-[2 alpha,5 alpha,6 beta(S*)]]-{R-16}. Molecular formula: AmoxicillinC16H19N3O5S3H2O{R-16}. AmpicillinC16H19N3O4S{R-16}. Ampicillin sodiumC16H18N3NaO4S{R-16}. Molecular weight: Amoxicillin419.45{R-16}. Ampicillin349.41{R-16}. Ampicillin sodium371.39{R-16}. Description: Amoxicillin USPWhite, practically odorless, crystalline powder{R-17}. Ampicillin USPWhite, practically odorless, crystalline powder{R-17}. Ampicillin Sodium USPWhite to off-white, odorless or practically odorless, crystalline powder. Is hygroscopic.{R-17} pKa:{R-22} Amoxicillin2.8 and 7.2. Ampicillin2.7 and 7.3. Solubility: Amoxicillin USPSlightly soluble in water and in methanol; insoluble in carbon tetrachloride and in chloroform{R-17}. Ampicillin USPSlightly soluble in water and in methanol; insoluble in carbon tetrachloride and in chloroform{R-17}. Ampicillin Sodium USPVery soluble in water and in isotonic sodium chloride and dextrose solutions{R-17}.

PHARMACOLOGY/PHARMACOKINETICS
Note: Unless otherwise noted, pharmacokinetic data in this section are based on intravenous administration of ampicillin or amoxicillin. There is evidence that administering ampicillin concurrently with either gentamicin or kanamycin does not alter the pharmacokinetics of either of the medications in horses{R-84; 89}. Mechanism of action/effect: Like other penicillins, the aminopenicillins produce their bactericidal effect by inhibiting bacterial cell wall synthesis.{R-18} These antibiotics must penetrate the cell wall to attach to specic proteins within the bacterial cell membrane. In actively growing cells, the binding of ampicillin or amoxicillin within the cell wall leads to interference with production of cell wall peptidoglycans and subsequent lysis of the cell in an iso-osmotic environment{R-1820}.

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38 AMINOPENICILLINS VeterinarySystemic Ampicillin Cattle: Low (18%).{R-43; 44} Horses: Very low (6.8 to 8%).{R-48} Rabbits: Low (17.5%).{R-44} Sheep: Low (13.8%).{R-43; 44} Guinea pigs, hamsters, and rabbitsOral ampicillin often disturbs the normal microora; the severity of this side effect makes the use of aminopenicillins in these species contraindicated.{R-58; 73} HorsesLarge oral doses of the aminopenicillins can disturb the normal cecal microora and are generally contraindicated.{R-49; 58} RuminantsOral ampicillin administration disrupts the rumen ora.

Half-life: DistributionAmpicillin: Cats13 minutes.{R-40} Pigs5 to 7 minutes.{R-39} Elimination Amoxicillin: Goats67 minutes.{R-47} Horses Adult: 39 minutes{R-42}; 85 minutes{R-45; 86}. Foal (6 to 7 days of age): 44 minutes.{R-41} Sheep46 minutes.{R-47} Ampicillin: Cats73 minutes.{R-40} Dogs20 minutes.{R-44} Horses37 minutes{R-23}; 42 minutes{R-85}; 93 minutes{R-48}; 103 minutes{R-86}. Pigs30 to 35 minutes.{R-39} Rabbits24 minutes.{R-44} Peak serum concentration: AmpicillinHorses: 6.2 to 9.7 mcg/mL at 16 minutes (intramuscular dose of 10 mg of ampicillin sodium per kg of body weight){R-84}. 21.6 mcg/mL in nonpregnant mares (intramuscular dose of 22 mg of ampicillin sodium per kg of body weight){R-87}. 8.9 mcg/mL in pregnant mares (intramuscular dose of 22 mg of ampicillin sodium per kg of body weight){R-87}. Elimination: Amoxicillin{R-6} and ampicillin{R-23} are primarily excreted unchanged in the urine. Ten to twenty-ve percent of the administered dose of amoxicillin is excreted in the form of penicilloic acid. Total clearance Amoxicillin: Goats11.4 mL per minute per kg of body weight (mL/min/kg).{R-47} Horses and foals, 6 to 7 days of age5.7 mL/min/kg.{R-41; 42} Sheep10.1 mL/min/kg.{R-47} Ampicillin: Horses3.5 mL/min/kg{R-89}.

PREGNANCY/REPRODUCTION
The safety of amoxicillin and ampicillin in the treatment of infections during pregnancy has not been established.{R-33} Penicillins have been shown to cross the placenta; however, laboratory animal reproduction studies have shown no evidence of adverse effects in the fetus.{R-28; 33; 36}

LACTATION
In humans, penicillins are distributed into milk{R-33; 37}. Ampicillin has been shown to be distributed into the milk of cows and ewes.{R-50}

DRUG INTERACTIONS AND/OR RELATED PROBLEMS

The following drug interactions and/or related problems have been selected on the basis of their potential clinical signicance (possible mechanism in parentheses where appropriate)not necessarily inclusive ( = major clinical signicance): Note: Combinations containing any of the following medications, depending on the amount present, may also interact with this medication. Antibacterials, bacteriostatic, such as: Tetracycline{R-46} (because the aminopenicillins act only on cells that are actively reproducing, bacteriostatic antibiotics may decrease the efcacy of amoxicillin and ampicillin by depressing the activity of target cells{R-53}; however, the clinical signicance of this interference is not well documented) Probenecid (probenecid is a competitive inhibitor of renal tubular secretion and slows the body clearance of aminopenicillins in horses, calves, pigs, and possibly other species, resulting in increased serum concentrations and longer elimination half-life){R-51; 52; 55}

LABORATORY VALUE ALTERATIONS

The following have been selected on the basis of their potential clinicalsignicance (possible effect in parentheses where appropriate)not necessarily inclusive ( = major clinical signicance): Note: Laboratory value alterations relating specically to use of aminopenicillins in animals appear to be rarely described. Human laboratory value alterations have been reported and are included in this section.

PRECAUTIONS TO CONSIDER CROSS-SENSITIVITY AND/OR RELATED PROBLEMS

Animals allergic to one penicillin may be allergic to other penicillins also.{R-49}

HUMAN LABORATORY VALUE ALTERATIONS{R-2} SPECIES SENSITIVITY

CalvesIn neonatal calves, ampicillin administered orally at 12 mg per kg of body weight (mg/kg) every eight hours has been shown to cause diarrhea and malabsorption. Aminopenicillins are not recommended for treatment of enteritis in calves unless secondary complications, such as septicemia or bacterial arthritis, are present.{R-9; 10} The following laboratory value alterations have been reported in humans, and are included in the human monograph Penicillins (Systemic) in USP DI Volume I; these laboratory value alterations are intended for informational purposes only and may or may not be applicable to the use of amoxicillin or ampicillin in the treatment of animals:

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AMINOPENICILLINS VeterinarySystemic 39 With diagnostic test results Glucose, urine (high urinary concentrations of a penicillin may produce false positive or falsely elevated test results with copper sulfate tests [Benedicts, Clinitest, or Fehlings]; glucose enzymatic tests [Clinistix or Testape] are not affected) Direct antiglobulin (Coombs) tests (false-positive result may occur during therapy with any penicillin) With physiology/laboratory test values Alanine aminotransferase (ALT [SGPT]) and Alkaline phosphatase and Aspartate aminotransferase (AST [SGOT]) and Lactate dehydrogenase (LDH) (serum values may be increased) Estradiol or Estriol, total conjugated, or Estriol-glucuronide or Estrone, conjugated (concentrations may be transiently decreased in pregnant women following administration of ampicillin) White blood cell count (leukopenia or neutropenia is associated with the use of all penicillins; the effect is more likely to occur with prolonged therapy and severe hepatic function impairment)

THOSE INDICATING NEED FOR MEDICAL ATTENTION

Incidence more frequent Calves Diarrhea and malabsorption{R-9} Note: In healthy neonatal calves, oral administration of 12 mg of ampicillin per kg of body weight (mg/kg) every eight hours has been shown to cause diarrhea and malabsorption.{R-9} Incidence unknown All species {R-1; 6; 8; 11; 49} Hypersensitivity reactions, specically acute anaphylaxis; hypersensitivity (urticaria, fever) Horses Diarrheaprimarily with oral dosage forms{R-49}

THOSE INDICATING NEED FOR MEDICAL ATTENTION ONLY IF THEY CONTINUE OR ARE BOTHERSOME
Incidence more frequent Horses Injection site reaction (mild to moderate heat, pain, or swelling)with ampicillin trihydrate{R-1; 57} Incidence less frequent{R-63} Cats and dogs Anorexia{R-28}; diarrhea{R-28}; vomiting{R-28}

MEDICAL CONSIDERATIONS/CONTRAINDICATIONS
The medical considerations/contraindications included have been selected on the basis of their potential clinical signicance (reasons given in parentheses where appropriate)not necessarily inclusive ( = major clinical signicance). Risk-benet should be considered when the following medical problems exist: Congestive heart failure or Renal function impairment or Electrolyte imbalance due to other causes (the sodium content of ampicillin sodium administered at high doses may contribute to electrolyte imbalances associated with congestive heart failure, renal function impairment, or other causes; also, because the aminopenicillins are excreted primarily by the kidneys, the dosage regimen should be adjusted to avoid unneccessary accumulation of medication in the plasma and tissues of animals with renal function impairment{R-54}) Patient monitoring The following may be especially important in patient monitoring (other tests may be warranted in some patients, depending on condition; = major clinical signicance): Culture and pathogen susceptibility, in vitro, and Minimum inhibitory concentration (MIC) (in vitro cultures and MIC tests should be done on samples collected prior to aminopenicillin administration to determine pathogen susceptibility)

HUMAN SIDE/ADVERSE EFFECTS{R-2}

In addition to the above side/adverse effects reported in animals, the following side/adverse effects have been reported in humans, and are included in the human monograph Penicillins (Systemic) in USP DI Volume I; these side/adverse effects are intended for informational purposes only and may or may not be applicable to the use of amoxicillin or ampicillin in the treatment of animals: Incidence more frequent Gastrointestinal reactions; headache; oral candidiasis; vaginal candidiasis Incidence less frequent Allergic reactions, specically anaphylaxis; exfoliative dermatitis; serum sicknesslike reactions; skin rash, hives, or itching Incidence rare Clostridium difcile colitis; interstitial nephritis; leukopenia or neutropenia; pain at site of injection; thrombocytopenia; seizures Note: Clostridium difcile colitis may occur up to several weeks after discontinuation of these medications. Interstitial nephritis is seen primarily with methicillin, and to a lesser degree with nafcillin and oxacillin, but may occur with any penicillin. Seizures are more likely to occur in patients receiving high doses of a penicillin and/or patients with severe renal function impairment.

OVERDOSE
For information in cases of overdose or unintentional ingestion, contact the American Society for the Prevention of Cruelty to Animals (ASPCA) National Animal Poison Control Center (888-426-4435 or 900-443-0000; a fee may be required for consultation) and/or the drug manufacturer.

SIDE/ADVERSE EFFECTS
The following side/adverse effects have been selected on the basis of their potential clinical signicance (possible signs and, for humans, symptoms in parentheses where appropriate)not necessarily inclusive: 2003 Thomson MICROMEDEX

VETERINARY DOSING INFORMATION

All species: Beta-lactam antibiotics are believed to produce timedependent bacterial killing; that is, efcacy is related to the time the All rights reserved

40 AMINOPENICILLINS VeterinarySystemic serum concentrations are maintained above the minimum inhibitory concentration (MIC) of the pathogen. As such, in critical cases frequent dosings (short dosage intervals) may be preferred. recommended to improve efcacy. Once daily dosing should be used only when organisms with very low MICs are suspected.{R-80} Strength(s) usually available: When reconstituted according to manufacturers instructions U.S.:{R-6; 13; 21; 38} Veterinary-labeled product(s) 50 mg per mL (Rx) [Amoxi-Drop; Biomox Oral Suspension; Robamox-V Oral Suspension]. Canada:{R-38} Veterinary-labeled product(s) 50 mg per mL (Rx) [Moxilean-50 Suspension]. Packaging and storage: Store below 40 C (104 F), preferably between 15 and 30 C (59 and 86 F). Store in a tight container. Preparation of dosage form: To reconstitute, add the amount of water recommended by the manufacturer and shake vigorously. Before each use, shake well to resuspend.{R-6; 21} Stability: After reconstitution, the suspension retains potency for 14 days. Some products require refrigeration.{R-6; 21} USP requirements: Preserve in tight containers, at controlled room temperature. Contains the labeled amount, within 10% to +20%. Contains one or more suitable buffers, colors, avors, preservatives, stabilizers, sweeteners, and suspending agents. Meets the requirements for Identication, Uniformity of dosage units (single-unit containers), Deliverable volume (multiple-unit containers), pH (5.07.5 in the suspension constituted as directed in the labeling), and Water (not more than 3.0%).{R-17}

FOR ORAL DOSAGE FORMS ONLY

CalvesBoth amoxicillin and ampicillin are more bioavailable in calves when administered in a glucose-glycine-electrolyte solution than when administered with water or milk; however, unlike ampicillin, the bioavailability of amoxicillin is not signicantly altered by administration with milk as compared with water.{R-60} DogsThere is some decrease in systemic availability when oral amoxicillin or ampicillin is administered after a standard meal instead of on an empty stomach.{R-25} However, because amoxicillin has twice the oral bioavailability of ampicillin in dogs, the therapeutic efcacy of amoxicillin may be less affected than that of ampicillin by administration with food.{R-25} HorsesOral ampicillin is not recommended in adult horses because of poor oral bioavailability (5%) and the risk of disturbing gastrointestinal bacterial balance, thus causing diarrhea.{R-49} Amoxicillin trihydrate is also poorly absorbed following oral administration, with a fractional absorption of 10%; oral amoxicillin trihydrate should be used to treat only highly susceptible pathogens.{R-42} SheepIn adult sheep, oral administration of ampicillin does not provide therapeutically signicant ampicillin plasma concentrations.{R-61}

FOR TREATMENT OF ADVERSE EFFECTS

Treatment includes the following: For anaphylaxis: {R-6} Administration of parenteral epinephrine. Oxygen administration and respiratory support. Parenteral uid administration as needed.

AMOXICILLIN TABLETS USP

Usual dose: AntibacterialCats and dogs: See Amoxicillin For Oral Suspension USP. Note: [Calves, nonruminating]1An oral dose of 10 to 22 mg per kg of body weight every eight, twelve, or twenty-four hours has been used in the treatment of suceptible bacterial infections.{R-69} As beta-lactams appear to have time-dependent bacterial killing properties, shorter dosing intervals, whenever possible, are recommended to improve efcacy. Once daily dosing should be used only when organisms with very low MICs are suspected.{R-80} Strength(s) usually available: U.S.{R-7; 8; 13; 14; 38} Veterinary-labeled product(s): 50 mg (Rx) [Amoxi-Tabs; Biomox Tablets; Robamox-V Tablets]. 100 mg (Rx) [Amoxi-Tabs; Biomox Tablets; Robamox-V Tablets]. 150 mg (Rx) [Amoxi-Tabs]. 200 mg (Rx) [Amoxi-Tabs; Biomox Tablets; Robamox-V Tablets]. 400 mg (Rx) [Amoxi-Tabs; Biomox Tablets; Robamox-V Tablets]. Canada{R-29; 38} Veterinary-labeled product(s): 50 mg (Rx) [Amoxil Tablets]. 100 mg (Rx) [Amoxil Tablets; GENERIC]. 200 mg (Rx) [Amoxil Tablets]. 400 mg (Rx) [Amoxil Tablets].

AMOXICILLIN SUMMARY OF DIFFERENCES

Pharmacology/pharmacokinetics: AbsorptionCats, dogs, pigs, and preruminant calves: A higher percentage of amoxicillin than of ampicillin is absorbed after oral administration.{R-2528; 46} In dogs, orally administered amoxicillin is about 70% absorbed.{R-46}

ORAL DOSAGE FORMS

Note: Bracketed information in the Dosage Forms section refers to uses that either are not included in U.S. product labeling or are for products not commercially available in the U.S.

AMOXICILLIN FOR ORAL SUSPENSION USP

Usual dose: AntibacterialCats and dogs: Oral, 10 to 22 mg per kg of body weight every eight, twelve, or twenty-four hours.{R-14; 26; 69} Note: Although the efcacy has not been established, amoxicillin is used in the treatment of [leptospirosis]1 in dogs at an intravenous or oral dose of 22 mg per kg of body weight every six to eight hours{R-91; 92}. It is not known if this therapy will eliminate the carrier state. Note: As beta-lactams appear to have time-dependent bacterial killing properties, shorter dosing intervals, whenever possible, are

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AMINOPENICILLINS VeterinarySystemic 41 Withdrawal times: There are no established withdrawal times for foodproducing animals in the United States or Canada because products labeled for this use are not available. Based on previously available U.S. product labeling, if oral amoxicillin is administered to nonruminating calves at a dose of 8.8 mg per kg of body weight every twelve hours for ve days or less, a meat withdrawal time of 20 days should be sufcient to avoid residues{R-8}. Packaging and storage: Store below 40 C (104 F), preferably between 15 and 30 C (59 and 86 F). Store in a tight container. USP requirements: Preserve in tight containers, at controlled room temperature. Label chewable Tablets to indicate that they are to be chewed before swallowing. Tablets intended solely for veterinary use are so labeled. Contain the labeled amount, within )10% to +20%. Meet the requirements for Thin-layer chromatographic identication test and Dissolution (80% in 90 minutes in water in Apparatus 2 at 75 rpm; and for products labeled as Chewable Tablets: 70% in 90 minutes in water in Apparatus 2 at 75 rpm).{R-17}
1

Withdrawal times:{R-11} U.S.

Withdrawal time Species Cattle Meat (days) 25 Milk (hours) 96

Note: Product labeling listing the above withdrawal times states that the recommended withdrawal times are based on a dose of 6.6 mg per kg of body weight every twenty-four hours and a course of therapy not exceeding ve days.{R-11} Packaging and storage: Store below 40 C (104 F), preferably between 15 and 30 C (59 and 86 F), unless otherwise specied by manufacturer. Preparation of dosage form: Dosage form is reconstituted by adding the amount of sterile water for injection recommended by the manufacturer.{R-11} Stability: After reconstitution, the suspension retains potency for twelve months when refrigerated or for three months when stored at room temperature (72 F).{R-11} USP requirements: Preserve in Containers for Sterile Solids. A sterile mixture of Amoxicillin and one or more suitable buffers, preservatives, stabilizers, and suspending agents. Label it to indicate that it is for veterinary use only. Contains the labeled amount, within )10% to +20%. Meets the requirements for Identication, Bacterial endotoxins, Sterility, pH (5.07.0, in the suspension constituted as directed in the labeling), and Water (11.014.0%).{R-17}
1

Not included in Canadian product labeling or product not commercially available in Canada.

PARENTERAL DOSAGE FORMS

Note: Bracketed information in the Dosage Forms section refers to uses that either are not included in U.S. product labeling or are for products not commercially available in the U.S.

AMOXICILLIN FOR INJECTABLE SUSPENSION USP

Usual dose: Antibacterial1 Cats and dogs: Intramuscular or subcutaneous, 11 to 22 mg per kg of body weight every eight, twelve, or twenty-four hours.{R-64; 69} Note: Although the efcacy has not been established, amoxicillin is used in the treatment of [leptospirosis]1 in dogs at an intravenous or oral dose of 22 mg per kg of body weight every six to eight hours{R-91; 92}. It is not known if this therapy will eliminate the carrier state. Cattle: Intramuscular or subcutaneous, 6.6 to 22 mg per kg of body weight every eight, twelve, or twenty-four hours.{R-69} Note: Maximum volume per injection site should not exceed thirty mL.{R-11} Note: As beta-lactams appear to have time-dependent bacterial killing properties, shorter dosing intervals, whenever possible, are recommended to improve efcacy. Once daily dosing should be used only when organisms with very low MICs are suspected.{R-80} Strength(s) usually available: When reconstituted according to manufacturers instructions U.S.:{R-11; 38; 64} Veterinary-labeled product(s) 100 mg per mL (Rx) [Amoxi-Inject (3-gram vial labeled for cats and dogs)]. 250 mg per mL (Rx) [Amoxi-Inject (3-gram vial labeled for cats and dogs or 25-gram vial labeled for cattle)]. Canada: Veterinary-labeled product(s) Not commercially available.{R-38} 2003 Thomson MICROMEDEX

Not included in Canadian product labeling or product not commercially available in Canada.

AMPICILLIN SUMMARY OF DIFFERENCES

Pharmacology/pharmacokinetics: AbsorptionCalves, nonruminating, cats, dogs, and pigs: With oral administration, ampicillin is more poorly absorbed than is amoxicillin; the dosage is adjusted to compensate.{R-25; 26} In dogs, orally administered ampicillin trihydrate is only about 35% absorbed{R-46}; in cats, oral anhydrous ampicillin is about 20 to 40% absorbed.{R-40}

ADDITIONAL DOSING INFORMATION

See also Veterinary Dosing Information. Pharmacology/pharmacokinetics: HorsesThere is evidence that administering ampicillin concurrently with either gentamicin or kanamycin does not alter the pharmacokinetics of either of the medications{R-84; 89} . Parenteral dosage formsAmpicillin sodium produces higher plasma concentrations than does ampicillin trihydrate; ampicillin trihydrate produces relatively low plasma concentrations but maintains measurable concentrations for a longer period of time.{R-49} All rights reserved

42 AMINOPENICILLINS VeterinarySystemic

ORAL DOSAGE FORMS

Note: Bracketed information in the Dosage Forms section refers to uses that either are not included in U.S. product labeling or are for products not commercially available in the U.S.

AMPICILLIN CAPSULES USP

Usual dose: [Antibacterial] Cats: Oral, 10 to 20 mg per kg of body weight every eight to twentyfour hours.{R-40; 69} Dogs: Oral, 20 to 40 mg per kg of body weight every eight to twelve hours.{R-32; 69} Note: As beta-lactams appear to have time-dependent bacterial killing properties, shorter dosing intervals, whenever possible, are recommended to improve efcacy. Once daily dosing should be used only when organisms with very low MICs are suspected.{R-80} Strength(s) usually available: U.S.{R-33; 34; 35} Veterinary-labeled product(s): Not commercially available. Human-labeled product(s): 250 mg (Rx) [Omnipen; Principen; Totacillin; GENERIC]. 500 mg (Rx) [Omnipen; Principen; Totacillin; GENERIC]. Canada{R-36; 37} Veterinary-labeled product(s): Not commercially available. Human-labeled product(s): 250 mg (Rx) [Apo-Ampi; Novo-Ampicillin; Nu-Ampi; Penbritin]. 500 mg (Rx) [Apo-Ampi; Novo-Ampicillin; Nu-Ampi; Penbritin]. Packaging and storage: Store below 40 C (104 F), preferably between 15 and 30 C (59 and 86 F), unless otherwise specied by manufacturer. Store in a tight container. USP requirements: Preserve in tight containers. Label Capsules to indicate whether the ampicillin therein is in the anhydrous form or is the trihydrate. Contain an amount of ampicillin (anhydrous or as the trihydrate) equivalent to the labeled amount of ampicillin, within )10% to +20%. Meet the requirements for Identication, Dissolution (75% in 45 minutes in water in Apparatus 1 at 100 rpm), Uniformity of dosage units, and Loss on drying (not more than 4.0% for the anhydrous and 10.015.0% for the trihydrate).{R-17}
1
1

Dogs: Intramuscular or subcutaneous, 10 to 50 mg per kg of body weight every twelve hours.{R-32} Cattle and calves1, including nonruminating calves1: Intramuscular, 4.4 to 11 mg per kg of body weight every twenty-four hours.{R-3} Note: As beta-lactams appear to have time-dependent bacterial killing properties, shorter dosing intervals, whenever possible, are recommended to improve efcacy. Once daily dosing should be used only when organisms with very low MICs are suspected.{R-80}

Size(s) usually available: U.S.{R-3; 38} Veterinary-labeled product(s): 10 grams (Rx) [Polyex]. 25 grams (Rx) [Polyex]. Canada{R-5; 38} Veterinary-labeled product(s): 10 grams (Rx) [Polyex]. 25 grams (Rx) [Polyex]. Withdrawal times:{R-3} U.S.{R-3}
Withdrawal time Species Cattle Meat (days) 6 Milk (hours) 48

Note: Product labeling listing the above withdrawal times states that treatment should not exceed seven days for withdrawal times to apply.{R-3} Canada{R-5}
Withdrawal time Species Cattle Pigs Meat (days) 6 4 Milk (hours) 48

Note: Product labeling listing the above withdrawal times states that the recommended withdrawal times are based on a dose of 6 mg per kg of body weight every twenty-four hours and a course of therapy not exceeding seven days.{R-5} Packaging and storage: Store below 40 C (104 F), preferably between 15 and 30 C (59 and 86 F), unless otherwise specied by manufacturer. Preparation of dosage form: The sizes may be reconstituted according to manufacturers directions to one of the following strengths: 100, 200, 250, 300, or 400 mg per mL. Before each use, shake well to resuspend.{R-5} Stability: After reconstitution, the solution retains potency for twelve months when refrigerated and for three months when stored at 25 C.{R-3} USP requirements: Preserve in Containers for Sterile Solids. A dry mixture of ampicillin trihydrate and one or more suitable buffers, All rights reserved

Not included in Canadian product labeling or product not commercially available in Canada.

PARENTERAL DOSAGE FORMS

Note: Bracketed information in the Dosage Forms section refers to uses that either are not included in U.S. product labeling or are for products not commercially available in the U.S. The dosing and strengths of the dosage forms available are expressed in terms of ampicillin free acid (not the sodium salt).

AMPICILLIN FOR INJECTABLE SUSPENSION USP

Usual dose: Antibacterial Cats: Intramuscular or subcutaneous, 10 to 20 mg per kg of body weight every twelve to twenty-four hours.{R-40}

2003 Thomson MICROMEDEX

AMINOPENICILLINS VeterinarySystemic 43 preservatives, stabilizers, and suspending agents. Contains the equivalent of the labeled amount of ampicillin, within -10% to +20%. Meets the requirements for Identication, Bacterial endotoxins, Sterility, pH (5.07.0, in the suspension constituted as directed in the labeling), and Water (11.414.0%), and for Uniformity of dosage units, and Labeling under Injections.{R-17} Concentrated solutions (100 mg per mL) prepared from pharmacy bulk vials retain their potency for 2 hours at room temperature or 4 hours if refrigerated.{R-75} Diluted solutions (20 mg per mL or less) in 5% dextrose injection retain their potency for 2 hours at room temperature or 3 hours if refrigerated.{R-75} Incompatibilities: Extemporaneous admixtures of beta-lactam antibacterials (penicillins and cephalosporins) and aminoglycosides may result in substantial mutual inactivation. These types of antibacterial agents should not be mixed in the same intravenous bag, bottle, or tubing. Additional information: This product contains approximately 3 milliequivalents (mEq; millimoles [mmol]) of sodium per gram of ampicillin and could result in electrolyte overload in some animals.{R-54} USP requirements: Preserve in Containers for Sterile Solids. Protect the constituted solution from freezing. Contains an amount of Ampicillin Sodium equivalent to the labeled amount of ampicillin within )10% to +15%. Meets the requirements for Constituted solution, Bacterial endotoxins, Particulate matter, Uniformity of dosage units, and for Identication tests, Crystallinity, pH, and Water under Ampicillin Sodium, and for Sterility tests, and Labeling under Injections{R-17}.
1

AMPICILLIN FOR INJECTION USP

Usual dose: [Antibacterial]1 Cats and dogs: Intramuscular or intravenous, 10 to 20 mg (free acid) per kg of body weight every six to eight hours.{R-32; 40} Horses: Intramuscular or intravenous, 10 to 20 mg (free acid) per kg of body weight every six to eight hours.{R-78; 79} Note: The dose of 10 to 20 mg per kg of body weight every six to eight hours is sufcient for most sensitive bacteria; however, for infections due to moderately resistant organisms or infections associated with natural tissue barriers, such as those of the central nervous system, doses of up to 25 to 40 mg per kg of body weight every six to eight hours have been used.{R-83} A possible increased risk of gastrointestinal side effects with increasing dose should be considered. Size(s) usually available: U.S.{R-1; 38; 76} Veterinary-labeled product(s): Not commercially available. Human-labeled product(s): 125 mg (free acid) (Rx) [Omnipen-N; Polycillin-N; GENERIC]. 250 mg (free acid) (Rx) [Omnipen-N; Polycillin-N; Totacillin-N; GENERIC]. 500 mg (free acid) (Rx) [Omnipen-N; Polycillin-N; Totacillin-N; GENERIC]. 1 gram (free acid) (Rx) [Omnipen-N; Polycillin-N; Totacillin-N; GENERIC]. 2 grams (free acid) (Rx) [Omnipen-N; Polycillin-N; Totacillin-N; GENERIC]. 10 grams (free acid) (Rx) [Omnipen-N; Polycillin-N; GENERIC]. Canada{R-77} Veterinary-labeled product(s): Not commercially available. Human-labeled product(s): 125 mg (free acid) (Rx) [Ampicin; Penbritin]. 250 mg (free acid) (Rx) [Ampicin; Penbritin]. 500 mg (free acid) (Rx) [Ampicin; Penbritin]. 1 gram (free acid) (Rx) [Ampicin; Penbritin]. 2 grams (free acid) (Rx) [Ampicin; Penbritin]. Packaging and storage: Prior to reconstitution, store below 40 C (104 F), preferably between 15 and 30 C (59 and 86 F), unless otherwise specied by manufacturer. Protect the reconstituted solution from freezing. Preparation of dosage form: Dosage form should be reconstituted according to manufacturers directions.{R-1} Stability: After reconstitution, the solution retains potency for 1 hour at room temperature (70 to 75 C).{R-1} After reconstitution for intravenous infusion, solutions with concentrations of up to 30 mg per mL retain at least 90% of their potency for 2 to 8 hours at room temperature or up to 72 hours if refrigerated in suitable diluents (see manufacturers package insert).{R-75} 2003 Thomson MICROMEDEX

Not included in Canadian product labeling or product not commercially available in Canada.

Developed: 07/25/95 Revised: 06/30/02 Interim revision: 07/18/96; 06/02/97; 05/27/98; 10/12/99; 04/04/03

REFERENCES
1. Ampicillin package insert (Amp-equine, SmithKline BeechamUS), Rev 5/91, Rec 10/18/94 [discontinued product]. 2. Klasco RK, editor. USP DI Drug information for the healthcare professional. Volume I. Greenwood Village, CO: MICROMEDEX; 2003. 3. Ampicillin package insert (Polyex, Fort Dodge Laboratories, Inc.US). Downloaded 2/11/03 from www.wyeth.com. 4. Nathwani D, Wood MJ. Penicillins. A current review of their clinical pharmacology and therapeutic use. Drugs 1993; 45(6): 86694. 5. Polyex. In: Bennett K, editor. Compendium of veterinary products. 3rd ed. Hensall, ON: North American Compendiums Inc., 1993: 407. 6. Amoxicillin package insert (Amoxi-Drop, SmithKline BeechamUS), Rev 9/90, Rec 10/18/94. 7. Amoxicillin package insert (Robamox-V, Fort Dodge Laboratories, Inc.US), Rev 10/93, Rec 10/24/94. 8. Amoxicillin package insert (Amoxi-Bol, SmithKline BeechamUS), Rev 4/92, Rec 10/18/94 [discontinued product]. 9. Rollins RE, et al. Diarrhea and malabsorption in calves associated with therapeutic doses of antibiotics: Absorptive and clinical changes. Am J Vet Res 1986 May; 47(5): 98791. 10. Hunt EH. Diarrheal diseases of neonatal ruminants. In: Howard JL. Current veterinary therapy 3. Food animal practice. Philadelphia: W.B. Saunders Company; 1993. p. 1039. 11. Amoxicillin package insert (Amoxi-Inject [Cattle], SmithKline BeechamUS), Rev 3/91, Rec 10/18/94. 12. Roudebush P. Infectious pneumonia. In: Kirk RW, Bonagura JD, editors. Current veterinary therapy XI. Small animal practice. Philadelphia: W.B. Saunders Company; 1992. p. 22836. 13. Amoxicillin package insert (Biomox, Biocraft Laboratories, Inc.US), Rev 1/ 93, Rec 9/27/94. 14. Amoxicillin package insert (Amoxi-Tabs, SmithKline BeechamUS), Rev 7/ 93, Rec 10/18/94.

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44 AMINOPENICILLINS VeterinarySystemic
15. Ling GV, Gilmore CJ. Penicillin G or ampicillin for oral treatment of canine urinary tract infections. J Am Vet Med Assoc 1977 Aug; 171(4): 35861. 16. USP dictionary of USAN and international drug names, 2002 ed. Rockville, MD: The United States Pharmacopeial Convention, Inc.; 2002. 17. The United States pharmacopeia. The national formulary. USP 26th revision (January 1, 2003). NF 21st ed (January 1, 2003). Rockville, MD: The United States Pharmacopeial Convention, Inc., 2002. p. 1413, 14850, 2548. 18. Donowitz GR, Mandell GL. Beta-lactam antibiotics. N Engl J Med 1988; 318: 41926. 19. Papich MG. The beta-lactam antibiotics: clinical pharmacology and recent developments. Compend Contin Educ Pract Vet 1987; 9(1): 6874. 20. Wright AJ, Wilkowski CJ. The penicillins. Mayo Clin Proc 1983: 58: 2132. 21. Amoxicillin package insert (Robamox-V, Fort Dodge Laboratories, Inc.US), Rev 9/92, Rec 10/24/94. 22. Riviere JE, Craigmill AL, Sundlof SF. Handbook of comparative pharmacokinetics and residues of veterinary antimicrobials. Boca Raton, FL: CRC Press, Inc.; 1991. p. 52. 23. Sarasola P, McKellar QA. Pharmacokinetics and applications of ampicillin sodium as an intravenous infusion in the horse. J Vet Pharmacol Ther 1993; 16: 639. 24. Ling GV. Therapeutic strategies involving antimicrobial treatment of the canine urinary tract. J Am Vet Med Assoc 1984; 185(10): 11624. 25. Watson ADJ, et al. Effect of ingesta on systemic availability of penicillins administered orally in dogs. J Vet Pharmacol Ther 1986; 9: 1409. 26. Papich MG. Therapy of gram-positive bacterial infections. Vet Clin North Am Small Anim Pract 1988; 18(6): 126785. 27. Spurlock SL, Wilcke JR. Penicillins and cephalosporins. In: Proceedings of the thirty-second annual convention of the American Association of Equine Practitioners. 1987. p. 17582. 28. Plumb DC. Veterinary drug handbook. White Bear Lake, MN: PharmaVet Publishing, 1991: 4679, 4806. 29. Amoxil tablets. In: Bennett K, editor. Compendium of veterinary products. 3rd ed. Hensall, ON: North American Compendiums Inc.; 1993. p. 96. 30. Greene CE, editor. Infectious diseases of the dog and cat, 2nd ed. Philadelphia: WB Saunders; 1998. p. 27980. 31. Ross LA. Leptospirosis. In: Bonagura J, Kersey R, editors. Kirks current veterinary therapy XIII: small animal practice. Philadelphia: WB Saunders. 1999. p. 30810. 32. Kirk RW, Bonagura JD, editors. Current veterinary therapy XI. Small animal practice. Philadelphia: W.B. Saunders Company; 1992. p. 1234. 33. Ampicillin package insert (Principen, ApotheconUS), Rev 4/90, Rec 7/93. 34. Ampicillin package insert (Totacillin, BeechamUS), Rev 5/88, Rec 7/93. 35. Ampicillin (Omnipen, Wyeth Ayerst). In: PDR Physicians desk reference. 48th ed. 1994. Montvale, NJ: Medical Economics Data Production Company; 1994. p. 256971. 36. Ampicillin package insert (Nu-Ampi, Nu-PharmCanada), Rev 1/94, Rec 4/94. 37. Ampicillin (Apo-Ampi, Apotex). In: Krogh CME, editor. CPS Compendium of pharmaceuticals and specialties. 29th ed. Ottawa: Canadian Pharmaceutical Association; 1994. p. 83, 893, 995. 38. Arrioja-Dechert A, editor. Compendium of veterinary products, CD edition. Port Huron, MI: North American Compendiums, Inc., 2002. 39. Galtier P, Charpenteau JL. Pharmacokinetics of ampicillin in pigs. J Vet Pharmacol Ther 1979; 2: 17380. 40. Mercer HD, et al. Bioavailability and pharmacokinetics of several dosage forms of ampicillin in the cat. Am J Vet Res 1977 Sep; 38(9): 13539. 41. Baggot JD, et al. Bioavailability and disposition kinetics of amoxicillin in neonatal foals. Equine Vet J 1988; 20(2): 1257. 42. Wilson WD, et al. Pharmacokinetics and estimated bioavailability of amoxicillin in mares after intravenous, intramuscular, and oral administration. Am J Vet Res 1988 Oct; 49(10): 168894. 43. Ziv G, Sulman FG. Binding of antibiotics to bovine and ovine serum. Antimicrob Agents Chemother 1972 Sep; 2(3): 20613. 44. Powers TE, Garg RC. Pharmacotherapeutics of newer penicillins and cephalosporins. J Am Vet Med Assoc 1980 May; 10(2): 105460. 45. Montesissa C, et al. Pharmacokinetics of sodium amoxicillin in horses. Res Vet Sci 1988; 44: 2336. 46. Yeoman GH. Microbiology and bioavailability of amoxicillin. Vet Med Small Anim Clin 1977; 4(suppl): 72038. 47. Craigmill AL, Pass MA, Wetzslich S. Comparative pharmacokinetics of amoxicillin administered intravenously to sheep and goats. J Vet Pharmacol Ther 1992; 15: 727. 48. Durr A. Comparison of the pharmacokinetics of penicillin G and ampicillin in the horse. Res Vet Sci 1976; 20: 249. 49. Sarasola P, McKellar QA. Ampicillin and its congener prodrugs in the horse. Br Vet J 1994; 150(2): 17387. 50. Ziv G, Shani J, Sulman FG. Pharmacokinetic evaluation of penicillin and cephalosporin derivatives in serum and milk of lactating cows and ewes. Am J Vet Res 1973 Dec; 34(12): 15615. 51. Ziv G, Horsey J. Elevation and prolongation of serum ampicillin and amoxycillin concentrations in calves by the concomitant administration of probenecid. J Vet Pharmacol Ther 1979; 2: 18794. 52. Sarasola P, McKellar QA. Effect of probenecid on disposition kinetics of ampicillin in horses. Vet Rec 1992; 131: 1735. 53. Huber WG. Penicillins. In: Booth NH, McDonald LE. Veterinary pharmacology and therapeutics, 5th ed. Ames, IA: Iowa State University Press; 1988. p. 796812. 54. Riviere JE, Coppoc GL. Dosage of antimicrobial drugs in patients with renal insufciency. J Am Vet Med Assoc 1981 Jan; 178(1): 702. 55. Galtier P, Alvinerie M. Enhancement of ampicillin bioavailability in pigs. J Vet Pharmacol Ther 1979; 2: 1816. 56. Mason MJ, Mason KV. A pemphigus foliaceus-like eruption associated with the use of ampicillin in a cat. Aust Vet J 1987 Jul; 64(7): 2234. 57. Traver DS, Riviere JE. Penicillin and ampicillin therapy in horses. J Am Vet Med Assoc 1981 Jun; 178(11): 11869. 58. Prescott JF, Baggot JD. Antimicrobial therapy in veterinary medicine, 2nd ed. Ames, IA: Iowa State University Press; 1993. p. 905. 59. Leib MS. Acute vomiting: a diagnostic approach and symptomatic management. In: Kirk RW, Bonagura JD, editors. Current veterinary therapy XI. Small animal practice. Philadelphia: W.B. Saunders Company; 1992. p. 5837. 60. Palmer GH, Bywater RJ, Stanton A. Absorption in calves of amoxicillin, ampicillin, and oxytetracycline given in milk replacer, water or an oral rehydration formulation. Am J Vet Res 1983 Jan; 44(1): 6871. 61. Oukessou M, Toutain PL. Effect of water deprivation on absorption (oral, intramuscular) and disposition of ampicillin in sheep. J Vet Pharmacol Ther 1992; 15: 42132. 62. Braun RK, et al. Efcacy of amoxicillin trihydrate for the treatment of experimentally induced foot rot in cattle. Am J Vet Res 1987 Dec; 48(12): 17514. 63. Francis ME, Marshall AB, Turner WT. Amoxycillin: clinical trials in dogs and cats. Vet Rec 1978 Apr; 102: 37780. 64. Amoxicillin package insert (Amoxi-Inject [Cats and Dogs], SmithKline BeechamUS), Rev 3/91, Rec 10/18/94. 65. Hjerpe CA. The bovine respiratory disease complex. In: Howard JL. Current veterinary therapy 3. Food animal practice. Philadelphia: W.B. Saunders Company; 1993. p. 65364. 66. Robinson NE, editor. Current therapy in equine medicine 3. Philadelphia: W.B. Saunders Company; 1992. p. 815. 67. Brown MP, et al. Ampicillin trihydrate in foals: serum concentrations and clearance after a single oral dose. Equine Vet J 1984; 16(4): 3713. 68. Panel comment, Rec 2/23/95. 69. Panel comment, Rec 3/9/95. 70. Panel comment, Rec 2/22/95. 71. Panel comment, Rec 3/6/95. 72. Panel comment, Rec 3/29/95. 73. Panel comment, Rec 2/17/95. 74. Panel comment, Rec 2/27/95. 75. Ampicillin package insert (Principen, ApotheconUS), Rev 4/90, Rec 7/93. 76. PDR Physicians desk reference, 48th ed. 1994. Montvale, NJ: Medical Economics Data Production Company; 1994. p. 2571. 77. Krogh, CME, editor. CPS Compendium of pharmaceuticals and specialities, 29th ed. Ottawa: Canadian Pharmaceutical Association; 1994. p. 634, 995. 78. Panel comment, Rec 6/22/95. 79. Panel comment, Rec 6/29/95. 80. Committee comment, Rec 1/15/02. 81. Bywater RJ, Palmer GH, Buswell JF, Stanton A. Clavulanate and amoxycillin: activity in vitro and bioavailability in the dog. Vet Rec 1985; 116: 336. 82. Soback S, Bor A, Kurtz B, et al. Clavulanate-potentiated amoxycillin: in vitro antibacterial activity and oral bioavailability in calves. J Vet Pharmacol Ther 1987; 10: 10513. 83. Panel comment, Rec 11/30/95. 84. Firth EC, Klein WR, Nouws JFM, et al. Effect of induced synovial inammation on pharmacokinetics and synovial concentration of sodium ampicillin and kanamycin sulfate after systemic administration in ponies. J Vet Pharmacol Ther 1988; 11: 5662.

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AMINOPENICILLINS VeterinarySystemic 45
85. Sarasola P, McKellar QA. Pharmacokinetics of bacampicillin in equids. Am J Vet Res 1995 Nov; 56(11): 148692. 86. Ensink JM, Klein WR, Mevius DJ, et al. Bioavailability of oral penicillins in the horse: a comparison of pivampicillin and amoxicillin. J Vet Pharmacol Ther 1992; 15: 22130. 87. Panel comment, Rec 11/28/95. 88. Traver DS, Riviere JE. Ampicillin in mares: a comparison of intramuscular sodium ampicillin or sodium ampicillin-ampicillin trihydrate injection. Am J Vet Res 1982 Mar; 43(3): 4024. 89. Bowman KF, Dix LP, Riond JL, Riviere JE. Prediction of pharmacokinetic proles of ampicillin sodium, gentamicin sulfate, and combination ampicillin sodium-gentamicin sulfate in serum and synovia of healthy horses. Am J Vet Res 1986; 47(7): 15906. 90. Beech J, Leitch M, Kohn CW, et al. Serum and synovial uid levels of sodium ampicillin and ampicillin trihydrate in horses. J Equine Med Surg 1979; 3: 3504. 91. Adin CA, Cowgill LD. Treatment and outcome of dogs with leptospirosis: 36 cases (1990-1998). J Am Vet Med Assoc 2000 Feb 1; 216(3): 3715. 92. Committee comment, 1/22/02.

2003 Thomson MICROMEDEX

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46 AMOXICILLIN AND CLAVULANATE VeterinarySystemic

AMOXICILLIN AND CLAVULANATE VeterinarySystemic

A commonly used brand name for a veterinary-labeled product is Clavamox. Note: For a listing of dosage forms and brand names by country availability, see the Dosage Forms sections(s). Urinary tract infections, bacterial (treatment)Cats{R-7} and [dogs]:{R-9 11} Amoxicillin and clavulanate combination is indicated in the treatment of urinary tract infections, including those caused by susceptible E. coli.

CATEGORY:
Antibacterial (systemic).

ACCEPTANCE NOT ESTABLISHED

[Osteomyelitis (treatment)]1Cats and dogs: There are insufcient data to show that amoxicillin and clavulanate combination is effective in the treatment of osteomyelitis in cats and dogs; however, in vitro studies show that the bacteria causing this type of infection are often susceptible.{R-3234; 37}
1

INDICATIONS
Note: Bracketed information in the Indications section refers to uses that either are not included in U.S. product labeling or are for products not commercially available in Canada.

Not included in Canadian product labeling or product not commercially available in Canada.

GENERAL CONSIDERATIONS
Amoxicillin has activity against penicillin-sensitive gram-positive bacteria as well as some gram-negative bacteria. The gram-positive spectrum of activity includes alpha- and beta-hemolytic streptococci, some Staphylococci species, Clostridia species, and some Bacillus anthracis{R-2}. Amoxicillin is also effective against gram-negative bacteria, including Escherichia coli (E. coli), many strains of Salmonella, and Pasteurella multocida.{R-2} Amoxicillin is sensitive to destruction by beta-lactamases and therefore when administered by itself is not effective against bacteria, such as Klebsiella and Proteus, that produce these enzymes.{R-2} Clavulanate is a naturally occurring noncompetitive inhibitor of betalactamase produced by gram-positive, and also many gram-negative, bacteria.{R-3; 4} Although it has a beta-lactam chemical structure, clavulanic acid has little antibacterial activity of its own. However, when clavulanic acid is administered concurrently with amoxicillin, it extends the activity of amoxicillin by preventing its destruction by bacterial enzymes. Beta-lactamase inhibitors will only assist in the destruction of bacteria that produce beta-lactamase enzymes; other forms of resistance, such as alteration of penicillin-binding protein, are not affected. Also, the beta-lactam structure of amoxicillin and clavulanate may stimulate some bacteria to produce more betalactamase; it is easier for clavulanate to protect amoxicillin against a small amount of enzyme than against a large amount. Clavulanate extends the spectrum of activity of amoxicillin to include beta-lactamase producing E. coli, Klebsiella, Proteus, and Staphylococcus species.{R-4; 6} Most anaerobes, including Bacterioides fragilis, are susceptible to the combination of clavulanic acid and amoxicillin.{R-5} However, some beta-lactamase enzymes, including those produced by Enterobacter and Pseudomonas, are unaffected by clavulanate.{R-6}

CHEMISTRY
Source: AmoxicillinSemisynthetic derivative of ampicillin.{R-12} ClavulanateA fermentation product of the actinomycete Streptomyces clavuligerus.{R-7; 8} Chemical name: Amoxicillin4-Thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid, 6[[amino(4-hydroxyphenyl)acetyl]amino]-3,3-dimethyl-7-oxo-, trihydrate[2S-[2alpha,5alpha,6beta(S*)]]-.{R-13} Clavulanate potassium4-Oxa-1-azabicyclo[3.2.0]heptane-2-carboxylic acid, 3-(2-hydroxyethylidene)-7-oxo-, monopotassium salt, [2R(2alpha,3Z,5alpha)]-.{R-13} Molecular formula: AmoxicillinC16H19N3O5S3H2O.{R-13} Clavulanate potassiumC8H8KNO5.{R-13} Molecular weight: Amoxicillin419.45.{R-13} Clavulanate potassium237.25.{R-13} Description: Amoxicillin USPWhite, practically odorless, crystalline powder.{R-14} Clavulanate Potassium USPWhite to off-white powder. Is moisturesensitive.{R-14} pKa: Amoxicillin2.8 and 7.2.{R-16} Clavulanate2.7.{R-17} Solubility: Amoxicillin USPSlightly soluble in water and in methanol; insoluble in carbon tetrachloride, and in chloroform.{R-14} Clavulanate Potassium USPFreely soluble in water, but stability in aqueous solution is not good; optimum stability at a pH of 6.0 to 6.3; soluble in methanol, with decomposition.{R-14}

ACCEPTED
Periodontal infections (treatment)Dogs: Amoxicillin and clavulanate combination is indicated in the treatment of periodontal infections caused by susceptible strains of aerobic and anaerobic bacteria{R-1; 31}. Skin and soft tissue infections (treatment)Cats and dogs:{R-7; 8} Amoxicillin and clavulanate combination is indicated in the treatment of skin and soft tissue infections caused by susceptible Staphylococcus species, E. coli, Pasteurella species, and Streptococcus species. 2003 Thomson MICROMEDEX

PHARMACOLOGY/PHARMACOKINETICS
Note: There is evidence that giving amoxicillin with clavulanate has little effect on the pharmacokinetics of either medication.{R-17; 24} Mechanism of action/effect: AmoxicillinBactericidal. Amoxicillin must reach and bind to the penicillin-binding proteins on the inner membrane of the bacterial All rights reserved

AMOXICILLIN AND CLAVULANATE VeterinarySystemic 47 cell wall. In actively growing cells, the binding of amoxicillin within the cell wall leads to interference with production of cell wall peptidoglycans and subsequent lysis of the cell in an iso-osmotic environment.{R-1820} ClavulanateBinds irreversibly to susceptible beta-lactamase enzymes, preventing hydrolysis of the amoxicillin beta-lactam ring. When clavulanate binds with the enzyme, a chemical complex is formed, which destroys the clavulanate and inactivates the beta-lactamase.{R-3; 4; 6} Absorption: Cats and dogsBoth amoxicillin and clavulanate are stable in gastric uid and, therefore, are well absorbed after oral administration.{R-6; 7; 2123} Calves Preruminant calves (2 weeks old): Absorption of amoxicillin when administered in combination with clavulanate at doses of 10 to 20 mg per kg of body weight (mg/kg) is 34 to 36%. Early ruminant calves (6 weeks old): Absorption of amoxicillin and clavulanate combination is much poorer than in preruminant calves given the same dose; early ruminant calves do not develop therapeutic serum amoxicillin concentrations.{R-26} HorsesOrally administered amoxicillin is only 10% absorbed in adult horses.{R-36} Peak serum concentration: Amoxicillin Calves, preruminant: Oral, 10 mg/kg dose2 mcg per mL (mcg/mL) at 78 minutes.{R-26} Oral, 20 mg/kg dose3.3 mcg/mL at 64 minutes.{R-26} Dogs: Oral, 12.5 mg/kg dose5 to 6 mcg/mL at 60 minutes.{R-38} Distribution: Cats and dogsAmoxicillin and clavulanate diffuse into most body tissues and uids; however, distribution of amoxicillin into cerebrospinal uid is low unless the meninges are inamed.{R-7; 8} Elimination: AmoxicillinPrimarily excreted unchanged in the urine. 10 to 25% is excreted in the form of penicilloic acid.{R-25}

LACTATION
In humans, penicillins are distributed into milk, and the same is true for many animals.{R-27; 28}

DRUG INTERACTIONS AND/OR RELATED PROBLEMS

The following drug interactions and/or related problems have been selected on the basis of their potential clinical signicance (possible mechanism in parentheses where appropriate)not necessarily inclusive ( = major clinical signicance): Note: Combinations containing any of the following medications, depending on the amount present, may also interact with this medication. Probenecid (probenecid decreases tubular secretion and slows the body clearance of amoxicillin, resulting in increased serum concentrations and longer elimination half-lives in many species{R-24; 29}; however, clavulanic acid is unlikely to be affected because it is cleared primarily by glomerular ltration{R-17})

LABORATORY VALUE ALTERATIONS

The following have been selected on the basis of their potential clinical signicance (possible effect in parentheses where appropriate)not necessarily inclusive ( = major clinical signicance): Note: Laboratory value alterations relating specically to use of amoxicillin and clavulanate in animals appear to be rare. Human laboratory value alterations have been reported and are included in this section.

HUMAN LABORATORY VALUE ALTERATIONS{R-15}

The following laboratory value alterations have been reported in humans, and are included in the human monograph Penicillins and Beta-lactamase Inhibitors (Systemic) in USP DI Volume I; these laboratory value alterations are intended for informational purposes only and may or may not be applicable to the use of amoxicillin and clavulanate combination in the treatment of animals: With diagnostic test results Glucose, urine (high urinary concentrations of a penicillin may produce falsepositive or falsely elevated test results with copper-reduction tests [Benedicts, Clinitest, or Fehlings]; glucose enzymatic tests [Clinistix or Testape] are not affected) Direct antiglobulin (Coombs) tests (false-positive result may occur during therapy with any penicillin) With physiology/laboratory test values Alanine aminotransferase (ALT [SGPT]) and Alkaline phosphatase and Aspartate aminotransferase (AST [SGOT]) and Lactate dehydrogenase (LDH), serum (values may be increased) Bilirubin, serum (concentrations may be increased) Estradiol or Estriol-glucuronide or Estriol, total conjugated, or Estrone, conjugated (concentrations may be transiently decreased in pregnant women following administration of amoxicillin) All rights reserved

PRECAUTIONS TO CONSIDER CROSS-SENSITIVITY AND/OR RELATED PROBLEMS

Animals allergic to one penicillin or cephalosporin may also be allergic to amoxicillin or clavulanate.{R-9}

SPECIES SENSITIVITY
Horses and rabbitsThis medication is generally contraindicated in these species because of the potential for disturbance of the normal gastrointestinal microora.{R-6}

PREGNANCY/REPRODUCTION
The safety of administration of amoxicillin and clavulanate to pregnant or breeding animals is unknown.{R-8; 9} Penicillins have been shown to cross the placenta; however, laboratory animal reproduction studies have shown no evidence of adverse effects on the fetus.{R-17} 2003 Thomson MICROMEDEX

48 AMOXICILLIN AND CLAVULANATE VeterinarySystemic White blood count (leukopenia or neutropenia is associated with the use of all penicillins; the effect is more likely to occur with prolonged therapy and severe hepatic function impairment) Seizures are more likely to occur in patients receiving high doses of a penicillin and/or patients with severe renal function impairment.

OVERDOSE
For information in cases of overdose or unintentional ingestion, contact the American Society for the Prevention of Cruelty to Animals (ASPCA) National Animal Poison Control Center (888-426-4435 or 900-443-000; a fee may be required for consultation) and/or the drug manufacturer.

PATIENT MONITORING
The following may be especially important in patient monitoring (other tests may be warranted in some patients, depending on condition; = major clinical signicance): Culture and susceptibility, in vitro, and Minimum inhibitory concentration (MIC) (in vitro cultures and MIC test should be done on samples collected prior to amoxicillin and clavulanate administration to determine pathogen susceptibility{R-7; 8})

VETERINARY DOSING INFORMATION

In cats and dogs, the therapeutic efcacy of amoxicillin{R-21} and clavulanate is not signicantly affected by administration with food.

FOR TREATMENT OF ADVERSE EFFECTS SIDE/ADVERSE EFFECTS

The following side/adverse effects have been selected on the basis of their potential clinical signicance (possible signs and, for humans, symptoms in parentheses where appropriate)not necessarily inclusive: For anaphylaxis {R-25} Parenteral epinephrine. Oxygen administration and breathing support.

ORAL DOSAGE FORMS

Note: The dosing and strengths of the dosage forms available are expressed in terms of clavulanic acid (not the potassium salt).

THOSE INDICATING NEED FOR MEDICAL ATTENTION

Incidence unknown All species{R-7; 8; 25} Hypersensitivity reactions, specically acute anaphylaxis, fever, or urticaria

AMOXICILLIN AND CLAVULANATE POTASSIUM FOR ORAL SUSPENSION USP

Usual dose: AntibacterialCats and dogs: Oral, 11 to 20 mg of amoxicillin and 2.75 to 5 mg of clavulanic acid per kg of body weight every eight to twelve hours.{R-3234} Note: Urinary tract infections should be treated for fourteen days or longer. Deep pyoderma may require treatment for twenty-one days. Treatment for any indication should not exceed thirty days.{R-8} Strength(s) usually available{R-30}: When reconstituted according to manufacturers instructions U.S.: Veterinary-labeled product(s) 50 mg of amoxicillin and 12.5 mg clavulanic acid per mL (Rx) [Clavamox]. Canada: Veterinary-labeled product(s) 50 mg of amoxicillin and 12.5 mg of clavulanic acid per mL (Rx) [Clavamox]. Packaging and storage: Store below 40 C (104 F), preferably between 15 and 30 C (59 and 86 F). Store in a tight container. Stability: After reconstitution, suspensions retain their potency for ten days if refrigerated.{R-8} Auxiliary labeling: Refrigerate. Shake well. USP requirements: Preserve in tight containers, at controlled room temperature. Contains the labeled amount of amoxicillin, within 10% to +20%, and an amount of clavulanate potassium equivalent to the All rights reserved

THOSE INDICATING NEED FOR MEDICAL ATTENTION ONLY IF THEY CONTINUE OR ARE BOTHERSOME
Incidence less frequent Cats and dogs{R-6; 17} Anorexia; diarrhea; vomiting
{R-15}

HUMAN SIDE/ADVERSE EFFECTS

In addition to the above side/adverse effects reported in animals, the following side/adverse effects have been reported in humans, and are included in the human monograph Penicillins and Beta-lactamase Inhibitors (Systemic) in USP DI Volume I; these side/adverse effects are intended for informational purposes only and may or may not be applicable to the use of amoxicillin and clavulanate in the treatment of animals: Incidence more frequent Gastrointestinal reactions; headache Incidence less frequent Allergic reactions, specically anaphylaxis; oral candidiasis; serum sicknesslike reactions; skin rash, hives, or itching; vaginal candidiasis Incidence rare Chest pain; chills; Clostridium difcile colitis; dysuria or urinary retention; edema; epistaxis; erythema multiforma or Stevens-Johnson syndrome; fatigue; glossitis; hepatic dysfunction, including cholestatic hepatitis; leukopenia or neutropenia; malaise; platelet dysfunction; proteinuria or pyuria; seizures; toxic epidermal necrolysis Note: Clostridium difcile colitis may occur up to several weeks after discontinuation of these medications. 2003 Thomson MICROMEDEX

AMOXICILLIN AND CLAVULANATE VeterinarySystemic 49 labeled amount of clavulanic acid, within )10% to +25%. Contains one or more suitable buffers, colors, avors, preservatives, stabilizers, sweeteners, and suspending agents. Meets the requirements for Identication, pH (3.86.6, in the suspension constituted as directed in the labeling, the test being performed immediately after constitution), and Water (not more than 7.5%, where the label indicates that after constitution as directed, the suspension contains 25 mg of amoxicillin per mL; not more than 8.5%, where the label indicates that after constitution as directed, the suspension contains 50 mg of amoxicillin per mL).{R-14}

REFERENCES
1. Clavamax Drops Freedom of Information Summary. NADA 055-101. 12/23/ 97. Sponsor: Pzer Inc. 2. Ampicillin package insert (Polyex, Fort DodgeUS), Rec 9/27/94. 3. Barragry TB. Veterinary drug therapy. Philadelphia: Lea & Febiger; 1994. p. 2214. 4. Kilgore WR, Simmons RD, Jackson JW. Beta-lactamase inhibition: a new approach in overcoming bacterial resistance. Compend Contin Educ Pract Vet 1986; 8: 325. 5. Indiveri MC, Hirsh DC. Clavulanic acid-potentiated activity of amoxicillin against Bacteroides fragilis. Am J Vet Res 1985; 46(10): 22079. 6. Prescott JF, Baggot JD, editors. Antimicrobial therapy in veterinary medicine. 2nd ed. Ames, IA: Iowa State University Press 1993: 11926. 7. Amoxicillin and clavulanic acid package insert (Clavamox Tablets, SmithKline BeechamUS), Rev 9/90, Rec 2/7/95. 8. Amoxicillin and clavulanic acid package insert (Clavamox Drops, SmithKline BeechamUS), Rev 9/90, Rec 2/7/95. 9. Clavamox drops. In: Bennett K, editor. Compendium of veterinary products. 3rd ed. Hensall, ON: North American Compendiums Inc., 1993; 1734. 10. Clavamox tablets. In: Bennett K, editor. Compendium of veterinary products. 3rd ed. Hensall, ON: North American Compendiums Inc., 1993: 173. 11. Senior, et al. Amoxycillin and clavulanic acid combination in the treatment of experimentally induced bacterial cystitis in cats. Res Vet Sci 1985; 39(1): 416. 12. Amoxicillin package insert (Amoxitabs, SmithKline BeechamUS), Rev 7/93, Rec 10/18/94. 13. USP dictionary of USAN and international drug names, 2002. Rockville, MD: The United States Pharmacopeial Convention, Inc.; 2002. 14. The United States pharmacopeia. The national formulary. USP 26th revision (January 1, 2003). NF 21st ed (January 1, 2003). Rockville, MD: The United States Pharmacopeial Convention, Inc.; 2002. p. 143, 144, 2548, 2555. 15. Klasco RK, editor. USP DI Drug information for the healthcare professional. Volume I. Greenwood Village, CO: MICROMEDEX, Inc.; 2003. 16. Riviere JE, Craigmill AL, Sundlof SF. Handbook of comparative pharmacokinetics and residues of veterinary antimicrobials. Boca Raton, FL: CRC Press, Inc. 1991. 17. Plumb DC. Veterinary drug handbook. White Bear Lake, MN: PharmaVet Publishing 1991: 4679, 4806. 18. Donowitz DR, Mandell GL. Beta-lactam antibiotic. N Engl J Med 1988; 318: 41926. 19. Wright AJ, Wilkowski CJ. The penicillins. Mayo Clin Proc 1983; 58: 2132. 20. Papich MG. The beta-lactam antibiotics: Clinical pharmacology and recent developments. Compend Contin Educ Pract Vet 1987; 9(1): 6874. 21. Watson ADJ, et al. Effect of ingesta on systemic availability of penicillins administered orally in dogs. J Vet Pharmacol Ther 1986: 9: 1409. 22. Papich MG. Therapy of gram-positive bacterial infections. Vet Clin North Am Small Anim Pract 1988; 18(6): 126785. 23. Spurlock SL, Wilcke JR. Penicillins and cephalosporins. In: Proceedings of the thirty-second annual convention of the American Association of Equine Practitioners; 1987. p. 17582. 24. Soback S, et al. Clavulanate-potentiated amoxycillin: in vitro antibacterial activity and oral bioavailability in calves. J Vet Pharmacol Ther 1987; 10: 10513. 25. Amoxicillin package insert (Amoxi-drops, SmithKline BeechamUS), Rev 9/90, Rec 10/18/94. 26. Soback S, Bor A, Kurtz B, et al. Clavulanate-potentiated amoxycillin: in vitro antibacterial activity and oral bioavailability in calves. J Vet Pharmacol Ther 1987; 10: 10513. 27. Ampicillin package insert (Principen, ApotheconUS), Rev 4/90, Rec 7/93. 28. Ampicillin (Apo-Ampi, Apotex). In: Krogh CME, editor. CPS Compendium of pharmaceuticals and specialties. 29th ed. Ottawa: Canadian Pharmaceutical Association, 1994; 83: 995. 29. Ziv G, Horsey J. Elevation and prolongation of serum ampicillin and amoxycillin concentrations in calves by the concomitant administration of probenecid. J Vet Pharmacol Ther 1979; 2: 18794. 30. Arrioja-Dechert A, editor. Compendium of veterinary products, CD ed. Port Huron, MI: North American Compendiums, Inc. 2002. 31. Clavamox Tabs Freedom of Information Summary. NADA 055-099. 12/23/ 97. Sponsor: Pzer Inc. 32. Panel comment, 4/7/95. 33. Budsberg SC, Kemp DT. Antimicrobial distribution and therapeutics in bone. Compend Contin Ed Small Animal Pract 1990; 12(12): 175862. 34. Fossum TW, Hulse DA. Osteomyelitis. Semin Vet Med Surg (Small Anim) 1992 Feb; 7(1): 8597.

AMOXICILLIN AND CLAVULANATE POTASSIUM TABLETS USP

Usual dose: See Amoxicillin and Clavulanate Potassium for Oral Suspension USP. Strength(s) usually available{R-30}: U.S. Veterinary-labeled product(s): 50 mg of amoxicillin and 12.5 mg of clavulanic acid (Rx) [Clavamox]. 100 mg of amoxicillin and 25 mg of clavulanic acid (Rx) [Clavamox]. 200 mg of amoxicillin and 50 mg of clavulanic acid (Rx) [Clavamox]. 300 mg of amoxicillin and 75 mg of clavulanic acid (Rx) [Clavamox]. Canada Veterinary-labeled product(s): 50 mg of amoxicillin and 12.5 mg of clavulanic acid (Rx) [Clavamox]. 100 mg of amoxicillin and 25 mg of clavulanic acid (Rx) [Clavamox]. 200 mg of amoxicillin and 50 mg of clavulanic acid (Rx) [Clavamox]. 300 mg of amoxicillin and 75 mg of clavulanic acid (Rx) [Clavamox]. Packaging and storage: Store below 25 C (77 F), unless otherwise specied by manufacturer. Store in a tight container. Auxiliary labeling: Do not remove from foil strip until ready to use. USP requirements: Preserve in tight containers. Label chewable Tablets to include the word chewable in juxtaposition to the ofcial name. The labeling indicates that chewable Tablets may be chewed before being swallowed or may be swallowed whole. Tablets intended for veterinary use only are so labeled. Contain the labeled amount of amoxicillin, within )10% to +20%, and an amount of clavulanate potassium equivalent to the labeled amount of clavulanic acid, within )10% to +20%. Meet the requirements for Identication, Disintegration (for Tablets labeled for veterinary use only, 30 minutes, in simulated gastric uid TS), Dissolution (85% of amoxicillin and 80% of clavulanic acid in 30 minutes [or 45 minutes where the Tablets are labeled as chewable] in water in Apparatus 2 at 75 rpm [Note: Tablets labeled for veterinary use only are exempt from this requirement]), Uniformity of dosage units, and Water (not more than 6.0% where the Tablets are labeled as being chewable; not more than 7.5% where the labeled amount of amoxicillin in each Tablet is 250 mg or less; not more than 10.5% where the labeled amount of amoxicillin in each Tablet is greater than 250 mg).{R-14} Developed: 06/30/95 Interim revision: 06/26/96; 05/14/97; 5/26/98; 10/12/99; 09/30/02; 04/04/03 2003 Thomson MICROMEDEX

All rights reserved

50 AMOXICILLIN AND CLAVULANATE VeterinarySystemic

35. Sarkiala E, Harvey C. Systemic antimicrobials in the treatment of periodontitis in dogs. Semin Vet Med Surg (Small Anim) 1993 Aug; 8(3): 197203. 36. Wilson WD, Spensley MS, Baggot JD, et al. Pharmacokinetics and estimated bioavailability of amoxicillin in mares after intravenous, intramuscular, and oral administration. Am J Vet Res 1988 Oct; 49(10): 168894. 37. Johnson KA. Osteomyelitis in dogs and cats. J Am Vet Med Assoc 1994 June; 205(12): 18827. 38. Bywater RJ, Palmer GH, Buswell JF, et al. Clavulanate and amoxycillin: activity in vitro and bioavailability in the dog. Vet Rec 1985; 116: 336. 39. Todd PA, Beneld P. Amoxicillin/Clavulanic acid. Drugs 1990; 39: 264307.

2003 Thomson MICROMEDEX

All rights reserved

CEPHALOSPORINS VeterinarySystemic 51

CEPHALOSPORINS VeterinarySystemic
This monograph includes information on the following: Cefaclor; Cefadroxil; Cefazolin; Cexime; Cefotaxime; Cefotetan; Cefoxitin; Ceftiofur; Cephalexin; Cephalothin; Cephapirin; Cephradine. Some commonly used brand names are: For veterinary-labeled products
Cefa-Drops [Cefadroxil] Cefa-Tabs [Cefadroxil] Excenel [Ceftiofur] Excenel RTU [Ceftiofur] Naxcel [Ceftiofur]

For selected human-labeled products

Ancef [Cefazolin] Apo-Cefaclor [Cefaclor] Apo-Cephalex [Cephalexin] Ceclor [Cefaclor] Cefadyl [Cephapirin] Cefotan [Cefotetan] Ceporacin [Cephalothin] Claforan [Cefotaxime] Keex [Cephalexin] Kein [Cephalothin] Keftab [Cephalexin] Kefzol [Cefazolin] Mefoxin [Cefoxitin] Novo-Lexin [Cephalexin] Nu-Cephalex [Cephalexin] PMS-Cephalexin [Cephalexin] Suprax [Cexime] Velosef [Cephradine]

Note: For a listing of dosage forms and brand names by country availability, see the Dosage Forms section(s). Not commercially available in Canada.

CATEGORY:
Antibacterial (systemic).

INDICATIONS
Note: Bracketed information in the Indications section refers to uses that either are not included in U.S. product labeling or are for products not commercially available in the U.S.

GENERAL CONSIDERATIONS
Cephalosporins are wide-spectrum antibiotics used to treat a variety of infections in animals. They have been grouped into three generations based primarily on their spectrum of antibacterial activity{R-1; 2}. Some of the more recently developed cephalosporins may not easily t into one of the generations, but are usually included in the generation their antibacterial properties most closely resemble. First-generation cephalosporins include cefadroxil, cefazolin, cephalexin, cephalothin, cephapirin, and cephradine. First-generation cephalosporins have the highest activity of the cephalosporins against gram-positive bacteria, including most Corynebacteria, Streptococci, and Staphylococci, particularly Staphylococcus aureus{R-3} and Staphylococcus intermedius{R-32}. Cephalothin and cephapirin generally have the greatest activity against staphylococci{R-2}; Staphylococcus epidermidis is only variably susceptible to cephalexin and cefadroxil.{R-1} Rhodococcus equi, methicillin-resistant S. aureus, and Enterococcus species are usually resistant.{R-1} The rstgeneration cephalosporins have activity against gram-negative bacteria, including some Escherichia coli{R-3}, Klebsiella pneumoniae, Haemophilus inuenzae, Proteus mirabilis{R-3}, Actinobacillus, Pasteurella, and Salmonella; however, Actinobacter, Citrobacter, Enterobacter, indole-positive Proteus, and Pseudomonas are resistant.{R-1; 4; 53} Many anaerobic bacteria are susceptible to these antibacterials, with 2003 Thomson MICROMEDEX

the exception of beta-lactamaseproducing Bacteroides{R-1; 4} and Clostridium difcile{R-98}. Second-generation cephalosporins include cefaclor, cefamandole, cefmetazole, cefonicid, cefotetan, cefoxitin, cefprozil, and cefuroxime. Second-generation cephalosporins have the same efcacy as or perhaps slightly less efcacy than rst-generation cephalosporins against gram-positive pathogens; however, this lack of efcacy is primarily against S. aureus and S. intermedius. Second-generation are more effective than rst-generation cephalosporins in the treatment of infections caused by gram-negative bacteria such as E. coli, Klebsiella, Enterobacter, and Proteus.{R-1; 4; 7} Many anaerobic bacteria are susceptible to second-generation cephalosporins; cefoxitin{R-79} and cefotetan{R-80} can also be effective against Bacteroides fragilis. However, Enterococcus and Pseudomonas species are resistant to second-generation cephalosporins{R-80}. Use of these antimicrobials is generally reserved for infections that are resistant to rst-generation cephalosporins. Third-generation cephalosporins include cexime, cefoperazone, cefotaxime, cefpodoxime, ceftazidime, ceftizoxime, and ceftriaxone. Third-generation cephalosporins are the most effective of the cephalosporins against antibiotic-resistant gram-negative bacteria{R-1; 2; 7}. Ceftazidime and cefoperazone are active against Pseudomonas, but the majority of the third-generation cephalosporins commonly used in veterinary practice are not{R-4; 80}. Third-generation cephalosporins, in general, are no more and perhaps are less effective than other cephaosporins against gram-positive bacteria{R-1; 4; 7}. Cefotaxime, ceftazidine, ceftizoxine, and ceftriaxone are the only cephalosporins that consistently reach effective antibacterial concentrations in the central nervous system in people with inamed meninges. Ceftiofur is a cephalosporin that does not clearly t into the thirdgeneration category and has been called a new-generation cephalosporin{R-91}. It has broader gram-positive activity, including good activity against Streptococci, and less activity against Pseudomonas than other third-generation cephalosporins{R-68}. It is active against beta-lactamaseproducing strains as well as anaerobes, such as Fusobacterium necrophorum and Bacteroides melaninogenicus{R-81}. Ceftiofur is rapidly metabolized to desfuroylceftiofur in vivo and S. aureus is four- to eightfold{R-100} less sensitive to desfuroylceftiofur than to the parent ceftiofur{R-63}. Proteus mirabilis has a widely variable susceptibility to some metabolites of ceftiofur{R-72}.

ACCEPTED
Escherichia coli infections (treatment)Chicks1 and turkey poults, day-old: Ceftiofur sodium for injection is indicated in the treatment of infections (colibacillosis) caused by susceptible E. coli{R-11; 12}. Metritis (treatment)1Cattle: Ceftiofur hydrochloride injection is indicated in the treatment of acute metritis (up to 14 days postpartum), caused by susceptible organisms{R-81}. Pododermatitis, acute (treatment)Cattle: Ceftiofur sodium for injection and ceftiofur hydrochloride injection are indicated in the treatment of bovine interdigital necrobacillosis associated with F. necrophorum and B. melaninogenicus{R-11; 12; 81; 99}. Respiratory tract infections (treatment) Cattle: Ceftiofur sodium for injection and ceftiofur hydrochloride injection are indicated in the treatment of respiratory tract infections, All rights reserved

52 CEPHALOSPORINS VeterinarySystemic including bovine respiratory disease complex (shipping fever), caused by susceptible organisms, including Mannheimia (Pasteurella) haemolytica, Pasteurella multocida, and Haemophilus somnus{R-11; 12; 81; 99} . Goats1: Ceftiofur sodium for injection is indicated in the treatment of caprine respiratory disease caused by susceptible organisms, including M. haemolytica and P. multocida{R-11}. Horses: Ceftiofur sodium for injection is indicated in the treatment of respiratory tract infections caused by susceptible organisms, including Streptococcus zooepidemicus{R-11; 12}. Pigs: Ceftiofur hydrochloride injection and ceftiofur sodium for injection are indicated in the treatment of respiratory tract infections caused by susceptible organisms, including Actinobacillus pleuropneumoniae, P. multocida, Salmonella choleraesuis, and Streptococcus suis type 2.{R-11; 81; 96; 99} Sheep: Ceftiofur sodium for injection is indicated in the treatment of respiratory tract infections caused by susceptible M. haemolytica and P. multocida{R-11; 12; 97}. Skin and soft tissue infections (treatment)Cats and dogs: Cefadroxil and [cephalexin]1{R-32} are indicated in the treatment of skin and soft tissue infections caused by susceptible organisms, including P. multocida, S. aureus, some S. epidermidis, S. intermedius{R-32}, and Streptococcus species.{R-3; 79} Urinary tract infections (treatment)Dogs: Cefadroxil and ceftiofur sodium for injection are indicated in the treatment of urinary tract infections caused by susceptible organisms, including E. coli, P. mirabilis, and S. aureus{R-3; 11; 12}. [Perioperative infections (prophylaxis)]1Dogs: Cefazolin is used in the prevention of infections associated with surgery, including bone surgery, and caused by susceptible organisms when the risk of infection is high or potentially severely damaging.{R-1; 2; 6; 82; 83}
1

determination of minimum inhibitory concentrations against common pathogens show that cexime is likely to be effective in the treatment of bone, bladder, skin, and soft tissue infections{R-77}. There are insufcient data to establish the clinical efcacy and safety of [cefotetan]1 and [cefoxitin]1 in the treatment of gram-negative or polymicrobial infections (such as Enterobacteriaceae species and an obligate anaerobe) in dogs; however, pharmacokinetics and a determination of minimum inhibitory concentrations against common pathogens show that cefotetan and cefoxitin are likely to be effective in the treatment of these types of infections{R-84}. [Foals]1 : There are insufcient data to establish the efcacy and safety of ceftiofur{R-48} and cephradine{R-85} in foals for the treatment of bacterial infections; however, based on the pharmacokinetics known, pathogen sensitivities, and the apparent wide margin of safety, these medications are used to treat a variety of susceptible infections, including certain bone, joint, respiratory, skin, soft tissue, and urinary tract infections. There are also insufcient data to establish the efcacy and safety of cefotaxime and other third-generation cephalosporins in the treatment of neonatal sepsis and secondary bacterial meningitis in foals; however, based on known human central nervous system distribution and clinical response in foals, cefotaxime is used to treat these infections when they are not responsive to other antimicrobials{R-62; 67}. Horses: There are insufcient data to establish the efcacy and safety of [cefoxitin]1{R-29} and [cephalothin]1 {R-9; 19} in horses for the treatment of bacterial infections; however, based on the pharmacokinetics known, pathogen sensitivities, and the apparent wide margin of safety, these medications are used to treat a variety of susceptible infections, including certain bone, joint, respiratory, skin, soft tissue, and urinary tract infections.1

ACCEPTANCE NOT ESTABLISHED

Infections, bacterial (treatment) [Birds]1: There are insufcient data to establish the efcacy and safety of cephalexin and cephalothin in the treatment of bacterial infections in birds, such as cranes, ducks, emu, pigeons, and quail; however, based on pharmacokinetic studies and the apparent wide margin of safety, they have been used in the treatment of susceptible bacterial infections{R-34}. Cats: There are insufcient data to establish the efcacy and safety of [cefotaxime] 1{R-42} and [cephalexin]1{R-49; 50} in the treatment of bacterial infections in cats; however, based on pharmacokinetics, pathogen sensitivities, and the apparent wide margin of safety, these medications are used to treat a variety of susceptible infections, including certain bone, respiratory, skin, soft tissue, and urinary tract infections. Dogs: There are insufcient data to establish the efcacy and safety of [cefaclor]1, [cefazolin]1, [cefotaxime]1, ceftiofur (for nonurinary tract infections), [cephalexin]1, [cephalothin]1, [cephapirin]1, and [cephradrine]1 for the treatment of bacterial infections in dogs; however, based on pharmacokinetic data{R-43; 49; 50; 72; 82; 83}, knowledge about in vitro efcacy, and the apparent wide margin of safety, these medications are used to treat a variety of susceptible infections, including certain bone, respiratory, skin, soft tissue, and urinary tract infections. Also, there are insufcient data to establish the clinical efcacy and safety of [cexime]1 in the treatment of bacterial infections in dogs; however, pharmacokinetics and 2003 Thomson MICROMEDEX

Not included in Canadian product labeling or product not commercially available in Canada.

REGULATORY CONSIDERATIONS
U.S. and Canada{R-11; 12} Withdrawal times have been established for ceftiofur (see the Dosage Forms section). Ceftiofur is not for use in horses intended for human consumption.

CHEMISTRY
Source: Most cephalosporins are semisynthetic derivatives of the metabolic products of the fungus Cephalosporium acremonium.{R-13} Chemical group: Beta-lactam antibiotics.{R-2; 7} Molecular formula:{R-13} CefaclorC15H14ClN3O4S H2O. CefadroxilC16H17N3O5S H2O. Cefazolin sodiumC14H13N8NaO4S3. CeximeC16H15N5O7S2 H2O. Cefotaxime sodiumC16H16N5NaO7S2. Cefotetan disodiumC17H15N7Na2O8S4. Cefoxitin sodiumC16H16N3NaO7S2. Ceftiofur hydrochlorideC19H17N5O7S3 HCl. Ceftiofur sodiumC19H16N5NaO7S3. CephalexinC16H17N3O4S H2O. Cephalexin hydrochlorideC16H17N3O4S HCl H2O. Cephalothin sodiumC16H15N2NaO6S2. All rights reserved

CEPHALOSPORINS VeterinarySystemic 53 Cephapirin sodiumC17H16N3NaO6S2. CephradineC16H19N3O4S. Molecular weight:{R-13} Cefaclor385.82. Cefadroxil381.40; 372.39 (hemihydrate); 363.4 (anhydrous){R-14}. Cefazolin sodium476.49. Cexime507.50. Cefotaxime sodium477.45. Cefotetan disodium619.59. Cefoxitin sodium449.44. Ceftiofur hydrochloride560.03. Ceftiofur sodium545.55. Cephalexin365.41. Cephalexin hydrochloride401.87. Cephalothin sodium418.42. Cephapirin sodium445.45. Cephradine349.41. Description:{R-14} Cefaclor USPWhite to off-white, crystalline powder. Cefadroxil USPWhite to off-white, crystalline powder. Cefazolin Sodium USPWhite to off-white, practically odorless, crystalline powder, or white to off-white solid. Cexime USPWhite to light yellow, crystalline powder. Cefotaxime Sodium USPOff-white to pale yellow crystalline powder. Cefotaxime sodium injectionSolutions of cefotaxime sodium range from very pale yellow to light amber depending on the concentration and the diluent used. Cefotetan disodiumWhite to pale yellow powder. Cefotetan disodium injectionSolution varies from colorless to yellow, depending on the concentration. Cefoxitin Sodium USPWhite to off-white, granules or powder, having a slight characteristic odor. Is somewhat hydroscopic. Cephalexin USPWhite to off-white, crystalline powder. Cephalexin Hydrochloride USPWhite to off-white crystalline powder. Cephalothin Sodium USPWhite to off-white, practically odorless, crystalline powder. Cephapirin Sodium USPWhite to off-white crystalline powder, odorless or having a slight odor. Cephradine USPWhite to off-white, crystalline powder. pKa: Cefotaxime3.35.{R-15} Cefoxitin2.2.{R-16; 17} Cephalexin5.3 and 7.3.{R-16; 17} Cephalothin5.0.{R-17} Cephapirin2.15 and 5.44.{R-16} Cephradine2.6 and 7.3.{R-17} Solubility:{R-14} Cefaclor USPSlightly soluble in water; practically insoluble in methanol and in chloroform. Cefadroxil USPSlightly soluble in water; practically insoluble in alcohol, in chloroform, and in ether. Cefazolin Sodium USPFreely soluble in water, in saline TS, and in dextrose solutions; very slightly soluble in alcohol; practically insoluble in chloroform; and in ether. Cexime USPFreely soluble in methanol; soluble in propylene glycol; slightly soluble in alcohol, in acetone, and in glycerin; very slightly soluble in 70% sorbitol and in octanol; practically insoluble in ether, in ethyl acetate, in hexane, and in water. Cefotaxime Sodium USPFreely soluble in water; practically insoluble in organic solvents. Cefotetan disodiumVery soluble in water. Cefoxitin Sodium USPVery soluble in water; soluble in methanol; sparingly soluble in dimethylformamide; slightly soluble in acetone; insoluble in ether and in chloroform. Ceftiofur sodiumSolubility is pH dependent (greater than 400 mg per mL at pH > 5.5){R-68}. Cephalexin USPSlightly soluble in water; practically insoluble in alcohol, in chloroform, and in ether. Cephalexin Hydrochloride USPSoluble to the extent of 10 mg per mL in water, in acetone, in acetonitrile, in alcohol, in dimethylformamide, and in methanol; practically insoluble in chloroform, in ether, in ethyl acetate, and in isopropyl alcohol. Cephalothin Sodium USPFreely soluble in water, in saline TS, and in dextrose solutions; insoluble in most organic solvents. Cephapirin Sodium USPVery soluble in water; insoluble in most organic solvents. Cephradine USPSparingly soluble in water; very slightly soluble in alcohol and in chloroform; practically insoluble in ether.

PHARMACOLOGY/PHARMACOKINETICS
Note: See also Table 1. Pharmacology/Pharmacokinetics at the end of this monograph. Mechanism of action/effect: Cephalosporins are beta-lactam antibiotics that produce their bactericidal effect by inhibition of cell wall synthesis. The site of action for beta-lactam antibiotics is the penicillinbinding proteins (PBPs) on the inner surface of the bacterial cell membrane that are involved in synthesis of the cell wall.{R-2} In actively growing cells, the cephalosporins bind to the PBPs within the cell wall and lead to interference in production of cell wall peptidoglycans and subsequent lysis of the cell in an iso-osmotic environment.{R-7; 9} Differences in afnity for the types of PBPs by different beta-lactam antibiotics and the bacterial defense mechanisms explain the variations in bactericidal activity among cephalosporins.{R-9} Distribution: Cephalosporins distribute into most body tissues and uids.{R-18} They penetrate into pleural uid, synovial uid, pericardial uid, and urine. Cephalosporins can be found in bile uid if no biliary obstruction is present.{R-1} The cephalosporins penetrate aqueous humor and prostatic uid less than other body uids. Most of the cephalosporins have poor penetration of the blood-brain barrier.{R-2} Cefuroxime is the only second-generation cephalosporin known to adequately penetrate into cerebrospinal uid in people; also, the thirdgeneration antibiotics cefotaxime and cefoxitin{R-1} have been shown to penetrate inamed meninges in people. Ceftriaxone has been shown to penetrate normal meninges in horses{R-103}. The high level of protein binding by ceftiofur in adult animals causes its distribution to differ from that of other cephalosporins{R-91}. Also, the primary metabolite of ceftiofur, desfuroylceftiofur, has a reactive sulfhydryl group that forms reversible covalent bonds with plasma and tissue proteins{R-63}. Free concentrations of ceftiofur and its active metabolites tend to be lower than expected when dosages shown to be effective in the treatment of a disease are administered, possibly because of their unique protein binding abilities{R-63}. Concentrations of ceftiofur and active metabolites in Pasteurella-infected tissue chambers implanted into cattle tend to be higher than concentrations in uninfected

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54 CEPHALOSPORINS VeterinarySystemic chambers{R-73}. Studies of distribution of ceftiofur into other tissues have also shown it to be unique, although the way in which this affects efcacy in the extra-label treatment of infections is not known. Biotransformation: Cefotaxime{R-20}, cephalothin{R-19}, and cephapirin undergo biotransformation in the liver to desacetyl derivatives.{R-1; 2} Ceftiofur is rapidly converted in vivo to desfuroylceftiofur, which is structurally similar to and, in most instances, equally active microbiologically to, ceftiofur.{R-30} The signicant exceptions are that Staphylococcus aureus is four- to eightfold{R-100} less sensitive to desfuroylceftiofur than to ceftiofur{R-63}, and that Proteus mirabilis has a widely variable susceptibility to some ceftiofur metabolites{R-72}. The metabolites of other cephalosporins may retain some antibacterial activity. Elimination: For most cephalosporins, elimination is by renal tubular secretion and/or glomerular ltration. Although cephalothin has been associated with an increased human risk of nephrotoxicity when administered with an aminoglycoside, this interaction may not apply to other cephalosporins{R-98}. In fact, there is some evidence that certain cephalosporins such as cefamandole, cefazolin, and cephalothin provide a protective effect against aminoglycoside-induced nephrotoxicity in rats{R-101} while others, such as cephalexin, have no effect{R-102}. Probenecid (probenecid administered concurrently with a cephalosporin will inhibit renal tubular secretion and in some cases increase the serum concentrations and prolong the serum half-life of the cephalosporin{R-2}, including cefadroxil{R-3}, cefoxitin{R-26}, cephalothin{R-30}, and cephapirin{R-27}; probenecid has not been shown to alter the renal tubular secretion of ceftiofur{R-70})

HUMAN DRUG INTERACTIONS{R-46}

In addition to the above drug interactions reported in animals, the following drug interactions have been reported in humans, and are included in the human monograph Cephalosporins (Systemic) in USP DI Volume I; these drug interactions are intended for informational purposes only and may or may not be applicable to the use of cephalosporins in the treatment of animals: Antacids (the extent of absorption of cefaclor is decreased with concurrent use of aluminum hydroxide- or magnesium-containing antacids; cefaclor should not be taken within 1 hour of taking these antacids) Anticoagulants, coumarin- or indandione-derivative, or Heparin or Thrombolytic agents (concurrent use of these medications with cefotetan may increase the risk of bleeding because of the N-methylthiotetrazole [NMTT] side chain on these medications; however, critical illness, poor nutritional status, and the presence of liver disease may be more important risk factors for hypoprothrombinemia and bleeding; because all cephalosporins can inhibit vitamin K synthesis by suppressing gut ora, prophylactic vitamin K therapy is recommended when any of these medications is used for prolonged periods in malnourished or seriously ill patients; dosage adjustments of anticoagulants may be necessary during and after therapy with cefotetan; concurrent use with thrombolytic agents may increase the risk of severe hemorrhage and is not recommended) (an increased anticoagulant effect has been reported with concurrent use of cefaclor and oral anticoagulants) Nephrotoxic medications (cephalothin has been associated with an increased incidence of nephrotoxicity when used concurrently with aminoglycosides; this effect has rarely been seen with other commercially available cephalosporins used at appropriate doses; the potential for increased nephrotoxicity exists when cephalosporins are used with other nephrotoxic medications, such as loop diuretics, especially in patients with pre-existing renal function impairment; renal function should be monitored carefully in patients receiving cephalosporins and aminoglycosides concurrently) Platelet aggregation inhibitors, other (hypoprothrombinemia induced by large doses of salicylates and/or cephalosporins, and the gastrointestinal ulcerative or hemorrhagic All rights reserved

PRECAUTIONS TO CONSIDER SPECIES SENSITIVITY

Rabbits and small rodents{R-80}Cephalosporins may disturb the normal intestinal microora, particularly when administered orally at high doses.{R-21}

CROSS-SENSITIVITY
The incidence of cross-sensitivity in animals is unknown. Caution should be used when cephalosporins are administered to patients with a history of an anaphylactic reaction to other beta-lactam antibiotics because cross-reaction may occur{R-1}; however, a history of a delayed allergic reaction to penicillin does not contraindicate use of a cephalosporin.{R-2}

PREGNANCY/REPRODUCTION
PregnancyCephalosporins have been shown to cross the placenta in animals. Studies in laboratory animals have not shown the cephalosporins to cause adverse effects in the fetus.{R-2224} Studies with cefoxitin have not shown that the medication is teratogenic or fetotoxic in mice and rats, but a slight decrease in fetal weight{R-21} has occurred.

LACTATION
Cephalosporins are distributed into milk{R-25}; however, when administered systemically at accepted doses, therapeutic concentrations are not reached in milk.{R-67; 69} When ceftiofur is administered systemically at recommended dosages, distribution is too low to produce residues greater than established regulatory tolerances.{R-68; 69}

DRUG INTERACTIONS AND/OR RELATED PROBLEMS

The following drug interactions and/or related problems have been selected on the basis of their potential clinical signicance (possible mechanism in parentheses where appropriate)not necessarily inclusive ( = major clinical signicance): Note: Combinations containing any of the following medications, depending on the amount present, may also interact with this medication. 2003 Thomson MICROMEDEX

CEPHALOSPORINS VeterinarySystemic 55 potential of nonsteroidal anti-inammatory drugs [NSAIDs], salicylates, or sulnpyrazone may increase the risk of hemorrhage) Creatinine, serum (concentrations may be increased) Complete blood count (CBC) or Platelet count (transient leukopenia, neutropenia, agranulocytosis, thrombocytopenia, eosinophilia, lymphocytosis, and thrombocytosis have been reported on rare occasions)

LABORATORY VALUE ALTERATIONS

The following have been selected on the basis of their potential clinical signicance (possible effect in parentheses where appropriate)not necessarily inclusive ( = major clinical signicance): With diagnostic test results Coombs test (positive reactions for the Coombs test may be seen in animals receiving cephalosporins; this may be due to changes in the red blood cells, but hemolytic anemia usually is not occurring{R-2}) With physiology/laboratory test values Ketones, urine (values may be increased){R-68}

MEDICAL CONSIDERATIONS/CONTRAINDICATIONS
The medical considerations/contraindications included have been selected on the basis of their potential clinical signicance (reasons given in parentheses where appropriate)not necessarily inclusive ( = major clinical signicance). Risk-benet should be considered when the following medical problems exist: Bleeding disorders, history of (some of the second- and third-generation cephalosporins have been associated with an increased risk of bleeding in people{R-65} due to a decrease in prothrombin activity, and bleeding is considered a potential human risk with all the cephalosporins; there is evidence of a signicant increase in bleeding time after cephalothin administration to beagles{R-28} but not outside normal reference ranges; clinical problems have not been reported in animals and the clinical signicance is unknown) Hepatic dysfunction, severe (because cefotaxime, cephalothin, and cephapirin are hepatically metabolized before renal elimination, severe liver dysfunction can inhibit metabolism{R-2}) Renal insufciency (nephrotoxicity may occur in patients with renal insufciency who are receiving the full dosage of cephalosporin; dosage should be adjusted){R-1}

HUMAN LABORATORY VALUE ALTERATIONS{R-46}

The following laboratory value alterations have been reported in humans, and are included in the human monograph Cephalosporins (Systemic) in USP DI Volume I; these laboratory value alterations are intended for informational purposes only and may or may not be applicable to the use of cephalosporins in the treatment of animals: With diagnostic test results Coombs (antiglobulin) tests (a positive Coombs reaction frequently appears in patients who receive large doses of a cephalosporin; hemolysis rarely occurs, but has been reported; test may be positive in neonates whose mothers received cephalosporins before delivery) Creatinine, serum and urine (cefotetan, cefoxitin, or cephalothin may falsely elevate test values when the Jaffes reaction method is used; serum samples should not be obtained within 2 hours after administration) Glucose, urine (some cephalosporins [cefaclor, cefazolin, cexime, cefotetan, cefoxitin, cephalexin, cephalothin, cephapirin, cephradine] may produce false-positive or falsely elevated test results with copper sulfate tests [Benedicts, Fehlings, or Clinitest]; glucose enzymatic tests, such as Clinistix and Tes-Tape, are not affected) Protein, urine (cefamandole may produce false-positive tests for proteinuria with acid and denaturization-precipitation tests) Prothrombin time (PT) (may be prolonged; cephalosporins may inhibit vitamin K synthesis by suppressing gut ora; also, cephalosporins with the NMTT side chain [cefamandole, cefoperazone, cefotetan] have been associated with an increased incidence of hypoprothrombinemia; patients who are critically ill, malnourished, or have liver function impairment may be at the highest risk of bleeding) With physiology/laboratory test values Alanine aminotransferase (ALT [SGPT]), serum, or Alkaline phosphatase, serum, or Aspartate aminotransferase (AST [SGOT]), serum, or Lactate dehydrogenase (LDH), serum (values may be increased) Bilirubin, serum, or Blood urea nitrogen (BUN) or

SIDE/ADVERSE EFFECTS
The following side/adverse effects have been selected on the basis of their potential clinical signicance (possible signs and, for humans, symptoms in parentheses where appropriate)not necessarily inclusive:

THOSE INDICATING NEED FOR MEDICAL ATTENTION

Incidence unknown All species Hypersensitivity reactions (acute anaphylaxis or angioedema, allergic agranulocytosis{R-31}, fever{R-31}, serum sickness, urticaria{R2} ) Dogs Anemia; thrombocytopenia{R-11} Note: Anemia and thrombocytopenia have been seen in dogs given ceftiofur at high doses (three to ve times the labeled dose) or for long periods of time (5 to 6 weeks). These side effects appear to be reversible when treatment is discontinued. Horses Diarrhea{R-11}with ceftiofur

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56 CEPHALOSPORINS VeterinarySystemic

THOSE INDICATING NEED FOR MEDICAL ATTENTION ONLY IF THEY CONTINUE OR ARE BOTHERSOME
All species Anorexia{R-10; 32}; diarrhea and vomiting{R-3}possibly due to local irritation from the oral dosage forms{R-1}; diarrhea caused by altered gut ora{R-2; 10}; local reactions{R-1; 11} (mild to moderate pain, heat, swelling)with parenteral dosage forms, especially cephalothin and cephapirin; phlebitis{R-2}with intravenous administration Note: Diarrhea and vomiting can occur with any dosage but are more common with high doses.{R-33} Administration of the antibiotic with food may decrease the incidence of gastrointestinal effects.{R-33}

FOR ORAL DOSAGE FORMS ONLY

Administration of oral cephalosporins, such as cefadroxil, with food appears to decrease nausea in those animals prone to the side effect{R-33}; however, administration of cexime with food can decrease by one half the bioavailability of the antibiotic{R-77}.

FOR PARENTERAL DOSAGE FORMS ONLY

Many cephalosporins can be reconstituted with 1% lidocaine to decrease injection pain. See the manufacturers package insert{R-80}.

FOR TREATMENT OF ADVERSE EFFECTS

For anaphylaxis Recommended treatment consists of the following: Parenteral epinephrine. Oxygen administration and breathing support. Parenteral uid administration as needed.

HUMAN SIDE/ADVERSE EFFECTS{R-46}

In addition to the above side/adverse effects reported in animals, the following side/adverse effects have been reported in humans, and are included in the human monograph Cephalosporins (Systemic) in USP DI Volume I; these side/adverse effects are intended for information purposes only and may or may not be applicable to the use of cephalosporins in the treatment of animals: Incidence more frequent Gastrointestinal reactions; headache; oral candidiasis; vaginal candidiasis Incidence less frequent or rare Hypoprothrombinemiamore frequent for cefotetan; pseudomembranous colitis Incidence rare Allergic reactions, specically anaphylaxis, erythema multiforme, or Stevens-Johnson syndrome (blistering, peeling, or loosening of skin and mucous membranes, which may involve the eyes or other organ systems); hearing losshas occurred rarely in pediatric patients being treated for meningitis, but more frequently with cefuroxime; hemolytic anemia, immune, drug-induced has occurred with many cephalosporins, but reported more commonly with cefotetan; hypersensitivity reactionshas occurred with many cephalosporins, but reported more commonly with cefazolin; renal dysfunction; serum sicknesslike reactionsmay be more frequent with cefaclor; seizuresespecially with high doses and in patients with renal function impairment; thrombophlebitis

CEFACLOR SUMMARY OF DIFFERENCES

Indications: General considerationsSecond-generation cephalosporin.

ORAL DOSAGE FORMS

Note: Bracketed information in the Dosage Forms section refers to uses that either are not included in U.S. product labeling or are for products not commercially available in the U.S.

CEFACLOR CAPSULES USP

Usual dose: Note: [Dogs]1Although the efcacy and safety of cefaclor in dogs have not been established, an oral dose of 4 to 20 mg per kg of body weight every eight hours has been used in the treatment of susceptible bacterial infections in dogs.{R-2} There is very little canine-specic information about cefaclor; therefore, dose recommendations are based primarily on human pharmacokinetics Strength(s) usually available: U.S.{R-24} Veterinary-labeled product(s): Not commercially available. Human-labeled product(s): 250 mg (Rx) [Ceclor]. 500 mg (Rx) [Ceclor]. Canada{R-36} Veterinary-labeled product(s): Not commercially available. Human-labeled product(s): 250 mg (Rx) [Apo-Cefaclor; Ceclor]. 500 mg (Rx) [Apo-Cefaclor; Ceclor]. Packaging and storage: Store below 40 C (104 F), preferably between 15 and 30 C (59 and 86 F), unless otherwise specied by manufacturer. Store in a tight container. USP requirements: Preserve in tight containers. Contain the equivalent of the labeled amount of anhydrous cefaclor, within )10% to All rights reserved

OVERDOSE
For information in cases of overdose or unintentional ingestion, contact the American Society for the Prevention of Cruelty to Animals (ASPCA) National Animal Poison Control Center (888-426-4435 or 900-443-0000; a fee may be required for consultation) and/or the drug manufacturer.

VETERINARY DOSING INFORMATION

Except for specic veterinary labeled medications, most doses listed have been derived from phamacokinetic data, rather than from clinical studies.{R-74} 2003 Thomson MICROMEDEX

CEPHALOSPORINS VeterinarySystemic 57 +20%. Meet the requirements for Identication, Dissolution (80% in 30 minutes in water in Apparatus 2 at 50 rpm), Uniformity of dosage units, and Water (not more than 8.0%).{R-14} Drug interactions and/or related problems: Concurrent administration of probenecid may prolong the serum half-life of cefadroxil.{R-3}

ORAL DOSAGE FORMS CEFACLOR FOR ORAL SUSPENSION USP

Usual dose: See Cefaclor Capsules USP. Strength(s) usually available: When reconstituted according to manufacturers instructions U.S.:{R-24} Veterinary-labeled product(s) Not commercially available. Human-labeled product(s) 25 mg per mL (Rx) [Ceclor; GENERIC]. 37.4 mg per mL (Rx) [Ceclor; GENERIC]. 50 mg per mL (Rx) [Ceclor; GENERIC]. 75 mg per mL (Rx) [Ceclor; GENERIC]. Canada:{R-36} Veterinary-labeled product(s) Not commercially available. Human-labeled product(s) 25 mg per mL (Rx) [Apo-Cefaclor; Ceclor]. 50 mg per mL (Rx) [Apo-Cefaclor; Ceclor]. 75 mg per mL (Rx) [Apo-Cefaclor; Ceclor]. Packaging and storage: Prior to reconstitution, store below 40 C (104 F), preferably between 15 and 30 C (59 and 86 F), unless otherwise specied by manufacturer. Store in a tight container. Stability: After reconstitution, suspensions retain their potency for 14 days if refrigerated. Auxiliary labeling: Refrigerate. Shake well. USP requirements: Preserve in tight containers. A dry mixture of Cefaclor and one or more suitable buffers, colors, diluents, and avors. Contains the equivalent of the labeled amount of anhydrous cefaclor, within 10% to +20%. Meets the requirements for Identication, Uniformity of dosage units (solid packaged in single-unit containers), Deliverable volume (solid packaged in multiple-unit containers), pH (2.55.0, in the suspension constituted as directed in the labeling), and Water (not more than 2.0%).{R-14}
1

CEFADROXIL FOR ORAL SUSPENSION USP

Usual dose: Skin and soft tissue infections Cats: Oral, 22 mg per kg of body weight every twenty-four hours{R-37; 38}. Dogs: Oral, 22 mg per kg of body weight every twelve hours{R-37; 38}. Urinary tract infectionsDogs: Oral, 22 mg per kg of body weight every twelve hours{R-37; 38}. Strength(s) usually available: When reconstituted according to manufacturers instructions U.S.: Veterinary-labeled product(s) 50 mg per mL (Rx) [Cefa-Drops]. Canada: Veterinary-labeled product(s) 50 mg per mL (Rx) [Cefa-Drops]. Packaging and storage: Store below 40 C (104 F), preferably between 15 and 30 C (59 and 86 F), unless otherwise specied by manufacturer. Store in a tight container. Stability: When reconstituted according to manufacturers directions and refrigerated, suspensions retain their potency for 14 days.{R-37} USP requirements: Preserve in tight containers. A dry mixture of Cefadroxil and one or more suitable buffers, colors, diluents, and avors. Contains the equivalent of the labeled amount of anhydrous cefadroxil, within 10% to +20%. Meets the requirements for Identication, Uniformity of dosage units (solid packaged in single-unit containers), Deliverable volume (solid packaged in multiple-unit containers), pH (4.56.0, in the suspension constituted as directed in the labeling), and Water (not more than 2.0%).{R-14}

CEFADROXIL TABLETS USP

Usual dose: See Cefadroxil for Oral Suspension USP. Strength(s) usually available: U.S. Veterinary-labeled product(s): 50 mg (Rx) [Cefa-Tabs]. 100 mg (Rx) [Cefa-Tabs]. 200 mg (Rx) [Cefa-Tabs]. 1 gram (Rx) [Cefa-Tabs]. Canada Veterinary-labeled product(s): 50 mg (Rx) [Cefa-Tabs]. 100 mg (Rx) [Cefa-Tabs]. 200 mg (Rx) [Cefa-Tabs]. Packaging and storage: Store below 40 C (104 F), preferably between 15 and 30 C (59 and 86 F), unless otherwise specied by manufacturer. Store in a tight container. All rights reserved

Not included in Canadian product labeling or product not commercially available in Canada.

CEFADROXIL SUMMARY OF DIFFERENCES

Indications: General considerationsFirst-generation cephalosporin. Indicated for treatment of susceptible genitourinary tract infections in dogs and skin and soft tissue infections in cats and dogs. 2003 Thomson MICROMEDEX

58 CEPHALOSPORINS VeterinarySystemic in a diluent containing one or more suitable tonicity-adjusting agents. It meets the requirements for Labeling under Injections. The label states that it is to be thawed just prior to use, describes conditions for proper storage of the resultant solution, and directs that the solution is not to be refrozen. Contains the labeled amount, within 10% to +15%. Meets the requirements for Identication, Bacterial endotoxins, Sterility, pH (4.57.0), and Particulate matter.{R-14}

USP requirements: Preserve in tight containers. The Tablets prepared using the hemihydrate form of Cefadroxil are so labeled. Contain the labeled amount of anhydrous cefadroxil, within 10% to +20%. Meet the requirements for Identication, Dissolution (75% in 30 minutes in water in Apparatus 2 at 50 rpm), Uniformity of dosage units, and Water (not more than 8.0%).{R-14}

CEFAZOLIN SUMMARY OF DIFFERENCES

Indications: General considerationsFirst-generation cephalosporin.

CEFAZOLIN FOR INJECTION USP

Usual dose: [Perioperative infections (prophylaxis)]1Dogs: Intravenous, 22 mg (base) per kg of body weight every two hours, or 8 mg (base) per kg of body weight every hour, starting at the beginning of surgery and continuing until the end of surgery{R-82}. Note: The above dose is based on pharmacokinetic studies, including studies performed during surgical procedures. Also for [dogs]1, based on pharmacokinetics studies, an intramuscular or intravenous dose of 20 to 35 mg (base) per kg of body weight every four to eight hours has been used for the treatment of susceptible bacterial infections{R-2; 38; 86}.

PARENTERAL DOSAGE FORMS

Note: Bracketed information in the Dosage Forms section refers to uses that either are not included in U.S. product labeling or are for products not commercially available in the U.S. The dosing and strengths of the dosage forms available are expressed in terms of cefazolin base (not the sodium salt).

CEFAZOLIN INJECTION USP

Usual dose: Although Cefazolin Injection USP is the same antimicrobial as Cefazolin For Injection USP, it is only available frozen in premixed dilute concentrations, making it less practical for veterinary use. For dosing information, see Cefazolin For Injection USP. Strength(s) usually available: U.S. Veterinary-labeled product(s): Not commercially available. Human-labeled product(s): 500 mg (base) in 50 mL (Rx) [Ancef]. 1 gram (base) in 50 mL (Rx) [Ancef]. Canada Not commercially available. Packaging and storage: Store at 10 C (14 F) or below, unless otherwise specied by the manufacturer. Preparation of dosage form: Cefazolin sodium injection should be thawed at room temperature, and all ice crystals should have melted, before administration. Thawing should not be forced by immersion in water baths or by microwave irradiation. Stability: See manufacturers product labeling for stability information. Incompatibilities: The admixture of cefazolin sodium injection with other medications is not recommended. The admixture of beta-lactam antibacterials (penicillins and cephalosporins) and aminoglycosides may result in substantial mutual inactivation; they should not be mixed in the same intravenous bag or bottle. USP requirements: Preserve in Containers for Injections. Maintain in the frozen state. A sterile solution of Cefazolin and Sodium Bicarbonate 2003 Thomson MICROMEDEX

Size(s) usually available: U.S.{R-39} Veterinary-labeled product(s): Not commercially available. Human-labeled product(s): 500 mg (base) (Rx) [Ancef; Kefzol; GENERIC]. 1 gram (base) (Rx) [Ancef; Kefzol; GENERIC]. 5 grams (base) (Rx) [Ancef]. 10 grams (base) (Rx) [Ancef; Kefzol; GENERIC]. Canada{R-40} Veterinary-labeled product(s): Not commercially available. Human-labeled product(s): 50 mg (base) (Rx) [Kefzol]. 500 mg (base) (Rx) [Ancef; Kefzol; GENERIC]. 1 gram (base) (Rx) [Ancef; Kefzol; GENERIC]. 10 grams (base) (Rx) [Ancef; Kefzol; GENERIC]. Packaging and storage: Prior to reconstitution, store below 40 C (104 F), preferably between 15 and 30 C (59 and 86 F), unless otherwise specied by manufacturer. Preparation of dosage form: To prepare the 100 mg of cefazolin (base) per mL dilution commonly used in veterinary practice for intramuscular or intravenous administration, 9.6 mL of sterile water for injection should be added to each 1-gram vial{R-39; 95}. See manufacturers package insert for other preparation instructions. Stability: See manufacturers product labeling for stability information. Incompatibilities: The admixture of beta-lactam antibacterials (penicillins and cephalosporins) and aminoglycosides may result in substantial mutual inactivation; they should not be mixed in the same intravenous bag or bottle. USP requirements: Preserve in containers for Sterile Solids. Contains an amount of Cefazolin Sodium equivalent to the labeled amount of All rights reserved

CEPHALOSPORINS VeterinarySystemic 59 cefazolin, within 10% to +15%. Meets the requirements for Constituted solution, Identication, Specic rotation (10 to 24), Bacterial endotoxins, Sterility, pH (4.06.0, in a solution containing 100 mg of cefazolin per mL), Uniformity of dosage units, Water (not more than 6.0%), and Particulate matter, and for Labeling under Injections {R-14}.
1

Not included in Canadian product labeling or product not commercially available in Canada.

therein is in the trihydrate form. Contains the labeled amount of anhydrous cexime, within 10% to +20%, per mL when constituted as directed in the labeling. Meets the requirements for Identication, Uniformity of dosage units (solid packaged in single-unit containers), Deliverable volume (solid packaged in multiple-unit containers), pH (2.54.5, in the suspension constituted as directed in the labeling), and Water (not more than 2.0%).{R-14}

CEFIXIME TABLETS USP

Usual dose: See Cexime for Oral Suspension USP.

CEFIXIME SUMMARY OF DIFFERENCES

Indications: General considerationsThird-generation cephalosporin. Veterinary Dosing Information: Administration with food decreases the bioavailability by one half. Strength(s) usually available: U.S. Veterinary-labeled product(s): Not commercially available. Human-labeled product(s): 200 mg (Rx) [Suprax]. 400 mg (Rx) [Suprax]. Canada Veterinary-labeled product(s): Not commercially available. Human-labeled product(s): 200 mg (Rx) [Suprax]. 400 mg (Rx) [Suprax]. Packaging and storage: Store below 40 C (104 F), preferably between 15 and 30 C (59 and 86 F), unless otherwise specied by manufacturer. USP requirements: Preserve in tight containers. Label Tablets to indicate that the cexime contained therein is in the trihydrate form. Contain the labeled amount of anhydrous cexime, within 10%. Meet the requirements for Identication, Dissolution (75% in 45 minutes in 0.05 M potassium phosphate buffer [pH 7.2] in Apparatus 1 at 100 rpm), Uniformity of dosage units, and Water (not more than 10.0%).{R-14}
1

ORAL DOSAGE FORMS

Note: Bracketed information in the Dosage Forms section refers to uses that either are not included in U.S. product labeling or are for products not commercially available in the U.S.

CEFIXIME FOR ORAL SUSPENSION USP

Usual dose: Note: [Dogs]1Although the efcacy and safety of cexime have not been established, an oral dose of 5 mg per kg of body weight every twelve to twenty-four hours has been used in the treatment of cystitis in dogs, based on pharmacokinetic data.{R-77} There are also some pharmacokinetic data to suggest that the same dose, administered for two to four weeks, is likely to be effective for treatment of bone, skin, and soft tissue infections in dogs{R-77}. Strength(s) usually available: When reconstituted according to manufacturers directions U.S. Veterinary-labeled product(s): Not commercially available. Human-labeled product(s): 20 mg per mL (Rx) [Suprax]. Canada Veterinary-labeled product(s): Not commercially available. Human-labeled product(s): 20 mg per mL (Rx) [Suprax]. Packaging and storage: Prior to reconstitution, store below 40 C (104 F), preferably between 15 and 30 C (59 and 86 F), unless otherwise specied by manufacturer. Stability: After reconstitution, suspension retains its potency for 14 days at room temperature or if refrigerated. Auxiliary labeling: Shake well. USP requirements: Preserve in tight containers. A dry mixture of Cexime and one or more suitable diluents, avors, preservatives, and suspending agents. Label it to indicate that the cexime contained 2003 Thomson MICROMEDEX

Not included in Canadian product labeling or product not commercially available in Canada.

CEFOTAXIME SUMMARY OF DIFFERENCES

Indications: General considerationsThird-generation cephalosporin. Pharmacology/pharmacokinetics: BiotransformationSignicant metabolism occurs with the major pathway yielding a desacetyl derivative. Desacetylcefotaxime is less active against staphylococci but acts synergistically with the parent compound against sensitive gram-negative bacteria.{R-1} DistributionIn people, when administered at high doses, cefotaxime enters the cerebrospinal uid in therapeutic concentrations when meninges are inamed.{R-1} Medical considerations/contraindications: Severe hepatic dysfunction can inhibit metabolism.{R-2}

PARENTERAL DOSAGE FORMS

Note: Bracketed information in the Dosage Forms section refers to uses that either are not included in U.S. product labeling or are for products not commercially available in the U.S. All rights reserved

60 CEPHALOSPORINS VeterinarySystemic The dosing and strengths of the dosage forms available are expressed in terms of cefotaxime free acid (not the sodium salt). Human-labeled product(s): 500 mg (free acid) (Rx) [Claforan]. 1 gram (free acid) (Rx) [Claforan]. 2 grams (free acid) (Rx) [Claforan]. 10 grams (free acid) (Rx) [Claforan]. Canada Veterinary-labeled product(s): Not commercially available. Human-labeled product(s): 500 mg (free acid) (Rx) [Claforan]. 1 gram (free acid) (Rx) [Claforan]. 2 grams (free acid) (Rx) [Claforan]. Packaging and storage: Prior to reconstitution, store below 30 C (86 F), preferably between 15 and 30 C (59 and 86 F), unless otherwise specied by manufacturer. Preparation of dosage form: Dilutions should be prepared according to manufacturers instructions. Stability: See manufacturers product labeling for stability information. Strength(s) usually available: U.S.{R-44} Veterinary-labeled product(s): Not commercially available. Human-labeled product(s): 20 mg (free acid) per mL (Rx) [Claforan]. 40 mg (free acid) per mL (Rx) [Claforan]. Canada Not commercially available. Packaging and storage: Store at 20 C (4 F) or below, unless otherwise specied by manufacturer.{R-44} Preparation of dosage form: {R-44} Cefotaxime sodium injection should be thawed at room temperature, and all ice crystals should have melted, before administration. Stability: See manufacturers product labeling for stability information. USP requirements: Preserve in single-dose containers. Maintain in the frozen state. A sterile solution of Cefotaxime Sodium in Water for Injection. Contains one or more suitable buffers. It meets the requirements for Labeling under Injections. The label states that it is to be thawed just prior to use, describes conditions for proper storage of the resultant solution, and directs that the solution is not to be refrozen. Contains an amount of cefotaxime sodium equivalent to the labeled amount of cefotaxime, within 10%. Meets the requirements for Identication, Bacterial endotoxins, Sterility, pH (5.07.5), Particulate matter, and Chromatographic purity.{R-14} Additional information: A solution containing 1 gram of cefotaxime sodium in 14 mL of sterile water for injection is isotonic{R-44}. USP requirements: Preserve in Containers for Sterile Solids. Contains an amount of Cefotaxime Sodium equivalent to the labeled amount of cefotaxime, within 10% to +15%. Meets the requirements for Constituted solution, Identication, Bacterial endotoxins, Sterility, Uniformity of dosage units, Particulate matter, and Chromatographic purity, for pH and Loss on drying under Cefotaxime Sodium, and for Labeling under Injections.{R-14}
1

CEFOTAXIME INJECTION USP

Usual dose: Note: [Cats]1Although the efcacy and safety have not been established, an intramuscular or intravenous dose of 20 to 80 mg (free acid) per kg of body weight every six hours has been used in the treatment of susceptible bacterial infections in cats, based on pharmacokinetic data{R-42}. [Dogs]1Although the efcacy and safety have not been established, a subcutaneous dose of 50 mg (free acid) per kg of body weight every twelve hours has been used in the treatment of susceptible bacterial infections in dogs, based on pharmacokinetic data. When administered intramuscularly, the dose should be repeated every eight hours{R-43}. [Foals]1Although the efcacy and safety have not been established, an intravenous dose of 40 mg (free acid) per kg of body weight every six hours has been used in the treatment of neonatal sepsis or susceptible bacterial meningitis in foals{R-62}.

Not included in Canadian product labeling or product not commercially available in Canada.

CEFOTETAN SUMMARY OF DIFFERENCES

Indications: General considerationsSecond-generation cephalosporin.

PARENTERAL DOSAGE FORMS

Note: Bracketed information in the Dosage Forms section refers to uses that either are not included in U.S. product labeling or are for products not commercially available in the U.S. The dosing and strengths of the dosage forms available are expressed in terms of cefotetan base (not the disodium salt).

CEFOTETAN FOR INJECTION USP CEFOTAXIME FOR INJECTION USP

Usual dose: See Cefotaxime Sodium Injection USP. Size(s) usually available: U.S.{R-44} Veterinary-labeled product(s): Not commercially available. 2003 Thomson MICROMEDEX Usual dose: Note: [Dogs]1Although the efcacy and safety have not been established, an intravenous dose of 30 mg (base) per kg of body weight every eight hours or the same dose administered subcutaneously every twelve hours has been used in the treatment of susceptible bacterial infections in dogs, based on pharmacokinetic data{R-80; 84}. All rights reserved

CEPHALOSPORINS VeterinarySystemic 61 Size(s) usually available: U.S. Veterinary-labeled product(s): Not commercially available. Human-labeled product(s): 1 gram (base) (Rx) [Cefotan]. 2 grams (base) (Rx) [Cefotan]. 10 grams (base) (Rx) [Cefotan]. Canada Veterinary-labeled product(s): Not commercially available. Human-labeled product(s): 1 gram (base) (Rx) [Cefotan]. 2 grams (base) (Rx) [Cefotan]. Packaging and storage: Prior to reconstitution, do not store above 22 C (72 F), unless otherwise specied by manufacturer. Protect from light. Preparation of dosage form: Dilutions should be prepared according to manufacturers instructions. Stability: See manufacturers product labeling for stability information. Incompatibilities: The admixture of beta-lactam antibacterials and aminoglycosides may result in substantial mutual inactivation. They should not be mixed in the same intravenous bag or bottle. USP requirements: Preserve in containers for Sterile Solids. Contains an amount of Cefotetan Disodium equivalent to the labeled amount of cefotetan, within 10 to +20%. Meets the requirements for Constituted solution, Bacterial endotoxins, Sterility, and Particulate matter, for Identication, pH, and Water under Cefotetan Disodium, for Uniformity of dosage units, and for Labeling under Injections.{R-14}
1

CEFOXITIN INJECTION USP

Usual dose: Note: [Dogs]1Although the efcacy and safety have not been established, an intravenous dose of 30 mg (base) per kg of body weight every six hours or the same dose administered subcutaneously every eight hours has been used in the treatment of susceptible bacterial infections in dogs, based on pharmacokinetic data{R-38; 84}. [Horses]1Although the efcacy and safety have not been established, an intravenous dose of 20 mg (base) per kg of body weight every four to six hours has been used in the treatment of susceptible bacterial infections in horses, based on pharmacokinetic data{R-29}. Strength(s) usually available:{R-45} U.S. Veterinary-labeled product(s): Not commercially available. Human-labeled product(s): 20 mg (base) per mL (Rx) [Mefoxin]. 40 mg (base) per mL (Rx) [Mefoxin]. Canada Not commercially available. Packaging and storage: {R-45} Store at 20 C (4 F) or below, unless otherwise specied by manufacturer. Preparation of dosage form: See manufacturers product labeling. USP requirements: Preserve in Containers for Injections. Maintain in the frozen state. A sterile solution of Cefoxitin Sodium and one or more suitable buffer substances in Water for Injection. Contains Dextrose or Sodium Chloride as a tonicity-adjusting agent. It meets the requirements for Labeling under Injections. The label states that it is to be thawed just prior to use, describes conditions for proper storage of the resultant solution, and directs that the solution is not to be refrozen. Contains an amount of cefoxitin sodium equivalent to the labeled amount of cefoxitin, within 10% to +20%. Meets the requirements for Identication, Bacterial endotoxins, Sterility, pH (4.58.0), and Particulate matter.{R-14}

Not included in Canadian product labeling or product not commercially available in Canada.

CEFOXITIN SUMMARY OF DIFFERENCES

Indications: General considerationsSecond-generation cephalosporin; good activity against anaerobic organisms, but only active against some Bacteroides fragilis.{R-1} Pharmacology/pharmacokinetics: DistributionIn people, when administered at high doses, cefoxitin enters the cerebrospinal uid in therapeutic concentrations when meninges are inamed.{R-1} Drug interactions and/or related problems: Concurrent administration with probenecid may prolong the serum half-life of cefoxitin.{R-26}

CEFOXITIN FOR INJECTION USP

Usual dose: See Cefoxitin Injection USP. Size(s) usually available: U.S.{R-21} Veterinary-labeled product(s): Not commercially available. Human-labeled product(s): 1 gram (base) (Rx) [Mefoxin]. 2 grams (base) (Rx) [Mefoxin]. 10 grams (base) (Rx) [Mefoxin]. Canada Veterinary-labeled product(s): Not commercially available. Human-labeled product(s): 1 gram (base) (Rx) [Mefoxin; GENERIC]. 2 grams (base) (Rx) [Mefoxin; GENERIC]. 10 grams (base) (Rx) [Mefoxin]. All rights reserved

PARENTERAL DOSAGE FORMS

Note: Bracketed information in the Dosage Forms section refers to uses that either are not included in U.S. product labeling or are for products not commercially available in the U.S. The dosing and strengths of the dosage forms available are expressed in terms of cefoxitin base (not the sodium salt). 2003 Thomson MICROMEDEX

62 CEPHALOSPORINS VeterinarySystemic Packaging and storage: Prior to reconstitution, store below 40 C (104 F), preferably between 15 and 30 C (59 and 86 F), unless otherwise specied by manufacturer. Preparation of dosage form: Dilutions should be prepared according to manufacturers instructions. Stability: See manufacturers product labeling for stability information. USP requirements: Preserve in Containers for Sterile Solids. Contains Cefoxitin Sodium equivalent to the labeled amount of cefoxitin, within 10% to +20%. Meets the requirements for Constituted solution, Bacterial endotoxins, Sterility, and Particulate matter, for Identication tests, pH, and Water under Cefoxitin Sodium, for Uniformity of dosage units, and for Labeling under Injections.{R-14}
1

Strength(s) usually available{R-81; 96; 99}: U.S. Veterinary-labeled product(s): 50 mg per mL (Rx) [Excenel RTU]. Note: Be aware that this product differs from Excenel available in Canada. Canada Veterinary-labeled product(s): 50 mg per mL (Rx) [Excenel RTU]. Withdrawal times{R-81; U.S.
96; 99}

Withdrawal time Species Meat (days) 2 0 Milk (hours) None

Not included in Canadian product labeling or product not commercially available in Canada.

Cattle Pigs

CEFTIOFUR SUMMARY OF DIFFERENCES

Indications: General considerationsNew-generation cephalosporin{R-11}. Indicated in the treatment of susceptible Escherichia coli infections in chicks and turkey poults; metritis and pododermatitis in cattle, respiratory tract infections in cattle, goats, horses, pigs, and sheep, and urinary tract infections in dogs. Pharmacology/pharmacokinetics: BiotransformationBiotransformation to an active antibacterial metabolite, desfuroylceftiofur, occurs.{R-66} Drug interactions and/or related problems: Probenecid has not been shown to alter the excretion of ceftiofur.{R-70} Side/adverse effects: Often-reversible anemia and thrombocytopenia can occur in animals given three to ve times the recommended dose of ceftiofur.{R-66}

Note: At labeled doses, discarding of milk during treatment is not required. Product labeling listing the above withdrawal times states that treatment should not exceed ve days for cattle or three days for pigs for these withdrawal times to apply. This product is not labeled for use in preruminating calves. Trim-out of edible tissue at slaughter may occur within 11 days of injection because of areas of discoloration associated with the injection site{R-81}. Canada
Withdrawal time Species Cattle Pigs Meat (days) 3 2 Milk (hours) None

PARENTERAL DOSAGE FORMS

Note: Bracketed information in the Dosage Forms section refers to uses that either are not included in U.S. product labeling or are for products not commercially available in the U.S. The dosing and strengths of the dosage forms available are expressed in terms of ceftiofur free acid (not the sodium salt).

Note: Product labeling listing the above withdawal times states that it applies to a dose for pigs of 3 mg per kg of body weight every twentyfour hours for three days and a dose for cattle of 1 mg per kg of body weight every twenty-four hours for up to ve days{R-99}. In pigs, trim-out of edible tissue at slaughter may occur within 11 days of intramuscular injection. In cattle, trim-out of edible tissue at slaughter may occur within 11 days of the last subcutaneous injection or within 28 days of the last intramuscular injection into the neck{R-99}. Packaging and storage: Store below 40 C (104 F), preferably between 15 and 30 C (59 and 86 F), unless otherwise specied by manufacturer. Protect from freezing. Auxiliary labeling: {R-35} Shake well before using . {R-81} Keep out of reach of children . USP requirements: Not in USP{R-14}.

CEFTIOFUR HYDROCHLORIDE INJECTION

Usual dose: Metritis1Cattle: Intramuscular or subcutaneous, 2.2 mg per kg of body weight every twenty-four hours for ve days{R-81}. PododermatitisCattle: Intramuscular or subcutaneous, 1.1 to 2.2 mg per kg of body weight every twenty-four hours{R-81}. Respiratory tract infections Cattle: Intramuscular or subcutaneous, 1.1 to 2.2 mg per kg of body weight every twenty-four hours{R-81}. Alternatively, the clinician may choose, based on the severity of disease, pathogen susceptibility, and the clinical response, to administer intramuscularly or subcutaneously, 2.2 mg per kg of body weight every forty-eight hours for two doses{R-81}. Pigs: Intramuscular, 3 to 5 mg per kg of body weight every twentyfour hours for three days{R-81; 96}. 2003 Thomson MICROMEDEX

CEFTIOFUR SODIUM FOR INJECTION

Usual dose: Escherichia coli infections Chicks1, day-old: Subcutaneous, 0.08 to 0.2 mg (free acid) per chick as a single dose{R-11}. All rights reserved

CEPHALOSPORINS VeterinarySystemic 63 Turkey poults, day-old: Subcutaneous, 0.17 to 0.5 mg (free acid) per poult as a single dose{R-11}. PododermatitisCattle: Intramuscular, 1.1 to 2.2 mg (free acid) per kg of body weight every twenty-four hours{R-11}. Respiratory tract infections Cattle: Intramuscular, 1.1 to 2.2 mg (free acid) per kg of body weight every twenty-four hours{R-11}. Goats1: Intramuscular, 1.1 to 2.2 mg (free acid) per kg of body weight every twenty-four hours{R-11}. Horses: Intramuscular, 2.2 to 4.4 mg (free acid) per kg of body weight every twenty-four hours{R-11; 12}. Note: For treatment of susceptible infections in foals, a dose of 2.2 to 6.6 mg (free acid) per kg of body weight every twelve to twentyfour hours has been used, based on pharmacokinetic data{R-48}. Pigs: Intramuscular, 3 to 5 mg (free acid) per kg of body weight every twenty-four hours{R-11}. Sheep: Intramuscular, 1.1 to 2.2 mg (free acid) per kg of body weight every twenty-four hours for three days{R-11; 97}. If a satisfactory response is not seen, the dose may be repeated on the fourth and fth days{R-11; 97}. Urinary tract infectionsDogs: Subcutaneous, 2.2 mg (free acid) per kg of body weight every twenty-four hours{R-11}. Note: Also for dogs, for treatment of [bacterial infections other than urinary tract infections]1 a dose of 2.2 to 4.4 mg (free acid) per kg of body weight every twenty-four hours has been used, based on pharmacokinetic data{R-74; 76}. Strength(s) usually available: When reconstituted according to manufacturers instructions U.S.:{R-11} Veterinary-labeled product(s) 50 mg per mL (Rx) [Naxcel]. Canada:{R-12} Veterinary-labeled product(s) 50 mg per mL (Rx) [Excenel]. Withdrawal times: U.S.{R-11}
Withdrawal time Species Cattle Goats, pigs, sheep Meat (days) 0 0 Milk (hours) None

Product labeling listing the above withdrawal times states that treatment should not exceed ve days for cattle or three days for lambs or pigs for these withdrawal times to apply. Packaging and storage: Store unreconstituted product at controlled room temperature, 20 to 25 C (68 to 77 F){R-11}, unless otherwise specied by manufacturer. Store reconstituted product either in a refrigerator at 2 to 8 C (36 to 46 F) for up to seven days or at controlled room temperature, 20 to 25 C (68 to 77 F), for up to twelve hours{R-11}, unless otherwise specied by manufacturer. Protect from light. Preparation of dosage form: To prepare dilution for intramuscular use, 20 or 80 mL of sterile water for injection should be added to the 1-gram or 4-gram vial, respectively{R-11}. Stability:{R-11} After reconstitution, solutions retain their potency for 7 days when refrigerated at 2 to 8 C (36 to 46 F) or 12 hours at room temperature, 15 to 30 C (59 to 86 F). After reconstitution, solutions may be frozen for up to eight weeks. Frozen ceftiofur sodium may be thawed at room temperature or under warm to hot running water. Solutions should not be refrozen. Variations in color do not affect potency. USP requirements: Not in USP{R-14}.
1

Not included in Canadian product labeling or product not commercially available in Canada.

CEPHALEXIN SUMMARY OF DIFFERENCES

Indications: General considerationsFirst-generation cephalosporin.

ORAL DOSAGE FORMS

Note: Bracketed information in the Dosage Forms section refers to uses that either are not included in U.S. product labeling or are for products not commercially available in the U.S.

Note: At labeled doses, discarding of milk during treatment is not required.{R-68} Product labeling listing the above withdrawal times states that treatment should not exceed ve days for cattle, goats, or sheep; or three days for pigs, for these withdrawal times to apply. Canada{R-12}
Withdrawal time Species Cattle Pigs, sheep Meat (days) 0 1 Milk (hours) None

CEPHALEXIN CAPSULES USP

Usual dose: Note: [Birds]1Although the efcacy and safety have not been established, an oral dose of 35 to 50 mg per kg of body weight every two to six hours has been used in the treatment of susceptible bacterial infections in birds, based on pharmacokinetic studies{R-34}. In general, larger birds maintain measurable serum concentrations of cephalexin longer than do smaller birds; adequate concentrations may be achieved in larger birds with a six-hour dosing interval{R-34}. [Dogs]1Although the efcacy and safety have not been established, an oral dose of 10 to 30 mg per kg of body weight every six to twelve hours has been used in the treatment of susceptible bacterial infections in dogs, based on pharmacokinetic data{R-49; 50}. All rights reserved

Note: At labeled doses, discarding of milk during treatment is not required. 2003 Thomson MICROMEDEX

64 CEPHALOSPORINS VeterinarySystemic For pyoderma in dogs, a dose of 25 mg per kg of body weight every twelve hours for three weeks has been used, based on clinical efcacy studies{R-32}. Recurrent pyodermas may require at least ve weeks of therapy and deep pyodermas, nine weeks{R-32}. Strength(s) usually available: U.S.{R-23} Veterinary-labeled product(s): Not commercially available. Human-labeled product(s): 250 mg (Rx) [Keex; GENERIC]. 500 mg (Rx) [Keex; GENERIC]. Canada Veterinary-labeled product(s): Not commercially available. Human-labeled product(s): 250 mg (Rx) [Novo-Lexin]. 500 mg (Rx) [Novo-Lexin]. Packaging and storage: Store below 40 C (104 F), preferably between 15 and 30 C (59 and 86 F), unless otherwise specied by manufacturer. Store in a tight container. USP requirements: Preserve in tight containers. Contain the equivalent of the labeled amount of anhydrous cephalexin, within 10% to +20%. Meet the requirements for Identication, Dissolution (80% in 30 minutes in water in Apparatus 1 at 100 rpm), Uniformity of dosage units, and Water (not more than 10.0%).{R-14} USP requirements: Preserve in tight containers. A dry mixture of Cephalexin and one or more suitable buffers, colors, diluents, and avors. Contains the equivalent of the labeled amount of anhydrous cephalexin per mL when constituted as directed in the labeling, within 10% to +20%. Meets the requirements for Identication, Uniformity of dosage units (solid packaged in single-unit containers), Deliverable volume (solid packaged in multiple-unit containers), pH (3.06.0, in the suspension constituted as directed in the labeling), and Water (not more than 2.0%).{R-14}

CEPHALEXIN TABLETS USP

Usual dose: See Cephalexin Capsules USP. Strength(s) usually available: U.S. Veterinary-labeled product(s): Not commercially available. Human-labeled product(s): 250 mg (Rx) [GENERIC]. 500 mg (Rx) [GENERIC]. Canada Veterinary-labeled product(s): Not commercially available. Human-labeled product(s): 250 mg (Rx) [Apo-Cephalex; Keex; Novo-Lexin; Nu-Cephalex; PMSCephalexin]. 500 mg (Rx) [Apo-Cephalex; Keex; Novo-Lexin; Nu-Cephalex; PMSCephalexin]. Packaging and storage: Store below 40 C (104 F), preferably between 15 and 30 C (59 and 86 F), unless otherwise specied by manufacturer. Store in a tight container. USP requirements: Preserve in tight containers. They are prepared from Cephalexin or Cephalexin Hydrochloride. The label states whether the Tablets contain Cephalexin or Cephalexin Hydrochloride. Contain the equivalent of the labeled amount of anhydrous cephalexin, within 10% to +20%. Meet the requirements for Identication, Dissolution (80% in 30 minutes in water in Apparatus 1 [use 40-mesh cloth] at 100 rpm for cephalexin and 75% in 45 minutes in water in Apparatus 1 [use 10-mesh cloth] at 150 rpm for cephalexin hydrochloride), Uniformity of dosage units, and Water (not more than 9.0% where Tablets contain cephalexin; not more than 8.0% where Tablets contain cephalexin hydrochloride).{R-14}

CEPHALEXIN FOR ORAL SUSPENSION USP

Usual dose: See Cephalexin Capsules USP. Strength(s) usually available: When reconstituted according to manufacturers instructions U.S.:{R-23} Veterinary-labeled product(s) Not commercially available. Human-labeled product(s) 25 mg per mL (Rx) [Keex; GENERIC]. 50 mg per mL (Rx) [Keex; GENERIC]. Canada: Veterinary-labeled product(s) Not commercially available. Human-labeled product(s) 25 mg per mL (Rx) [Keex; Novo-Lexin; PMS-Cephalexin]. 50 mg per mL (Rx) [Keex; Novo-Lexin; PMS-Cephalexin]. Packaging and storage: Prior to reconstitution, store below 40 C (104 F), preferably between 15 and 30 C (59 and 86 F), unless otherwise specied by manufacturer. Store in a tight container. Stability: {R-23} After reconstitution, suspensions retain their potency for 14 days if refrigerated. Auxiliary labeling: Refrigerate. Shake well. 2003 Thomson MICROMEDEX

CEPHALEXIN HYDROCHLORIDE TABLETS USP

Usual dose: See Cephalexin Capsules USP. Strength(s) usually available: U.S.{R-51} Veterinary-labeled product(s): Not commercially available. Human-labeled product(s): 500 mg (Rx) [Keftab]. Canada Not commercially available. Packaging and storage: Store between 15 and 30 C (59 and 86 F), unless otherwise specied by manufacturer. Store in a tight container. All rights reserved

CEPHALOSPORINS VeterinarySystemic 65 USP requirements: Preserve in tight containers. They are prepared from Cephalexin or Cephalexin Hydrochloride. The label states whether the Tablets contain Cephalexin or Cephalexin Hydrochloride. Contain the equivalent of the labeled amount of anhydrous cephalexin, within 10% to +20%. Meet the requirements for Identication, Dissolution (80% in 30 minutes in water in Apparatus 1 [use 40-mesh cloth] at 100 rpm for cephalexin and 75% in 45 minutes in water in Apparatus 1 [use 10-mesh cloth] at 150 rpm for cephalexin hydrochloride), Uniformity of dosage units, and Water (not more than 9.0% where Tablets contain cephalexin; not more than 8.0% where Tablets contain cephalexin hydrochloride).{R-14}
1

Human-labeled product(s): Not commercially available. Canada{R-54} Veterinary-labeled product(s): Not commercially available. Human-labeled product(s): 1 gram (base) (Rx) [Ceporacin; Kein]. Packaging and storage: Prior to reconstitution, store below 40 C (104 F), preferably between 15 and 30 C (59 and 86 F), unless otherwise specied by manufacturer. Preparation of dosage form: {R-22; 53} Dilutions should be prepared according to manufacturers instructions. Stability:{R-22} After reconstitution, solutions retain their potency for 96 hours if refrigerated. Solutions for intramuscular use retain their potency for 12 hours at room temperature. A precipitate may form in the solution. Upon being warmed to room temperature and shaken, the precipitate will dissolve. Concentrated solutions will darken in color, especially at room temperature. However, slight discoloration does not affect potency. If frozen immediately after reconstitution with sterile water for injection, 5% dextrose injection, or 0.9% sodium chloride injection, solutions retain their potency in the original container up to 12 weeks at 20 C (4 F). Once thawed, solutions should not be refrozen. Incompatibilities: The admixture of other medications with cephalothin sodium injection is not recommended. The admixture of beta-lactam antibiotics (penicillins and cephalosporins) and aminoglycosides may result in substantial mutual inactivation; they should not be mixed in the same intravenous bag or bottle. USP requirements: Preserve in Containers for Sterile Solids. Contains an amount of Cephalothin Sodium equivalent to the labeled amount of cephalothin, within 10% to +15%. May contain Sodium Bicarbonate. Meets the requirements for Constituted solution, Specic rotation (+124 to +134, calculated on the dried and sodium bicarbonate-free basis), Content of sodium bicarbonate (if present), Bacterial endotoxins, Sterility, pH (6.08.5, in the solution constituted as directed in the labeling), Uniformity of dosage units, and Particulate matter, for Identication test A and Loss on drying under Cephalothin Sodium, and for Labeling under Injections.{R-14}
1

Not included in Canadian product labeling or product not commercially available in Canada.

CEPHALOTHIN SUMMARY OF DIFFERENCES

Indications: General considerationsFirst-generation cephalosporin. Drug interactions and/or related problems: Concurrent administration with probenecid may prolong the serum half-life of cephalothin.{R-30} Medical considerations/contraindications: Severe hepatic dysfunction may inhibit metabolism.{R-2} Side/adverse effects: Local irritation may occur.{R-1}

PARENTERAL DOSAGE FORMS

Note: Bracketed information in the Dosage Forms section refers to uses that either are not included in U.S. product labeling or are for products not commercially available in the U.S. The dosing and strengths of the dosage forms available are expressed in terms of cephalothin base (not the sodium salt).

CEPHALOTHIN FOR INJECTION USP

Usual dose: Note: [Birds]1Although the efcacy and safety have not been established, an intramuscular dose of 100 mg (base) per kg of body weight every two to six hours has been used in the treatment of susceptible bacterial infections in birds, based on pharmacokinetic studies{R-34}. In general, larger birds maintain measurable serum concentrations of cephalothin longer than do smaller birds; adequate concentrations may be achieved in larger birds with a six-hour dosing interval{R-34}. [Dogs]1Although the efcacy and safety have not been established, an intramuscular or intravenous dose of 10 to 30 mg (base) per kg of body weight every four to eight hours has been used in the treatment of susceptible bacterial infections in dogs, based on pharmacokinetic data{R-38}. [Horses]1Although the efcacy and safety have not been established, an intramuscular or intravenous dose of 10 to 25 mg (base) per kg of body weight every four hours has been used in the treatment of susceptible bacterial infections in horses, based on pharmacokinetic data{R-9; 19}. Size(s) usually available: U.S.{R-22; 53} Veterinary-labeled product(s): Not commercially available. 2003 Thomson MICROMEDEX

Not included in Canadian product labeling or product not commercially available in Canada.

CEPHAPIRIN SUMMARY OF DIFFERENCES

Indications: General considerationsFirst-generation cephalosporin. Pharmacology/pharmacokinetics: Human biotransformationHepatic metabolism to the desacetyl form occurs.{R-2} Drug interactions and/or related problems: Concurrent administration with probenicid may prolong the serum half-life of cephapirin.{R-30} All rights reserved

66 CEPHALOSPORINS VeterinarySystemic Medical considerations/contraindications: In people, severe hepatic dysfunction can inhibit metabolism.{R-2} Side/adverse effects: Local reactions may occur.{R-1}
1

Sodium, and for Uniformity of dosage units and Labeling under Injections.{R-14} Not included in Canadian product labeling or product not commercially available in Canada.

PARENTERAL DOSAGE FORMS

Note: Bracketed information in the Dosage Forms section refers to uses that either are not included in U.S. product labeling or are for products not commercially available in the U.S. The dosing and strengths of the dosage forms available are expressed in terms of cephapirin base (not the sodium salt).

CEPHRADINE SUMMARY OF DIFFERENCES

Indications: General considerationsFirst-generation cephalosporin.

ORAL DOSAGE FORMS CEPHAPIRIN FOR INJECTION USP

Usual dose: Note: [Dogs]1Although the efcacy and safety have not been established, an intramuscular or intravenous dose of 10 to 30 mg (base) per kg of body weight every four to eight hours has been used in the treatment of susceptible bacterial infections in dogs, based on pharmacokinetic data{R-2; 38; 86}. [Horses]1Although the efcacy and safety have not been established, an intramuscular or intravenous dose of 20 to 30 mg per kg of body weight every four to eight hours has been used in the treatment of susceptible bacterial infections in horses, based on pharmacokinetic data{R-18; 29; 35; 86}. Size(s) usually available: U.S.{R-55} Veterinary-labeled product(s): Not commercially available. Human-labeled product(s): 500 mg (base) (Rx) [Cefadyl]. 1 gram (base) (Rx) [Cefadyl]. 2 grams (base) (Rx) [Cefadyl]. 4 grams (base) (Rx) [Cefadyl]. 20 grams (base) (Rx) [Cefadyl]. Canada Not commercially available. Packaging and storage: Prior to reconstitution, store below 40 C (104 F), preferably between 15 and 30 C (59 and 86 F), unless otherwise specied by manufacturer. Preparation of dosage form: Dilutions should be prepared according to manufacturers instructions. Stability: See manufacturers product labeling for stability information. Incompatibilities: The admixture of beta-lactam antibiotics (penicillins and cephalosporins) and aminoglycosides may result in substantial mutual inactivation; they should not be mixed in the same intravenous bag or bottle. USP requirements: Preserve in Containers for Sterile Solids. Contains an amount of Cephapirin Sodium equivalent to the labeled amount of cephapirin, within 10% to +15%. Meets the requirements for Constituted solution, Bacterial endotoxins, Sterility, and Particulate matter, for Identication, Crystallinity, pH, and Water under Cephapirin 2003 Thomson MICROMEDEX Note: Bracketed information in the Dosage Forms section refers to uses that either are not included in U.S. product labeling or are for products not commercially available in the U.S.

CEPHRADINE CAPSULES USP

Usual dose: Note: [Dogs]1Although the efcacy and safety have not been established, an oral dose of 10 to 25 mg per kg of body weight every six to twelve hours has been used in the treatment of susceptible bacterial infections in dogs, based on pharmacokinetic data{R-2; 38}. [Foals]1Although the efcacy and safety have not been established, an oral dose of 25 mg per kg of body weight every six to eight hours has been used in the treatment of susceptible bacterial infections in foals, based on pharmacokinetic data{R-85}. Strength(s) usually available: U.S. Veterinary-labeled product(s): Not commercially available. Human-labeled product(s): 250 mg (Rx) [Velosef; GENERIC]. 500 mg (Rx) [Velosef; GENERIC]. Canada Not commercially available. Packaging and storage: Store below 30 C (86 F), preferably between 15 and 30 C (59 and 86 F), unless otherwise specied by manufacturer. Store in a tight container. USP requirements: Preserve in tight containers. The quantity of cephradine stated in the labeling is in terms of anhydrous cephradine. Contain the labeled amount of cephradine, within 10% to +20%, calculated as the sum of cephradine and cephalexin. Meet the requirements for Identication, Dissolution (75% in 45 minutes in 0.12 N hydrochloric acid in Apparatus 1 at 100 rpm), Uniformity of dosage units, and Loss on drying (not more than 7.0%).{R-14}

CEPHRADINE FOR ORAL SUSPENSION USP

Usual dose: See Cephradine Capsules USP. Strength(s) usually available: When reconstituted according to manufacturers instructions U.S.: Veterinary-labeled product(s) Not commercially available. All rights reserved

CEPHALOSPORINS VeterinarySystemic 67 Human-labeled product(s) 25 mg per mL (Rx) [Velosef; 50 mg per mL (Rx) [Velosef; Canada: Not commercially available. USP requirements: Preserve in tight containers. A dry mixture of Cephradine and one or more suitable buffers, colors, diluents, and avors. Contains the labeled amount of cephradine, within 10% to +25%, calculated as the sum of cephradine and cephalexin. Meets the requirements for Identication, Uniformity of dosage units (solid packaged in single-unit containers), Deliverable volume (solid packaged in multiple-unit containers), pH (3.56.0, in the suspension constituted as directed in the labeling), and Water (not more than 1.5%).{R-14}

GENERIC]. GENERIC].

Packaging and storage: Prior to reconstitution, store below 40 C (104 F), preferably between 15 and 30 C (59 and 86 F), unless otherwise specied by manufacturer. Store in a tight container. Stability: After reconstitution, suspensions retain their potency for 7 days at room temperature or for 14 days if refrigerated. Auxiliary labeling: Refrigerate. Shake well.

Not included in Canadian product labeling or product not commercially available in Canada.

Developed: 08/02/95 Interim revision: 07/08/98; 11/5/99; 09/30/02; 04/04/03

Table 1. Pharmacology/Pharmacokinetics*.
Protein binding (%) Half-life of elimination (hr) VolD Steady state (L/kg) Clearance (mL/min/kg) Route; Dose (mg/kg) Tmax (min) Cmax (mcg/mL) Bioavailability (%)

Drug First-Generation Cefadroxil Cats {R-3} Dogs {R-3} Horses Adult{R-78} Foal{R-56} Cefazolin Dogs{R-5} Horses{R-57} Pigs{R-5} Cephalexin Birds{R-34} Cats{R-50}
{R-49}

Low (20) Low (20) 0.8 1.4 0.81.2 0.60.8 0.27 0.46 7

Oral; 22 Oral; 22 IV; 25 Oral; 100 IV; 15 IV; 11 IV; 15 Oral; 2550 Oral; 15 Oral; 25 SQ; 20 IM; 20 1.3 Oral; 1015 SQ; 10 IM; 10 IV; 15 IM; 100 IV; 15 IV; 11 IM; 11

60120 60120

17.4 18.6

90

23.4

37100

Low (8)

0.19

5.51

3060 120 60120 66 42 108 72 54

20 1129 15 54 61.8 18.6 24.9 31.9

Dogs{R-2;

49}

Pigs{R-5} Cephalothin Birds{R-34} Dogs{R-5} Horses{R-19} Cephapirin Calves{R-58} (316 wks) Cows{R-25} Dogs{R-2} Foals{R-59} (46 days) Horses{R-18} Cephradine Dogs{R-2} Foals{R-85} Second-Generation Cefaclor Dogs{R-5}

30

18

Low (18)

0.7 0.25

0.15

13.6

47

11.3

65

IM; 10 IM; 10 0.4 IM; 20 0.9 0.17 10 IV; 20 IM; 20

20 10 10

6.3 13.3 21.2

25

14.8

95

1.4 1.6

0.4

6.7

IV; 25 Oral; 25

90

13.2

IV; 3.75

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68 CEPHALOSPORINS VeterinarySystemic

Table 1 (Contd.)
Protein Binding (%) Half-life of Elimination (hr) VolD Steady state (L/kg) Clearance (mL/min/kg) Route; Dose (mg/kg) Tmax (min) Cmax (mcg/mL) Bioavailability (%)

Drug Cefotetan Dogs{R-84} Cefoxitin Calves{R-26} Dogs Horses{R-29} Third-Generation Cexime Calves{R-78} Dogs{R-77; 8789} Cefotaxime Cats{R-42}
{2; 84)

1.1

IV; 30 SC; 30 0.32 4.9 IV; 20 IM; 20 IV; 20 IM; 20

30-60

84

Moderate (4255)

1.1 0.7; 1.3 0.8

74

0.12

4.32

77

High (90) High (8292)

3.54 7 to 8

0.34 0.22

Oral; 5 Oral; 5 Oral; 5 (6 days) 2.8 IV; 10 IM; 10 IM; 50 SQ; 50 IV; 50 IM; 50 SQ; 50 IV IV

240 360 144

3.4 2 4.8

Fed; 2028 55

0.18

42 2436 3660 30 48

36 47 30 47 30

9398 86.5 100 85 100

Dogs{R-2;

43}

0.8

0.4

10.5

Goats Sheep{R-20;

{R-15} 60}

0.4 0.304

0.78

2.9

New Generation Ceftiour Calves{R-61} Cows Cows, lactating Dogs{R-72}

{R-70}

7.1 3.6 5 to 7

0.2 0.39

0.5 1.27

Foals{R-48} Horses{R-93} Pigs{R-75} Sheep{R-97}

35{R-75} 12-13 5-6

IM; 2.2 IM; 4.4 IV; 2 IV; 2 IM; 2 SQ; 0.22 SQ; 2.2 SQ; 4.4 IM; 2.2 IM; 2.2 IM; 3 IV; 1.12.2 IM; 1.12.2

120 120

8.8 17.3

60 45 60 90 45 60 35 30

4.6 1.7 8.9 26.7 3.6 4.4 19.2 4.16.2

100

* Abbrevations: IM = Intramuscular, IV = Intravenous, SQ = Subcutaneous, VolD = Volume of distribution, Tmax = Time to peak concentration, Cmax = Peak serum concentration. Assays for serum concentrations of ceftiofur listed include ceftiofur and its active desfuroylceftiofur metabolite.

REFERENCES
1. Caprile KA. The cephalosporin antimicrobial agents: a comprehensive review. J Vet Pharmacol Ther 1988; 11(1): 132. 2. Papich MG. Clinical pharmacology of cephalosporin antibiotics. J Am Vet Med Assoc 1984; 184(3): 3447. 3. Cefadroxil package insert (Cefa-Tabs, Fort DodgeUS), Rev 9/93, Rec 1/20/95. 4. Barragry TB. Veterinary drug therapy. Baltimore: Lea & Febiger; 1994. p. 23140. 5. Thomson TD. Cephalosporin group of antimicrobial drugs. J Am Vet Med Assoc 1984; 185(10): 110914. 6. Rosin E, et al. Cefazolin antibacterial activity and concentrations in serum and the surgical wound in dogs. Am J Vet Res 1993; 54(8): 131721. 7. Donowitz GR, Mandell GL. Beta-lactam antibiotics. N Engl J Med 1988; 318: 41926. 8. Thompson RL, Wright AJ. Cephalosporin antibiotics. Mayo Clin Proc 1983; 58: 7987. 9. Papich MG. The beta-lactam antibiotics: clinical pharmacology and recent developments. Compend Contin Educ Pract Vet 1987; 9: 6875.

10. Plumb DC. Veterinary drug handbook. White Bear Lake, MN: PharmaVet Publishing; 1991. p. 452-67. 11. Ceftiofur package insert (Naxcel, UpjohnUS), Rev 9/01. Downloaded8/1/02 from www.pharmaciaah.com. 12. Ceftiofur package insert (Excenel, UpjohnCanada). In: Arrioja-Dechert A, editor. Compendium of veterinary products, CD ed. Port Huron, MI: North American Compendiums, Inc. 2002. 13. USP dictionary of USAN and international drug names, 2002 ed. Rockville, MD: The United States Pharmacopeial Convention, Inc.; 2002. 14. The United States pharmacopeia. The national formulary. USP 26th revision (January 1, 2003). NF 21st ed (January 1, 2003). Rockville, MD: The United States Pharmacopeial Convention, Inc.; 2002. p. 351-4, 357, 361, 362, 370, 371, 373, 376, 377, 3959, 401, 402. 15. Atef M, et al. Pharmacokinetic prole of cefotaxime in goats. Res Vet Sci 1990; 49: 348. 16. Gennaro AR, editor. Remingtons pharmaceutical sciences. 18th ed. Easton, PA: Mack Publishing Company; 1990. p. 1196, 1199.

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CEPHALOSPORINS VeterinarySystemic 69
17. Riviere JE, Cragmill AL, Sundlof SF. Handbook of comparative pharmacokinetics and residues of veterinary antimicrobials. Boca Raton, FL: CRC Press; 1991. p. 523. 18. Brown MP, Gronwall RR, Houston AE. Pharmacokinetics and body uid and endometrial concentrations of cephapirin in mares. Am J Vet Res 1986; 47(4): 7848. 19. Ruoff WW, Sams RA. Pharmacokinetics and bioavailability of cephalothin in horse mares. Am J Vet Res 1985; 46(10): 208590. 20. Guerrini VH, et al. Effect of probenecid on the pharmacokinetics of cefotaxime in sheep. J Vet Pharmacol Ther 1985; 89: 3846. 21. Cefoxitin package insert (Mefoxin, MerckUS), Rev 10/92, Rec 9/94. 22. Cephalothin package insert (Kein, LillyUS), Rev 12/91, Rec 1/3/93. 23. Cephalexin package insert (Keex, LillyUS), Rev 12/91, Rec 6/30/93. 24. Cefaclor package insert (Ceclor, LillyUS), Rev 7/93, Rec 10/20/93. 25. Prades M, Brown MP, Gronwall R, et al. Pharmacokinetics of sodium cephapirin in lactating dairy cows. Am J Vet Res 1988; 49(11): 188890. 26. Soback S. Pharmacokinetics of single doses of cefoxitin given by the intravenous and intramuscular routes to unweaned calves. J Vet Pharmacol Ther 1988; 11: 15562. 27. Juzwiak JS, Brown MP, Gronwall R, et al. Effect of probenecid administration on cephapirin pharmacokinetics and concentrations in mares. Am J Vet Res 1989; 50(10): 17427. 28. Schermerhorn T, et al. Whole-blood platelet aggregation, buccal mucosa bleeding time, and serum cephalothin concentration in dogs receiving a presurgical antibiotic protocol. Am J Vet Res 1994; 55(1): 16027. 29. Brown MP, Gronwall RR, Houston AE. Pharmacokinetics and body uid and endometrial concentrations of cefoxitin in mares. Am J Vet Res 1986; 47(8): 17348. 30. Jaglan PS, et al. Metabolism of ceftiofur. Nature of urinary and plasma metabolites in rats and cattle. J Agric Food Chem 1989; 37: 11128. 31. Davis LE. Hypersensitivity reactions induced by antimicrobial drugs. J Am Vet Med Assoc 1984; 185(10); 11315. 32. Frank LA, Kunkle GA. Comparison of the efcacy of cefadroxil and generic and proprietary cephalexin in the treatment of pyoderma in dogs. J Am Vet Med Assoc 1993: 203(4): 5302. 33. Chateld RC, Gingerich DA, Rourke JE, et al. Cefadroxil: a new orally effective cephalosporin antibiotic. Vet Med 1984; 79(3); 33945. 34. Bush M, Locke D, Neal LA, et al. Pharmacokinetics of cephalothin and cephalexin in selected avian species. Am J Vet Res 1981; 42: 10147. 35. Robinson NE, editor. Current therapy in equine medicine 3. Philadelphia: W.B. Saunders; 1992. p. 816. 36. Cefaclor (Ceclor, Lilly). In: Krogh CME, editor. CPS Compendium of pharmaceuticals and specialities. 29th ed. Ottawa: Canadian Pharmaceutical Association; 1995. p. 2212. 37. Cefadroxil package insert (Cefa-Drops, Fort DodgeUS), Rev 9/93, Rec 1/20/95. 38. Kirk RW, Bonagura JD, editors. Current veterinary therapy XI small animal practice. Philadelphia: W.B. Saunders; 1992. p. 1235. 39. Cefazolin (Ancef, SKF). In: PDR Physicians desk reference. 49th ed. 1995. Montvale, NJ: Medical Economics Data Production Company; 1995. p. 23524. 40. Cefazolin (Ancef, SmithKline Beecham). In: Krogh CME, editor. CPS Compendium of pharmaceuticals and specialities. 29th ed. Ottawa: Canadian Pharmaceutical Association; 1994. p. 723. 41. Cefazolin (Kefzol, Lilly). In: PDR Physicians desk reference. 49th ed. 1995. Montvale, NJ: Medical Economics Data Production Company; 1995. p. 13468. 42. McElroy D, Ravis WR, Clark CH. Pharmacokinetics of cefotaxime in the domestic cat. Am J Vet Res 1986; 47(1): 868. 43. Guerrini VH, English PB, Filippich LJ, et al. Pharmacokinetics of cefotaxime in the dog. Vet Rec 1986; 119: 813. 44. Cefotaxime package insert (Claforan, HoechstUS), Rev 5/91, Rec 6/21/93. 45. Cefoxitin (Mefoxin, Merck). In PDR Physicians desk reference. 49th ed. 1995. Montvale, NJ: Medical Economics Data Production Company; 1995. p. 15802. 46. Klasco RK, editor. USP DI Drug information for the healthcare professional. Volume I. Greenwood Village, CO: MICROMEDEX, Inc.; 2003. 47. Cervantes CC, et al. Pharmacokinetics and concentrations of ceftiofur sodium in body uids and endometrium after repeated intramuscular injections in mares. Am J Vet Res 1993; 54(4): 5735. 48. Meyer JC, et al. Pharmacokinetics of ceftiofur sodium in neonatal foals after intramuscular injection. Equine Vet J 1992; 24(6): 4856. 49. Silley P, Brown MP, Gronwall RR, et al. Pharmacokinetics of cephalexin in dogs and cats after oral, subcutaneous, and intramuscular administration. Vet Rec 1988; 122: 157. 50. Crosse R, Burt DG. Antibiotic concentration in the serum of dogs and cats following a single oral dose of cephalexin. Vet Rec 1984; 115: 1067. 51. Cephalexin package insert (Keftab, LillyUS), Rev 9/92, Rec 5/8/92. 52. Riviere JE. Dosage of antimicrobial drugs in patients with renal insufciency. J Am Vet Med Assoc 1981; 178(1); 702. 53. Cephalothin sodium package insert (LyphomedUS), Rev 3/91, Rec 7/8/91. 54. Cephalothin (Kein, Lilly). In: Krogh CME, editor. CPS Compendium of pharmaceuticals and specialities. 29th ed. Ottawa: Canadian Pharmaceutical Association; 1994. p. 6534. 55. Cephapirin package insert (Cefadyl, BristolUS), Rec 7/13/93. 56. Duffee NE, Christensen JM, Craig AM. The pharmacokinetics of cefadroxil in the foal. J Vet Pharmacol Ther 1989; 12: 3226. 57. Sams RA, Ruoff WW. Pharmacokinetics and bioavailability of cefazolin in horses. Am J Vet Res 1985; 46(2): 34852. 58. Brown MP, Gronwall RR, Pattio N, et al. Pharmacokinetics and synovial uid concentrations of cephapirin in calves with suppurative arthritis. Am J Vet Res 1991; 52(9): 143840. 59. Brown MP, Gronwall RR, Gossman TB, et al. Pharmacokinetics and serum concentrations of cephapirin in neonatal foals. Am J Vet Res 1987; 49(5): 8056. 60. Guerrini VH, Filippich L, English PB, et al. Pharmacokinetics of cefotaxime in sheep. Am J Vet Res 1983; 44: 148891. 61. Halstead SL, Walker RD, Baker JC, et al. Pharmacokinetic evaluation of ceftiofur in serum, tissue chamber uid, and bronchial secretions from healthy beef-bred calves. Can J Vet Res 1992; 56: 26974. 62. Morris DD, Rutkowski J, Lloyd KCK. Therapy in two cases of neonatal foal septicaemia and meningitis with cefotaxime sodium. Equine Vet J 1987; 19(2): 1514. 63. Jaglan PS, Roof RD, Yein FS, et al. Concentration of ceftiofur metabolites in the plasma and lungs of horses following intramuscular treatment. J Vet Pharmacol Ther 1994; 17: 2430. 64. Kietzmann M, Nolte I, Strothmann A, et al. Tolerance and pharmacokinetics of cephalexin in cats after oral administration. J Small Anim Pract 1992; 33: 5215. 65. Cefotetan package insert (Cefotan, Zeneco, Inc.US), Rev 7/93, Rec 10/8/ 93. 66. Freedom of Information Summary, Naxcel Sterile Powder for treatment of canine urinary tract infections. New Animal Drug Application 140338 (UpjohnUS), 9/94. 67. Panel comment, 4/26/95. 68. Manufacturer comment, 4/24/95. 69. Erskine RJ, Wilson RC, Tyler JW, et al. Ceftiofur distribution in serum and milk from clinically normal cows and cows with experimental Escherichia coli-induced mastitis. Am J Vet Res 1995 Apr; 56(4): 4815. 70. Whittem T, Freeman DA, Hanlon D, et al. The effects on pharmacokinetics of intravenous ceftiofur sodium in dairy cattle of simultaneous intravenous acetyl salicylate (aspirin) or probenecid. J Vet Pharmacol Ther 1995; 18: 617. 71. Soback S, Ziv G, Winkler M, et al. Pharmacokinetics of ceftiofur administered intravenously and intramuscularly to lactating cows. Isr J Vet Med 1989; 45: 11823. 72. Brown SA, Arnold TS, Hamlow PJ, et al. Plasma and urine disposition and dose proportionality of ceftiofur and metabolites in dogs after a subcutaneous administration of ceftiofur sodium. J Vet Pharmacol Ther 1995 Oct; 18(5): 3639. 73. Clarke CR, Brown SA, Streeter RN, et al. Penetration of parenterally administered ceftiofur into sterile vs. Pasteurella haemolytica-infected tissue chambers in cattle. J Vet Pharmacol Ther 1996 Oct; 19(5): 37681. 74. Panel comment, 6/16/95. 75. Manufacturer comment, 9/25/95. 76. Panel comment, 5/25/95. 77. Lavy E, Ziv G, Aroch I, et al. Clinical pharmacologic aspects of cexime in dogs. Am J Vet Res 1995 May; 56 (5): 6338. 78. Wilson WD, Baggot JD, Adamson PJW, et al. Cefadroxil in the horse: pharmacokinetics and in vitro antibacterial activity. J Vet Pharmacol Ther 1985; 8: 24653. 79. Angarano DW, MacDonald JM. Efcacy of cefadroxil in the treatment of bacterial dermatitis in dogs. J Am Vet Med Assoc 1989 Jan; 194 (1): 579. 80. Panel comment, 6/16/95. 81. Ceftiofur package insert (Excenel RTU, Pharmacia Animal HealthUS), Rev 1/02. Downloaded 8/1/02 from www.pharmaciaah.com. 82. Marcellin-Little D, Papich MG, DeYoung DJ, et al. A pharmacokinetic model for cefazolin distribution during total hip arthroplasty in dogs. Am J Vet Res 1996; 57(5): 7203.

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70 CEPHALOSPORINS VeterinarySystemic
83. Richardson DC, Aucoin DP, DeYoung DJ, et al. Pharmacokinetic disposition of cefazolin in serum and tissue during canine total hip replacement. Vet Surg 1992; 21 (1): 14. 84. Petersen SW, Rosin E. In vitro antibacterial activity of cefoxitin and cefotetan and pharmacokinetics in dogs. Am J Vet Res 1993 Sep; 54(9): 14969. 85. Henry MM, Morris DD, Lakritz J, et al. Pharmacokinetics of cephradine in neonatal foals after single oral dosing. Equine Vet J 1992; 24(3): 2423. 86. Vaden SL, Riviere JE. Penicillins. In: Adams HR, editor. Veterinary pharmacology and therapeutics. 7th ed. Ames, Iowa: Iowa State University Press; 1995. p. 77883. 87. Bialer M, Wu WH, Look ZM, et al. Pharmacokinetics of cexime after oral and intravenous doses in dogs: bioavailability assessment for a drug showing nonlinear serum protein binding. Res Commun Chem Pathol Pharmacol 1987; 56: 2132. 88. Bialer M, Tonelli AP, Kantrowitz JD, et al. Serum protein binding of a new oral cephalosporin, CL 284,635, in various species. Drug Metab Dispos 1986; 14: 1326. 89. Bialer M, Barta VK, Morrison JA, et al. Dose-dependent pharmacokinetics of a new oral cephalosporin, cexime, in the dog. Pharm Res 1987; 4: 326. 90. Ziv G, Lavy E, Glickman A, et al. Clinical pharmacology of cexime in unweaned calves. J Vet Pharmacol Ther 1995; 18: 94100. 91. Panel comment, 6/19/96. 92. Panel comment, 6/18/96. 93. Reviewer comment, 8/30/96. 94. Salmon SA, Watts JL, Yancey RJ. In vitro activity of ceftiofur and its primary metabolite desfuroylceftiofur, against organisms of veterinary importance. J Vet Diagn Invest 1996 Jul; 8(3): 3326. 95. Panel comment, 8/29/96. 96. Freedom of Information Summary. Ceftiofur hydrochloride sterile suspension for the control and treatment of swine respiratory disease. NADA 140-890. The Upjohn Company. 97. Freedom of Information Summary. Ceftiofur sodium sterile powder for the treatment of sheep respiratory disease. Public Master File Number 5544. NRSP-7 Minor Use Animal Drug Program. 98. Panel comment, 10/2/96. 99. Ceftiofur package insert (Excenel RTU, Pharmacia Animal HealthCanada). In: Arrioja-Dechert A, editor. Compendium of veterinary products, CD ed. Port Huron, MI: North American Compendiums, Inc. 2002. 100. Manufacturer comment, Rec 2/24/97. 101. Barza M, Pinn V, Tanguay P, et al. Nephrotoxicity of newer cephalosporins and aminoglycosides alone and in combination in a rat model. J Antimicrob Chemother 1978; 4(Suppl A): 5968. 102. Diaz JAO, Sumano LH, Ocampo CL. Evaluacion de la nefrotoxicidad de cejelexiuagentamicin eu perros. Vet Mex 1995; 26: 2479. 103. Ringer NC, Pearson EG, Gronwall R, et al. Pharmacokinetics of ceftriaxone in healthy horses. Equine Vet J 1996; 28(6): 4769.

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CEPHAPIRIN VeterinaryIntramammary-Local 71

CEPHAPIRIN VeterinaryIntramammary-Local
Some commonly used brand names for veterinary-labeled products are: Cefa-Dri; Cefa-Lak; ToDay; and ToMorrow. Note: For a listing of dosage forms and brand names by country availability, see the Dosage Forms section(s). pKa: Cephapirin sodium2.15 and 7.3.{R-13} Solubility: Cephapirin Benzathine USPPractically insoluble in water, in ether, and in toluene; freely soluble in alcohol; soluble in 0.1 N hydrochloric acid{R-21}. Cephapirin Sodium USPVery soluble in water; insoluble in most organic solvents{R-21}.

CATEGORY:
Antibacterial (intramammary-local).

PHARMACOLOGY/PHARMACOKINETICS INDICATIONS GENERAL CONSIDERATIONS

Cephapirin is a rst-generation cephalosporin that has a wide spectrum of activity against gram-positive and gram-negative organisms.{R-5} Cephapirin is more resistant to beta-lactamases than are the penicillins{R-6} and so is effective against staphylococci, with the exception of methicillin-resistant staphylococci.{R-5} Mechanism of action/effect: Cephapirin produces its bactericidal effect by inhibiting cell wall synthesis. Its action is only effective in actively growing cells. Distribution: Medications infused into a teat are considered to be fairly evenly distributed in the treated quarter of the healthy mammary gland; however, in an udder affected by moderate to severe mastitis, the presence of edema, blockage of milk ducts, and reduced blood circulation can cause uneven distribution of medication.{R-14}

ACCEPTED
Mastitis (treatment)Cattle: Cephapirin is indicated in the treatment of mastitis caused by susceptible bacteria, such as Staphylococcus aureus{R-1-4; 7} and Streptococcus agalactiae.{R-14} Cephalosporins are the primary treatment of choice for acute staphylococcal mastitis{R-9}; however, cows with acute or peracute mastitis are often given other medications, such as systemic antibiotics and/or supportive therapy, concurrently with intramammary therapy.{R-10}

PRECAUTIONS TO CONSIDER PATIENT MONITORING

The following may be especially important in patient monitoring (other tests may be warranted in some patients, depending on condition; = major clinical signicance): Bacterial pathogens in milk (milk samples should be tested 3 weeks after treatment is discontinued; mastitis is not considered bacteriologically cured until samples show an absence of the mastitis-causing organisms) Clinical signs (although resolution of clinical signs of mastitis is not an indication that a bacteriologic cure has been achieved{R-15}, monitoring of the clinical condition of the mammary gland, teat, and milk produced can aid in diagnosis of a recurrence of mastitis or initial diagnosis of mastitis in another cow in the herd) Somatic cell count (somatic cell counts performed on milk to monitor the dairy herd are used primarily to maintain milk quality but are also used to assess the approximate overall effectiveness of mastitis control programs, which may include antibiotic treatment of cows){R-10}

REGULATORY CONSIDERATIONS
U.S. and Canada Withdrawal times have been established for cephapirin benzathine and cephapirin sodium intramammary infusion (see the Dosage Forms section).{R-14; 17; 18}

CHEMISTRY
Source: Cephalosporins are semi-synthetic derivatives of metabolic products of the fungus Cephalosporium acremonium.{R-6; 11} Chemical group: Beta-lactam antibiotics.{R-5} Chemical name: Cephapirin benzathine5-Thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, 3-[(acetyloxy)methyl]-8-oxo-7-[[(4-pyridinylthio)acetyl]amino]-, (6R-trans)-, cmpd. with N,N-bis(phenylmethyl)-1,2-ethanediamine (2:1){R-12}. Cephapirin sodium5-Thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, 3-[(acetyloxy)methyl]-8-oxo-7-[[(4-pyridinylthio)acetyl]amino]-, monosodium salt, [6R-trans]-.{R-12} Molecular formula: Cephapirin benzathine(C17H17N3O6S2)2 C16H20N2{R-12}. Cephapirin sodiumC17H16N3NaO6S2.{R-12} Molecular weight: Cephapirin benzathine1087.27{R-12}. Cephapirin sodium445.45.{R-12} Description: Cephapirin Benzathine USPWhite, crystalline powder{R-21}. Cephapirin Sodium USPWhite to off-white crystalline powder, odorless or having a slight odor{R-21}.

SIDE/ADVERSE EFFECTS
The following side/adverse effects have been selected on the basis of their potential clinical signicance (possible signs in parentheses where appropriate)not necessarily inclusive:

THOSE INDICATING NEED FOR MEDICAL ATTENTION

Incidence unknown Cows Allergic reactions{R-1;

2}

local or systemic; drug fever{R-19}

OVERDOSE
For information in cases of overdose or unintentional ingestion, contact the American Society for the Prevention of Cruelty to Animals

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72 CEPHAPIRIN VeterinaryIntramammary-Local (ASPCA) National Animal Poison Control Center (888-426-4435 or 900-443-0000; a fee may be required for consultation) and/or the drug manufacturer. Note: Cephapirin benzathine intramammary infusion should not be used any later than thirty days prior to calving. Canada{R-17;
22}

CLIENT CONSULTATION
Treatment of mastitis in dairy cattle is best achieved by a comprehensive mastitis control program in which herd management is the primary focus. The program should include routine milk testing, good maintenance of milking equipment, and constant evaluation of milking procedures and teat health as well as strategic treatment of clinical cases of mastitis.{R-16}
Withdrawal time Species Cows, nonlactating Meat (days) 42 Milk (hours) 84

Note: Cephapirin benzathine intramammary infusion should not be used any later than thirty days prior to calving. Packaging and storage: Store between 15 and 30 C (59 and 86 F), unless otherwise specied by manufacturer. Protect from freezing. USP requirements: Preserve in well-closed unit-dose disposable syringes at controlled room temperature. A suspension of Cephapirin Benzathine in a suitable vegetable oil vehicle. Contains a suitable dispersing agent. Label Intramammary Infusion to indicate that it is for veterinary use only. Contains an amount of cephapirin benzathine equivalent to the labeled amount of cephapirin, within -10% to +20%. Meets the requirements for Identication and Water (not more than 1.0%){R-21}.

VETERINARY DOSING INFORMATION

Antibiotic therapy in the dry cow is more effective than treatment during lactation for mastitis caused by Staphylococcus aureus.{R-15; 16; 20} Choice of antibiotic for treatment of mastitis should be based on knowledge of identity and sensitivity of pathogens causing mastitis in the cow and the dairy herd. Before intramammary administration of cephapirin, the following actions should be taken:{R-14} The udder should be milked out completely and the teats washed with warm water and a disinfectant. Care should be taken to avoid washing excess dirt down from the udder onto the teat ends. The area should be dried thoroughly. An effective germicidal teat dip should be applied for one minute and then each teat wiped with a separate cotton ball soaked with an antiseptic such as 70% alcohol. Persons performing the treatment should wash and dry their hands before each treatment. The tip of the syringe should be inserted into the teat end as little as possible and the contents of the syringe should be injected into each streak canal while the teat is held rmly. The medication should then be gently massaged up the teat canal into the udder. Following treatment, an effective teat dip is recommended on all teats.

CEPHAPIRIN SODIUM INTRAMAMMARY INFUSION USP

Usual dose: MastitisCows, lactating: Intramammary, 200 mg into each affected quarter of the udder every twelve hours for two treatments.{R-3; 4} Strength(s) usually available: U.S.{R-3; 4; 22} Veterinary-labeled product(s): 200 mg per 10 mL (OTC) [Cefa-Lak; ToDay]. Canada{R-18; 22} Veterinary-labeled product(s): 200 mg per 10 mL (Rx) [Cefa-Lak]. Withdrawal times: U.S. and Canada{R-3;

INTRAMAMMARY DOSAGE FORMS CEPHAPIRIN BENZATHINE INTRAMAMMARY INFUSION USP

Usual dose: MastitisCows, nonlactating: Intramammary, 300 mg administered into each quarter of the udder at the time of dryingoff.{R-1; 2} Strength(s) usually available: U.S.{R-1; 2; 22} Veterinary-labeled product(s): 300 mg per 10 mL (OTC) [Cefa-Dri; ToMorrow]. Canada{R-17; 22} Veterinary-labeled product(s): 300 mg per 10 mL (Rx) [Cefa-Dri]. Withdrawal times: U.S.{R-1; 2; 22}
Withdrawal time Species Cows, nonlactating Meat (days) 42 Milk (hours) 72

4; 18; 22}

Withdrawal time Species Cows, lactating Meat (days) 4 Milk (hours) 96

Packaging and storage: Store between 15 and 30 C (59 and 86 F), unless otherwise specied by manufacturer. Protect from freezing. USP requirements: Preserve in well-closed unit-dose disposable syringes at controlled room temperature. A suspension of Cephapirin Sodium in a suitable vegetable oil vehicle. Contains a suitable dispersing agent. Label Intramammary Infusion to indicate that it is for veterinary use only. Contains an amount of cephapirin sodium equivalent to the labeled amount of cephapirin, within )10% to +20%. Meets the requirements for Identication and Water (not more than 1.0%){R-21}. All rights reserved

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CEPHAPIRIN VeterinaryIntramammary-Local 73 Developed: 06/30/95 Interim revision: 04/24/96; 05/19/97; 5/26/98; 10/15/99; 06/30/02; 02/28/03
11. Papich MG. Clinical pharmacology of cephalosporin antibiotics. J Am Vet Med Assoc 1984; 184(3): 3447. 12. USP dictionary of USAN and international drug names, 2002 ed. Rockville, MD: The United States Pharmacopeial Convention, Inc., 2002. 13. Gennaro AR, editor. Remingtons pharmaceutical sciences. 18th ed. Easton, PA: Mack Publishing Company, 1990. p. 1199. 14. Jarp J, Bugge HP, Larsen S. Clinical trial of three therapeutic regimens for bovine mastitis. 1989; 124: 6304. 15. Craven N. Efcacy and nancial value of antibiotic treatment of bovine clinical mastitis during lactationa review. Br Vet J 1987; 143: 41022. 16. Hady PJ, Lloyd JW, Kaneene JB. Antibacterial use in lactating dairy cattle. J Am Vet Med Assoc 1993 Jul; 203(2): 21020. 17. Cephapirin (Cefa-Dri, Wyeth AyerstCanada). In: Bennett K, editor. Compendium of veterinary products. 3rd ed. Hensall, ON: North American Compendiums Inc., 1993. p. 163. 18. Cephapirin (Cefa-Lak, Wyeth AyerstCanada). In: Bennett K, editor. Compendium of veterinary products. 3rd ed. Hensall, ON: North American Compendiums Inc., 1993. p. 164. 19. Panel comment, Rec 3/24/95. 20. Manufacturer comment, Rec 4/20/95. 21. The United States pharmacopeia. The national formulary. USP 26th revision (January 1, 2003). NF 21st ed (January 1, 2003). Rockville, MD: The United States Pharmacopeial Convention, Inc., 2002. p. 398, 400, 2554. 22. Arrioja-Dechert A, editor. Compendium of Veterinary Products, CD edition. Port Huron, MI: North American Compendiums, Inc., 2002.

REFERENCES
1. Cefa-Dri package insert (Fort DodgeUS). Downloaded 2/16/03 from www.wyeth.com. 2. ToMorrow package insert (Fort DodgeUS). Downloaded 8/6/03 from www.wyeth.com. 3. Cefa-Lak package insert (Fort DodgeUS), Rev 3/00. Downloaded 8/6/03 from www.wyeth.com. 4. ToDay package insert (Fort DodgeUS). Downloaded 8/6/03 from www. wyeth.com. 5. Donowitz GR, Mandell GL. Beta-lactam antibiotics. N Engl J Med 1988; 318: 41926. 6. Caprile KA. The cephalosporin antimicrobial agents: a comprehensive review. J Vet Pharmacol Ther 1988; 11(1): 132. 7. Owens WE, et al. Efcacy of a cephapirin dry cow product for treatment of experimentally induced Staphylococcus aureus mastitis in heifers. J Dairy Sci 1991; 74(10): 337682. 8. Watson ADJ. Penicillin G and the alternatives. Vet Annu 1985; 25: 277-83. 9. Barragry TB. Veterinary drug therapy. Philadelphia: Lea & Febiger, 1994. p. 665. 10. Heath SE. Bovine mastitis. In: Howard JL. Current veterinary therapy 3 food animal practice. Philadelphia: W.B. Saunders, 1993. p. 7629.

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74 CHLORAMPHENICOL VeterinarySystemic

CHLORAMPHENICOL VeterinarySystemic
Some commonly used brand names are: For veterinary-labeled productsAmphicol Film-Coated Tablets; Azramycine S125; Azramycine S250; Chlor 100; Chlor 250; Chlor 500; Chlor 1000; Chlor Palm 125; Chlor Palm 250; Duricol; Karomycin Palmitate 125; Karomycin Palmitate 250; and Viceton. For human-labeled productsChloromycetin and Novochlorocap. Note: For a listing of dosage forms and brand names by country availability, see the Dosage Forms section(s). Molecular formula: ChloramphenicolC11H12Cl2N2O5.{R-9} Chloramphenicol palmitateC27H42Cl2N2O6.{R-9} Chloramphenicol sodium succinateC15H15Cl2N2NaO8.{R-9} Molecular weight: Chloramphenicol323.13.{R-9} Chloramphenicol palmitate561.54.{R-9} Chloramphenicol sodium succinate445.18.{R-9} Description:{R-10} Chloramphenicol USPFine, white to grayish white or yellowish white, needle-like crystals or elongated plates. Its solutions are practically neutral to litmus. Is reasonably stable in neutral or moderately acid solutions. Its alcohol solution is dextrorotatory and its ethyl acetate solution is levorotatory. Chloramphenicol Palmitate USPFine, white, unctuous, crystalline powder, having a faint odor. Chloramphenicol Sodium Succinate USPLight yellow powder. Solubility:{R-10} Chloramphenicol USPSlightly soluble in water; freely soluble in alcohol, in propylene glycol, in acetone, and in ethyl acetate. Chloramphenicol Palmitate USPInsoluble in water; freely soluble in acetone and in chloroform; soluble in ether; sparingly soluble in alcohol; very slightly soluble in solvent hexane. Chloramphenicol Sodium Succinate USPFreely soluble in water and in alcohol.

CATEGORY:
Antibacterial (systemic).

INDICATIONS
Note: Bracketed information in the Indications section refers to uses that either are not included in U.S. product labeling or are for products not commercially available in the U.S.

ACCEPTED
Chloramphenicol is a broad-spectrum antibiotic shown to have specic activity against a wide variety of organisms that are the causative agents of several disease conditions in domestic animals. Such organisms include Staphylococcus aureus, Streptococcus pyogenes, Brucella bronchoseptica, Escherichia coli, Proteus vulgaris, Aerobacter aerogenes, Corynebacterium renale, Salmonella species, Pseudomonas species, Shigella species, Neisseria catarrhalis, anaerobic bacteria, and many rickettsiae. The species treated with chloramphenicol include dogs, [cats]1, and [horses]1.
1

PHARMACOLOGY/PHARMACOKINETICS
Note: See also Table 1. Pharmacokinetic Parameters at the end of this monograph. Mechanism of action/effect: Chloramphenicol is bacteriostatic. However, it may be bactericidal in high concentrations or when used against highly susceptible organisms. Chloramphenicol, which is lipid soluble, diffuses through the bacterial cell membrane and reversibly binds to the 50 S subunit of the bacterial ribosomes where transfer of amino acids to growing peptide chains is prevented (perhaps by suppression of peptidyl transferase activity), thus inhibiting peptide bond formation and subsequent protein synthesis. Absorption: Chloramphenicol is rapidly absorbed from the gastrointestinal tract after oral administration in many simple-stomach animals. CatsChloramphenicol palmitate is not absorbed well after oral administration to fasted cats.{R-1; 2} Distribution: Chloramphenicol diffuses readily into all body tissues, but at different concentrations. Highest concentrations are found in the liver and kidneys of dogs. The lungs, spleen, heart, and skeletal muscles contain concentrations similar to that in the blood. Chloramphenicol reaches signicant concentrations in the aqueous and vitreous humors of the eye. Within 3 to 4 hours after administration, the concentration in the cerebrospinal uid reaches, on the average, 50% of the concentration in the serum. The percentage increases if there is inammation of the meninges. All rights reserved

Not included in Canadian product labeling or product not commercially available in Canada.

REGULATORY CONSIDERATIONS
U.S. Food and Drug Administration regulations ban chloramphenicol from use in animals that are used for food production. There are no safe residue levels, and no withdrawal times have been established. Chloramphenicol Tablets USP are labeled for veterinary use only. Canada Chloramphenicol is prohibited from use in food-producing animals by the Canadian Health Protection Branch. Chloramphenicol Tablets USP are labeled for veterinary use only.

CHEMISTRY
Source: Originally derived from Streptomyces venezuelae.{R-8} Chemical name: ChloramphenicolAcetamide, 2,2-dichloro-N-[2-hydroxy-1-(hydroxymethyl)-2-(4-nitrophenyl)ethyl]-, [R-(R*,R*)]-.{R-9} Chloramphenicol palmitateHexadecanoic acid, 2-[(2,2-dichloroacetyl)amino]-3-hydroxy-3-(4-nitrophenyl) propyl ester, [R-(R*,R*)]-.{R-9} Chloramphenicol sodium succinateButanedioic acid, mono[2-[(2,2dichloroacetyl)amino]-3-hydroxy-3-(4-nitrophenyl)propyl]ester,monosodium salt, [R-(R*,R*)]-{R-9}. 2003 Thomson MICROMEDEX

CHLORAMPHENICOL VeterinarySystemic 75 Chloramphenicol diffuses readily into milk and pleural and ascitic uids and crosses the placenta, attaining concentrations of about 75% of that in maternal blood.

PATIENT MONITORING
The following may be especially important in patient monitoring (other tests may be warranted in some patients, depending on condition; = major clinical signicance): Complete blood counts (CBCs) (CBCs may be required during therapy with chloramphenicol, particularly during prolonged administration, to detect aplastic anemia or bone marrow depression) Culture and susceptibility, in vitro, and Minimum inhibitory concentration (MIC) (in vitro cultures and MIC tests should be done on samples collected prior to chloramphenicol administration to determine pathogen susceptibility)

Biotransformation: Chloramphenicol is rather rapidly metabolized, mainly in the liver, by conjugation with glucuronic acid.

Elimination: Approximately 55% of a single daily dose can be recovered from the urine of a treated dog. A small fraction of this is in the form of unchanged chloramphenicol. The unchanged chloramphenicol is excreted by glomerular ltration (5 to 10%), whereas 80% is excreted via tubular secretion as inactive metabolite.

PRECAUTIONS TO CONSIDER SPECIES SENSITIVITY

CatsChloramphenicol should not be used in the cat for more than 14 days{R-2} because it can cause dose-related blood dyscrasias. The reported increased susceptibility of cats to development of blood dyscrasias relative to dogs or horses may be attributable to chloramphenicols signicantly longer elimination half-life in the cat.{R-6}

SIDE/ADVERSE EFFECTS
Note: Although aplastic anemia has occurred in human patients as a result of chloramphenicol administration, it has not been documented in animals.{R-6; 7} A dose-related reversible bone marrow suppression may occur, sometimes manifesting as pancytopenia or agranulocytosis. The following side/adverse effects have been selected on the basis of their potential clinical signicance (possible signs and, for humans, symptoms in parentheses where appropriate)not necessarily inclusive:

PEDIATRICS
All species In the fetus and neonate, the immature liver cannot conjugate chloramphenicol, and toxic concentrations of active drug accumulate. Dogs and cats Sudden death has been reported in puppies and kittens receiving intravenous chloramphenicol.

THOSE INDICATING NEED FOR MEDICAL ATTENTION

All species Anorexia; bone marrow suppression{R-7}; depression; diarrhea and vomiting{R-6} Note: Intermediate metabolites are thought to be responsible for the reversible bone marrow suppression seen in domestic animals. The effect is dose-dependent, often occurring with long-term therapy.

DRUG INTERACTIONS AND/OR RELATED PROBLEMS

The following drug interactions and/or related problems have been selected on the basis of their potential clinical signicance (possible mechanism in parentheses where appropriate)not necessarily inclusive ( = major clinical signicance): Note: Combinations containing any of the following medications, depending on the amount present, may also interact with this medication. Digitalis glycosides (chloramphenicol decreases the rate of elimination of digitalis glycosides, which may lead to their accumulation to toxic concentrations{R-3}) Erythromycin (erythromycin and chloramphenicol compete for the same ribosome; therefore, the 2 medications may antagonize each other if used concurrently) Medications metabolized by mixed function oxidase system, especially: Phenobarbital or Primidone (chloramphenicol irreversibly inhibits the hepatic microsomal enzymes of the cytochrome P450 complex, which may potentiate the effects of other medications that are metabolized by this complex) Pentobarbital (pentobarbital-induced anesthesia in dogs can be signicantly prolonged by concurrent administration of chloramphenicol{R-4}) 2003 Thomson MICROMEDEX

HUMAN SIDE/ADVERSE EFFECTS{R-12}

In addition to the above side/adverse effects reported in animals, the following side/adverse effects have been reported in humans, and are included in the human monograph Chloramphenicol (Systemic) in USP DI Volume I; these side/adverse effects are intended for informational purposes only and may or may not be applicable to the use of chloramphenicol in the treatment of animals: Note: The hematologic toxicity of chloramphenicol can manifest itself in 1 of 2 wayseither as a reversible bone marrow depression or an idiosyncratic aplastic anemia. Bone marrow depression is dose-related and most commonly seen when serum concentrations of chloramphenicol exceed 25 mcg/mL. Bone marrow changes are usually reversible when chloramphenicol is discontinued. Aplastic anemia is an idiosyncratic reaction that occurs in 1 of every 25,000 to 40,000 courses of treatment. It is not related to dose or duration of therapy. Most cases have been associated with oral chloramphenicol, and the onset of aplasia may not occur until weeks or months after treatment with chloramphenicol has been discontinued. Incidence less frequent Blood dyscrasias; gastrointestinal reaction Incidence rare Gray syndromein neonates only; hypersensitivity reactions; neurotoxic reactions; optic neuritis; peripheral neuritis All rights reserved

76 CHLORAMPHENICOL VeterinarySystemic Note: Gray syndrome (or gray baby syndrome) almost always occurs in newborn infants treated with inappropriately high doses of chloramphenicol. Typically, the infant has been started on chloramphenicol within the rst 48 hours of life; symptoms rst appear after 3 to 4 days of continued treatment with high doses of chloramphenicol; and serum concentrations are high, often between 40 and 200 mcg/mL. If detected early and chloramphenicol is discontinued, the infant may have a complete recovery. On rare occasion, older patients, including adults with severe liver disease, have also had a gray syndrometype reaction. Symptoms of possible fatal, irreversible bone marrow depression Pale skin; sore throat and fever; unusual bleeding or bruising; unusual tiredness or weakness Note: Pale skin, sore throat and fever, unusual bleeding or bruising, unusual tiredness or weakness may be symptoms of irreversible bone marrow depression leading to aplastic anemia, and the need for immediate medical attention if they occur weeks or months after medication is discontinued. The dosing and strengths of the dosage forms available are expressed in terms of chloramphenicol base.

CHLORAMPHENICOL CAPSULES USP

Usual dose: Antibacterial1 Dogs: Oral, 45 to 60 mg per kg of body weight every eight hours. [Cats]: Oral, 13 to 20 mg per kg of body weight every twelve hours. Note: The oral dose for cats is based on the best information available, which may, however, underestimate the dose needed in some cases. Doses of 25 to 50 mg per kg of body weight every twelve hours have been recommended, and may be necessary for some infections, but could increase the risk of side effects. [Horses]: Oral, 45 to 60 mg per kg of body weight every eight hours. Strength(s) usually available: U.S.{R-11; 12} Veterinary-labeled product(s): 50 mg (Rx) [Duricol]. 100 mg (Rx) [Duricol]. 250 mg (Rx) [Duricol]. 500 mg (Rx) [Duricol]. Human-labeled product(s): 250 mg (Rx) [GENERIC]. Canada Veterinary-labeled product(s): Not commercially available. Human-labeled product(s): 250 mg (Rx) [Novochlorocap]. Packaging and storage: Store below 40 C (104 F), preferably between 15 and 30 C (59 and 86 F), unless otherwise specied by manufacturer. Store in a tight container. USP requirements: Preserve in tight containers. Contain the labeled amount, within 10 to +20%. Meet the requirements for Identication, Dissolution (85% in 30 minutes in 0.01 N hydrochloric acid in Apparatus 1 at 100 rpm), and Uniformity of dosage units{R-10}.

OVERDOSE
For information in cases of overdose or unintentional ingestion, contact the American Society for the Prevention of Cruelty to Animals (ASPCA) National Animal Poison Control Center (888-426-4435 or 900-443-0000; a fee may be required for consultation) and/or the drug manufacturer.

CLIENT CONSULTATION
Because of the risk of idiosyncratic aplastic anemia that occurs in people after exposure to chloramphenicol, extreme care during administration to animals should be exercised. Animals do not appear prone to develop the idiosyncratic aplastic anemia that can occur in people weeks or months after cessation of drug therapy.{R-5} In humans, the reported incidence of idiosyncratic aplastic anemia following chloramphenicol exposure ranges from 1/25,000 to 1/ 40,000. Aplastic anemia in humans may occur following oral, intramuscular, intravenous, ophthalmic, and/or topical administration. Due to these risks, chloramphenicol is banned in foodproducing animals in the United States and people should avoid other types of exposure as well. When administering chloramphenicol to animals, people should avoid direct contact with the medication (for example, avoid opening the capsules).

CHLORAMPHENICOL PALMITATE ORAL SUSPENSION USP

Usual dose: [Antibacterial] Dogs: Oral, 45 to 60 mg per kg of body weight every eight hours. Cats1: Oral, 13 to 20 mg per kg of body weight every twelve hours. Note: The oral dose for cats is based on the best information available, which may, however, underestimate the dose needed in some cases. Doses of 25 to 50 mg every twelve hours have been recommended, and may be necessary for some infections, but could increase the risk of side effects. Strength(s) usually available: U.S. Veterinary-labeled product(s): Not commercially available. Canada{R-11} Veterinary-labeled product(s): 25 mg (base) per mL (Rx) [Azramycine S125; Chlor Palm 125; Karomycin Palmitate 125]. All rights reserved

VETERINARY DOSING INFORMATION

Most susceptible infectious disease organisms will respond to chloramphenicol therapy in 3 to 5 days when the recommended dosage regimen is followed. If no response to chloramphenicol therapy is obtained in 3 to 5 days, use should be discontinued and the diagnosis reviewed. CatsChloramphenicol should not be used in the cat for more than 14 days{R-2} because it can cause dose-related blood dyscrasias. Chloramphenicol palmitate is not absorbed well after oral administration to fasted cats.{R-1; 2}

ORAL DOSAGE FORMS

Note: Bracketed information in the Dosage Forms section refers to uses that either are not included in U.S. product labeling or are for products not commercially available in the U.S. 2003 Thomson MICROMEDEX

CHLORAMPHENICOL VeterinarySystemic 77 50 mg (base) per mL (Rx) [Azramycine S250; Chlor Palm 250; Karomycin Palmitate 250].

PARENTERAL DOSAGE FORMS

Note: Bracketed information in the Dosage Forms section refers to uses that either are not included in U.S. product labeling or are for products not commercially available in the U.S. The dosing and strengths of the dosage forms available are expressed in terms of chloramphenicol base.

Packaging and storage: Store below 40 C (104 F), preferably between 15 and 30 C (59 and 86 F), unless otherwise specied by manufacturer. Store in a tight, light-resistant container. Protect from freezing.

CHLORAMPHENICOL SODIUM SUCCINATE FOR INJECTION USP

Usual dose: [Antibacterial]1 Cats: Intramuscular, intravenous, or subcutaneous, 12 to 30 mg (base) per kg of body weight every twelve hours. Dogs and horses: Intramuscular, intravenous, or subcutaneous, 45 to 60 mg (base) per kg of body weight every six to eight hours. Strength(s) usually available{R-8; 12}: U.S. Veterinary-labeled product(s): Not commercially available. Human-labeled product(s): 1 gram (base) per vial (Rx) [Chloromycetin; Canada Veterinary-labeled product(s): Not commercially available. Human-labeled product(s): 1 gram (base) (Rx) [Chloromycetin].

USP requirements: Preserve in tight, light-resistant containers. Contains an amount of chloramphenicol palmitate equivalent to the labeled amount of chloramphenicol, within )10 to +20%. Contains one or more suitable buffers, colors, avors, preservatives, and suspending agents. Meets the requirements for Identication, Uniformity of dosage units (suspension packaged in single-unit containers), Deliverable volume (suspension packaged in multiple-unit containers), pH (4.57.0), and Limit of polymorph A{R-10}.

CHLORAMPHENICOL TABLETS USP

Usual dose: Antibacterial Dogs: Oral, 45 to 60 mg per kg of body weight every eight hours. [Cats]1: Oral, 13 to 20 mg per kg of body weight every twelve hours. Note: The oral dose for cats is based on the best information available, which may, however, underestimate the dose needed in some cases. Doses of 25 to 50 mg per kg of body weight every twelve hours have been recommended, and may be necessary for some infections, but could increase the risk of side effects. [Horses]1: Oral, 45 to 60 mg per kg of body weight every eight hours. Strength(s) usually available{R-11}: U.S. Veterinary-labeled product(s): 100 mg (Rx) [Viceton]. 250 mg (Rx) [Amphicol Film-Coated Tablets; Viceton]. 500 mg (Rx) [Amphicol Film-Coated Tablets; Viceton]. 1000 mg (Rx) [Amphicol Film-Coated Tablets; Viceton]. Canada Veterinary-labeled product(s): 100 mg (Rx) [Chlor 100]. 250 mg (Rx) [Chlor 250]. 500 mg (Rx) [Chlor 500]. 1000 mg (Rx) [Chlor 1000].

GENERIC].

Packaging and storage: Prior to reconstitution, store below 40 C (104 F), preferably between 15 and 30 C (59 and 86 F), unless otherwise specied by manufacturer. Preparation of dosage form: To prepare a 10% (100-mg-per-mL) solution, add 10 mL of an aqueous diluent such as sterile water for injection or 5% dextrose injection to each 1-gram vial{R-8}. USP requirements: Preserve in Containers for Sterile Solids. Contains an amount of chloramphenicol sodium succinate equivalent to the labeled amount of chloramphenicol, within 10 to +15%. Meets the requirements for Bacterial endotoxins, Sterility, Particulate matter, and Limit of free chloramphenicol (not more than 2.0%), and for Identication, Specic rotation, pH, and Water under Chloramphenicol Sodium Succinate{R-10}.
1

Not included in Canadian product labeling or product not commercially available in Canada.

Packaging and storage: Store below 40 C (104 F), preferably between 15 and 30 C (59 and 86 F), unless otherwise specied by manufacturer. Store in a tight container.

Revised: 07/28/94 Interim revision: 03/30/95; 04/24/96; 05/07/97; 05/27/98; 10/15/99; 09/30/02; 04/04/03

USP requirements: Preserve in tight containers. Label Tablets to indicate that they are for veterinary use only and are not to be used in animals raised for food production. Contain the labeled amount, within 10 to +20%. Meet the requirements for Identication, Disintegration (60 minutes), and Uniformity of dosage units.
1

Table 1. Pharmacokinetic Parameters

First order elimination rate constant (min)1) 0.0023 0.0098 0.001 0.0188 0.001 Total body clearance (mL/min/kg) 5.55 8.57 0.83 26.14 1.28

Species Cats Dogs Horses

Elimination half-life (hours) 5.1 1.20 0.10 0.63 0.04

VolD (L/kg) 2.36 0.85 0.06 1.41 0.08

Not included in Canadian product labeling or product not commercially available in Canada.

2003 Thomson MICROMEDEX

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78 CHLORAMPHENICOL VeterinarySystemic

REFERENCES
1. Watson ADJ. Effect of ingesta on systemic availability of chloramphenicol from 2 oral preparations in cats. J Vet Pharm Ther 1979; 2: 11721. 2. Panel comment, Rec 3/8/94. 3. Davis LE. Emergency drugs. In: Zaslow IM, editor. Veterinary trauma and critical care. Philadelphia: Lea and Febiger 1984. p. 287338. 4. Teske RH, Carter GG. Effect of chloramphenicol on pentobarbitalinduced anesthesia in dogs. J Am Vet Med Assoc 1971 Sep; 159(6): 77780. 5. Booth NH, McDonald LE. Veterinary pharmacology and therapeutics, 6th ed. Ames: Iowa State University Press 1988. p. 8378. 6. Plumb DC. Veterinary drug handbook. St. Paul: PharmaVet Publishing 1991. p. 5304. 7. Weiss DJ. Aplastic anemia. In: Kirk RW, Bonagura JD, editors. Current veterinary therapy XI small animal practice. Philadelphia: W.B. Saunders 1992. p. 47984.

8. Chloromycetin Sodium Succinate Product Information (King PharmaceuticalsUS), Rev 5/99. Downloaded 2/16/03 from www.kingpharm.com. 9. USP dictionary of USAN and international drug names, 2002 ed. Rockville, MD: The United States Pharmacopeial Convention, Inc., 2002. 10. The United States pharmacopeia. The national formulary. USP 26th revision (January 1, 2003). NF 21st ed (January 1, 2003). Rockville, MD: The United States Pharmacopeial Convention, Inc., 2002. p. 407, 413, 414, 2554. 11. Arrioja-Dechert A, editor. Compendium of veterinary products, CD ed. Port Huron, MI: North American Compendiums, Inc. 2002. 12. Klasco RK, editor. USP DI Drug information for the healthcare professional. Volume I. Greenwood Village, CO: MICROMEDEX, Inc.; 2003.

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ERYTHROMYCIN VeterinaryIntramammary-Local 79

ERYTHROMYCIN VeterinaryIntramammary-Local
Some commonly used brand names for veterinary-labeled products are: Erythro-36; Erythro-Dry Cow; Gallimycin-36; and Gallimycin-Dry Cow. Note: For a listing of dosage forms and brand names by country availability, see the Dosage Forms section(s). synthesis.{R-11} Erythromycin is effective only against rapidly dividing bacteria. Bacterial resistance occurs by alteration of the ribosome receptor site and/or by not allowing erythromycin to enter the cell. Distribution: Medications infused into a teat are thought to be fairly evenly distributed in that quarter of the healthy mammary gland; however, in an udder affected by moderate to severe mastitis, the presence of edema, blockage of milk ducts, and reduced blood circulation can cause uneven distribution.{R-12}

CATEGORY:
Antibacterial (intramammary-local).

INDICATIONS GENERAL CONSIDERATIONS

Erythromycin is an antibiotic that is active primarily against grampositive bacteria, such as Staphylococcus and Streptococcus species, including many that are, by means of beta-lactamase production, resistant to penicillins. Resistant strains of streptococci have been reported{R-1}, particularly in populations recently treated with erythromycin.{R-2} Cross-resistance to the other macrolide antibiotics can also occur.{R-2}

PRECAUTIONS TO CONSIDER PREGNANCY/REPRODUCTION

PregnancyErythromycin crosses the placenta; however, there was no evidence of teratogenicity or other adverse effects when pregnant rats were fed erythromycin base{R-13}.

PATIENT MONITORING
The following may be especially important in patient monitoring (other tests may be warranted in some patients, depending on condition; = major clinical signicance): Bacteriologic pathogens in milk (milk samples should be tested 3 weeks after treatment is discontinued; mastitis is not considered bacteriologically cured until samples show an absence of the mastitis-causing organisms) Clinical signs of mastitis (although a resolution of clinical signs of mastitis is not an indication that a bacteriologic cure has been achieved, monitoring of the clinical condition of the mammary gland, teat, and milk produced can aid in diagnosis of a recurrence of mastitis or initial diagnosis of mastitis in another cow in the herd) Somatic cell count (somatic cell counts performed on milk to monitor the dairy herd are used primarily to maintain milk quality, but they are also used to assess the approximate overall effectiveness of mastitis control programs, which may include antibiotic treatment of cows)

ACCEPTED
Mastitis (treatment)Cattle: Erythromycin is indicated in the treatment of mastitis caused by susceptible Staphylococcus aureus{R-4}, Streptococcus agalactiae, Streptococcus dysgalactiae, and Streptococcus uberis{R-3; 14}. It may be most effective against Streptococcus agalactiae{R-5; 17} and Streptococcus dysgalactiae{R-4}. Intramammary therapy alone is indicated only in the treatment of subacute or subclinical mastitis manifested by mild changes in the milk or udder. Cows with acute or peracute mastitis, which has been dened as the presence of gross changes in the milk or udder or systemic signs, should be administered other medications also, which may include systemic antibiotics and/or supportive therapy.{R-6}

REGULATORY CONSIDERATIONS
U.S. and Canada{R-3} Withdrawal times have been established. See the Dosage Forms section.

CHEMISTRY
Source: Produced from a strain of Streptomyces erythraeus. Chemical group: Macrolide group of antibiotics.{R-2} Chemical name: Erythromycin.{R-7} Molecular formula: C37H67NO13.{R-7} Molecular weight: 733.93.{R-7} Description: Erythromycin USPWhite or slightly yellow, crystalline powder. Is odorless or practically odorless.{R-8} pKa: Erythromycin base8.8.{R-9; 10} Solubility: Erythromycin USPSlightly soluble in water; soluble in alcohol, in chloroform, and in ether.{R-8}

SIDE/ADVERSE EFFECTS
The following side/adverse effects have been selected on the basis of their potential clinical signicance (possible signs in parentheses where appropriate)not necessarily inclusive:

THOSE INDICATING NEED FOR MEDICAL ATTENTION

Incidence unknown Cows Allergic reactionlocal or systemic

OVERDOSE PHARMACOLOGY/PHARMACOKINETICS
Mechanism of action/effect: Bacteriostatic; however, high concentrations may be bactericidal.{R-2; 11} Erythromycin is thought to enter the cell and reversibly bind to the 50S ribosomal subunit, inhibiting translocation of peptides and therefore inhibiting protein For information in cases of overdose or unintentional ingestion, contact the American Society for the Prevention of Cruelty to Animals (ASPCA) National Animal Poison Control Center (888-426-4435 or 900-443-0000; a fee may be required for consultation) and/or the drug manufacturer.

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80 ERYTHROMYCIN VeterinaryIntramammary-Local

CLIENT CONSULTATION
Treatment of mastitis in dairy cattle is best achieved by a comprehensive mastitis control program in which herd management is the primary focus. The program should include good maintenance of milking equipment and constant evaluation of milking procedures and teat health as well as strategic treatment of clinical cases of mastitis.{R-15}

Note: Also, for nonlactating cows, treated animals should not be slaughtered for food within 96 hours post-calving. Calves born to treated cows should not be slaughtered for food until they are 10 days of age.{R-3} Canada{R-16; 17}
Withdrawal time

VETERINARY DOSING INFORMATION

The choice of antibiotic for the treatment of mastitis should be based on knowledge of the identity and sensitivity of the pathogens causing mastitis in the cow and the dairy herd. Before administration of intramammary erythromycin, the following actions should be taken: The udder should be milked out completely and the teats and udder washed with warm water and a disinfectant. Care should be taken to avoid washing excess dirt down from the udder onto the teat ends. The area should be dried thoroughly and each teat wiped with a separate cotton ball soaked with an antiseptic such as 70% isopropyl alcohol. Persons performing the treatment should wash and dry their hands before each treatment. The tip of the syringe should be inserted into the teat end as little as possible and the contents of the syringe should be injected into each streak canal while the teat is held rmly. The medication should then be gently massaged up the teat canal into the udder. A teat dip is recommended on all teats following treatment.

Species Cows, lactating

Milk (hours) 36

Packaging and storage: Store at 15 to 30 C (59 to 86 F). Protect from freezing. USP requirements: Preserve in single-dose disposable syringes that are well-closed containers. A solution of Erythromycin in a suitable vegetable oil vehicle. Contains one or more suitable preservatives. Label it to state that it is for veterinary use only. Contains the labeled amount, within )10% to +20%. Meets the requirements for Identication, Minimum ll, and Water (not more than 1.0%).{R-8}

Developed: 07/25/95 Interim revision: 04/24/96; 05/07/97; 06/16/98; 10/15/99; 9/30/02; 03/28/03

REFERENCES INTRAMAMMARY DOSAGE FORMS ERYTHROMYCIN INTRAMAMMARY INFUSION USP

Usual dose: Mastitis Cows, lactating: Intramammary, 300 mg administered into each affected quarter every twelve hours for three treatments.{R-14; 17} Cows, nonlactating: Intramammary, 600 mg administered into each quarter at the time of drying-off.{R-3; 17} Strength(s) usually available: U.S.{R-3; 14; 16} Veterinary-labeled product(s): 50 mg per mL (OTC) [Gallimycin-36 (lactating cows); Gallimycin-Dry Cow (dry cows only)]. Canada{R-16; 17} Veterinary-labeled product(s): 50 mg per mL (OTC) [Erythro-36 (dry or lactating cows); Erythro-Dry Cow (dry cows only); Gallimycin-36 (dry or lactating cows)].
1. Mondel GL, Douglas RG, Bennett JE, editors. Principles and practice of infectious diseases. 3rd ed. New York: Churchill Livingstone, 1990. p. 30812, 800, 1594, 1818, 1940. 2. Barragry TB. Veterinary drug therapy. Philadelphia: Lea & Febiger, 1994. p. 2246, 256. 3. Gallimycin-Dry Cow package insert (BimedaUS), Rec 2/17/03. 4. Craven N. Efcacy and nancial value of antibiotic treatment of bovine clinical mastitis during lactationa review. Br Vet J 1987; 143: 41022. 5. Edmonson PW. An economic justication of blitz therapy to eradicate Streptococcus agalactiae from a dairy herd. Vet Rec 1989; 125: 5913. 6. Heath SE. Bovine mastitis. In: Howard JL. Current veterinary therapy 3 food animal practice. Philadelphia: W.B. Saunders, 1993. p. 7629. 7. USP dictionary of USAN and international drug names, 2002 ed. Rockville, MD: The United States Pharmacopeial Convention Inc. 2002. 8. The United States pharmacopeia. The national formulary. USP 26th revision (January 1, 2003). NF 21st ed. (January 1, 2003). Rockville, MD: The United States Pharmacopeial Convention Inc. 2002. p. 729, 2560. 9. Ewing PJ, Burrows G, MacAllister C, et al. Comparison of oral erythromycin formulations in the horse using pharmacokinetic proles. J Vet Pharmacol Ther 1994; 17: 1723. 10. Clarke CR, Barron SJ, Ayalew S, et al. Response of Pasteurella haemolytica to erythromycin and dexamethasone in calves with established infection. Am J Vet Res 1992; 53(5): 6847. 11. Prescott JF, Baggot JD, editors. Antimicrobial therapy in veterinary medicine. 2nd ed. Ames, Iowa: State University Press, 1993. p. 11926. 12. Jarp J, Bugge JP, Larsen S. Clinical trial of three therapeutic regimens for bovine mastitis. 1989; 124: 6304. 13. Erythromycin base (Novo-rythro Encap, Novopharm). In: Krogh CME. CPS Compendium of pharmaceuticals and specialties. 28th ed. Ottawa: Canadian Pharmaceutical Association, 1993. 14. Gallimycin-36 package insert (BimedaUS), Rec 2/17/03. 15. Hady PJ, Lloyd JW, Kaneene JB. Antibacterial use in lactating dairy cattle. J Am Vet Med Assoc 1993; 203(2): 1920. 16. Arrioja-Dechert A, editor. Compendium of veterinary products, CD ed. Port Huron, MI: North American Compendiums, Inc. 2002. 17. Gallimycin-36 package insert (A.P.A. of SanoCanada), Rec 2/13/95.

Withdrawal times: U.S.{R-3; 14; 16}

Withdrawal time Species Cows Meat (day) 14 Milk (hours) 36

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FLORFENICOL VeterinarySystemic 81

FLORFENICOL VeterinarySystemic
Some commonly used brand names for veterinary-labeled products are: Aquaor and Nuor. Note: For a listing of dosage forms and brand names by country availability, see the Dosage Forms section(s).

REGULATORY CONSIDERATIONS
U.S. Withdrawal times have been established for orfenicol in cattle; however, it is not labeled for use in lactating dairy cattle or in veal calves{R-1} (see the Dosage Forms section). Canada Withdrawal times have been established for orfenicol in cattle and salmon; however, it is not labeled for use in lactating dairy cattle{R-1} (see the Dosage Forms section).

CATEGORY:
Antibacterial (systemic).

INDICATIONS
Note: Bracketed information in the Indications section refers to uses that either are not included in U.S. product labeling or are for products not commercially available in the U.S.

CHEMISTRY
Source: A uorinated derivative of thiamphenicol{R-12}. Chemical name: Acetamide, 2,2-dichloro-N-[1-(ouromethyl)-2-hydroxy-2-[4-(methylsulfonyl)phenyl]ethyl]-[R-(R*,S*)]-{R-4}. Molecular formula: C12H14Cl2FNO4S{R-14}. Molecular weight: 358.21{R-4}. Description: Melting point 153 to 154 C{R-12}. Solubility: Soluble in water{R-12; 13}. Lipid soluble{R-13}.

GENERAL CONSIDERATIONS
Florfenicol is a broad-spectrum, primarily bacteriostatic, antibiotic with a range of activity similar to that of chloramphenicol, including many gram-negative and gram-positive organisms{R-1}; however, orfenicol does not carry the risk of inducing human aplastic anemia that is associated with chloramphenicol{R-13}. Florfenicol has been demonstrated to be active in vitro and in vivo against Mannheimia (Pasteurella) haemolytica, Pasteurella multocida, and Haemophilus somnus{R-1; 2}. In vitro studies have demonstrated orfenicol activity against Enterobacter cloacae, Escherichia coli, Klebsiella pneumoniae, Salmonella typhi, and Shigella dysenteriae{R-2; 15; 16} but with at least a 2- to 10-fold higher minimum inhibitory concentration than that for the Mannheimia, Pasteurella and Haemophilus species listed above{R-15; 16}. It also has activity against some chloramphenicol-resistant strains of bacteria{R-17}, possibly because it is less affected by the major enzyme produced in plasmid-mediated bacterial resistance against chloramphenicol and thiamphenicol{R-2; 26}. Although the activity of orfenicol against obligate anaerobes is not addressed in the literature, it is likely to be quite effective{R-28}.

PHARMACOLOGY/PHARMACOKINETICS
Mechanism of action/effect: Florfenicol is a bacteriostatic antibiotic that inhibits protein synthesis by binding to ribosomal subunits of susceptible bacteria, leading to the inhibition of peptidyl transferase{R-1; 13; 26} and thereby preventing the transfer of amino acids to growing peptide chains and subsequent protein formation. The bacterial receptor that is the site of action for orfenicol is considered to be the same as that for chloramphenicol and thiamphenicol{R-13; 26}. In the treatment of bovine respiratory disease, orfenicol may be considered bactericidal against some Mannheimia (Pasteurella) hemolytica and Pasteurella multocida when it is administered to achieve minimum inhibitory concentrations (MICs){R-14}; the minimum bactericidal concentrations (MBCs) are very close to the MICs. Florfenicol has a uorine atom instead of the hydroxyl group located at C-3 in the structure of chloramphenicol and thiamphenicol{R-13}. This may allow orfenicol to be less susceptible to deactivation by bacteria with plasmid-transmissible resistance that involves acetylation of the C-3 hydroxyl group in chloramphenicol and thiamphenicol, and prevents their interaction with bacterial ribosomes{R-13; 26}. Other actions/effects: Florfenicol, like thiamphenicol, lacks the nitro group located on the chloramphenicol aromatic ring that has been associated with chloramphenicol-induced, nondose-related, irreversible aplastic anemia in people{R-13; 24; 25}. However, chloramphenicol and thiamphenicol also cause a dose-dependent, reversible bone marrow suppression in some animals and people{R-13} due to mitochondrial injury{R-24}. It is theoretically possible that orfenicol could cause some dose-dependent, reversible bone marrow suppression, but it has not been clinically reported{R-13}.

ACCEPTED
Pneumonia, bacterial (treatment and control1)Cattle: Florfenicol injection is indicated in the treatment of bacterial pneumonia and associated respiratory infections (bovine respiratory disease) in cattle caused by susceptible M. haemolytica, P. multocida, and H. somnus{R-1; 3}. Florfenicol injection is also indicated in the control of bacterial pneumonia and associated respiratory disease in cattle at high risk of developing bovine respiratory disease associated with susceptible M. haemolytica, P. multocida, and H. somnus{R-1; 3; 32}. Pododermatitis (treatment)Cattle: Florfenicol injection is indicated in the treatment of infectious pododermatitis (interdigital phlegmon) associated with susceptible Fusobacterium necrophorum and Bacteroides melaninogenicus{R-1; 3; 30}. [Furunculosis (treatment)]Salmon: Florfenicol premix is indicated in the treatment of furunculosis caused by susceptible strains of Aeromonas salmonicida in salmon{R-11}. [Keratoconjunctivitis (treatment)]Cattle: Florfenicol injection is indicated in Canadian product labeling in the treatment of infectious bovine keratoconjunctivitis caused by Moraxella bovis{R-3; 33; 34}.
1

Not included in Canadian product labeling or product not commercially available in Canada.

Absorption: Bioavailability Intramuscular administration: Calves, 3 to 6 months of age78.5% (range 59.3 to 106%), with a dose of 20 mg per kg of body weight (mg/kg){R-1; 2; 8}. Cattle, lactating38 14%, with a dose of 20 mg/kg{R-9}. All rights reserved

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82 FLORFENICOL VeterinarySystemic Horses81%, with a dose of 22 mg/kg{R-19}. Oral administration: Calves, 2 to 5 weeks of age89%, at a dose of either 11 or 22 mg/kg; however, the absorption was widely variable{R-6; 7}. Oral absorption may decrease when orfenicol is administered with milk replacers{R-6; 7}; one study reported bioavailability that ranged from 44 to 86% among calves when orfenicol was administered 5 minutes after feeding{R-7}. Horses83.3%, with a dose of 22 mg/kg{R-19}. Salmon, Atlantic96.5%, with a dose of 10 mg/kg when water temperature is 10.8 1.5 C{R-22}. Note: After intramammary administration of a 20 mg/kg dose to lactating dairy cows, the systemic bioavailability was found to be 54 18%{R-9}. Distribution: Cattle, 2 to 5 weeks of ageAfter multiple oral dosing (11 mg/kg every twelve hours for seven doses), orfenicol was well distributed into many tissues, reaching concentrations of 4 to 8 mcg per gram (mcg/ gram) in lungs, heart, pancreas, skeletal muscle, spleen, and synovia{R-6}. These concentrations were at least as high as serum concentrations{R-6}. Relatively high concentrations were found in bile, kidney, small intestine, and urine{R-6}. Concentrations in the brain (1 to 2 mcg/gram), cerebrospinal uid (2 to 3 mcg/mL), and aqueous humor (2 to 3 mcg/mL) have been found to be one quarter to one half the serum concentration in healthy calves{R-6}. Salmon, AtlanticFlorfenicol is distributed to all organs and tissues with a dose of 10 mg/kg when the water temperature is 8.5 to 11.5 C{R-23}. Concentrations in muscle and blood are similar to serum concentrations, while fat and the central nervous system (CNS) have lower concentrations. Only 25% of serum drug and metabolite concentrations are found in the brain{R-23}. Volume of distribution (VolD) Intravenous administration: Calves, 2 weeks to 6 months of age Area: 0.88 liter per kg (L/kg){R-2}; 0.91 L/kg{R-6}. Steady state: 0.77 L/kg{R-1; 2; 8}; 0.87 L/kg{R-6}. Cattle Lactating: Steady state0.35 L/kg{R-9}. Nonlactating: Area0.67 L/kg (range, 0.62 to 0.76 L/kg){R-5}. Steady state0.62 L/kg (range, 0.57 to 0.68 L/kg){R-5}. Note: Although the data above imply that lactation causes a decrease in the volume of distribution of orfenicol, other data from these studies, including half-life of elimination and clearance, correlate well between the two trials, one conducted in lactating and one in nonlacting cattle. The apparent difference here between lactating and nonlactating cattle may be due to calculation methods or dosing{R-27}. Goats, lactatingSteady state: 0.98 0.09 L/kg{R-18}. HorsesSteady state: 0.72 0.17 L/kg{R-19}. Salmon, AtlanticSteady state: 1.12 L/kg at a water temperature of 10.8 1.5 C{R-22}. Protein binding: Calves, 3 to 6 months of age Low (12.7%), with serum concentration of 0.5 mcg/mL{R-2}. Low (13.2%), with serum concentration of 3 mcg/mL{R-1; 2}. Low (18.3%), with serum concentration of 16 mcg/mL{R-1; 2}. CattleConsidered independent of drug concentration: Low (17.5%), with serum concentration of 5 mcg/mL{R-5}. Low (18.6%), with serum concentration of 50 mcg/mL{R-5}. Biotransformation: CattleApproximately 64% of a 20 mg/kg dose of intramuscular orfenicol administered two times, 48 hours apart, is excreted as parent drug in the urine{R-13}. Urinary metabolites include orfenicol amine, orfenicol alcohol, orfenicol oxamic acid, and monochloroorfenicol{R-13}. Florfenicol and its metabolites, such as monochloroorfenicol and orfenicol oxamic acid, also are eliminated in the feces{R-13}. Florfenicol amine is the longest-lived major metabolite in the liver, and, therefore, it was used as the marker residue for withdrawal calculations{R-13}. Salmon, AtlanticFlorfenicol is rapidly metabolized at water temperatures of 8.5 to 11.5 C and the major metabolite is orfenicol amine{R-23}.

Half-life: DistributionIntravenous administration: Calves, less than 8 weeks of age0.13 hour (range, 0.075 to 0.27 hour){R-6}; 0.098 hour (range, 0.081 to 0.17 hour){R-7}. Elimination Intravenous administration: Calves, less than 8 weeks of age2.86 hours (range, 2.3 to 3.39 hours){R-7}; 3.71 hours (range, 3.5 to 4.11 hours){R-6}. Calves, 3 to 6 months of age2.6 hours (range, 2.4 to 3 hours){R-2; 8}. Cows Lactating: 2.9 hours{R-9}. Nonlactating: 3.2 hours{R-5}. Goats, lactating2.3 0.2 hours{R-18}. Horses1.8 0.9 hours{R-19}. Salmon, Atlantic12.2 hours at a water temperature of 10.8 1.5 C{R-22}. Intramuscular administration (terminal half-life): Calves, 3 to 6 months of age18.3 hours (range, 8.3 to 44 hours){R-1; 2}.

Concentrations: Peak serum concentration Intramuscular administration: Calves, 3 to 6 months of age3 mcg per mL (range, 1.43 to 5.6 mcg/ mL), with a dose of 20 mg/kg{R-1; 2; 8}. Cows, lactating2.3 mcg/mL, with a dose of 20 mg/kg{R-9}. Horses4 1.2 mcg/mL, with a dose of 22 mg/kg{R-19}. Oral administration: Calves, less than 8 weeks of age11.32 4.04 mcg/mL, with a dose of 22 mg/kg{R-7}. Horses13.8 4.8 mcg/mL, with a dose of 22 mg/kg{R-19}. Salmon, Atlantic4 mcg/mL, with a dose of 10 mg/kg when water temperature is 10.8 1.5 C{R-22}. Note: After intramammary administration of 20 mg/kg to lactating dairy cows, the peak serum concentration was 6.9 mcg/mL at 6 hours{R-9}. Time to peak serum concentration Intramuscular administration: Calves, 3 to 6 months of age3.33 hours (range, 0.75 to 8 hours), with a dose of 20 mg/kg{R-1; 2; 8}. Cows, lactating3 hours, with a dose of 20 mg/kg{R-9}. Horses1.3 0.5 hours, with a dose of 22 mg/kg{R-19}.

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FLORFENICOL VeterinarySystemic 83 Oral administration: Calves, less than 8 weeks of age2.5 0.72 hours, with a dose of 22 mg/kg{R-7}. Horses1.1 0.5 hours, with a dose of 22 mg/kg{R-19}. Salmon, Atlantic10.3 hours, with a dose of 10 mg/kg when water temperature is 10.8 1.5 C{R-22}. Other peak concentrationsIn milk: Intramuscular administration Cows, lactating: 1.6 mcg/mL at 10 hours, with a 20 mg/kg dose{R-9}. Intravenous administration: Cows, lactating: 5.4 mcg/mL at 3 hours, with a 20 mg/kg dose{R-9}. Goats, lactating: 13.2 1.9 mcg/mL at 1 hour, with a 25 mg/kg dose{R-18}. Duration of action: Calves, 3 to 6 months of ageThe serum concentration of orfenicol was maintained above 1 mcg per mL for 22.3 5.9 hours after intramuscular administration and 11.5 1.1 hours after intravenous administration of 20 mg/kg{R-2}. Salmon, AtlanticPlasma concentrations were maintained above the minimum inhibitory concentration of 0.8 mcg/mL reported for Aeromonas salmonicida, Vibrio anguillarum, and V. salmonicida for 36 to 40 hours after a single oral orfenicol dose of 10 mg/kg in water temperatures of 10.8 1.5 C{R-22}. Elimination: Calves, less than 8 weeks of ageApproximately 50% of a 22 mg/ kg intravenous dose is eliminated unchanged in the urine within 30 hours{R-7}. CattleApproximately 64% of a 20 mg/kg intramuscular dose administered two times, 48 hours apart, is excreted as parent drug in the urine{R-13}. HorsesApproximately 13% of a 22 mg/kg intravenous dose, 7% of the same dose given intramuscularly, and 6% when given orally, is excreted unchanged in the urine in the rst 30 hours{R-19}. RatsApproximately 60 to 70% of a 20 mg/kg oral dose administered once a day for 7 days is eliminated in the urine{R-13}. Approximately 20 to 30% is eliminated in the feces in the rst 24 hours after a 20 mg/kg oral dose{R-13}. Total clearanceIntravenous administration: Calves Less than 8 weeks of age: 2.9 mL per minute per kg (range, 2.44 to 4 mL/min/kg){R-6; 7}. 3 to 6 months of age: 3.75 mL/min/kg (range, 3.17 to 4.31 mL/ min/kg){R-1; 2; 8}. Cows Lactating: 2.7 0.6 mL/min/kg{R-9}. Nonlactating: 2.45 mL/min/kg (range, 2.25 to 2.67 mL/min/kg){R-5}. Goats, lactating8.1 2.6 mL/min/kg{R-18}. Horses6.7 1.7 mL/min/kg{R-19}. Salmon, Atlantic1.4 mL/min/kg when water temperature is 10.8 1.5 C{R-22}.

LACTATION
The effect of orfenicol on lactation has not been determined{R-1}. Goats: Florfenicol concentrations in milk equal serum concentrations when serum concentrations are nearly constant{R-18}.

MEDICAL CONSIDERATIONS/CONTRAINDICATIONS
The medical considerations/contraindications included have been selected on the basis of their potential clinical signicance (reasons given in parentheses where appropriate)not necessarily inclusive ( = major clinical signicance). Except under special circumstances, this medication should not be used when the following medical problem exists: Previous allergy or toxic reaction to orfenicol

SIDE/ADVERSE EFFECTS
The following side/adverse effects have been selected on the basis of their potential clinical signicance (possible signs in parentheses where appropriate)not necessarily inclusive:

THOSE INDICATING NEED FOR MEDICAL ATTENTION

Note: There is no documentation of dose-dependent, reversible bonemarrow suppression caused by orfenicol use in animals; however, the protection against human aplastic anemia, due to the difference in structure of orfenicol from chloramphenicol, does not necessarily protect against suppression of mitochondrial protein synthesis in bone marrow and subsequent reversible anemia{R-13}. This phenomenon is not considered a side/adverse effect with normal clinical use, but an awareness of this possibility may be useful if long-term therapy with this medication is considered. Incidence unknown Horses, ponies Diarrhea, mildin one study, occurred in all three horses and three ponies administered a single dose of 22 mg per kg of body weight by either the oral or parenteral route{R-19}.

THOSE INDICATING NEED FOR MEDICAL ATTENTION ONLY IF THEY CONTINUE OR ARE BOTHERSOME
Incidence unknown Cattle Decreased food consumption{R-1}usually transient; decreased water consumption{R-1}usually transient; diarrhea{R-1}usually transient; local tissue reactionsmore severe if administered at injection sites other than the neck{R-10}. Note: In a controlled study over 43 days, orfenicol administration had no long-term effect on body weight, rate of weight gain, or feed consumption, although a transient decrease in food and water consumption occurred at the start of therapy{R-1; 10}.

PRECAUTIONS TO CONSIDER PREGNANCY/REPRODUCTION

The effects of orfenicol on reproductive performance and pregnancy have not been determined{R-1}. Administration to breeding cattle is not recommended by product labeling{R-3}. 2003 Thomson MICROMEDEX

OVERDOSE
For more information in cases of overdose or unintentional ingestion, contact the American Society for the Prevention of Cruelty to Animals (ASPCA) National Animal Poison Control Center (888426-4435 or 900-443-0000; a fee may be required for consultation) and/or the drug manufacturer. All rights reserved

84 FLORFENICOL VeterinarySystemic

CLINICAL EFFECTS OF OVERDOSE

The following effects have been selected on the basis of their potential clinical signicance (possible signs in parentheses where appropriate)not necessarily inclusive: Acute Calves, with intramuscular administration of 200 mg per kg of body weight (mg/kg) repeated in forty-eight hours (10 times the label dose){R-1} Anorexia, marked{R-1}; decreased body weight{R-1}; decreased rumen activity{R-10}; decreased water consumption{R-1; 10}; ketosis, slight{R-10}secondary to anorexia; serum enzymes, including alanine aminotransferase [SGPT], aminoacyltransferase [GGT], aspartate aminotransferase [SGOT], and lactase dehydrogenase [LDH], mildy increased{R-1; 10}; soft feces{R-10} Chronic Dogs, 4- to 6-months old, with oral administration of 12 mg/kg a day for thirteen weeks{R-10} Hepatotoxicity Note: Oral dosing of 100 mg/kg for thirteen weeks resulted in CNS vacuolation, hematopoietic toxicity, renal tubule dilation, and testicular atrophy{R-10}.

ORAL DOSAGE FORMS

Note: Bracketed information in the Dosage Forms section refers to uses that either are not included in U.S. product labeling or are for products not commercially available in the U.S.

FLORFENICOL FOR MEDICATED FEED

Usual dose: [Furunculosis]Salmon: Oral, 10 mg per kg of body weight a day, administered in the only ration, according to manufacturer labeling{R-11}. Strength(s) usually available{R-35}: U.S. Veterinary-labeled product(s): Not commercially available. Canada Veterinary-labeled product(s): 500 grams per kg of premix (Rx) [Aquaor{R-11}]. Withdrawal times: Canada
Withdrawal time

TREATMENT OF OVERDOSE
There is no specic treatment for orfenicol overdose. Therapy should be supportive.

Species Salmon

Meat (days) 12

VETERINARY DOSING INFORMATION

Minimum inhibitory concentrations (MICs) of orfenicol were determined for pathogens involved in natural bovine respiratory complex in the U.S., Canada, and Europe between 1990 and 1993{R-1; 3}:
Number of Isolates MIC50 (mcg/mL) 0.5 0.5 0.25

Note: Not labeled for use in sh maintained at water temperatures less than 5 C. Packaging and storage: Store between 2 and 30 C (36 and 86 F), unless otherwise specied by the manufacturer. Keep separate from other feeds{R-11}. Store in a dry place{R-29}. Stability: Premix should be used within 12 months of opening pouch{R-11}. Medicated feed should be used within 6 months of the manufacture date{R-11}. Caution: Product labeling recommends that handlers avoid inhalation of dust and contact with skin and eyes{R-11}. Protective clothing should be worn when handling the medication and hands should be washed after administration{R-11}. USP requirements: Not in USP{R-31}.

Organism

MIC90 (mcg/mL) 1 0.5 0.5

Mannheimia (Pasteurella) 398 haemolytica Pasteurella multocida 350 Haemophilus somnus 66

Note: MIC can vary according to pathogen strain; therefore, cattle in different geographic locations may harbor organisms with different MICs{R-10}. Safety considerationsPrecautions for personnel administering orfenicol injection include the recommendation to avoid direct contact with eyes, skin, and clothing{R-1}. In case of accidental eye exposure, ush with water for 15 minutes; for skin exposure, wash with soap and water{R-1}. Remove exposed clothing and consult a physician if irritation persists. Accidental injection may cause local irritation and a physician should be consulted immediately{R-1}.

PARENTERAL DOSAGE FORMS

Note: Bracketed information in the Dosage Forms section refers to uses that either are not included in U.S. product labeling or are for products not commercially available in the U.S.

FLORFENICOL INJECTION FOR TREATMENT OF ADVERSE EFFECTS

Recommended treatment consists of the following: For anaphylaxis Parenteral epinephrine and cardiovascular support. Oxygen administration and respiratory support. Usual dose: Pneumonia (bovine respiratory disease) (treatment); or PododermatitisCattle: Intramuscular, 20 mg per kg of body weight to be repeated in fortyeight hours{R-1; 3}. Subcutaneous, 40 mg per kg of body weight as a single dose{R-1}.

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FLORFENICOL VeterinarySystemic 85 Note: Canadian product labeling lists the same dose as above, a single subcutaneous dose of 40 mg per kg of body weight or two intramuscular doses of 20 mg per kg of body weight, administered forty-eight hours apart, in the treatment of [keratoconjunctivitis] in cattle{R-3}. Pneumonia (bovine respiratory disease) (control)1Cattle: Subcutaneous, 40 mg per kg of body weight as a single dose{R-1; 32} Note: No more than 10 mL should be injected at each site{R-1}. Injections should be given in the neck to avoid local reaction and trim loss of edible tissues at slaughter{R-1}. According to the product labeling, if clinical improvement is not noted within twenty-four hours, the diagnosis should be reevaluated{R-1}. Strength(s) usually available{R-35}: U.S. Veterinary-labeled product(s): 300 mg per mL (Rx) [Nuor{R-1}]. Canada Veterinary-labeled product(s): 300 mg per mL (Rx) [Nuor{R-3}]. Withdrawal times: U.S.{R-1}
Withdrawal time Species Cattle Intramuscular injection Subcutaneous injection Meat (days)

Developed: 07/08/98 Revised: 6/30/02 Interim revision: 10/15/99; 04/04/03

REFERENCES
1. Nuor product information (Schering-PloughUS). Downloaded 1/16/03 from www.spah.com. 2. Lobell RD, Varma KJ, Johnson JC, et al. Pharmacokinetics of orfenicol following intravenous and intramuscular doses to cattle. J Vet Pharmacol Ther 1994; 17: 2538. 3. Nuor product information (Schering-PloughCanada). Downloaded from Schering-Plough Animal Health Product Label Retrieval Service on 2/21/03. 4. USP dictionary of USAN and international drug names, 2002 ed. Rockville, MD: The United States Pharmacopeial Convention, Inc.; 2002. 5. Bretzlaff KM, Neff-Davis CA, Ott RS, et al. Florfenicol in nonlactating dairy cows: pharmacokinetics, binding to plasma proteins, and effects on phagocytosis by blood neutrophils. J Vet Pharmacol Ther 1987; 10: 23340. 6. Adams PE, Varma KJ, Powers TE, et al. Tissue concentrations and pharmacokinetics of orfenicol in male veal calves given repeated doses. Am J Vet Res 1987 Dec; 48(12): 172532. 7. Varma KJ, Adams PE, Powers TE, et al. Pharmacokinetics of orfenicol in veal calves. J Vet Pharmacol Ther 1986; 9: 41225. 8. Varma KJ, Sams RA, Lobell RD, et al. Pharmacokinetics and efcacy of a new broad spectrum antibiotic, orfenicol in cattle. Acta Vet Scand Suppl 1991; 87: 1024. 9. Soback S, Paape MJ, Filep R, et al. Florfenicol pharmacokinetics in lactating cows after intravenous, intramuscular and intramammary administration. J Vet Pharmacol Ther 1995; 18: 4137. 10. Freedom of Information Summary. Nuor Injectable Solution for the treatment of bovine respiratory disease. NADA 141-063. Sponsor: Schering-Plough. June 1996. 11. Aquaor product labeling (Schering-PloughCanada). Downloaded from Schering-Plough Animal Health Product Label Retrieval Service on 2/21/03. 12. Budavari S, editor. The Merck Index. An encyclopedia of chemicals, drugs, and biologicals. 12th ed. Whitehouse Station, NJ: Merck Research Laboratories; 1996. p. 4146. 13. Sams RA. Florfenicol: chemistry and metabolism of a novel broad-spectrum antibiotic. In: Proceedings of the XVIII World Buiatrics Congress. Bologna, Italy; 1994. p. 137. 14. Varma KJ. Microbiology, pharmacokinetic disposition and safety of orfenicol in cattle. In: Proceedings of the XVIII World Buiatrics Congress. Bologna, Italy; 1994. p. 1824. 15. Syriopoulou VP, Harding AL, Goldmann DA, et al. In vitro antibacterial activity of ourinated analogs of chloramphenicol and thiamphenicol. Antimicrob Agents Chemother 1981 Feb; 19(2): 2947. 16. Marshall SA, Jones RN, Wanger A, et al. Proposed MIC quality control guidelines for national committee for clinical laboratory standards susceptibility tests using seven veterinary antimicrobial agents: ceftiofur, enrooxacin, orfenicol, penicillin G-novobiocin, pirlimycin, premaoxacin, and spectinomycin. J Clin Microbiol 1996 Aug; 34(8): 20279. 17. Martel J. In vitro activity of orfenicol on the primary pathogenic bacteria of the respiratory tract in european cattle. In: Proceedings of the XVIII World Buiatrics Congress. Bologna, Italy; 1994. p. 2530. 18. Lavy E, Ziv G, Soback S, et al. Clinical pharmacology of orfenicol in lactating goats. Acta Vet Scand 1991; 87 Suppl: 1336. 19. McKeller QA, Varma KJ. Pharmacokinetics and tolerance of orfenicol in Equidae. Equine Vet J 1996; 28(3): 20913. 20. Wilson DJ, Sears PM, Gonzalez RN, et al. Efcacy of orfenicol for treatment of clinical and subclinical bovine mastitis. Am J Vet Res 1996 Apr; 57(4): 5268. 21. Paape MJ, Miller RH. Effects of orfenicol, chloramphenicol, and thiamphenicol on phagocytosis, chemiluminescence, and morphology of bovine polymorphonuclear neutrophil leukocytes. J Dairy Sci 1990; 73: 173444. 22. Martinsen B, Horsberg TE, Varma KJ, et al. Single dose pharmacokinetic study of orfenicol in Atlantic salmon (Salmo salar) in seawater at 11 C. Aquaculture 1993; 112: 111. 23. Horsberg TE, Martinsen B, Varma KJ. The disposition of 14C-orfenicol in Atlantic salmon (Salmo salar). Aquaculture 1994; 122: 97106. 24. Yunis AA. Chloramphenicol: relation of structure to activity and toxicity. Annu Rev Pharmacol Toxicol 1988; 28: 83100. 25. Skolimowski IM, Knight RC, Edwards DI. Molecular basis of chloramphenicol and thiamphenicol toxicity to DNA in vitro. J Antimicrob Chemother 1983; 12: 53542.

28 38

Note: This product is not labeled for use in dairy cattle 20 months of age or older, veal calves, calves under 1 month of age, or calves being fed an all-milk diet{R-1} as withdrawal times have not been studied. If orfenicol is injected at sites other than the neck, local reaction may result in trim loss of edible tissue at slaughter{R-1}. Canada{R-3}
Withdrawal time Species Cattle Intramuscular injection Subcutaneous injection Meat (days)

36 55

Note: This product is not labeled for use in lactating dairy cattle{R-3}. Packaging and storage: Store below 40 C (104 F), preferably between 15 and 30 C (59 and 86 F), unless otherwise specied by the manufacturer. Protect from freezing. Caution: Florfenicol injection can be irritating to eyes and skin; therefore, avoid direct contact with skin, eyes, and clothes{R-1}. Accidental injection may cause local irritation{R-1}. Additional information: The light yellow to straw color of the solution does not affect potency{R-1}. USP requirements: Not in USP{R-31}.
1

Not included in Canadian product labeling or product not commercially available in Canada.

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86 FLORFENICOL VeterinarySystemic
26. Cannon M, Harford S, Davies J. A comparative study on the inhibitory actions of chloramphenicol, thiamphenicol and some uorinated derivatives. J Antimicrob Chemother 1990; 26: 30717. 27. Panel comment, Rec 8/25/97. 28. Panel comment, Rec 1/5/98. 29. Manufacturer comment, Rec 12/2/97. 30. Freedom of information summary. Nuor Injectable Solution for the treatment of bovine interdigital phlegmon. NADA 141-063 Sponsor: Schering-Plough Animal Health. Rev 1/99, Rec 5/5/99. 31. The United States pharmacopeia. The national formulary. USP 26th revision (January 1, 2003). NF 21st ed (January 1, 2003). Rockville, MD: The United States Pharmacopeial Convention, Inc., 2002. 32. Freedom of Information Summary. Nuor injectable solution for the control of respiratory disease in cattle at high risk. NADA 141-063. Sponsor: ScheringPlough Animal Health. December 17, 1998. 33. Dueger EL, Angelos JA, Cosgrove S, et al. Efcacy of orfenicol in the treatment of experimentally induced infectious bovine keratoconjunctivitis. Am J of Vet Res 1999; 60(8), 960964. 34. Angelos JA, Dueger EL, George LW, et al. Efcacy of orfenicol for treatment of naturally occurring infectious bovine keratoconjunctivitis. J Am Vet Med Assoc 2000 January 1; 216(1): 624. 35. Arrioja-Dechert A, editor. Compendium of veterinary products, CD ed. Port Huron, MI: North American Compendiums, Inc. 2003.

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FLUOROQUINOLONES VeterinarySystemic 87

FLUOROQUINOLONES VeterinarySystemic
This monograph includes information on the following: Ciprooxacin, Dioxacin, Enrooxacin, Marbooxacin, and Orbioxacin. Some commonly used brand names for veterinary-labeled products are:
Baytril 3.23% Concentrate Solution [Enrooxacin] Baytril Injectable Solution [Enrooxacin] Baytril Injectable Solution 2.27% [Enrooxacin] Baytril 100 Injectable Solution [Enrooxacin] Baytril Tablets [Enrooxacin] Baytril Taste Tabs [Enrooxacin] Dicural Tablets [Dioxacin] Orbax Tablets [Orbioxacin] Zeniquin Tablets [Marbooxacin]

Some commonly used brand names for human-labeled products are: Cipro [Ciprooxacin] and Cipro I.V. [Ciprooxacin]. Note: For a listing of dosage forms and brand names by country and availability, see the Dosage Forms section(s).

positive bacteria, mutation occurs at the topoisomerase-IV target (parC){R-9; 21; 86}. Other mechanisms of resistance occur when bacteria decrease the ability of the drug to enter the cell or increase active transport out of the cell{R-9; 21}. Resistance is usually chromosomally developed and, therefore, remains after antimicrobial therapy ends{R-90; 95}. While there is evidence for plasmid-mediated resistance, its clinical signicance in veterinary medicine has not been shown{R-90}. Cross-resistance of enrooxacin with other uoroquinolones can occur{R-9; 10; 50}. Changes in levels of resistance to uoroquinolones over time by Campylobacter and Salmonella species are being monitored because of their possible impact on human health{R-55; 56; 91}.

ACCEPTED
Colibacillosis (treatment)1Chickens and turkeys: Enrooxacin oral solution is indicated in the control of mortality associated with Escherichia coli infection in chickens and turkeys{R-3; 49}. Fowl cholera (treatment)1Turkeys: Enrooxacin oral solution is indicated in the control of mortality associated with Pasteurella multocida infection in turkeys{R-3}. Infections, bacterial (treatment), including Cystitis, urinary, bacterial (treatment); Respiratory infections, bacterial (treatment); or Skin and soft tissue infections (treatment) Cats: Enrooxacin [injection]1 and tablets{R-1; 104}, marbooxacin tablets1{R-97; 101}, and orbioxacin tablets{R-98; 100} are indicated in the treatment of susceptible bacterial infections in cats. Clinical efcacy has been established specically in the treatment of skin and soft tissue infections{R-1; 97; 98; 100; 102}. Dogs: Dioxacin tablets{R-96; 99}, enrooxacin injection and tablets{R-1; 104} , marbooxacin tablets{R-97; 101}, and orbioxacin tablets{R-98; 100} are indicated in the treatment of susceptible bacterial infections in dogs. Clinical efcacy has been established specically in the treatment of skin and soft tissue infections and urinary tract infections, as noted on product labeling{R-96101}. Clinical efcacy has also been established for enrooxacin injection and tablets in the treatment of respiratory tract infections in dogs{R-1}. [There is evidence to suggest that enrooxacin is as effective as chloramphenicol or tetracycline in the treatment of Rocky Mountain spotted fever in dogs{R-84}.]1 Pneumonia (treatment)1Cattle: Enrooxacin injection is indicated in the treatment of bovine respiratory disease caused by susceptible organisms, including Mannheimia (Pasteurella) haemolytica, Pasteurella multocida, and Haemophilus somnus{R-2; 57}.

CATEGORY:
Antibacterial (systemic).

INDICATIONS
Note: Bracketed information in the Indications section refers to uses that either are not included in U.S. product labeling or are for products not commercially available in the U.S.

GENERAL CONSIDERATIONS
The uoroquinolone antimicrobials are rapidly bactericidal against a variety of clinically important organisms, are well tolerated by animals, and can be administered by a variety of routes{R-95}. The members of this group that are currently labeled for use in animals have the same quinolone structure, each with modications that account for pharmacokinetic variations in the medications but do not signicantly change the antibacterial spectrum of activity.{R-1; 9598; 100; 102; 112} . Fluoroquinolones exhibit good activity against most gram-negative bacteria, including Escherichia coli, Enterobacter species, Klebsiella species, Pasteurella species, Proteus species, and Salmonella species. Pseudomonas aeruginosa is variably susceptible, usually having a higher minimum inhibitory concentration (MIC) than other susceptible organisms.{R-1; 9598; 100; 102; 112}. Some gram-positive bacteria are susceptible to uoroquinolones. Staphylococcus aureus and Staphylococcus intermedius usually are susceptible{R-1; 9698; 112}. However, the MIC values for staphylococci typically are higher than for gram-negative bacteria and staphylococcal resistance to uoroquinolones has been a problem in human patients{R-95}. Chlamydia, mycobacteria, mycoplasma, and ureaplasma can also be moderately to very susceptible to uoroquinolones{R-9}. Local factors that affect activity are cations at the site of infection and low pH; however, uoroquinolones are active in abscesses in spite of often unfavorable environmental conditions {R-95}. Bacterial resistance to uoroquinolones most commonly occurs by alteration of the target, DNA-gyrase (topoisomerase II), via mutation (gyr-A). Less commonly, but perhaps more importantly for gram 2003 Thomson MICROMEDEX

ACCEPTANCE NOT ESTABLISHED

Infections, bacterial (treatment) [Bustards, camels, ducks, emus, llamas, oryx, red pacu, African grey parrots, and pythons]1: In the U.S., for use only in animals not to be used for food productionAlthough the safety and efcacy of enrooxacin have not been established, dose recommendations for use in the treatment of susceptible bacterial infections have been made, based on pharmacokinetic data, for bustards{R-41}, camels{R-45}, ducks{R-42}, emus{R-43}, llamas{R-46}, oryx{R-47}, red pacu{R-44}, All rights reserved

88 FLUOROQUINOLONES VeterinarySystemic African grey parrots{R-39; 40}, and pythons{R-48}. Further clinical studies are necessary. See also the Regulatory Considerations section. [Horses]1: For use only in animals not to be used for food productionAlthough the safety and efcacy of enrooxacin and orbioxacin in the treatment of susceptible bacterial infections in horses have not been established, pharmacokinetic evidence and case reports are available to suggest that they may be safe and effective{R-2527; 7980; 136}. Due to reports of articular cartilage damage in foals from administration of enrooxacin, neither enrooxacin nor orbioxacin should be administered to horses less than 3 years of age, except as a last resort for severe infections not treatable with other medications{R-25; 26; 85}. Although there have been reports of unpublished studies showing articular damage from enrooxacin administration to adult horses, subsequent studies have shown no effect on cartilage in adults when used continuously for up to 21 days{R-86}. [Pigs, potbellied and minature]1: In the U.S., for use only in animals not to be used in food productionAlthough the safety and efcacy of enrooxacin in the treatment of susceptible bacterial infections in pigs have not been established, there is some pharmacokinetic evidence to suggest that this therapy may be effective{R-29}. See also the Regulatory Considerations section. [Sheep, pet and research]1: In the U.S., for use only in animals not to be used in food productionAlthough the safety and efcacy of enrooxacin in the treatment of susceptible bacterial infections in sheep have not been established, there is some pharmacokinetic evidence to suggest that this therapy may be effective{R-28}. See also the Regulatory Considerations section. [Bartonella infections (treatment)]1; or [Hemobartonella felis infections (treatment)]1Cats: Although the safety and efcacy have not been established, enrooxacin has been used in an attempt to eradicate Bartonella bacteremia in cats{R-72; 73}. Controlled therapeutic trials investigating the efcacy of enrooxacin in clearing Bartonella from cats show a positive response in some animals, but tests used to document that an infection has been cleared remain unreliable, making the results difcult to interpret{R-72}. It should not be assumed that a Bartonella infection is cleared by a course of enrooxacin. Long-term monitoring is necessary{R-72; 73}. Although the safety has not been clearly established, a controlled, randomized study demonstrated the efcacy of enrooxacin in the treatment of Hemobartonella felis infection, by showing it more quickly resolved clinical signs, raised hematocrit, and decreased organism counts than in control animals. In this study, some cats treated with a high dose of enrooxacin or with doxycycline were apparently cleared of the organism{R-83; 148}. [Brucellosis (treatment)]1Dogs: Historically, the treatment of dogs infected with Brucella canis has been controversial. Due to the zoonotic potential and the difculty in clearing the infection, some have advocated euthanasia of infected animals. Studies using a combination of tetracycline and dihydrostreptomycin did demonstrate that infected animals, following neutering, could be cured of the infection{R-139}. However, dihydrostreptomycin is no longer available in the US. The Centers for Disease Control recommend a combination of doxycycline and rifampin for the treatment of brucellosis in human patients{R-140}. In a clinical trial, rifampin plus ciprooxacin, a metabolite of enrooxacin, was shown to be as effective as the standard rifampin and doxycyline regimen in the treatment of human brucellosis{R-137}. It is not known whether the uoroquinolones have any efcacy in the treatment of canine brucellosis. [Chlamydial infections (treatment)]1Cats: There are no studies to document the effectiveness of the veterinary uoroquinolones, dioxacin, enrooxacin, marbooxacin, and orbioxacin, in the treatment of chlamydial infections in cats. Clinical trials of related human-labeled uoroquinolones in the treatment of genital, respiratory, or ocular chlamydial infections in human patients have shown efcacy; however, concern exists that the organisms are not eradicated and recrudecense is common. [Endophthalmitis, bacterial (treatment)]1Cats and dogs: There are no specic studies to document the effectiveness of the veterinary uoroquinolones, dioxacin, enrooxacin, marbooxacin and orbioxacin, in the treatment of bacterial endophthalmitis due to susceptible organisms. However, these bactericidal drugs have been shown to produce aqueous and vitreous humor concentrations within the therapeutic range for many pathogens{R-1; 102}. Also, related humanlabeled uoroquinolones, including ciprooxacin (a metabolite of enrooxacin), have been reported as efcacious in several small studies and case reports in human patients{R-120125}. [Meningitis, bacterial (treatment)]1Cats and dogs: There are no studies to document the effectiveness of the veterinary uoroquinolones, dioxacin, enrooxacin, marbooxacin, and orbioxacin, in the treatment of bacterial meningitis due to susceptible organisms. However, these bactericidal drugs have been shown to obtain central nervous system concentrations within the therapeutic range for many pathogens{R-1; 102}. Also, related human-labeled uoroquinolones, including ciprooxacin (a metabolite of enrooxacin), have been reported as efcacious in several small studies and case reports in human patients{R-126132}. Although the potential for uoroquinolones to induce seizures has been suggested as a reason to avoid these drugs in the treatment of meningitis, the above mentioned human studies, as well as disease models in animals, have failed to indicate an increased incidence of seizures in uoroquinolone-treated subjects. Careful monitoring for seizures is nevertheless advised if uoroquinolones are used in such infections. [Mycobacterial infections (treatment)]1Cats: Although the safety and efcacy have not been established, enrooxacin and ciprooxacin have been used in the treatment of mycobacterial infections in cats, based on case reports of successful treatment of cutaneous lesions of opportunistic mycobacteria{R-75; 76; 142}. There is some evidence to suggest that uoroquinolones are effective in the treatment of tubercular mycobacteriosis, an often serious but also often asymptomatic or insidious disease in cats. Cats are also prone to infection with Mycobacterium lepraemurium, which is a nontubercular form of mycobacteria. Safety and efcacy of uoroquinolones have not yet been proven in the treatment of M. lepraemurium, but successful treatment of the cutaneous form of mycobacterial infection with enrooxacin indicates possible efcacy in the treatment of nontubercular forms.{R-142} [Mycoplasmal infections (treatment)]1Although the efcacy has not been established, uoroquinolones have been used to treat infections caused by Mycoplasma species in animals. Activity of these antibiotics against Mycoplasma can be variable but enrooxacin and danooxacin have been shown to be consistently more active in vitro (minimum inhibitory concentrations [MIC] of 0.05 to 1.0 mcg/mL) against veterinary isolates than umequine{R-143}.

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FLUOROQUINOLONES VeterinarySystemic 89 [Pasteurellosis (treatment)]1Rabbits, pet and research: In the U.S., for use only in animals not to be used for food productionAlthough the safety and efcacy have not been established, there are some research data suggesting that parenteral enrooxacin can resolve clinical signs of pasteurellosis in many naturally infected rabbits, even though the organism is not consistently eradicated{R-6769}. See also the Regulatory Considerations section. Orbioxacin1-Cyclopropyl-7-(cis-3,5-dimethyl-1-piperazinyl)-5,6,8-triuoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid{R-7}. Molecular formula: CiprooxacinC17H28FN3O3{R-7}. Dioxacin hydrochlorideC21H19F2N3O3HCl{R-7}. EnrooxacinC19H22FN3O3{R-7}. MarbooxacinC17H19FN4O4{R-7; 97}. OrbioxacinC19H20F3N3O3{R-7; 98}. Molecular weight: Ciprooxacin331.34{R-7}. Dioxacin hydrochloride435.85{R-7}. Enrooxacin359.39{R-7}. Marbooxacin362.36{R-7; 97}. Orbioxacin395.38{R-7; 98}. Description: Ciprooxacin Hydrochloride USPFaintly yellowish to light yellow crystals{R-105}. Dioxacin hydrochlorideWhite to light yellow powder. EnrooxacinPale yellow crystals with a melting point of 219 to 221 C. OrbioxacinWhite to pale yellow crystalline powder{R-82}. pKa: CiprooxacinCarboxylic acid group, 6.1; tertiary amine, 7.8{R-95}. DioxacinCarboxylic acid group, 4.33; methyl substituted nitrogen group, 9.05{R-96}. EnrooxacinCarboxylic acid group, 6.0; tertiary amine, 8.8{R-95}. Orbioxacin5.95 and 9.01{R-98}. Solubility: Ciprooxacin hydrochlorideSparingly soluble in water; slightly soluble in acetic acid and in methanol; very slightly soluble in dehydrated alcohol; practically insoluble in acetone, in acetonitrile, in ethyl acetate, in hexane, and in methylene chloride{R-105}. DioxacinPoorly water soluble at neutral pH, more soluble under acidic conditions, and highly water soluble under basic conditions{R-96}. EnrooxacinSlightly soluble in water at pH 7. MarbooxacinSoluble in water; less soluble under alkaline conditions{R-97}. OrbioxacinSlightly soluble in water; more soluble in both acidic and alkaline conditions{R-98}.

UNACCEPTED
[Ehrlichiosis (treatment)]1Cats and dogs: The American College of Veterinary Internal Medicine Infectious Disease Study Group has stated that the treatment of choice for ehrlichiosis is doxycycline and that enrooxacin has not been found to be an effective treatment{R-149}. A small, short-term (15-day) study without follow-up showed that enrooxacin can be as effective as doxycycline in the treatment of naturally aquired ehrlichiosis in dogs{R-77}; however, another study of experimentally induced disease in which dogs were monitored after 21-day enrooxacin therapy showed poor efcacy in clearing the infection{R-138}.
1

Not included in Canadian product labeling or product not commercially available in Canada.

REGULATORY CONSIDERATIONS
U.S. Federal law prohibits the extralabel use of uoroquinolones in food-producing animals (21 CFR 530.41). The prohibition is based on a nding by the Food and Drug Administration that the extralabel use of these antibiotics in food-producing animals presents a risk to the public health because such use could increase the level of drug-resistant zoonotic pathogens at the time of slaughter{R-106}. Some researchers are concerned that such use can lead to the transfer of pathogens resistant to uoroquinolones from animals to human beings. Dioxacin, enrooxacin, marbooxacin, and orbioxacin are restricted to use by or on the order of a licensed veterinarian{R-1; 2; 94; 9698}. Ciprooxacin is not labeled for veterinary use. Canada Dioxacin, enrooxacin, marbooxacin, and orbioxacin are restricted to use by or on the order of a licensed veterinarian. They are not labeled for use in food-producing animals. Ciprooxacin is not labeled for veterinary use.

PHARMACOLOGY/PHARMACOKINETICS
Note: See also Table 1 and Table 2 at the end of this monograph.

CHEMISTRY
Chemical group: Quinolone carboxylic acid derivatives{R-1}. Chemical name: Ciprooxacin3-Quinolinecarboxylic acid, 1-cyclopropyl-6-uoro-1, 4-dihydro-4-oxo-7-(1-piperazinyl)-{R-7}. Dioxacin hydrochloride3-Quinolinecarboxylic acid, 6-uoro-1-(4-uorophenyl)-1,4-dihydro-7-(4-methyl-1-piperazinyl)-4-oxo, monohydrochloride{R-7}. Enrooxacin3-Quinolinecarboxylic acid, 1-cyclopropyl-7-(4-ethyl1-piperazinyl)-6-uoro-1,4-dihydro-4-oxo-{R-7}. Marbooxacin9-Fluoro-2,3-dihydro-3-methyl-10-(4-methyl-1-piperazinyl)-7-oxo-7H-pyrido[3,2,1-ij][4,1,2]benzoxadiazine-6-carboxylic acid{R-7}. 2003 Thomson MICROMEDEX Mechanism of action/effect: Bactericidal{R-2; 95100}. The uoroquinolones inhibit bacterial DNA gyrase or topoisomerase IV (a type II topoisomerase), thereby preventing DNA supercoiling and replication{R-1; 2; 86}. Cell respiration and division end, and other processes are interrupted, including membrane integrity{R-1}. Mammalian cell topoisomerase II is not affected by uoroquinolones until drug concentrations are at least 100 times higher than concentrations recommended to inhibit the bacteria{R-95}. Fluoroquinolones enter cells via porins and accumulate rapidly in susceptible bacteria{R-9}. Some bacteria are able to pump the antibiotic agent back out of the cell by an energy-dependent efux transport system{R-9}. All rights reserved

90 FLUOROQUINOLONES VeterinarySystemic The efcacy of the uoroquinolones is concentration dependent as measured by either the maximum concentration above MIC (Cmax: MIC) or the area under the curve above MIC (AUC : MIC; AUIC){R-9}. A post-antibiotic effect, in which growth of pathogens may remain inhibited for varying periods after uoroquinolone concentrations fall below inhibitory concentrations, has been demonstrated with enrooxacin and orbioxacin in some bacteria{R-9; 82}. Absorption: Oral absorption of uoroquinolones is high for most animals studied{R-1; 10; 97; 98}. It is not affected by administration with food, although absorption may be delayed{R-95}. Divalent and trivalent cations can affect absoprtion (see the Drug interactions section in this monograph){R-96}. In cats, dogs, and pigs, oral absorption of uoroquinolones approaches 100%, but in ruminants, it is generally less.{R-95} The horse may be unique regarding oral absorption patterns in that while enrooxacin is well absorbed, ciprooxacin is poorly absorbed.{R-144} Other uoroquinolones have not been studied as to oral bioavailability in horses. Absorption from parenteral administration of uoroquinolones is rapid and often nearly complete{R-9; 11; 22; 28; 29; 32; 41; 45}. In some animals, there is delayed absorption from intramuscular or subcutaneous administration, producing longer half-lives from these routes compared to intravenous absorption.{R-95} Enrooxacin OralRapidly absorbed in monogastric species and preruminant calves{R-1; 10}. Absorption in adult ruminants is variable and has ranged from 10 to 50%{R-86}. Distribution: Fluoroquinolones achieve concentrations that are at least as high as plasma in a wide range of tissues, with the exception of the central nervous system and the eye{R-1; 26; 9598}. This is true in many species, including cats, cattle, chickens, dogs, horses, and rabbits{R-1; 5; 15; 18; 26; 31; 32} . Differences in volume of distribution among the uoroquinolones however, account for a range of maximum plasma concentrations among the drugs. Drugs with the lowest volume of distribution are diluted less in body uid and produce higher plasma concentrations than drugs with a higher volume. The consequence of this difference is reected in the dose administered; to achieve the same peak serum concentration, drugs with a high volume of distribution require a higher dose{R-95}. Fluoroquinolones are rapidly accumulated in macrophages and neutrophils. Unlike other antibiotics that concentrate in subcellular sites within phagocytic cells, the quinolones are distributed into the cytosol where they can reach intracellular pathogens{R-20}. This concentration in leukocytes may explain the higher uoroquinolone concentrations in infected tissue compared to healthy tissue{R-95}. Because of renal elimination, urine concentration of uoroquinolones occurs in many species. Enrooxacin concentration in canine prostate tissue matches that in the serum and concentration in urine reaches about 100 times that in the serum{R-18; 19}. The orbioxacin concentration in canine prostate tissue exceeds that in serum and concentration in urine reaches about 50 times that in serum{R-82}. Even dioxacin, for which less than 5% of the dose is excreted into the urine in the dog, concentrations in the urine are 10 times plasma concentration after a single dose of 10 mg per kg of body weight (mg/kg){R-96}. After multiple oral doses in horses, urine concentrations are higher than serum concentrations{R-27}. MarbooxacinDogs: Tissue concentrations of marbooxacin were determined in healthy male beagle dogs at 2, 18, and 24 hours after a single oral dose (2.75 or 5.5 mg/kg). Based on the terminal elimination half-life and the dosing interval, steady-state levels are reached after the third dose and are expected to be approximately 25% greater than those achieved after a single dose.

Protein binding: CiprooxacinDogs: 44 3%{R-12}. DioxacinDogs: 46 to 52%{R-97}. Enrooxacin Camels: Concentration dependent 1.7% at 1.8 mcg of enrooxacin per mL of serum (mcg/mL){R-45}. 5% at 0.6 mcg/mL{R-45}. 24.2% at 0.33 mcg/mL{R-45}. Cattle, lactating: 36 to 45%{R-11}. Chickens: 24 2%{R-30}; 21 0.1{R-12}. Dogs: 72% at 1 mcg/mL{R-86}. Horses: 22 2%{R-12}. Pigs: 27 3%{R-12}. Rabbits: Up to 30 days of age40 to 50%{R-34; 35}. Adult53 1%{R-12}. Does, pregnant35 5%{R-63}. Marbooxacin{R-97} Cats: 7.3% Dogs: 9.1% OrbioxacinDogs: 7.7 to 14.5%{R-82}.

Biotransformation: DioxacinIn the dog, dioxacin is metabolized to an ester glucuronide and the desmethyl derivative{R-96}. EnrooxacinEnrooxacin is de-ethylated to form ciprooxacin, an antimicrobically active metabolite in many species{R-11; 13; 18; 22; 24; 28; 29; 31; 39; 42; 46; 71; 72} . Therefore, microbiologic assays in pharmacokinetic studies are likely to measure the activity of both enrooxacin and ciprooxacin combined. Because minimum inhibitory concentrations for some pathogens are lower for ciprooxacin than for enrooxacin{R-13}, therapeutic concentrations of ciprooxacin can be reached with dosing calculated to achieve effective enrooxacin concentrations{R-16; 25; 28}. Ciprooxacin can be considered an important contributor to the activity of enrooxacin{R-16; 28}. Evaluations of enrooxacin activity based on serum or tissue concentrations should consider the contributions of both enrooxacin and ciprooxacin. It is also possible that other as yet undiscovered metabolites have antimicrobial activity{R-16}. Cats: After oral administration, the half-time for conversion of enrooxacin to ciprooxacin is about 13 minutes{R-22}. Ciprooxacin serum concentration is about 20% of the enrooxacin concentration in the serum at any one time; about 10% at maximum serum concentrations{R-22; 72; 86}. Cattle, lactating: The serum concentration of ciprooxacin is 35% that of enrooxacin during the elimination phase, after an intravenous dose of 5 mg/kg{R-11}. Chickens: Enrooxacin is extensively metabolized to ciprooxacin{R-31}.

2003 Thomson MICROMEDEX

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FLUOROQUINOLONES VeterinarySystemic 91 Dogs: Overall, 40% of the oral or intravenous enrooxacin dose administered is metabolized to ciprooxacin{R-23}. Ciprooxacin makes up about 20% of the total serum concentration of enrooxacin and ciprooxacin after enrooxacin administration; ciprooxacin makes up about 35% of the total body concentration when calculated based on the area under the concentration-time curve (AUC){R-16; 18; 86}. Ducks: Less than 10% of the administered enrooxacin dose is converted to ciprooxacin after a 10 mg/kg dose{R-42}. Horses: The concentration of ciprooxacin in the serum reaches 20 to 35% of the enrooxacin concentration in adult horses{R-24}. In foals, the amount of ciprooxacin measured is negligible{R-85}. Llamas: Approximately 36% of enrooxacin administered is converted to ciprooxacin in llamas{R-46}. Macaques, long-tailed: Ciprooxacin makes up about 22% of the total amount of active drug measured in the serum after intramuscular administration of 5 mg/kg of enrooxacin{R-71}. Parrots, African grey: Ciprooxacin concentration in the serum reaches 3 to 78% of the enrooxacin dose administered{R-39}. The ratio of ciprooxacin to enrooxacin in the serum increases with multiple dosing over 10 days{R-39}. Pigs: The concentration of ciprooxacin in the plasma comprises less than 10% of the amount of enrooxacin present in the plasma{R-29}. Sheep: In one study, the concentration of ciprooxacin in the plasma reached 35 and 55% of the serum enrooxacin concentrations, with intravenous and intramuscular administration, respectively, of a 2.5 mg/kg dose{R-28}. Another study found the concentration of ciprooxacin in the plasma to be 10 to 20% of the serum drug concentration{R-86}. MarbooxacinDogs: 10 to 15% of the dose is metabolized in the liver{R-97}. feces while renal clearance accounts for less than 5% of dioxacin elimination{R-96}. EnrooxacinRenal. Primarily by glomerular ltration and tubular secretion{R-10}. Marbooxacin Cats: Primarily renal. 70% of an oral dose is excreted into the urine as parent drug and metabolites{R-97}. Dogs: 40% of an oral or subcutaneous dose is excreted as parent drug into the urine. Elimination of parent drug into the feces is also a signicant route of elimination{R-97; 115}. Orbioxacin Cats: Of the orbioxacin eliminated in urine after subcutaneous administration, 96% is unchanged parent drug and 4% is N-hydroxy orbioxacin, an active metabolite with somewhat higher MICs for pathogens sensitive to orbioxacin{R-111}. Dogs: 40% of an oral dose is excreted as parent drug into the urine{R-97}. Of the orbioxacin eliminated in the urine after a subcutaneous dose, 87% is parent compound and 13% is glucuronide metabolite{R-111}.

PRECAUTIONS TO CONSIDER BACTERIAL RESISTANCE

Concerns about the risk of increasing resistance of human pathogens to uoroquinolones as well as the ability of infections in animals to resist treatment should be considered by health practitioners when prescribing these medications. There have been warnings by infectious disease experts that widespread use of uoroquinolones may lead to increased resistance, and transfer of resistance to humans has been suggested for Campylobacter species and Salmonella typhimurium type DT-104. Increased resistance in Campylobacter jejuni infecting people was reported after 1995, the same period in which uoroquinolones were rst approved for use in poultry. There has also been discussion about the appearance of resistant strains of Salmonella typhimurium during the time uoroquinolones have been used in livestock. However, some resistant strains have been traced to farms that were not administering uoroquinolones, leading to the suggestion that the resistance may have arisen spontaneously{R-95}. As scientists continue to uncover evidence pertaining to the potential for transfer of uoroquinolone-resistant pathogens from animals to man, uoroquinolones have had limited approval for use in foodproducing animals and extra-label use in these animals is prohibited in the United States{R-95; 106}.

Serum concentrations: Chickens Mean plasma concentrations at 6, 12, and 24 to 168 hours after beginning oral administration of enrooxacin at a dose of 25 parts per million (ppm) in the drinking water were 0.241, 0.317, and 0.381 mcg/mL, respectively{R-3}. Mean plasma concentrations at 6, 12, and 24 to 168 hours after beginning oral administration of enrooxacin at a dose of 50 ppm in the drinking water were 0.464, 0.653, and 0.712 mcg/mL, respectively{R-3}. Turkeys Mean plasma concentrations at 6 hours and 24 to 168 hours after beginning oral administration of enrooxacin at a dose of 25 ppm in the drinking water were 0.204 and 0.240 mcg/mL, respectively{R-3}. Mean plasma concentrations at 6 hours and 24 to 168 hours after beginning oral administration of enrooxacin at a dose of 50 ppm in the drinking water were 0.352 and 0.458 mcg/mL, respectively{R-3}.

SPECIES SENSITIVITY
Cats: Because of the risk of retinal degeneration that has been associated with enrooxacin administration at high doses (20 mg per kg of body weight [mg/kg] a day){R-1}, it has been recommended that administration of high doses of all uoroquinolones be avoided in cats whenever possible. However, it may be that not all uoroquinolones have the same potential to cause retinal damage. Limited studies show that marbooxacin caused no retinal changes visible with fundiscopic or histologic examination when administered to 8-month-old cats at 10 times the recommended dosage for 2 weeks{R-97}, whereas enrooxacin has been shown to cause ocular lesions at 4 times the recommended dosage{R-1}. A study with orbioxacin showed that no All rights reserved

Elimination: DioxacinDogs: Primarily through glucuronidation and subsequent biliary secretion. The glucuronide metabolite may be hydrolyzed back to the parent compound and reabsorbed in the gastrointestinal tract. After intravenous administration, 80% of the dose is eliminated in the 2003 Thomson MICROMEDEX

92 FLUOROQUINOLONES VeterinarySystemic retinal changes were visible with fundoscopic or histologic examination when administered to cats at levels which exceeded the highest recommended dose of 7.5 mg/kg{R-146}. Cattle: Federal law prohibits the extra-label use of uoroquinolones in food-producing animals (see the Regulatory Considerations section). The following information is included in case of accidental dosing. Enrooxacin appears rapidly in milk after parenteral administration, reaching a peak concentration at 30 to 60 minutes after intravenous injection, followed by a gradual decline in milk concentration similar to that occurring in serum concentration{R-11; 14}. Approximately 0.2% of a 5 mg per kg of body weight dose of enrooxacin is measured in milk in the rst 24 hours; therapeutic antimicrobial concentrations can be reached{R-11}. The ciprooxacin metabolite of enrooxacin also appears rapidly in milk, but this occurs 4 to 8 hours after parenteral administration. It concentrates to a higher peak than enrooxacin itself{R-11; 14}. Horses: Following an oral dose of 5 mg/kg to lactating mares, concentration of ciprooxacin and enrooxacin in milk ranged from 0.25 to 0.78 mcg per mL. At this concentration, a nursing foal would ingest a dose of less than 0.1 mg per kg of body weight a day, producing plasma concentrations in the foal below detection limits{R-86}. Rabbits: Therapeutic concentrations of enrooxacin are reached in milk following a dose of 7.5 mg per kg of body weight{R-34}.

CARCINOGENICITY
EnrooxacinNo evidence of carcinogenicity was found in studies of laboratory animal models{R-3}.

PREGNANCY/REPRODUCTION
The attributes of uoroquinolones make them likely to cross the placenta in many species; however, adverse effects have not yet been reported when uoroquinolones have been administered to pregnant animals{R-95}. Adequate and well-controlled studies of the effects of uoroquinolones in pregnant human beings have not been done; however, administration during human pregnancy is generally not recommended, based on reports of arthropathy in immature animals{R-107}. CiprooxacinCiprooxacin crosses the human placenta{R-107}. Intravenous doses of ciprooxacin of up to 20 mg per kg of body weight (mg/kg) in pregnant rats and mice have not shown evidence of maternal toxicity, embryotoxicity, or teratogenic effects{R-107}. Dioxacin, marbooxacin, and orbioxacinSafety in breeding or pregnant animals has not been determined{R-9698}. Enrooxacin Cats, cattle, turkeys: Effect on reproduction or pregnancy has not been established{R-13}. Chickens: No adverse effects were noted in measured reproductive parameters when male and female chickens were given an enrooxacin dose of 150 parts per million in the drinking water for 7 days. This regimen was repeated at ve different ages between 1 day and 206 days of age with no reproductive effect noted{R-3}. The parameters measured included egg production, egg weight, hatchability, chick viability, and reproductive histology of treated birds and their hatched chicks{R-4}. Dogs: No adverse effects were noted in measured reproductive parameters, including libido, successful pregnancy, and number of pups per litter, when male dogs were administered 5 to 15 mg/kg a day for 10 days beginning at 90, 45, or 14 days before breeding{R-1; 5}. No adverse effects were noted in female dogs administered 15 mg/kg a day for 10 days in the last 30 days before breeding, between the 10th and 30th days of gestation, between the 40th and 60th days of gestation, or during the rst 28 days of lactation{R-1; 5; 6}. Rabbits: Enrooxacin is transferred across the placenta in rabbits{R-63}; adverse effects on pups have not been reported. Ciprooxacin also crosses the placenta but at a much slower pace (6% of the rate of enrooxacin){R-63}.

PEDIATRICS
See also the Side/Adverse Effects section for information on risk of arthropathies in immature animals. Enrooxacin Calves: Until at least 1 week of age, the elimination of enrooxacin is slower in calves than in adult cattle{R-13}. Adjustment of dosage, including increased dosing interval, may be necessary{R-13}. Foals: Elimination of enrooxacin in foals (half-life = 18 hrs) is slower than in adult horses and oral absorption in foals is approximately 42%{R-86; 88}. Administering enrooxacin at a dose of 10 mg per kg a day caused every one of ve healthy foals to have lesions on articular cartilage{R-85}. Rabbits: Elimination of enrooxacin is signicantly less in neonates until at least 16 days of age compared with that in adult rabbits{R-34}. The ease of penetration of enrooxacin into milk should be considered when treating lactating does that continue to nurse{R-35}. Enrooxacin pharmacokinetics in 30-day-old rabbits are similar to those in adult rabbits{R-35}.

DRUG INTERACTIONS AND/OR RELATED PROBLEMS

The following drug interactions and/or related problems have been selected on the basis of their potential clinical signicance (possible mechanism in parentheses where appropriate)not necessarily inclusive ( = major clinical signicance): Note: Combinations containing any of the following medications, depending on the amount present, may also interact with this medication. Digoxin: A small study investigating specically the effect of enrooxacin administration on digoxin clearance and serum concentrations in dogs showed no effect with concomitant administration{R-59}. Antacids, aluminum-, calcium-, or magnesium-containing or Laxatives, magnesium-containing or Multivitamins or Sucralfate or All rights reserved

LACTATION
Because of the risk of producing arthropathies in immature animals, it has been recommended that signicant levels of uoroquinolones in the milk of nursing animals be avoided{R-95; 107}. Fluoroquinolones can be distributed into milk, sometimes at a higher concentration than in plasma,{R-1114; 34} but it is not known under what conditions signicant amounts might be absorbed by nursing animals{R-86}. MastitisIt has not been shown that uoroquinolones are effective in treating mastitis{R-95}, perhaps because of factors in milk that inhibit activity{R-11}. 2003 Thomson MICROMEDEX

FLUOROQUINOLONES VeterinarySystemic 93 Zinc (compounds containing divalent or trivalent cations, such as aluminum, calcium, iron, magnesium, or zinc, administered concurrently with a uoroquinolone, may reduce the absorption of the uoroquinolone{R-1; 9698}) Theophylline{R-61} or Hepatically metabolized drugs, other{R-1} (in dogs, the clearance of theophylline was reduced by 43% with the concurrent administration of enrooxacin [5 mg per kg of body weight every 24 hours]; peak serum concentration of theophylline was signicantly increased; the pharmacokinetics of enrooxacin were unaffected{R-62}) (the concurrent administration of a uoroquinolone with other drugs metabolized by hepatic enzymes may affect the pharmacokinetics of one or both drugs{R-1}; enrooxacin has been shown to inhibit liver microsomal mixed-function oxidases in broiler chicks, including aniline hydroxylase and aminopyrine N-demethylase{R-60}; cytochrome P450 activity was not signicantly affected in chickens{R-60}; in mice, there is indirect evidence that cytochrome P450 enzymes may be affected by enrooxacin administration{R-62}; the effect of these enzyme inhibitions on specic drugs has not yet been demonstrated) quinolone antibiotics may increase the risks of CNS stimulation and convulsions) Cyclosporine (concurrent use with ciprooxacin has been reported to elevate serum creatinine and serum cyclosporine concentrations; other studies have not found ciprooxacin to alter the pharmacokinetics of cyclosporine; cyclosporine concentrations should be monitored when used concurrently with uoroquinolones, and dosage adjustments may be required) Probenecid (concurrent use of probenecid decreases the renal tubular secretion of uoroquinolones, resulting in decreased urinary excretion of the uoroquinolone, prolonged elimination half-life, and increased risk of toxicity; this interaction is more signicant with uoroquinolones excreted largely unchanged in the urine, and of less clinical signicance with uoroquinolones that have larger nonrenal elimination, such as ciprooxacin) Warfarin (concurrent use of warfarin with ciprooxacin has been reported to increase the anticoagulant effect of warfarin, increasing the chance of bleeding; other studies have not found uoroquinolones to alter the prothrombin time [PT] signicantly; however, it is recommended that the PT of patients receiving warfarin and uoroquinolones concurrently be monitored carefully)

HUMAN DRUG INTERACTIONS AND/OR RELATED PROBLEMS{R-107}

In addition to the above drug interactions reported in animals, the following drug interactions have been reported in humans, and are included in the human monograph Fluoroquinolones (Systemic) in USP DI Volume I; these drug interactions are intended for informational purposes only and may or may not be applicable to the use of uoroquinolones in animals: Note: There are no dioxacin, enrooxacin, marbooxacin, or orbioxacin products labeled for use in human beings. Anticonvulsants, hydantoin, especially: Phenytoin (concurrent administration of ciprooxacin with phenytoin has resulted in a 34 to 80% decrease in the plasma concentration of phenytoin; caution should be used when administering quinolones, especially ciprooxacin, to patients stabilized on phenytoin; careful monitoring of phenytoin dosage after discontinuation of quinolones is highly recommended) Antidiabetic agents, sulfonylurea, especially: Glyburide or Insulin (concurrent use of ciprooxacin with glyburide or other antidiabetic agents has, on rare occasions, resulted in hypoglycemia; also, hyperglycemia and hypoglycemia have been reported in patients taking quinolone antibiotics and antidiabetic agents concurrently; since the mechanism is not understood, similar effects with other sulfonylurea antidiabetic agents may be expected when these medications are used with uoroquinolones; careful monitoring of blood glucose concentrations is recommended when these medications are used concurrently) Anti-inammatory drugs, nonsteroidal (NSAIDs) (uoroquinolones are competitive inhibitors of gamma-aminobutyric acid receptor binding, and some NSAIDs have been shown to enhance this effect; concurrent administration of NSAIDs with 2003 Thomson MICROMEDEX

HUMAN LABORATORY VALUE ALTERATIONS{R-107}

The following laboratory value alterations have been reported in humans, and are included in the human monograph Fluoroquinolones (Systemic) in USP DI Volume I; these laboratory value alterations are intended for informational purposes only and may or may not be applicable to the use of uoroquinolones in the treatment of animals: Note: There are no dioxacin, enrooxacin, marbooxacin, or orbioxacin products labeled for use in human beings. With physiology/laboratory test values Alanine aminotransferase (ALT [SGPT]) and Alkaline phosphatase and Amylase and Aspartate aminotransferase (AST [SGOT]) and Lactate dehydrogenase (LDH) (serum values may be increased)

MEDICAL CONSIDERATIONS/CONTRAINDICATIONS
The medical considerations/contraindications included have been selected on the basis of their potential clinical signicance (reasons given in parentheses where appropriate)not necessarily inclusive ( = major clinical signicance). Except under special circumstances, this medication should not be used when the following medical problems exist: Hypersensitivity to quinolones{R-1; 3} (animals with a history of hypersensitivity to quinolones are at risk for developing reactions to them{R-1; 97; 98}) Immature animals in some species{R-1} (uoroquinolone administration during rapid growth has been associated with arthropathies and cartilage erosions in weightbearing joints in immature cats, dogs, and horses{R-1; 4; 5; 25; 26; 85; 96-98} ; in dogs, enrooxacin has been shown to cause abnormal carriage of the carpal joint and hindlimb weakness, as well as All rights reserved

94 FLUOROQUINOLONES VeterinarySystemic cartilage lesions; administration of enrooxacin should be avoided in small and medium breed dogs during rapid growth, typically 2 to 8 months of age; large or giant breeds may rapidly grow until 18 months of age{R-1}) Risk-benet should be considered when the following medical problems exist: Central nervous system (CNS) disorders{R-1} Seizures, history of (uoroquinolones have been associated with CNS stimulation that may lead to seizures in a few rare cases and should be used with caution{R-1; 2}; the clinical signicance of a report of increased seizure incidence with enrooxacin administration to dogs with phenobarbital-controlled seizures is not known{R-10}) Hepatic disease, severe Renal failure (uoroquinolones are primarily eliminated by a combination of renal clearance and hepatic metabolism, sometimes with signicant biliary secretion; the predominance of one route over another depends on the quinolone and the animal species; there is little research information on changes in elimination in various disease states in animals; the induction of moderate renal impairment in dogs [glomerular ltration rate decreased 37% and serum creatinine values increased 85% from normal controls] had only a minor effect on the clearance of marbooxacin{R-108}) In unpublished manufacturer data, a dose of 5 mg/kg administered to foals once a day was reported to cause cartilage lesions and signs of arthropathy after 6 days{R-25}; however, studies have shown no effect on cartilage in adults when used continuously for up to 21 days{R-86; 136}. In 23-day-old calves, a dose of 25 mg/kg a day for 15 days had no measurable effect on articular cartilage in the stie joint at 2 and 9 days after the end of treatment{R-2}. MarbooxacinLameness and articular cartilage lesions were reported in large breed, 3- to 4-month-old dogs administered 11 mg/kg a day for 14 days{R-97}. OrbioxacinMicroscopic cartilage lesions typical of uoroquinolone arthropathy have also been reported with orbioxacin administration; in one of eight, 8- to 10-week-old puppies given 12.5 mg/kg a day and all 8 puppies given 25 mg/kg a day{R-98}. Cats appear to be resistant to this effect, showing no cartilage lesions after one month of a 25 mg/kg-a-day dose{R-98}. Cats Retinal degeneration (acute blindness, mydriasis)reported with enrooxacin at doses higher than 5 mg per kg of body weight (mg/kg) a day Note: Administering enrooxacin to cats at a dose of 20 mg/kg can cause retinal degeneration{R-1; 103}, often manifested as temporary or permanent blindness with mydriasis{R-1; 103; 119}. Mild to severe fundic lesions are observed on ophthalmologic exam of affected cats, including changes in the color of the fundus and central or generalized retinal degeneration. There are also abnormal electroretinogram results and diffuse light microscopic changes in the retinas{R-1}. Retinal degeneration has not been reported in cats in association with other uoroquinolones; however, caution is recommended when considering high dose therapy of any uoroquinolone in cats. Cats and dogs Ataxia; seizureswith enrooxacin Note: Although ataxia and seizures were not observed during preapproval clinical eld trials, they have been noted as part of voluntary postapproval adverse drug experience reporting{R-1}. Parrots, African grey Appetite, decreased{R-40}; polydipsia and polyuria{R-39; 40}with a dose of 30 mg/kg every 12 hours for 10 days{R-39} or in drinking water with 1.5 to 3 mg/mL of water{R-40}; may resolve within 2 or 3 days of treatment cessation{R-39}

PATIENT MONITORING
The following may be especially important in patient monitoring (other tests may be warranted in some patients, depending on condition; = major clinical signicance): Culture and sensitivity in vitro and Minimum inhibitory concentration (MIC) (in vitro cultures and MIC tests should be done on samples collected prior to uoroquinolone administration to determine pathogen susceptibility)

SIDE/ADVERSE EFFECTS
The following side/adverse effects have been selected on the basis of their potential clinical signicance (possible signs in parentheses where appropriate)not necessarily inclusive:

THOSE INDICATING NEED FOR MEDICAL ATTENTION

Incidence unknown Multiple species Arthropathyin immature animals, especially dogs and foals Note: The risk of arthropathy increases with increasing dose but has been reported to occur at recommended dosages in young dogs. DioxacinArticular cartilage lesions were seen in 15- to 16-weekold puppies administered dioxacin at 5, 25, or 35 mg per kg of body weight (mg/kg) a day for 90 days{R-96}. Cartilage lesions and lameness were observed in puppies administered 50 and 125 mg/kg a day{R-96}. EnrooxacinCartilage damage has been observed in 10- to 28week-old puppies with an oral enrooxacin dose of 5 to 25 mg/kg a day for 30 days and 5- to 7-month-old kittens with an oral dose of 25 mg/kg a day for 30 days{R-1; 5}; changes include splitting of the articular cartilage surface and, in some cases, necrosis of the hyaline cartilage{R-4}. Arthropathy has been reported in growing horses{R-25; 26}. 2003 Thomson MICROMEDEX

THOSE INDICATING NEED FOR MEDICAL ATTENTION ONLY IF THEY CONTINUE OR ARE BOTHERSOME
Incidence more frequent Cats Vomitingwith enrooxacin, occasional vomiting was observed in up to 75% of 7- to 10-month-old cats administered a 5 to 15 mg/kg dose for 30 days; however, 25% of untreated cats also vomited occasionally{R-1}. Incidence less frequent Cats Diarrheareported with marbooxacin (2.1% of cats in one report){R-97} Dogs Decreased activityreported with marbooxacin (4.4% of dogs in one report){R-97}; decreased appetitereported with marbooxacin (5.4%){R-97}; vomitingreported with marbooxacin (2.9%){R-97} All rights reserved

FLUOROQUINOLONES VeterinarySystemic 95 Incidence rare Cats Vomitingwith marbooxacin (<1%){R-97} Dogs Vomitingwith enrooxacin (0.7% of dogs){R-1} Incidence unknown Cattle{R-2}, horses{R-24}, and rabbits{R-68; 69} Local tissue reaction, transientin cattle, can cause trim loss of edible tissue at slaughter{R-2} Dogs Anorexia; decreased appetite; diarrhea; vomitingwith dioxacin Note: No adverse effects were reported in association with a clinical study using recommended dosages of dioxacin in dogs. Anorexia, decreased appetite, diarrhea, and vomiting have been reported in clinical cases{R-96} but the incidence is unknown. Some patients note a reduced incidence of nausea and taste perversion if the dose is administered in the evening. Photosensitivity reactions generally appear within a few days of the start of uoroquinolone treatment but can occur up to 3 weeks after its discontinuation. The reactions usually subside within 1 month of discontinuation. Indicating possible phototoxicity, pseudomembranous colitis, or tendinitis or tendon rupture and the need for medical attention if they occur after medication is discontinued: Abdominal or stomach cramps and pain, severe; abdominal tenderness; blisters; diarrhea, watery and severe, which may also be bloody; fever; pain in calves, radiating to heels; sensation of skin burning; skin rash, itching, or redness; swelling of calves or lower legs

OVERDOSE
For more information in cases of overdose or unintentional ingestion, contact the American Society for the Prevention of Cruelty to Animals (ASPCA) National Animal Poison Control Center (888426-4435 or 900-443-0000; a fee may be required for consultation) and/or the drug manufacturer. Reported lethal doses of enrooxacin Cats: 125 mg per kg of body weight (mg/kg) a day for 5 days{R-1}. Dogs: Oral125 mg/kg a day for up to 11 days{R-1; 5}. Mice: OralLD50 for female mice is 4335 mg/kg and for male mice is 5000 mg/kg{R-4}. Rabbits: OralLD50 for male and female rabbits is 500 to 800 mg/ kg{R-4}. Rats: OralLD50 for male and female rats is more than 5000 mg/kg{R-2; 3; 4} . A dose of 500 parts per million (40 mg/kg) has no observable effect{R-4}. Turkey poults, 1-day-old: Oral626 parts of enrooxacin per million parts of drinking water administered for 21 days caused the death of 11 out of 40 birds in the rst 10 days{R-3; 4}. Surviving birds showed signs of listlessness and decreased body weight gain{R-3}.

HUMAN SIDE/ADVERSE EFFECTS

{R-107}

In addition to the above side/adverse effects reported in animals, the following side/adverse effects have been reported in humans and are included in the human monograph Fluoroquinolones (Systemic) in USP DI Volume I; these side/adverse effects are intended for informational purposes only and may or may not be applicable to the use of uoroquinolones in the treatment of animals: Note: The following human side/adverse effects are those pertaining to ciprooxacin or uoroquinolones in general. Dioxacin, enrooxacin, marbooxacin, and orbioxacin are not available as products labeled for human use. Note: The relative insolubility of ciprooxacin at an alkaline pH has resulted in crystalluria, usually when the urinary pH exceeds 7. Seizures have been reported very rarely with ciprooxacin therapy; however, the patients who did have seizures either had a previous seizure history, were alcoholic, or were taking ciprooxacin concurrently with theophylline. Incidence more frequent Central nervous system (CNS) toxicity; gastrointestinal reactions; vaginitis Incidence less frequent or rare Arthralgia; back pain; cardiovascular reactions such as palpitation, vasodilation, or tachycardia; central nervous system (CNS) stimulation; change in sense of taste; dreams, abnormal; dysuria; headache; hematuria; hepatotoxicity; hypersensitivity reactions; interstitial nephritis; moniliasis, oral; moniliasis, vaginal; myalgia; phlebitisfor intravenous ciprooxacin; photosensitivity; phototoxicity; pseudomembranous colitis; Stevens-Johnson Syndrome (blistering, itching, loosening, peeling, or redness of skin; diarrhea); tendinitis or tendon rupture; vision, abnormal Note: Achilles tendinitis and tendon rupture have been reported in patients receiving uoroquinolones. The ruptures occurred 2 to 42 days after the start of therapy. Concommitant use of corticosteroids with uoroquinolones may increase the risk of tendon disorders or ruptures. These injuries may require surgical repair or result in prolonged disability. It is recommended that uoroquinolone treatment be discontinued at the rst sign of tendon pain or inammation, and that patients refrain from exercising until the diagnosis of tendinitis has been excluded. 2003 Thomson MICROMEDEX

CLINICAL EFFECTS OF OVERDOSE

The following effects have been selected on the basis of their potential clinical signicancenot necessarily inclusive: For dioxacin Dogs, with doses of 5, 15, or 25 mg/kg a day for 30 consecutive days{R-96} Decreased appetite; diarrhea; erythema/edema on the facial area, transient; weight loss For enrooxacin Calves, feeder, with a dose of 15 or 25 mg/kg a day for 10 to 15 days or a dose of 50 mg/kg a day for 3 days{R-2} Note: Federal law prohibits the extra-label use of uoroquinolones in food-producing animals (see the Regulatory Considerations section). The following information is included in case of accidental dosing. Depression; decreased appetite; incoordination; muscle fasciculations Cats, with a dose of 20 mg/kg a day for 21 days{R-1} Depression; retinal degenerative effects; salivation; vomiting Cats, with a dose 50 mg/kg a day for 6 days{R-1} Convulsions; depression; incoordination; loss of appetite; retinal degenerative effects; vomiting All rights reserved

96 FLUOROQUINOLONES VeterinarySystemic Chicks, 1-day-old, with a dose in drinking water of 625 ppm for 21 to 28 days{R-4} Decreased water consumption; decreased weight Dogs, with an oral dose of 50 to 125 mg/kg a day for 11 to 14 days{R-1;
5; 8}

Convulsions; depression or excitation; incoordination; loss of appetite; muscle tremors; salivation; vomiting For marbooxacin Cats, with a dose of 5.5, 16.5, or 27.5 mg/kg a day for 42 days Dermatitis, perivascular to diffuse (often reddened pinnae); excessive salivation; softened stools Cats, with a dose of 55 mg/kg a day for 14 days Decreased activity; decreased food consumption; dermatitis, perivascular to diffuse (often reddened pinnae); excessive salivation; vomiting, occasional Dogs, with a dose of 5.5, 16.5, or 27.5 mg/kg a day for 42 days Decreased food consumption; reddened mucous membranes; reddened skin (usually involving the ears); vomiting; weight loss Dogs, with a dose of 55 mg/kg a day for 12 days Decreased food consumption; dehydration; decreased activity; excessive salivation; facial swelling; reddened skin (usually the ears); tremors; vomiting; weight loss For orbioxacin Cats, with a dose of 22.5 and 37.5 mg/kg a day{R-98} Softened stools Cats, with a dose of 75 mg/kg a day for 10 days{R-98} Decreased food consumption; diarrhea, vomiting

create a exible product label that includes a dosage range allowing for doses at the low end to be used to treat pathogens susceptible at a lower MIC and higher doses for less susceptible organisms. The upper end of the dosage range is determined by safety factors. Product labeling for veterinary uoroquinolone products include MIC data for bacterial pathogens for specic indications in which efcacy was conrmed, and a dosage range{R-1; 9698}. It is recommended that the dose be chosen based on clinical experience, the type and severity of infection, and susceptibility of the pathogen{R-1}. The effective treatment of canine infections caused by Pseudomonas aeruginosa {R-17} and Staphylococcus species{R-21} may require the high end of the dosage range. Breakpoints determined for ciprooxacin by the National Committee for Clinical Laboratory Standards{R-95}
MIC (mcg/mL) 1.0 2.0 4 Interpretation Susceptible Intermediacate Resistant

Note: Be aware that ciprooxacin may not be appropriate for use as a representative of veterinary uoroquinolones in susceptibility testing. Use of specic antibiotic MIC ranges has been recommended{R-110}. Breakpoints determined for dioxacin for veterinary pathogens by the National Committee for Clinical Laboratory Standards{R-147}
Zone diameter (millimeters) 21 1820 17

TREATMENT OF OVERDOSE
Although there is no specic information available on treatment of uoroquinolone overdose in animals, treatment of human overdose includes induction of vomiting or use of gastric lavage, observation, and supportive care, including hydration and dialysis.

MIC (mcg/mL) 0.5 12 4

Interpretation Susceptible Intermediate Resistant

Note: The disk content is 10 mcg. Breakpoints determined for oral dosing of enrooxacin for cats and dogs by the National Committee for Clinical Laboratory Standards{R-87;
88}

CLIENT CONSULTATION
Care should be exercised to avoid contact of medication with the eyes or skin while handling solutions{R-3}.

Zone diameter (millimeters)

MIC (mcg/mL) 0.5 12 4

Interpretation Susceptible Flexible* Resistant

VETERINARY DOSING INFORMATION

Flouroquinolone antibiotics have concentration-dependent bactericidal activity or AUIC{R-21}. Serum and tissue concentrations must be high enough for a long enough period of time to be effective against the target pathogen. Fortunately, minimum inhibitory concentrations (MIC) for uoroquinolones are relatively low. Depending on many variables, such as the organism treated and the presence of neutrophils, uoroquinolones can also produce a post-antibiotic effect, suppressing bacterial growth after local drug concentrations have fallen{R-21; 112}. Cats: Because of the risk of retinal damage associated with high dosages of enrooxacin, it is recommended that caution be used when considering administering uoroquinolone at dosages higher than those recommended for cats. Flexible LabelingBecause there is a wide minimum inhibitory range among bacteria susceptible to uoroquinolones, it was possible to 2003 Thomson MICROMEDEX

23 1722 16

*Flexible indicates the availability of an FDA-approved Flexible Label; the pathogens originating from dermal, respiratory tract, and other tissues could be considered susceptible with an MIC 2 if appropriate dosing, explained in the package insert, is used{R-86; 87}. Breakpoints recommended for marbooxacin by the manufacturer{R-145}
Zone diameter (millimeters) 17 1416 13

MIC (mcg/mL) 1 2 4

Interpretation Susceptible Intermediate Resistant

Note: The disk content is 5 mcg. All rights reserved

FLUOROQUINOLONES VeterinarySystemic 97 Breakpoints recommended for orbioxacin by the National Committee for Clinical Laboratory Standards{R-147}
Zone diameter (millimeters) 23 1822 17

CIPROFLOXACIN TABLETS
Usual dose: See Ciprooxacin for Oral Suspension. Strength(s) usually available: U.S. Veterinary-labeled product(s): Not commercially available. Human-labeled product(s): 100 mg (base) (Rx) [Cipro]. 250 mg (base) (Rx) [Cipro]. 500 mg (base) (Rx) [Cipro]. 750 mg (base) (Rx) [Cipro]. Canada Veterinary-labeled product(s): Not commercially available. Human-labeled product(s): 100 mg (base) (Rx) [Cipro]. 250 mg (base) (Rx) [Cipro]. 500 mg (base) (Rx) [Cipro]. 750 mg (base) (Rx) [Cipro]. Packaging and storage: Store below 30 C (86 F), in a well-closed container, unless otherwise specied by manufacturer.

MIC (mcg/mL) 1 24 8

Interpretation Susceptible Intermediate Resistant

Note: The disk content is 10 mcg.

CIPROFLOXACIN SUMMARY OF DIFFERENCES

Regulatory considerations: Ciprooxacin is not labeled for use in animals.

ORAL DOSAGE FORMS

Note: Bracketed information in the Dosage Forms section refers to uses that either are not included in U.S. product labeling or are for products not commercially available in the U.S.

CIPROFLOXACIN FOR ORAL SUSPENSION

Usual dose: Note: [Dogs]1Although the safety and efcacy have not been established, an oral dose of 10 to 20 mg per kg of body weight every twenty-four hours has been recommended in the treatment of susceptible bacterial infections, based on pharmacokinetic data{R-95; 118; 134}. For empiric treatment of infections in dogs caused by probable Pseudomonas aeruginosa or Staphylococcus infections, the higher end of the dosage range may be preferable, pending susceptibility results. [Horses]1Due to poor bioavailability{R-144}, oral ciprooxacin should not be used in horses. USP requirements: Preserve in well-closed containers. Contain an amount of ciprooxacin hydrochloride equivalent to the labeled amount of ciprooxacin, within 10%. Meet the requirements for Identication, Dissolution (80% in 30 minutes in 0.01 N hydrochloric acid in Apparatus 2 at 50 rpm), and Uniformity of dosage units{R-105}.
1

Not included in Canadian product labeling or product not commercially available in Canada.

Strength(s) usually available: U.S. Veterinary-labeled product(s): Not commercially available. Human-labeled product(s): 250 mg per 5 mL (5%) (Rx) [Cipro]. 500 mg per 5 mL (5%) (Rx) [Cipro]. Canada Not commerically available. Packaging and storage: Prior to reconsitution, store below 25 C (77 F). Protect from freezing. After reconstitution, store below 30 C (86 F). Protect from freezing. Preparation of dosage form: To prepare the oral suspension, the small bottle containing the microcapsules should be emptied into the large bottle containing the diluent. Water should not be added to the suspension. The large bottle should be closed and shaken vigorously for about 15 seconds. Stability: The suspension is stable for 14 days when stored in a refrigerator or at room temperature (below 30 C [86 F]). USP requirements: Not in USP{R-105}. 2003 Thomson MICROMEDEX

PARENTERAL DOSAGE FORMS

Note: Bracketed information in the Dosage Forms section refers to uses that either are not included in U.S. product labeling or are for products not commercially available in the U.S.

CIPROFLOXACIN INJECTION USP

Usual dose: Note: [Dogs]1Although the safety and efcacy have not been established, an intravenous dose of 10 to 15 mg per kg of body weight, administered slowly every twenty-four hours has been recommended in the treatment of susceptible bacterial infections{R-81}.

Strength(s) usually available: U.S. Veterinary-labeled product(s): Not commercially available. Human-labeled product(s): 200 mg per 20 mL (Rx) [Cipro I.V. (in sterile water for injection; requires dilution prior to administration)]. 200 mg per 100 mL (Rx) [Cipro I.V. (in 5% dextrose injection; premixed)]. 400 mg per 40 mL (Rx) [Cipro I.V. (in sterile water for injection; requires dilution prior to administration)]. All rights reserved

98 FLUOROQUINOLONES VeterinarySystemic 400 mg per 200 mL (Rx) [Cipro I.V. (in 5% dextrose premixed)]. 1200 mg per 120 mL (Rx) [Cipro I.V. (in sterile water for requires dilution prior to administration)]. Canada Veterinary-labeled product(s): Not commerically available. Human-labeled product(s): 200 mg per 20 mL (Rx) [Cipro I.V. (in sterile water for requires dilution prior to administration)]. 400 mg per 40 mL (Rx) [Cipro I.V. (in sterile water for requires dilution prior to administration)]. injection; injection; where the Injection is labeled as being a concentrated form, its pH is between 3.3 and 3.9), Particulate matter, Limit of ciprooxacin ethylenediamine analog (not more than 0.5%), Lactic acid content (0.2880.352 mg per mg of ciprooxacin claimed on label, except that where the Injection is labeled as being a concentrated form, it contains between 0.335 and 0.409 mg per mg of ciprooxacin claimed on the label), Dextrose content (if present), and Sodium chloride content (if present), and for Volume in Container under Injections.{R-105}.
1

injection; injection;

Not included in Canadian product labeling or product not commercially available in Canada.

Packaging and storage: Store in a cool place (between 8 and 15 C [46 and 59 F]) or at controlled room temperature (between 20 and 25 C [68 and 77 F]), unless otherwise specied by manufacturer. Protect from light and freezing.

DIFLOXACIN ORAL DOSAGE FORMS DIFLOXACIN HYDROCHLORIDE TABLETS

Usual dose: Bacterial infectionsDogs: Oral, 5 to 10 mg per kg of body weight every twenty-four hours{R-96; 99}. Note: The 5 mg per kg dose was found to be clinically effective in the treatment of susceptible skin, soft tissue, and urinary tract infections{R-99}. For empiric treatment of probable Pseudomonas aeruginosa or Staphylococcus infections in dogs, the higher end of the dosage range may be preferable, pending susceptibility results. Strength(s) usually available: U.S.{R-96} Veterinary-labeled product(s): 11.4 mg (Rx) [Dicural Tablets]. 45.4 mg (Rx) [Dicural Tablets]. 136 mg (Rx) [Dicural Tablets]. Canada{R-99} Veterinary-labeled product(s): 11.4 mg (Rx) [Dicural Tablets]. 45.4 mg (Rx) [Dicural Tablets]. 136 mg (Rx) [Dicural Tablets]. Packaging and storage: Store below 40 C (104 F), preferably between 15 and 30 C (59 and 86 F), unless otherwise specied by manufacturer. USP requirements: Not in USP{R-105}.

Preparation of dosage form: To prepare a solution for intravenous infusion, the concentrate in sterile water for injection should be withdrawn aseptically from the vial and diluted to a nal concentration of 1 to 2 mg per mL with a suitable intravenous solution (see manufacturers package insert). Solutions that come from the manufacturer in 5% dextrose injection should not be diluted prior to intravenous infusion. The resulting solution should be infused over a period of at least 60 minutes by direct infusion or through a Y-type intravenous infusion set. It is recommended that administration of any other solutions be discontinued during infusion of ciprooxacin. Stability: When diluted with appropriate intravenous uids (see manufacturers package insert) to concentrations from 0.5 to 2 mg per mL, solutions retain their potency for up to 14 days when refrigerated or stored at room temperature. Incompatibilities: Ciprooxacin is incompatible with aminophylline, amoxicillin, cefepime, clindamycin, dexamethasone, oxacillin, furosemide, heparin, and phenytoin. If ciprooxacin is to be given concurrently with another medication, each medication should be administered separately according to the recommended dosage and route of administration for each medication. USP requirements: Preserve in single-dose containers, preferably of Type I glass, in a cool place or at controlled room temperature. Avoid freezing and exposure to light. A sterile solution of Cipooxacin in Sterile Water for Injection, in 5% Dextrose Injection, or in 0.9% Sodium Chloride Injection prepared with the aid of Lactic Acid. The label indicates whether the vehicle is Sterile Water for Injection, 5% Dextrose Injection, or 0.9% Sodium Chloride Injection. Label the Injection that has Sterile Water for Injection as the vehicle to indicate that it is a concentrated form that must be diluted to appropriate strength (1 to 2 mg per ml) with 5% Dextrose Injection or 0.9% Sodium Chloride Injection before administration, and that the resulting solution is stable for up to 14 days when stored in a cool place or at controlled room temperature. Contains the labeled amount, within 10%. Meets the requirements for Color (where it is labeled as being in a concentrated form), Identication, Pyrogen, Sterility, pH (3.54.6, except that 2003 Thomson MICROMEDEX

ENROFLOXACIN SUMMARY OF DIFFERENCES

Pharmacology/pharmacokinetics: BiotransformationEnrooxacin is de-ethylated to form ciprooxacin; therapeutic concentrations of ciprooxacin can be reached with dosing calculated to achieve effective enrooxacin concentrations. Side/adverse effects: CatsRetinal degeneration (acute blindness, mydriasis) has been reported with enrooxacin at doses higher than 5 mg per kg of body weight a day. All rights reserved

FLUOROQUINOLONES VeterinarySystemic 99

ORAL DOSAGE FORMS

Note: Bracketed information in the Dosage Forms section refers to uses that either are not included in U.S. product labeling or are for products not commercially available in the U.S.

following exposure. In human beings, there is a risk of user photosensitization within a few hours of signicant exposure to quinolones. USP requirements: Not in USP{R-105}.

ENROFLOXACIN ORAL SOLUTION

Usual dose: Escherichia coli infection1Chickens and turkeys: Oral, 25 to 50 parts enrooxacin per million parts water (ppm), administered as the only source of drinking water for three to seven days{R-3}. Fowl cholera1Turkeys: Oral, 25 to 50 parts enrooxacin per million parts water (ppm), administered as the only source of drinking water for three to seven days{R-3}. Note: Medication should be initiated as soon after diagnosis as possible{R-3}. The effects of environment and other factors on water consumption should be considered{R-3}. Strength(s) usually available: U.S. Veterinary-labeled product(s): 32.3 mg per mL (Rx) [Baytril 3.23% Concentrate Solution]. Canada Veterinary-labeled product(s): Not commercially available. Withdrawal times: U.S.{R-3}
Withdrawal time Species Chickens, turkeys Meat (days) 2

ENROFLOXACIN TABLETS
Usual dose: Bacterial infections Cats: Oral, 5 mg per kg of body weight a day{R-1}. The dose may be administered as a single daily dose or divided into two equal doses administered every twelve hours{R-1}. Note: The above dose recommendation is based on risk of retinal damage in cats administered doses higher than 5 mg/kg{R-1}. Dogs: Oral, 5 to 20 mg per kg of body weight a day{R-1}. The dose may be administered as a single daily dose or divided into two equal doses administered every twelve hours{R-1}. Note: For empiric treatment of probable Pseudomonas aeruginosa or Staphylococcus infections in dogs, the higher end of the dosage range may be preferable, pending susceptibility results. Note: [Bustards]1Although the safety and efcacy have not been established, an oral dose of 10 mg per kg of body weight every twelve hours has been suggested for the treatment of susceptible bacterial infections, based on pharmacokinetic data{R-41}. CatsAlthough the efcacy has not been established, if enrooxacin is used in the treatment of [Bartonella henselae]1 infection or [hemobartonellosis]1 in cats, the USP Veterinary Medicine Committee currently recommends the administration of 5 mg per kg of body weight a day. Limited research studies on the treatment of these infections have sometimes led to recommendations for higher dosages; however, there is concern about the occurrence of retinal degeneration when a dose of 20 mg/kg is administered to cats and the lack of information on relative risk of retinal damage at dosages between 5 and 20 mg/kg a day. The following information is provided in the event other therapies have failed: [An oral dose of 5 to 8 mg per kg of body weight every twelve hours (10 to 16 mg per kg a day) for four to six weeks has been recommended in the treatment of Bartonella henselae infection, based on efcacy trials{R-72}.]1 [An oral dose of 5 to 10 mg per kg of body weight every twenty-four hours for two weeks has been recommended in the treatment of hemobartonellosis{R-148}. Cats apparently completely cleared of infection were treated with the high end of this dosage range; however, the low end is the labeled dose.1 DogsAlthough the efcacy has not been established, an oral dose of 5 mg per kg of body weight every twenty-four hours for fteen days has been used in the treatment of [ehrlichiosis]1 in dogs, based on a comparative, randomized therapeutic trial{R-77}. An oral dose of 3 mg per kg of body weight every twelve hours for seven days has been used in the treatment of [Rocky Mountain spotted fever]1 in dogs, based on a controlled therapeutic trial using disease models{R-84}. [Ducks, pet or research]1In the U.S., for use only in animals not to be used for food production: Although the safety and efcacy have not been established, an oral dose of 10 mg per kg of body weight a day has been suggested for the treatment of susceptible bacterial infections in Muscovy ducks, based on pharmacokinetic data{R-42}. [Foals]1Although the safety and efcacy have not been established, an oral dose of 2.5 mg per kg of body weight once a day for eight days has been recommended in the treatment of susceptible bacterial All rights reserved

Note: This product is not labeled for use in laying hens producing eggs for human consumption{R-3}. Packaging and storage: Store below 40 C (104 F), preferably between 15 and 30 C (59 and 86 F), unless otherwise specied by manufacturer. Store container in an upright position{R-3}. Preparation of dosage form: Product labeling recommends that stock solutions be prepared fresh daily{R-3}. Once stock solution or medicated water is prepared, protect it from freezing or direct sunlight{R-3}. This product should not be used in automatic water proportioners if the water hardness is greater than 196 parts per million (ppm){R-3}. Galvanized metal watering systems or containers should not be used to carry or store this product and chlorinators should not be operated while administering this medication{R-3}. Additional information: Product labeling recommends that poultry litter from treated ocks spread on agricultural land be incorporated into the soil whenever possible{R-3}. It also recommends a 10- to 14day interval between ocks, top dressing with clean litter, and an increased frequency of removal of caked litter from each house{R-3}. Poultry litter from treated ocks should not be used in cattle feed. Caution: Those who administer medication should avoid contact with their eyes and skin. If contact occurs, immediately ush eyes with copious amounts of water for 15 minutes. In case of dermal contact, wash skin with soap and water. Consult a physician if irritation persists 2003 Thomson MICROMEDEX

100 FLUOROQUINOLONES VeterinarySystemic infections in foals. Because of the potential for arthropathy in immature animals, use is recommended in foals only when other antimicrobials are inappropriate{R-85}. [Horses]1In the U.S., for use only in animals not to be used for food productionAlthough the safety and efcacy have not been established, an oral dose of 7.5 to 10 mg per kg of body weight every twenty-four hours has been recommended{R-2427; 93}. Tablets have been crushed and suspended in water for administration{R-27} or ground into a powder and mixed in sugar syrup{R-25}. [Pacu, red]1Although the safety and efcacy have not been established, administration of enrooxacin by immersion of sh in a bath of a 2.5 mg per liter solution of enrooxacin for ve hours, every twenty-four to forty-eight hours, has been suggested for the treatment of susceptible bacterial infections in red pacu sh, based on pharmacokinetic data{R-44}. [Parrots, African grey]1Although the safety and efcacy have not been established, an oral dose of 7.5 to 30 mg per kg of body weight every twelve hours has been suggested in the treatment of susceptible bacterial infections in African grey parrots, based on pharmacokinetic data{R-39}. The risk of side effects increases with higher doses; polyuria and polydipsia have been reported at the 30 mg per kg of body weight dose{R-39}. [Rabbits, pet or research]1In the U.S., for use only in animals not to be used for food production: Although the safety and efcacy have not been established, an oral dose of 5 mg per kg of body weight every twelve hours for fourteen days has been recommended in the treatment of pasteurellosis in rabbits, based on clinical efcacy studies{R-6769}. Strength(s) usually available: U.S. Veterinary-labeled product(s): 22.7 mg (Rx) [Baytril Tablets (lm-coated){R-1}; Baytril Taste Tabs]. 68 mg (Rx) [Baytril Tablets (lm-coated){R-1}; Baytril Taste Tabs]. 136 mg (Rx) [Baytril Taste Tabs{R-1}]. Canada Veterinary-labeled product(s): 15 mg (Rx) [Baytril Tablets{R-102}]. 50 mg (Rx) [Baytril Tablets{R-102}]. 150 mg (Rx) [Baytril Tablets{R-102}]. Packaging and storage: Store below 40 C (104 F), preferably between 15 and 30 C (59 and 86 F), unless otherwise specied by manufacturer. Store in a tight container. USP requirements: Not in USP{R-105}.
1

Not included in Canadian product labeling or product not commercially available in Canada.

PARENTERAL DOSAGE FORMS

Note: Bracketed information in the Dosage Forms section refers to uses that either are not included in U.S. product labeling or are for products not commercially available in the U.S.

ENROFLOXACIN INJECTION
Usual dose: Bacterial infections Dogs: 2003 Thomson MICROMEDEX

Intramuscular2.5 mg per kg of body weight{R-86}. U.S. product labeling recommends that this be an initial single dose, to be followed by a dosage regimen using enrooxacin tablets; this was based on studies establishing the efcacy of 2.5 mg per kg of body weight every twelve hours{R-104}. Canadian product labeling recommends a maximum of six doses{R-102}. [Intravenous]15 to 20 mg per kg of body weight a day. The dose may be administered as a single daily dose or divided into two equal doses administered every twelve hours. To avoid adverse effects, the drug should be diluted in a 2X volume of saline and infused over 15 to 20 minutes. Note: For empiric treatment of probable Pseudomonas aeruginosa or Staphylococcus infections, the higher end of the dosage range may be preferable, pending susceptibility results. [Cats]1: Intramuscular2.5 mg per kg of body weight. For dogs, U.S. product labeling recommends that this be an initial single dose, to be followed by a dosage regimen using enrooxacin tablets; this was based on studies establishing the efcacy of 2.5 mg per kg of body weight every twelve hours{R-104}. Intravenous5 mg per kg of body weight a day. The dose may be administered as a single daily dose or divided into two equal doses administered every twelve hours. To avoid adverse effects, the drug should be diluted in a 2X volume of saline and infused over 15 to 20 minutes. Note: The above dosage recommendations are based on risk of retinal damage in cats administered doses higher than 5 mg/kg a day{R-1}. Bacterial pneumonia1Cattle: Subcutaneous, 7.5 to 12.5 mg per kg of body weight as a single dose or 2.5 to 5 mg per kg of body weight every twenty-four hours for three to ve days{R-2}. Note: Up to at least 1 week of age, calves eliminate enrooxacin and the active metabolite ciprooxacin more slowly than do adult cattle{R-13}. Note: [Bustards]1Although the safety and efcacy have not been established, a parenteral dose of 10 mg per kg of body weight every twelve hours or 15 mg per kg of body weight every twenty-four hours has been suggested for the treatment of susceptible bacterial infections, based on pharmacokinetic data{R-41}. [Camels]1Although the safety and efcacy have not been established, an intramuscular or subcutaneous dose of 2.5 mg per kg of body weight every twelve hours has been suggested for the treatment of susceptible bacterial infections in camels, based on pharmacokinetic data{R-45}. [Ducks, pet or research]1In the U.S., for use only in animals not to be used for food production: Although the safety and efcacy have not been established, a parenteral dose of 10 mg per kg of body weight every twenty-four hours has been suggested for the treatment of susceptible bacterial infections, based on pharmacokinetic data{R-42}. [Emus, pet or research]1In the U.S., for use only in animals not to be used for food production: Although the safety and efcacy have not been established, a parenteral dose of 2.2 mg per kg of body weight every twelve hours has been suggested for the treatment of susceptible bacterial infections in emus, based on pharmacokinetic data{R-43}. [Horses]1In the U.S., for use only in animals not to be used for food production: Although the safety and efcacy have not been established, an intravenous dose of 5 mg per kg of body weight every twenty-four hours has been used in the treatment of susceptible

All rights reserved

FLUOROQUINOLONES VeterinarySystemic 101 bacterial infections in horses.{R-93} If a dose higher than 5 mg per kg of body weight is administered, slow injection by indwelling catheter is recommended to avoid adverse effects; dilution in 500 mL of sterile saline solution may also be necessary{R-136}. [Llamas, pet or research]1In the U.S., for use only in animals not to be used for food production: Although the safety and efcacy have not been established, an intramuscular or subcutaneous dose of 5 mg per kg of body weight every twelve hours has been suggested for the treatment of susceptible bacterial infections in llamas, based on pharmacokinetic data{R-45}. [Oryx]1Although the safety and efcacy have not been established, a parenteral dose of 1.6 mg per kg of body weight every six to eight hours has been suggested for the treatment of susceptible bacterial infections in oryx, based on pharmacokinetic data{R-45}. [Pacu, red]1Although the safety and efcacy have not been established, an intramuscular dose of 5 mg per kg of body weight every forty-eight hours has been suggested for the treatment of susceptible bacterial infections in the red pacu, based on pharmacokinetic data{R-44}. [Parrots, African grey]1Although the safety and efcacy have not been established, an intramuscular dose of 7.5 to 30 mg per kg of body weight every twelve hours has been suggested in the treatment of susceptible bacterial infections in African grey parrots, based on pharmacokinetic data{R-39}. The risk of side effects increases with higher doses; polyuria and polydipsia have been reported with the 30 mg per kg of body weight dose{R-39}. [Pigs, potbellied and minature]1In the U.S., for use only in animals not to be used in food production: Although the safety and efcacy have not been established, an oral dose of 10 mg per kg of body weight every 24 hours has been recommended for pigs in the treatment of susceptible bacterial infections, based on pharmacokinetic data{R-25}. See also the Withdrawal times section. [Pythons]1Although the safety and efcacy have not been established, an intramuscular dose of 10 mg per kg of body weight as a loading dose followed by 5 mg per kg of body weight every forty-eight hours has been suggested for the treatment of susceptible bacterial infections in pythons{R-48}. For the treatment of Pseudomonas species infections, 10 mg per kg of body weight every forty-eight hours has been suggested, based on pharmacokinetic data{R-48}. [Rabbits, pet or research]1In the U.S., for use only in animals not to be used in food production: Although the safety and efcacy have not been established, a subcutaneous dose of 5 mg per kg of body weight every twelve hours for fourteen days has been recommended in the control of pasteurellosis in rabbits{R-33; 6769}. [Sheep, pet or research]1In the U.S., for use only in animals not to be used in food productionAlthough the safety and efcacy have not been established, an intramuscular or intravenous dose of 2.5 to 5 mg per kg of body weight every twenty-four hours has been recommended for sheep in the treatment of susceptible bacterial infections{R-28}, based on pharmacokinetic data. See also the Withdrawal times section. Note: The more concentrated enrooxacin injection, 100 mg per mL, is labeled only for use in cattle{R-2}, while the less concentrated injection, 22.7 mg per mL, is labeled for use in dogs{R-104}. The product used for cattle contains different excipients than the injectable solution for dogs; the safety of using the cattle product in other species has not been demonstrated{R-2}. Canada Veterinary-labeled product(s): 50 mg per mL (Rx) [Baytril Injectable Solution{R-102}]. Withdrawal times: U.S.{R-2}Federal law prohibits the extralabel use of enrooxacin in food-producing animals and restricts enrooxacin to use by or on the order of a licensed veterinarian.
Withdrawal time Species Cattle Meat (days) 28

Note: Not labeled for use in cattle intended for dairy production or in calves to be processed for veal{R-2}. Subcutaneous injection can cause a local tissue reaction that is transient but can cause trim loss of edible tissue at slaughter{R-2}. CanadaThere is no established withdrawal time for cattle in Canada because enrooxacin is not labeled for use in cattle.

Packaging and storage: Store below 40 C (104 F), preferably between 15 and 30 C (59 and 86 F), unless otherwise specied by manufacturer. Protect from direct sunlight{R-1; 2}. Do not freeze{R-1; 2}.

Caution: Those who administer medication should avoid contact with their eyes and skin. If contact occurs, immediately ush eyes with copious amounts of water for 15 minutes. In case of dermal contact, wash skin with soap and water. A physician should be consulted if irritation persists following exposure. In human beings, there is a risk of user photosensitization within a few hours of signicant exposure to quinolones. USP requirements: Not in USP{R-105}.
1

Not included in Canadian product labeling or product not commercially available in Canada.

MARBOFLOXACIN ORAL DOSAGE FORMS MARBOFLOXACIN TABLETS

Usual dose: Bacterial infectionsCats and dogs: Oral, 2.75 to 5.5 mg per kg of body weight every twenty-four hours{R-97; 101}. Note: The 2.75 mg per kg dose was found to be clinically effective in the treatment of susceptible skin, soft tissue, and urinary tract infections{R-97}. For empiric treatment of probable Pseudomonas aeruginosa or Staphylococcus infections, the higher end of the dosage range may be preferable, pending susceptibility results. All rights reserved

Strength(s) usually available: U.S. Veterinary-labeled product(s): 22.7 mg per mL (Rx) [Baytril Injectable Solution 2.27%{R-104}]. 100 mg per mL (Rx) [Baytril 100 Injectable Solution{R-2}]. 2003 Thomson MICROMEDEX

102 FLUOROQUINOLONES VeterinarySystemic Strength(s) usually available: U.S.{R-97} Veterinary-labeled product(s): 25 mg (Rx) [Zeniquin Tablets]. 50 mg (Rx) [Zeniquin Tablets]. 100 mg (Rx) [Zeniquin Tablets]. 200 mg (Rx) [Zeniquin Tablets]. Canada{R-101} Veterinary-labeled product(s): 25 mg (Rx) [Zeniquin Tablets]. 50 mg (Rx) [Zeniquin Tablets]. 100 mg (Rx) [Zeniquin Tablets]. 200 mg (Rx) [Zeniquin Tablets]. Note: [Horses]1In the U.S., for use only in animals not to be used for food production: Although the safety and efcacy have not been established, an oral dose of 5 to 7.5 mg per kg of body weight every twenty-four hours has been recommended for the treatment of susceptible bacterial infections in adult horses{R-133}. Tablets have been crushed and suspended in water for administration{R-133}.

Packaging and storage: Store below 40 C (104 F), preferably between 15 and 30 C (59 and 86 F), unless otherwise specied by manufacturer. USP requirements: Not in USP{R-105}.

Strength(s) usually available: U.S.{R-98} Veterinary-labeled product(s): 5.7 mg (Rx) [Orbax Tablets]. 22.7 mg (Rx) [Orbax Tablets]. 68 mg (Rx) [Orbax Tablets]. Canada{R-100} Veterinary-labeled product(s): 5.7 mg (Rx) [Orbax Tablets]. 22.7 mg (Rx) [Orbax Tablets]. 68 mg (Rx) [Orbax Tablets].

ORBIFLOXACIN ORAL DOSAGE FORMS

Note: Bracketed information in the Dosage Forms section refers to uses that either are not included in U.S. product labeling or are for products not commercially available in the U.S.

Packaging and storage: Store between 2 and 30 C (36 and 86 F){R-98}, unless otherwise specied by manufacturer. USP requirements: Not in USP{R-105}.
1

ORBIFLOXACIN TABLETS
Usual dose: Bacterial infectionsCats and dogs: Oral, 2.5 to 7.5 mg per kg of body weight every twenty-four hours{R-98}. Note: For empiric treatment of probable Pseudomonas aeruginosa or Staphylococcus infections, the higher end of the dosage range may be preferable, pending susceptibility results.

Not included in Canadian product labeling or product not commercially available in Canada.

Developed: 02/17/00 Revised: 09/30/02 Interim revision: 03/28/03

Table 1. Pharmacology/PharmacokineticsIntravenous administration.

Compound measured Elimination half-life (hours) VolD Area (L/kg) VolD, Steady state (L/kg) Clearance (mL/min/kg)

Species CIPROFLOXACIN Dogs{R-117} ENROFLOXACIN Birds Bustards{R-41} Chickens{R-30} Chickens{R-31} Emus{R-43} Calves{R-13} One day of age One week old Cattle, lactating{R-11}
{R-15}

Dose (mg/kg)

2.5 to 10

2.2

3.06 0.75

O.26 0.11

10 10 10 2.2 2.5 2.5 2.5 2.5 5 5 5 2.5 5 1.25 to 5 5 5 5.8 5.8

Enrooxacin Enrooxacin Enrooxacin Enrooxacin Enrooxacin Ciprooxacin Enrooxacin Ciprooxacin Enrooxacin Enrooxacin Ciprooxacin Enrooxacin Enrooxacin Ciprooxacin Enrooxacin Enrooxacin Ciprooxacin Enrooxacin Ciprooxacin

5.63 0.54 4.16 0.19 10.29 0.45 3.33 6.61 1.12 9.19 1.46 4.87 0.68 8.19 0.85 1.68 0.18 1.09 2.67 3.6 0.89 6.7 2.3 6.1 1.3 >3 2.4 0.87 3.9 1.3 4.4 1 5.2 0.4

2.82 2.20 4.31 1.49

0.37 0.17 0.15 0.52

2.98 2.43 2.77 1.62

0.32 0.19 0.09 1.04

5.71 0.41 2.2 0.09 4.8 0.17 6.00 3.17 3.16 0.5 6.5 1

1.81 0.1 2.28 0.14 >1 2.1 1.13 0.126 4.0 0.3

21 4.61 1.03 9.5 0.7 9 27.1 16.2 10.88 0.68

Camels{R-45} Cats{R-22} Dogs{R-5}

{R-16}

7.0 6.4 3.7 0.6

{R-18}

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FLUOROQUINOLONES VeterinarySystemic 103 Table 1. (Contd.)

Elimination half-life (hours) VolD Area (L/kg) VolD, Steady state (L/kg) Clearance (mL/min/kg)

Species Fish Salmon{R-37} Trout, rainbow{R-36} Foals{R-85} Horses{R-27}

{R-24}

Dose (mg/kg)

10 5 10 5 2.5 5 5 5 1.3 5

Llamas{R-46} Oryx (antelope){R-47} Pigs{R-29} Neonatal rabbits

{R-35}

Enrooxacin Enrooxacin Enrooxacin Enrooxacin Enrooxacin Enrooxacin Enrooxacin Ciprooxacin Enrooxacin Enrooxacin Enrooxacin

34.2 24.4 30.4 17.10 0.09 5.94 6.09 4.4 5.1 2.1 3.38 2.13 0.69 0.46

3.22 2.56 2.49 0.43 1.22 0.07 0.77 0.11

6.1 2.77 2.34 2.47 0.04

2.3 0.5 3.46 0.98 0.80 0.3 3.9 0.5

2.3 1.52 0.97 1.73 2.33 1.50 0.51

0.001 0.17 0.17 0.11

11.7 3.5 12.07 7.12 6.17 1.83

1 day of age 8 days 16 days 30 days Rabbits{R-32}

{R-33} {R-33}

Sheep{R-46} MARBFLOXACIN Dogs{R-108}

{R-115} {R-97}

7.5 7.5 7.5 7.5 5 5 7.5 2.5 2 2 5.5 2.5 2,5

(IP) (IP) (IP) (IP)

Enrooxacin Enrooxacin Enrooxacin Enrooxacin Enrooxacin Enrooxacin Enrooxacin Enrooxacin

5.01 8.5 6.1 2 2.19 0.29 2.5 1.9 3.73 0.44 10.8 1.3 12.4 2.6 9.5 0.7 4.5 1.8 5.4 1.1

2.03 2.02 2.52 6.52 4.4 1.4 2.12 3.97 0.9

3.4 0.9 0.93 3.02 0.22 1.33 0.10 1.37 0.19 1.19 0.08 1.3 0.13 1.2 0.2

4.7 2.7 4.8 33.8 22.8 6.8 10.1 23.9 3.5 9.17 2.3 1.60 0.21 1.56 0.13

1.90 0.76

ORBIFLOXACIN Cats{R-98} Dogs{R-98} Note: IP = Intraperitoneal

Table 2. Pharmacology/Pharmacokinetics: Other systemic data

Dose (mg/kg)/Route, Water temperature Peak serum concentration (mcg/mL) Time to peak serum concentration (hours)

Species

Number of doses

Compound measured

Absorption half-life (hours)

Half-life, terminal (hours)

Bioavailability (%)

CIPROFLOXACIN Dogs{R-134} 10/PO 20/PO 40/PO {R-118} 11/PO

23/PO

Single Single Single Single Every 12 hours for 7 doses Single Every 12 hours for 7 doses Single Single Every 24 hours for 5 days

1.4 (fr. graph) 2.8 (fr. graph) 6.6 (fr. graph)

2(fr. graph) 2(fr. graph) 6(fr. graph)

4.91 1.26 5.30 1.15 8.86 2.78 4.65 7.48 3.95 4.48

5.68 0.54

1.53 0.52

DIFLOXACIN Dogs{R-96}
{R-113} {R-116}

5/PO 5/PO 5/PO

1.8 1.11 0.07 1.79 0.11

2.8 2.84 0.31 2.17 0.26

9.3 6.94 0.54 8.52 0.84

>80

ENROFLOXACIN Birds Bustards{R-41} 10/IM 10/PO Chickens{R-30} 10/IM 10/PO 10/SC {R-31} Chickens 10/PO Ducks{R-42} 10/IM 10/PO Parrots{R-39} 15/IM 3/PO 15/PO 30/PO

Single Single Single Single Single Single Single Single Single Single Single Single

Enrooxacin Enrooxacin Enrooxacin Enrooxacin Enrooxacin Enrooxacin Enrooxacin Enrooxacin Enrooxacin Enrooxacin Enrooxacin Enrooxacin

0.23 0.17 1.83 0.92 0.36 0.67

0.07 0.02 0.04 0.05 0.02 0.05

2.75 1.84 2.45 1.69 2.41 2.44 1.67 0.99 3.87 0.31 1.12 1.69

0.11 0.16 0.1 0.08 0.06 0.64 0.29 0.08 0.27 0.11 0.11 0.23

1.72 0.66 1.43 2.52 1.46 1.64 0.94 1.38 1 4 2 4

0.19 0.05 0.02 0.08 0.06 0.04 0.18 0.18

6.39 1.49 6.80 0.79 4.06 0.06 4.29 0.1 4.48 0.04 14.23 0.46

97 62 88 60 81 64

2.31 2.59 2.52 2.74

0.09 0.36 0.33 0.37

48

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104 FLUOROQUINOLONES VeterinarySystemic Table 2. (Contd.)

Dose (mg/kg)/Route, Water temperature 2.5/IM 2.5/PO 2.5/SC 5/PO Peak serum concentration (mcg/mL) 1.44 0.8 Not detected 1.23 0.27 1.67 0.11 0.13 0.01 0.73 0.12 0.98 0.2 1.09 0.25 (from graph) 1 (from graph) 1.5 (from graph) 1.16 0.6 0.29 0.19 1.03 0.28 2.45 0.84 4.56 0.49 1.43 0.12 0.36 0.03 0.6 0.03 5.77 0.41 1.64 0.92 0.05 0.01 0.8 1.17 0.02 0.008 0.17 0.04 0.024 0.001 0.53 0.27 1.54 0.37 0.55 1.93 2.12 0.51 0.89 0.8 2.62 0.61 5.97 1.56 1.85 0.86 0.57 0.06 6.44 0.46 1.4 0.5 1.66 0.42 0.35 0.21 3.04 0.34 0.452 2.07 0.78 0.07 0.14 0.02 4.8 0.7 0.83 0.26 1.38 0.40 2.93 0.58 Time to peak serum concentration (hours) 1 1 0.6 0.1 2.3 0.5 2.4 0.68 3.2 1.09 0.5 1 1 1 0.9 0.8 3.6 0.3 1.88 0.72 1.55 0.56 2.31 0.82 1.8 0.2 2.2 0.3 2.25 0.09 3.92 0.16 4 4 36 36 2 2 2.87 0.42 6 24 6 6 2.20 2.17 1 0.35 1.25 0.43 0.92 0.59 0.37 0.02 0.54 0.06 4.8 1.9 5.75 1.47 13 5.9 0.17 2.3 0.9 1.25 0.11 5 0.45 1.2 1.7 2.5 2.0 0.6 1.2 1.2 1.1 7.75 0.3 0.03 0.54 0.04 83 6.37 1.81 0.3 2.41 3.65 0.31 9.98 2.33 12.7 14.7 14.0 12.5 1.1 4.9 4.9 2.7 92 61 72 85 2.61 0.15 6.42 0.29 28.9 53 5.9 1.44 5.55 0.52 >3 >3 >3 2.4 0.5 3.9 3.2 3.07 1 4.04 0.78 4.26 1.03 83 82 137

Species Camels{R-45}

Number of doses Single Single Single Every 24 hours for 10 days Every 24 hours for 10 days Single Single Single Single Single Single Single Single Every 12 hours for 7 doses Every 12 hours for 7 doses Every 12 hours for 7 doses Every 12 hours for 15 days Every 12 hours for 15 days Single Single Single Single Single 5 hour dose Single Single Single Single Single Single Single Single Every 12 hours for 3 days Every 12 hours for 3 days Single Single Single Single Single Single Single Single Single Single Single Single Single Single Single

Compound measured Enrooxacin Enrooxacin Enrooxacin Enrooxacin Ciprooxacin Enrooxacin Enrooxacin Enrooxacin Enrooxacin Enrooxacin Enrooxacin Enrooxacin Ciprooxacin Enrooxacin Enrooxacin Enrooxacin Enrooxacin Ciprooxacin Active drug* Active drug Enrooxacin Ciprooxacin Enrooxacin Ciprooxacin Enrooxacin Ciprooxacin Enrooxacin Enrooxacin Enrooxacin Enrooxacin Enrooxacin Enrooxacin Enrooxacin Enrooxacin Enrooxacin Enrooxacin Enrooxacin Active drug Active drug Enrooxacin Enrooxacin Ciprooxacin Enrooxacin Enrooxacin Enrooxacin Enrooxacin Ciprooxacin

Absorption half-life (hours) 0.76 0.46 0.5 0.12 0.2 0

Half-life, terminal (hours) 6.36 2.03 10.58 6.78

Bioavailability (%) 85 92

Cats

{R-22}

5/PO Cattle, lactating

{R-45}

Dogs
{R-5}

{R-8}

{R-16}

{R-17}

5/IM 5/SC 1.25/IM 1.25/PO 2.5/PO 5/PO 5/PO 5/PO 2.75/PO 5.5/PO 11/PO

{R-18}

5.8/PO 5.8/PO

{R-21}

2.5/SC 25/SC 5/IM 5/PO 2.5 mg per Liter/bath immersion 5/PO, 9.7 C 10/PO, 9.7 C 10/PO (in feed), 10 C 5/PO, 10 C 10/PO, 10 C 50/PO, 10 C 10/PO 5/IM 2.5/PO 5/PO

Fish Pacu{R-44}

Salmon{R-38}
{R-37}

48.2 105.1

46 49 56 35 24 17 42 57 63

Trout{R-36}

Foals{R-85} Horses{R-24}
{R-5}

44.2 29.5 29.5 18.4 0.06 9.9

{R-5}

Mice{R-21} Pigs{R-39} Pythons{R-24} Rabbits{R-32}

{R-33}

Sheep{R-28}

5/PO 1.56/SC 25/SC 10/PO 5/IM 5/IM 5/IM 5/PO 5/SC 2.5/IM 2.5/IM

0.07 0.02

MARBOFLOXACIN 6.2/PO Cats{R-97} Dogs{R-115} 1/PO 2/PO 4/PO

0.38 0.35 0.53 0.24 0.68 0.59

100

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FLUOROQUINOLONES VeterinarySystemic 105 Table 2. (Contd.)

Dose (mg/kg)/Route, Water temperature 1/SC 2/SC 4/SC 2/PO 2/PO 2.7/PO 5.6/PO Peak serum concentration (mcg/mL) 0.78 1.52 3.04 1.47 1.37 0.08 0.13 0.24 0.09 0.21 Time to peak serum concentration (hours) 1.0 0.6 0.9 0.2 1.3 0.61 1.83 0.17 1.97 0.97 1.5 0.3 1.8 0.3 1 0.45 0.77 0.45 2.42 0.36 1.5

Species Dogs

Number of doses Single Single Single Single Every 24 hours for 8 days Single Single Single Single Single Single

Compound measured

Absorption half-life (hours) 0.20 0.11 0.20 0.07 0.25 0.12

Half-life, terminal (hours) 11.5 13.0 13.4 9.07 1.9 3.3 2.8 1.90

Bioavailability (%) 100

{R-113} {R-108}

{R-108}

2.0 0.2 4.2 0.5 2.06 0.6 2.3 0.3 1.37 0.01 2.41 0/03

10.7 1.6 10.9 0.6 5.52 2.66 5.6 1.1 7.14 0.42 9.06 1.33

94

ORBIFLOXACIN 2.5/PO Cats{R-98} Dogs{R-98} 2.5/PO {R-113} 2.5/PO 7.5/PO Mares{R-133}

97

Note IMIntramuscular administration, POOral administration, SCSubcutaneous administration. *These agar plate diffusion assays used bacillus subtills or Klebsiella pneumoniae as the test organism and, therefore, measured enrooxacin, cigrooxacin, and any other unidentied metabolites with antimicrobial activity against it.

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106 FLUOROQUINOLONES VeterinarySystemic

31. Anadon A, Martinez-Larranaga MR, Diaz MJ, et al. Pharmacokinetics and residues of enrooxacin in chickens. Am J Vet Res 1995 Apr; 56(4): 5016. 32. Cabanes A, Arboix M, Garcia Anton JM, et al. Pharmacokinetics of enrooxacin after intravenous and intramuscular injection in rabbits. Am J Vet Res 1992 Nov; 53(11): 20903. 33. Broome RL, Brooks DL, Babish JG, et al. Pharmacokinetic properties of enrooxacin in rabbits. Am J Vet Res 1991 Nov; 52(11): 183541. 34. Aramayona JJ, Mora J, Fraile LJ, et al. Penetration of enrooxacin and ciprooxacin into breast milk, and pharmacokinetics of the drugs in lactating rabbits and neonatal offspring. Am J Vet Res 1996 Apr; 57(4): 54753. 35. Fraile LJ, Martinez C, Aramayona JJ, et al. Limited capacity of neonatal rabbits to eliminate enrooxacin and ciprooxacin. Vet Q 1997; 19: 1627. 36. Bowser PR, Wooster GA, St Leger J, et al. Pharmacokinetics of enrooxacin in ngerling rainbow trout (Oncorhynchus mykiss). J Vet Pharmacol Ther 1992; 15: 6271. 37. 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Intorre L, Mengozzi G, Bertini S, et al. The plasma kinetics and tissue distribution of enrooxacin and its metabolite ciprooxacin in the Muscovy duck. Vet Res Commun 1997; 21: 12736. 43. Helmick KE, Boothe DM, Jensen JM. Disposition of single-dose intravenously administered enrooxacin in emus (Dromaius novaehollandiae). J Zoo Wildl Med 1997; 28(1): 438. 44. Lewbart G, Vaden S, Deen J, et al. Pharmacokinetics of enrooxacin in the red pacu (Colossoma brachypomum) after intramuscular, oral and bath administration. J Vet Pharmacol Ther 1997; 20: 1248. 45. Gavrielli R, Yagil R, Ziv G, et al. Effect of water deprivation on the disposition kinetics of enrooxacin in camels. J Vet Pharmacol Ther 1995; 18: 3339. 46. Christensen JM, Smith BB, Murdane SB, et al. The disposition of ve therapeutically important antimicrobial agents in llamas. J Vet Pharmacol Ther 1996; 19: 4318. 47. Gamble KC, Boothe DM, Jensen JM, et al. Pharmacokinetics of a single intravenous enrooxacin dose in a scimitar-horned oryx (Oryx Dammah). J Zoo Wildl Med 1997; 28(1): 3642. 48. Young LA, Schumacher J, Papich MG, et al. Disposition of enrooxacin and its metabolite ciprooxacin after intramuscular injection in juvenile burmese pythons (Python molurus bivittatus). J Zoo Wildl Med 1997; 28(1): 719. 49. Charleston B, Gate JJ, Aitken IA, et al. Comparison of the efcacies of three uoroquinolone antimicrobial agents, given as continuous or pulsed-water medication, against Escherichia coli infection in chickens. Antimicrob Agents Chemother 1998 Jan; 42(1): 837. 50. Jacobs-Reitsma WF, Koenraad PMFJ, Bolder NM, et al. In vitro susceptibility of campylobacter and salmonella isolates from broilers to quinolones, ampicillin, tetracycline, and erythromycin. Vet Q 1994; 16(4): 2068. 51. Barbour EK, Hamadeh S, Talhouk, et al. Evaluation of an enrooxacintreatment program against Mycoplasma gallisepticum infection in broilers. Prev Vet Med 1998 May; 35(2): 919. 52. Sumano LH, Ocampo CL, Brumbaugh GW, et al. Effectiveness of two uoroquinolones for the treatment of chronic respiratory disease outbreak in broilers. Br Poult Sci 1998 Mar; 39(1): 426. 53. Jordan FTW, Horrocks BK, Froyman R. A model for testing the efcacy of enrooxacin (Baytril) administered to turkey hens in the control of Mycoplasma iowae infection in eggs and embryos. Avian Dis 1993; 37: 105761. 54. Hannan PCT, Windsor GD, De Jong A, et al. Comparative susceptibilities of various animal-pathogenic mycoplasmas to uoroquinolones. Antimicrob Agents Chemother 1997 Sept; 41(9): 203740. 55. Endtz HP, Ruijs GJ, van Klingeren B, et al. Quinolone resistance in campylobacter isolated from man and poultry following the introduction of uoroquinolones in veterinary medicine. J Antimicrob Chemother 1991; 27: 199208. 56. Griggs DJ, Hall MC, Jin YF, et al. Quinolone resistance in veterinary isolates of Salmonella. J Antimicrob Chemother 1994; 33: 117389. 57. Lekeux P, Art T. Effect of enrooxacin therapy on shipping fever pneumonia in feedlot cattle. Vet Rec 1988 Aug 20; 123(8): 205. 58. Pellerin JL, Bourdeau P, Sebbag H, et al. Epidemiosurveillance of antimicrobial compound resistance of Staphylococcus intermedius clinical isolates from canine pyodermas. Comp Immunol Microbial Infect Dis 1998 Apr; 21(2): 11533. 59. Novotny MJ, Shaw DH. Effect of enrooxacin on digoxin clearance and steady-state serum concentrations in dogs. Can J Vet Res 1991; 55: 1136. 60. Shlosberg A, Ershov E, Bellaiche M, et al. The effects of enrooxacin on hepatic microsomal mixed function oxidases in broiler chickens. J Vet Pharmacol Ther 1995; 18: 3113. 61. Intorre L, Mengozzi G, Maccheroni M, et al. Enrooxacin-theophylline interaction: inuence of enrooxacin on theophylline steady-state pharmacokinetics in the beagle dog. J Vet Pharmacol Ther 1995; 18: 3526. 62. Vancutsem PM, Babish JG. Effects of ciprooxacin and enrooxacin on zoxazolamine kinetics, plasma concentration and sleeping times in mice. Toxicol Lett 1993; 69: 114. 63. Aramayona JJ, Garcia MA, Fraile LJ, et al. Placental transfer of enrooxacin and ciprooxacin in rabbits. Am J Vet Res 1994 Sep; 55(9): 13138. 64. Butaye P, Ducatelle R, De Backer P, et al. In vitro activities of doxycycline and enrooxacin against European Chlamydia psittaci strains from turkeys. Antimicrob Agents Chemother 1997 Dec; 41(12): 28001. 65. Gutierrez CB, Piriz S, Vadillo S, et al. In vitro susceptibility of actinobacillus pleuropneumoniae strains to 42 antimicrobial agents. Am J Vet Res 1993 Apr; 54(4): 54650. 66. Prescott JF, Yielding KM. In vitro susceptibility of selected veterinary bacterial pathogens to ciprooxacin, enrooxacin and noroxacin. Can J Vet Res 1990; 54: 1957. 67. Suckow MA, Martin BJ, Bowersock TL, et al. Derivation of Pasteurella multocida-free rabbit litters by enrooxacin treatment. Vet Microbiol 1996; 51: 1618. 68. Mahlet M, Stunkel S, Ziegowski C, et al. Inefcacy of enrooxacin in the elimination of Pasteurella multocida in rabbits. Lab Anim 1995; 29: 1929. 69. Broome RL, Brooks DL. Efcacy of enrooxacin in the treatment of respiratory pasteurellosis in rabbits. Lab Anim Sci 1991 Dec; 41(6): 5726. 70. Banish LD, Sins R, Bush M, et al. Clearance of Shigella exneri carriers in a zoologic collection of primates. J Am Vet Med Assoc 1993 Jul 1; 203(1): 1336. 71. Line AS, Paul-Murphy J, Aucoin DP, et al. Enrooxacin treatment of longtailed macaques with acute bacillary dysentery due to multiresistant Shigella exneri IV. Lab Anim Sci 1992 Jun; 42(3): 2404. 72. Kordick DL, Papich MG, Breitschwerdt EB. Efcacy of enrooxacin or doxycycline for treatment of Bartonella henselae or Bartonella clarridgeiae infection in cats. Antimicrob Agents Chemother 1997 Nov; 41(11): 244855. 73. Regnery RL, Rooney JA, Johnson AM, et al. Experimentally induced Bartonella henselae infections followed by challenge exposure and antimicrobial therapy in cats. Am J Vet Res 1996 Dec; 57(12): 12149. 74. Schroder J. Enrooxacin: a new antimicrobial agent. J S Afr Vet Assoc 1989 Jun; 60(2): 1224. 75. Studdert VP, Hughes KL. Treatment of opportunistic mycobacterial infections with enrooxacin in cats. J Am Vet Med Assoc 1992 Nov 1; 201(9): 138890. 76. White PD, Kowalski JJ. Enrooxacin-responsive cutaneous atypical mycobacterial infection in two cats. Proceedings of the 7th meeting of the American College of Veterinary Dermatology. 1991. p. 95. 77. Kontos VJ, Athanasiou LV. Use of enrooxacin in the treatment of acute canine ehrlichiosis. Canine Pract 1998; 23(3): 104. 78. Giguere S, Sweeney RW, Habecker PL, et al. Tolerability of orally administered enrooxacin in adult horses: a pilot study. J Vet Pharmacol Ther 1999; 22: 3437. 79. Rodger LD, Carlson GP, Moran ME, et al. Resolution of a left ureteral stone using electrohydraulic lithotripsy in a thoroughbred colt. J Vet Int Med 1995 Jul/Aug; 9(4): 2802. 80. Heath SE, Townsend HGG, Pharr J, et al. Chronic pleuritis in a horse. Can Vet J 1989 Jan; 30: 69. 81. Committee consensus, 8/26/02. 82. Manufacturer comment, 8/13/02.

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FLUOROQUINOLONES VeterinarySystemic 107

83. Winter RB. Using quinolones to treat haemobartonellosis [letter]. Vet Med Small Animal Clin 1993 Apr; 3067. 84. Breitschwerdt EB, Davidson MG, Aucoin DP, et al. Efcacy of chloramphenicol, enrooxacin, and tetracycline for treatment of experimental Rocky Mountain spotted fever in dogs. Antimicrob Agents Chemother 1991 Nov; 35(11): 237581. 85. Bermingham E, Papich MG, Vivrette SL. Pharmacokinetics of enrooxacin administered intravenously and orally to foals. Am J Vet Res 2000 Jun; 61(6): 7069. 86. Panel comment, Rec 8/5/99. 87. New breakpoints of enrooxacin (dogs/cats) approved by NCCLS. Bayer Animal Health paper. 88. National Committee for Clinical Laboratory Standards. M-31 Document: Performance Standards for Antimicrobial Disk and Dilution Susceptibility Tests for bacteria isolated from animals. Vol 19 No. 11 June 1999. 89. Panel comment, Rec 7/21/99. 90. Martinez-Martinez L, Pascual A, Jacoby GA. Quinolone resistance from a transferable plasmid. Lancet 1998; 351: 7979. 91. Smith KE, Besser JM, Hedberg CW, et al. Quinolone resistant Campylobacter jejuni infections in Minnesota, 19921998. New Eng J Med 1999; 340(20): 152532. 92. Panel comment, Rec 12/29/99. 93. Panel consensus, 1/6/00. 94. Ofce of the Federal Register. Code of Federal Regulations. 21 Parts 500 to 599. April 1, 1999. US Government Printing Ofce: Washington, D.C. 1999. p. 329. 95. Papich MG, Riviere JE. Fluoroquinolone antimicrobial drugs. In: Adams HR, editor. Veterinary Pharmacology and Therapeutics, 8th ed. Ames: Iowa State University Press, 2001. p. 898912. 96. Dioxacin Tablets package insert (Dicural, Fort DodgeUS). Downloaded from www.wyeth.com/divisions/fort_dodge.asp on 6/10/02. 97. Marbooxacin Tablets package insert (Zeniquin, PzerUS). Downloaded from www.zeniquin.com on 6/10/02. 98. Orbioxacin Tablets package insert (Orbax, Schering-PloughUS). Downloaded from www.spah.com on 6/10/02. 99. Dioxacin Tablets package insert (Dicural, AyerstCanada). In: ArriojaDechert A, editor. Compendium of veterinary products, CD ed. Port Huron, MI: North American Compendiums, Inc. 2002. 100. Orbioxacin Tablets package insert (Orbax, Schering-PloughCanada). In: Arrioja-Dechert A, editor. Compendium of veterinary products, CD ed. Port Huron, MI: North American Compendiums, Inc. 2002. 101. Marbooxacin Tablets package insert (Orbax, Schering-PloughCanada). In: Arrioja-Dechert A, editor. Compendium of veterinary products, CD ed. Port Huron, MI: North American Compendiums, Inc. 2002. 102. Enrooxacin package insert (Baytril, BayerCanada). In: Arrioja-Dechert A, editor. Compendium of veterinary products, CD ed. Port Huron, MI: North American Compendiums, Inc. 2002. 103. Fluoroquinolone therapy for cats: Concerns about altered vision. (PzerUS), 2001. 104. Enrooxacin injection package insert (Baytril [dogs], BayerUS), Rev 8/00. In: Entriken TL, editor. Veterinary pharmaceuticals and biologicals, 12th ed. Lenexa, KS: Veterinary Healthcare Communications. 2001. P. 11313. 105. The United States pharmacopeia. The national formulary. USP 26th revision (January 1, 2003). NF 21st ed (January 1, 2003). Rockville, MD: The United States Pharmacopeial Convention, Inc., 2002. p. 45861, 2555. 106. AMDUCA uoroquinolone and glycopeptide prohibition: analysis of comments. May 14, 1998. Food and Drug Administration Center for Veterinary Medicine. Downloaded from www.fda.gov/cvm on 4/11/02. 107. Klasco RK, editor. USP DI Drug information for the healthcare professional. Volume I. Greenwood Village, CO: MICROMEDEX, Inc.; 2003. 108. Lefebvre HP, Schneider M, Dupouy V, et al. Effect of experimental renal impairment on disposition of marbooxacin and its metabolites in the dog. J Vet Pharmacol Ther 1998 Dec; 21(6): 45361. 109. Dicural Tablets freedom of information summary. NADA 141096. Approval date: November 20, 1997. Sponsor: Fort Dodge Animal Health. Downloaded from www.fda.gov/cvm on 6/7/02. 110. Riddle C, Lemons CL, Papich MG, et al. Evaluation of ciprooxacin as a representative of veterinary uoroquinolones in susceptibility testing. J Clin Microbiol 2000; 38(4): 16367. 111. Matsumoto S, Takahashi M, Kitadai N, et al. A study of metabolites isolated from the urine samples of cats and dogs administered orbioxacin. J Vet Med Sci 1998; 60(11): 125961. 112. Spreng M, Deleforge J, Thomas V, et al. Antibacterial activity of marbooxacin. A new uoroquinolone for veterinary use against canine and feline isolates. J Vet Pharmacol Ther 1995; 18: 2849. 113. Heinen E. Comparative serum pharmacokinetics of the uoroquinolones enrooxacin, dioxacin, marbooxacin, and orbioxacin in dogs after single oral administration. J Vet Pharmacol Ther 2002; 25(1): 15. 114. Bryant RE, Mazza JA. Effect of the abscess environment on the antimicrobial activity of ciprooxacin. Am J Med 1989; 87(Suppl 5A): 2317S. 115. Schneider M, Thomas V, Boisrame B, et al. Pharmacokinetics of marbooxacin in dogs after oral and parenteral administration. J Vet Pharmacol Ther 1996; 19(1): 5661. 116. Frazier DL, Thompson L, Trettien A, et al. Comparison of uoroquinolone pharmacokinetic parameters after treatment with marbooxacin, enrooxacin, and dioxacin in dogs. J Vet Pharmacol Ther 2000; 23(5): 293302. 117. Abadia AR, Aramayona JJ, Munoz MJ, et al. Disposition of ciprooxacin following intravenous administration in dogs. J Vet Pharmacol Ther 1994; 17(5): 3848. 118. Walker RD, Stein GE, Hauptman JG, et al. Serum and tissue cage uid concentrations of ciprooxacin after oral administration of the drug to healthy dogs. Am J Vet Res 1990; 51(6): 896900. 119. Gelatt KN, van der Woerdt A, Ketring KL, et al. Enrooxacin-associated retinal degeneration in cats. Vet Ophthalmol 2001 Jun; 4(2): 99106. 120. Ozturk F, Kurt E, Inan UU, et al. Penetration of topical and oral ooxacin into the aqueous and vitreous humor of inamed rabbit eyes. Int J Pharm 2000 Aug 25; 204(12): 915. 121. Garcia-Saenz MC, Arias-Puente A, Fresnadillo-Martinez MJ, et al. Human aqueous humor levels of oral ciprooxacin, levooxacin, and moxioxacin. J Cataract Refract Surg 2001 Dec; 27(12): 196974. 122. Hanioglu-Kargi S, Basci N, Soysal H, et al. The penetration of ooxacin into human aqueous humor given by various routes. Eur J Ophthalmol 1998 Jan-Mar; 8(1): 336. 123. Donnenfeld ED, Perry HD, Snyder RW, et al. Intracorneal, aqueous humor, and vitreous humor penetration of topical and oral ooxacin. Arch Ophthalmol 1997 Feb; 115(2): 1736. 124. Fiscella RG, Nguyen TK, Cwik MJ, et al. Aqueous and vitreous penetration of levooxacin after oral administration. Ophthalmology 1999 Dec; 106(12): 228690. 125. Cekic O, Batman C, Yasar U, et al. Subretinal uid levels of topical, oral, and combined administered ciprooxacin in humans. Br J Ophthalmol 2000: 84: 10613. 126. Saez-Llorens X, McCoig C, Feris JM, et al. Trovan Meningitis Study Group. Quinolone treatment for pediatric bacterial meningitis: A comparative study of trovaoxacin and ceftriaxone with or without vancomycin. The Pediatric Infectious Disease Journal 2002; 21(1): 1422. 127. Rodriguez-Cerrato V, McCoig CC, Michelow IC, et al. Pharmacodynamics and bactericidal activity of moxioxacin in experimental Escherichia coli meningitis. Antimicrob Agents Chemother 2001; 45(11): 309297. 128. Destache CJ, Pakiz CB, Larsen, C, et al. Cerebrospinal uid penetration and pharmacokinetics of levooxacin in an experimental rabbit meningitis model. J Antimicrob Chemother. 2001; 47: 6115. 129. Scotton PG, Pea F, Giobbia M, et al. Cerebrospinal uid penetration of levooxacin in patients with spontaneous acute bacterial meningitis. Clin Infect Dis 2001; 33: 10911. 130. Lipman J, Allworth A, Wallis SC. Cerebrospinal uid penetration of high doses of intravenous ciprooxacin in meningitis. Clin Infect Dis 2000; 31: 11313. 131. Krcmery V, Filka J, Uher J, et al. Ciprooxacin in treatment of nosocomial meningitis in neonates and in infants: report of 12 cases and review. Elsevier Science Inc., 1999. p. 7580. 132. DAntuono VS, Brown I. Successful treatment of enterobacter meningitis with ciprooxacin. Clin Infect Dis 1998; 26: 2067. 133. Haines GR, Brown MP, Gronwall RR, et al. Pharmacokinetics of orbioxacin and its concentration in body uids and in endometrial tissues of mares. Can J Vet Res 2001 Jul; 65(3): 1817. 134. Abadia AR, Aramayona JJ, Munoz MJ, et al. Ciprooxacin pharmacokinetics in dogs following oral administration. J Vet Med A 1995; 42: 50511. 135. Haines GR, Brown MP, Gronwall RR, et al. Serum concentrations and pharmacokinetics of enrooxacin after intravenous and intragastric administration to mares. Can J Vet Res 2000; 64: 1717. 136. Bertone AL, Tremaine WH, Macoris DG, et al. Effect of long-term administration of an injectable enrooxacin solution on physical and musculoskeletal variables in adult horses. J Am Vet Med Assoc 2000; 217(10): 151421.

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108 FLUOROQUINOLONES VeterinarySystemic

137. Agalar C, Usubutun S, Turkyilmaz R. Ciprooxacin and rifampicin versus doxycycline and rifampicin in the treatment of brucellosis. Eur J Clin Microbiol Infect Dis. 1999; 18: 5358. 138. Neer TM, Eddlestone SM, Gaunt SD, et al. Efcacy of enrooxacin for the treatment of experimentally induced ehrlichia canis infection. J Vet Intern Med 1999; 13: 5014. 139. Nicoletti P. Further studies on the use of antibiotics in canine brucellosis. The compendium. Small animal. 1991 June; 13(6): 9447. 140. Corbel MJ. Brucellosis: an overview. Emerging Infect Dis 1997 April-June; 3(2): 21321. 141. Mycobacteriosis. In: Ettinger SJ, Feldman EC, editors. Textbook of Veterinary Internal Medicine, 5th ed. Philadelphia: W.B. Saunders, 2000. p. 3934. 142. Malik R, Hunt GB, Goldsmid SE, et al. Diagnosis and treatment of pyogranulomatous panniculitis due to Mycobacterium smegmatis in cats. J Small Anim Pract 1994; 35: 52430. 143. Hannan PC, Windsor GD, de Jong A, et al. Comparative susceptibilities of various animal-pathogenic mycoplasmas to uoroquinolones. Antimicrob Agents Chemother 1997 Sep; 41(9): 203740. 144. Dowling PM, Wilson RC, Tyler JW, et al. Pharmacokinetics of ciprooxacin in ponies. J Vet Pharmacol Ther 1995, 18(1): 712. 145. Manufacturer comment, Rec 6/26/02. 146. Kay-Mugford PA, Ramsey DT, Dubielzig RR, et al. Ocular effects of orally administered orbioxacin in cats. Proceedings 32nd Annual Meeting American College of Veterinary Ophthalmology 2001. p. 56. 147. National Committee for Clinical Laboratory Standards documents M31-A2 and M37-A2. May 2002. 148. Dowers KL, Olver C, Radecki SV, et al. Use of enrooxacin for treatment of large-form Haemobartonella felis in experimentally infected cats. J Am Vet Med Assoc 2002 Jul 15; 221(2): 2503. 149. Neer TM, Breitschwerdt EB, Greene RT, et al. Consensus statement on ehrlichial disease of small animals from the Infectious Disease Study Group of the ACVIM. J Vet Intern Med 2002; 16: 30915.

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LINCOSAMIDES VeterinarySystemic 109

LINCOSAMIDES VeterinarySystemic
This monograph includes information on the following: Clindamycin; Lincomycin. Some commonly used brand names are: For veterinary-labeled products
AmTech Clindamycin Hydrochloride Capsules [Clindamycin] AmTech Clindamycin Hydrochloride Oral Liquid [Clindamycin] Antirobe [Clindamycin] Antirobe Aquadrops [Clindamycin] Clincaps [Clindamycin] ClindaCure [Clindamycin] Clinda-Guard [Clindamycin] Clindrops [Clindamycin] Lincocin [Lincomycin] Lincocin Aquadrops [Lincomycin] Lincocin Injectable [Lincomycin] Lincocin Sterile Solution [Lincomycin] Lincomix 20 Feed Medication [Lincomycin] Lincomix 50 Feed Medication [Lincomycin] Lincomix Injectable [Lincomycin] Lincomix Injectable Solution [Lincomycin] Lincomix 44 Premix [Lincomycin] Lincomix 110 Premix [Lincomycin] Lincomix Soluble Powder [Lincomycin] Lincomycin 44 Premix [Lincomycin] Lincomycin 44G Premix [Lincomycin] Lincomycin 110 Premix [Lincomycin] Lincomycin 110G Premix [Lincomycin] Lincomycin Soluble [Lincomycin] Moormans LN 10 [Lincomycin] nvClindamycin Capsules [Clindamycin]

ACCEPTED
Dysentery, swine (treatment)Pigs: Lincomycin hydrochloride for medicated feed and soluble powder are indicated in the treatment and control of swine dysentery caused by susceptible organisms.{R-21; 28;
38; 41; 63}

Note: For a listing of dosage forms and brand names by country availability, see the Dosage Forms section(s).

CATEGORY:
Antibacterial (systemic).

INDICATIONS
Note: Bracketed information in the Indications section refers to uses that either are not included in U.S. product labeling or are for products not commercially available in the U.S.

GENERAL CONSIDERATIONS
The lincosamides have activity against many gram-positive bacteria and many anaerobic bacteria, but are not effective against most gramnegative organisms. Lincomycin has been shown to have efcacy against Staphylococcus species, Streptococcus species (except Streptococcus faecalis), Erysipelothrix insidiosa, Leptospira pomona, and Mycoplasma species.{R-3; 4} The activity of lincomycin against obligate anaerobes is seldom addressed in published literature. According to the National Committee for Clinical Laboratory Standards in the United States, clindamycin is the class antibiotic for the lincosamide family and the clindamycin disk is used in in vitro testing to assess susceptibility to both clindamycin and lincomycin{R-31}. Therefore, it is presumed that most anaerobes susceptible to clindamycin would likewise be susceptible to lincomycin, provided compensations for potency and kinetic disposition are made{R-39}. Clindamycin has a spectrum of activity that includes Staphylococcus species, Streptococcus species (except Streptococcus faecalis), and Mycoplasma species, as well as anaerobic organisms, such as Bacteroides species, Fusobacterium species, Clostridium perfringens (but not necessarily other clostridia), Actinomyces species, Peptostreptococcus species, and many Propionibacterium species.{R-1}

Enteritis, necrotic (treatment)Chickens: Lincomycin hydrochloride for medicated feed1 and soluble powder are indicated in the control of necrotic enteritis in chickens caused by susceptible organisms, such as Clostridium perfringens.{R-22; 28; 38; 41; 42; 56} Growth promotion and feed efciency, increasedChickens and pigs1: Lincomycin hydrochloride for medicated feed is indicated for increased weight gain in growing-nishing pigs and for increased weight gain and feed efciency in broiler chickens.{R-38; 63} Joint infections (treatment)Pigs: Lincomycin injection is indicated in the treatment of infectious arthritis caused by susceptible organisms, including susceptible Staphylococcus species, Streptococcus species, Erysipelothrix rhusiopathiae, and Mycoplasma species.{R-4; 5} Metritis (treatment)1Dogs: Lincomycin injection, syrup, and tablets are indicated in the treatment of metritis caused by susceptible organisms.{R-3} Osteomyelitis (treatment)Dogs: Clindamycin capsules and oral solution are indicated in the treatment of osteomyelitis caused by susceptible organisms,{R-1; 2} such as Staphylococcus aureus.{R-35; 36; 62} Periodontal infections (treatment) Cats: Clindamycin oral solution is indicated in the treatment of periodontal infections caused by susceptible bacteria{R-2; 30; 62}. Dogs: Clindamycin capsules and oral solution are indicated in the treatment of periodontal infections caused by susceptible bacteria.{R-1; 2; 62} Porcine proliferative enteropathies (treatment)1Pigs: Lincomycin hydrochloride for medicated feed is indicated in the control of porcine proliferative enteropathies (ileitis) caused by Lawsonia intracellularis{R-38}. Pneumonia, bacterial (treatment)Pigs: Lincomycin injection1 and lincomycin hydrochloride for medicated feed are indicated in the treatment of pneumonia caused by susceptible Mycoplasma species.{R-4;
5; 63}

Respiratory tract infections (treatment)1 Cats: Lincomycin injection, syrup, and tablets are indicated in the treatment of respiratory tract infections caused by susceptible organisms.{R-3} Dogs: Lincomycin injection, syrup, and tablets are indicated in the treatment of respiratory tract infections caused by susceptible organisms.{R-3} Skin infections (treatment)1Dogs: Lincomycin injection, syrup, and tablets are indicated and [clindamycin]{R-20} is effective in the treatment of skin infections, such as pustular dermatitis, caused by susceptible organisms.{R-3} To assure efcacy in the treatment of skin infections, underlying primary disorders, such as allergic inhalant dermatitis, should be identied and controlled{R-1; 30}. Soft tissue infections (treatment) Cats: Clindamycin oral solution and lincomycin injection1, syrup1, and tablets1 are indicated in the treatment of soft tissue infections, including abscesses, caused by susceptible organisms.{R-2; 3; 30; 62}

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110 LINCOSAMIDES VeterinarySystemic Dogs: Clindamycin capsules and oral solution, and lincomycin injection1, syrup1, and tablets1 are indicated in the treatment of soft tissue infections, including abscesses and infected wounds, caused by susceptible organisms.{R-13; 62} Canada Withdrawal times have been established for the use of lincomycin in chickens and pigs (see the Dosage Forms section). Lincomycin is not labeled for use in chickens producing eggs for human consumption.{R-6; 41}

ACCEPTANCE NOT ESTABLISHED

Metritis (treatment)Dogs: There are insufcient data to conrm specically the efcacy of [clindamycin]1 in the treatment of metritis in dogs; however, because lincomycin is indicated for this use, clindamycin can be expected to be at least equally effective{R-15}. Osteomyelitis (treatment)[Cats]1: There are insufcient data to conrm specically the efcacy of clindamycin in the treatment of osteomyelitis in cats; however, the safety and predicted antimicrobial efcacy are supported by research.{R-24; 53; 54; 57} Respiratory tract infections (treatment)Cats and dogs: There are insufcient data to conrm specically the efcacy of [clindamycin]1 in the treatment of respiratory infections in cats and dogs; however, because lincomycin is indicated for this use, clindamycin can be expected to be at least equally effective{R-15}. [Abscesses, laryngeal (treatment)]1Cattle: There are insufcient data to conrm the efcacy and safety of lincomycin injection in the treatment of laryngeal abscesses in cattle. Reports of three cases showed a good response in laryngeal abscesses treated{R-44}. [Arthritis, septic (treatment)]1Cattle and sheep: There are insufcient data to conrm the efcacy and safety of lincomycin injection in the treatment of septic arthritis in cattle and sheep. Case reports of a dozen cases show a resolution of clinical signs in approximately one-half of refractory joint infections treated (mixed infections of streptococci, staphylococci, and Corynebacterium pyogenes).{R-44} [Mastitis (treatment)]1Cattle: There are insufcient data to conrm the efcacy and safety of parenteral lincomycin in the treatment of mastitis in cattle; however, there is evidence of distribution into milk in ruminants in concentrations sufcient to treat susceptible infections that are refractory to other antimicrobials.{R-14; 58} Although no studies have been performed to demonstrate the efcacy of lincomycin against gram-positive mastitis pathogens such as Staphylococcus or Corynebacterium, given lincomycins distribution and the susceptibility patterns of these organisms, lincomycin therapy may be a legitimate choice when other conventional treatments are deemed unlikely to be effective. [Toxoplasmosis (treatment)]1Cats: There are insufcient data to establish the efcacy of clindamycin in the treatment of Toxoplasma gondii infection in cats; however, it is considered to have fewer side effects and perhaps to be more effective in treating some aspects of the disease than is pyrimethamine{R-1719; 34; 59}. Clindamycin may not effectively clear organisms from areas such as the central nervous system in chronically infected animals{R-18} and, in some cases, may be ineffective in resolving clinical signs involving the eye.{R-17}
1

CHEMISTRY
Source: Clindamycin hydrochloride7(S)-Chloro derivative of lincomycin.{R-27} Lincomycin hydrochlorideProduced by the growth of a member of the lincolnensis group of Streptomyces lincolnensis (family Streptomycetaceae).{R-3} Chemical name: Clindamycin hydrochloridel-threo-alpha-d-galacto-octopyranoside, methyl 7-chloro-6,7,8-trideoxy-6-[[(1-methyl-4-propyl-2-pyrrolidinyl)carbonyl]amino]-1-thio-, (2s-trans)-, monohydrochloride.{r-25} Lincomycin hydrochlorided-erythro-alpha-d-galacto-octopyranoside, methyl 6,8-dideoxy-6-[[(1-methyl-4-propyl-2-pyrrolidinyl)carbonyl]amino]-1-thio-, monohydrochloride, monohydrate, (2s-trans)-.{r-25} Molecular formula: Clindamycin hydrochlorideC18H33ClN2O5S HCl.{R-25} Lincomycin hydrochlorideC18H34N2O6SHCl H2O.{R-25} Molecular weight: Clindamycin hydrochloride461.44.{R-25} Lincomycin hydrochloride461.01.{R-25} Description: Clindamycin Hydrochloride USPWhite or practically white, crystalline powder. Is odorless or has a faint mercaptan-like odor. Is stable in the presence of air and light. Its solutions are acidic and are dextrorotatory.{R-26} Lincomycin Hydrochloride USPWhite or practically white, crystalline powder. Is odorless or has a faint odor. Is stable in the presence of air and light. Its solutions are acid and are dextrorotatory.{R-26} Lincomycin Hydrochloride Injection USPClear, colorless to slightly yellow solution, having a slight odor.{R-26} pKa: Clindamycin7.7.{R-14} Lincomycin7.6.{R-14} Solubility: Clindamycin Hydrochloride USPFreely soluble in water, in dimethylformamide, and in methanol; soluble in alcohol; practically insoluble in acetone.{R-26} Lincomycin Hydrochloride USPFreely soluble in water; soluble in dimethylformamide; very slightly soluble in acetone.{R-26}

PHARMACOLOGY/PHARMACOKINETICS
Mechanism of action/effect: The lincosamides inhibit protein synthesis in susceptible bacteria by binding to the 50 S ribosomal subunits of bacterial ribosomes and preventing peptide bond formation.{R-43} The lincosamides are usually considered bacteriostatic{R-43}; however, when clindamycin is present at sufcient concentrations, it may act as a bactericidal antibiotic against sensitive organisms.{R-43} Other actions/effects: Clindamycin may interfere with the attachment and entry of Toxoplasma gondii tachyzoites into host cells.{R-33} All rights reserved

Not included in Canadian product labeling or product not commercially available in Canada.

REGULATORY CONSIDERATIONS
U.S. Withdrawal times have been established for the use of lincomycin in chickens and pigs (see the Dosage Forms section). Lincomycin is not labeled for use in chickens producing eggs for human consumption.{R-4; 38; 42} 2003 Thomson MICROMEDEX

LINCOSAMIDES VeterinarySystemic 111 Absorption: Oral absorption of the lincosamides is rapid, but orally administered lincomycin is less well absorbed than clindamycin. ClindamycinOral absorption of clindamycin is high{R-1}and is unaffected by food. LincomycinOral absorption of lincomycin may be greatly reduced by the presence of food in the stomach.{R-48} Oral absorption: Pigs20 to 50%.{R-49} Rats45 to 60%.{R-49} Intramuscular absorption: Lincomycin hydrochloride is rapidly absorbed after intramuscular administration.{R-3} Distribution: Clindamycin and lincomycin are widely distributed into most tissues, including respiratory tissue, soft tissue, bones, and joints{R-13; 23; 24}. The lincosamides are weak bases (commercial preparations are acidic) and are very lipid soluble at physiologic pH (7.4). Tissue concentrations may be higher than serum concentrations.{R-48} Small amounts are distributed into pancreatic and prostatic secretions.{R-48} There is evidence that clindamycin hydrochloride accumulates in polymorphonuclear granulocytes.{R-20} The lincosamides do not penetrate cerebrospinal uid (CSF) well;{R-24} however, in healthy cats, concentrations of clindamycin in brain tissue after 10 days of therapy were 10 to 20% of serum concentration and were consistently higher than CSF concentrations.{R-24} Volume of distribution (area)Intravenous administration: Clindamycin phosphateDogs: 1.4 L per kg (L/kg).{R-16} LincomycinCalves: 6 weeks of age1 to 1.2 L/kg (healthy calves or calves with induced Pasteurella haemolytica pneumonia).{R-46; 47} 9 months of age1.3 L/kg.{R-47} Protein binding: ClindamycinSheep: Moderate (40 to 50%).{R-14; 51} Lincomycin CowsLow to moderate (26 to 46%).{R-52} SheepLow (30 to 40%).{R-14; 51} Note: Human protein binding of lincomycin decreases with increased plasma concentrations; the range of protein binding varies from low to high. Biotransformation: ClindamycinActive metabolites of clindamycin measured in urine along with parent compound include N-demethylclindamycin and clindamycin sulfoxide.{R-1} LincomycinThe percentage of administered lincosamide metabolized by the liver is unknown.{R-49} Half-life: EliminationIntravenous administration: Clindamycin phosphateDogs: 3.2 hours.{R-16} Lincomycin: Calves, newborn to 2 weeks of age3 hours.{R-47} Calves, 4 weeks to 9 months of age2 to 2.5 hours.{R-46; Clindamycin phosphateDogs: Intramuscular1 hour (dose of 11 mg/ kg).{R-16} Lincomycin hydrochloride Dogs: Intramuscular10 minutes to 2 hours (dose of 22 mg/kg).{R-3} Oral2 to 4 hours (dose of 22 mg/kg).{R-3} Sheep: Intramuscular1 hour (dose of 20 mg/kg).{R-14} Serum concentrations: Peak serum concentration Clindamycin hydrochloride: SheepIntramuscular: 13.8 mcg/mL (single dose of 20 mg/kg).{R-14} Clindamycin phosphate: DogsIntramuscular: 5.3 mcg/mL (dose of 11 mg/kg){R-16}. Lincomycin: SheepIntramuscular: 12.6 mcg/mL (dose of 20 mg/ kg).{R-14} Serum concentration after multiple dosingClindamycin hydrochloride (sample 12 hours after the last dose of an every-twelve-hour oral dose for 10 days): Cats{R-53} 3.5 mcg/mL (dose of 5.5 mg/kg). 5.4 mcg/mL (dose of 11 mg/kg). 6.5 mcg/mL (dose of 22 mg/kg). Duration of action: ClindamycinCats and dogs:{R-15} 12 hours, with an oral dose of 11 mg/kg. 24 hours, with an oral dose of 22 mg/kg. LincomycinDogs: OralFor gram-positive organisms: 6 to 8 hours (22 mg/kg dose).{R-3} Note: Efcacy studies based on a 22 mg/kg dose every 12 hours for 3 weeks in dogs show that duration of action for lincomycin is sufcient for it to be effective when administered every twelve hours{R-20}. Elimination: Parent drug and metabolites are primarily excreted in the urine and the bile.{R-1; 3; 24; 48; 49} Small amounts are excreted in intestinal contents and pancreatic and prostatic uids.{R-48} When lincomycin is administered orally to dogs, 77% of the dose is excreted in the feces and 14% of the dose is excreted in the urine. When administered intramuscularly, 38% of the dose is excreted in the feces and 49% is excreted in the urine.{R-3} Less clindamycin than lincomycin is excreted in the urine.{R-50} ClearanceIntravenous administration: Clindamycin phosphateDogs: 5.3 mL per minute per kg (mL/min/ kg).{R-16} LincomycinCalves: 6 weeks of age3.9 to 8.1 mL/min/kg.{R-46} 9 months of age4.4 mL/min/kg.{R-46}

PRECAUTIONS TO CONSIDER
47}

CROSS-SENSITIVITY AND RELATED PROBLEMS

Animals sensitive to clindamycin may be sensitive to lincomycin and the reverse may also be true.

Time to peak concentration: Clindamycin hydrochloride Dogs: Oral1.3 hours (single dose of 5.5 to 11 mg per kg of body weight [mg/kg]).{R-1} Sheep: Intramuscular1 hour (dose of 20 mg/kg).{R-14}

SPECIES SENSITIVITY
Chinchillas, guinea pigs, hamsters, horses, ponies, and rabbits:{R-79; 11} The use of oral clindamycin or lincomycin is generally contraindicated in

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112 LINCOSAMIDES VeterinarySystemic these species because of the risk of altering the gastrointestinal microora and causing serious or fatal enterocolitis and diarrhea. Overgrowth of organisms such as Clostridium or Salmonella species has been suspected as the cause in many species. Cecal Escherichia coli, but not Clostridium species, have been cultured from rabbits showing adverse effects after lincomycin exposure.{R-9} Contamination of feed with lincomycin at or below feed additive concentrations used for pigs has caused severe or fatal diarrhea in rabbits, ponies, and horses.{R-79} Ruminants: Ruminants exposed to oral lincomycin have also been reported to have side effects such as anorexia, ketosis, and sometimes severe diarrhea,{R-10; 12; 55} possibly caused by overgrowth of nonsusceptible bacteria; however, case reports and research studies using parenteral lincomycin have reported that only a small percentage of treated animals developed diarrhea and/or decreased milk production.{R-4447} Feeds contaminated with 3 to 24 parts per million (ppm) of lincomycin have caused ketosis and diarrhea in dairy cows{R-12}. After treatment with oral lincomycin for Campylobacter, two thirds of a range ock of sheep died; however, the ock had a history of Salmonella infections and grazed in an area with some oxalate-containing range plants, both of which were believed to play a role in the losses.{R-10} Neuromuscular blocking agents (concurrent use of these medications with clindamycin or lincomycin may enhance the neuromuscular blockade, resulting in respiratory depression or paralysis;{R-1; 48} caution is also recommended during surgery or the postoperative period; treatment with cholinesterase agents or calcium salts may help reverse the blockade{R-48})

HUMAN DRUG INTERACTIONS{R-61}

In addition to the above drug interactions reported in animals, the following drug interactions have been reported in humans, and are included in the human monographs Clindamycin (Systemic) and Lincomycin (Systemic) in USP DI Volume I; these drug interactions are intended for informational purposes only and may or may not be applicable to the use of clindamycin and lincomycin in the treatment of animals: Antidiarrheals, adsorbent (concurrent use of kaolin- or attapulgite-containing antidiarrheals with oral lincomycin may signicantly decrease absorption of oral lincomycin; concurrent use with oral clindamycin may delay absorption; concurrent use should be avoided or patients should be advised to take adsorbent antidiarrheals not less than 2 hours before or 3 to 4 hours after oral lincosamides) Antidiarrheals, antiperistaltic (antiperistaltic agents, such as opiates, difenoxin, diphenoxylate, or loperamide, may prolong or worsen pseudomembranous colitis by delaying toxin elimination) Antimyasthenics (concurrent use of medications with neuromuscular blocking action may antagonize the effect of antimyasthenics on skeletal muscle; temporary dosage adjustments of antimyasthenics may be necessary to control symptoms of myasthenia gravis during and following concurrent use) Chloramphenicol or Erythromycins (may displace clindamycin or lincomycin from or prevent their binding to 50 S subunits of bacterial ribosomes, thus antagonizing the effects of the lincosamides; concurrent use is not recommended) Opioid (narcotic) analgesics (respiratory depressant effects of drugs with neuromuscular blocking activity may be additive to central respiratory depressant effects of opioid analgesics, possibly leading to increased or prolonged respiratory depression or paralysis [apnea]; caution and careful monitoring of the patient are recommended)

PREGNANCY/REPRODUCTION
The safety of clindamycin in pregnant or breeding animals has not been established.{R-1; 2; 13} When lincomycin was given to pregnant dogs at 50 mg per kg of body weight (mg/kg) per day, no evidence of teratogenic effects on the embryos was seen.{R-3} Also, 75 mg of lincomycin per kg a day administered to breeding male and female rats during a breeding cycle had no observed effect on breeding or teratogenic effects on offspring.{R-3}

LACTATION
Clindamycin and lincomycin are distributed into milk{R-14} in therapeutic concentrations.{R-40} With constant serum lincomycin concentrations, milk concentrations range from 2.5 to 6.2 times the serum concentration, depending on the pH of the milk.{R-14}

PEDIATRICS
No evidence of side effects was noted in newborn puppies and rats given lincomycin at doses of 30 to 90 mg/kg a day.{R-3}

DRUG INTERACTIONS AND/OR RELATED PROBLEMS

The following drug interactions and/or related problems have been selected on the basis of their potential clinical signicance (possible mechanism in parentheses where appropriate)not necessarily inclusive ( = major clinical signicance): Note: Combinations containing any of the following medications, depending on the amount present, may also interact with this medication. Anesthetics, hydrocarbon inhalation, such as: Enurane Halothane Isourane Methoxyurane, or

LABORATORY VALUE ALTERATIONS

The following have been selected on the basis of their potential clinical signicance (possible effect in parentheses where appropriate)not necessarily inclusive ( = major clinical signicance): Note: No signicant laboratory value alterations have been reported in animals. Human laboratory value alterations have been reported and are included in this monograph.

HUMAN LABORATORY VALUE ALTERATIONS{R-61}

The following laboratory value alterations have been reported in humans, and are included in the human monographs Clindamycin (Systemic) and Lincomycin (Systemic) in USP DI Volume I; these laboratory value alterations are intended for informational purposes

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LINCOSAMIDES VeterinarySystemic 113 only and may or may not be applicable to the use of clindamycin and lincomycin in the treatment of animals: With physiology/laboratory test values Alanine aminotransferase (ALT [SGPT]), serum, and Alkaline phosphatase, serum, and Aspartate aminotransferase (AST [SGOT]), serum (values may be increased) Cats and dogs Anorexia; diarrhea; vomiting{R-1; 3; 54} Note: Anorexia, diarrhea, and vomiting in cats and dogs are believed to result from local irritation because side effects have not been seen with parenteral treatment. Side effects are more likely with higher doses.{R-54} Ruminants With lincomycin Anorexia; decreased milk production; diarrhea; ketosis Note: Anorexia, decreased milk production, ketosis, and severe diarrhea have been reported to be most likely in ruminants administered lincomycin orally.{R-10; 12} However, some animals may develop adverse effects with parenterally administered lincomycin.{R-45} Incidence unknown All species Hypersensitivity reactions{R-1; 3}

MEDICAL CONSIDERATIONS/CONTRAINDICATIONS
The medical considerations/contraindications included have been selected on the basis of their potential clinical signicance (reasons given in parentheses where appropriate)not necessarily inclusive ( = major clinical signicance). Risk-benet should be considered when the following medical problems exist: Hepatic function impairment, severe (because clindamycin and lincomycin are metabolized by the liver{R-1; 49}, it is possible that severe hepatic function impairment could prolong the half-lives of these medications; adjustments in dosage might be required{R-37}) Hypersensitivity to clindamycin or lincomycin{R-1; 3} (sensitivity or cross-sensitivity may occur) Renal function impairment, severe (lincomycin is eliminated by the kidneys of dogs to a greater degree than is clindamycin{R-50}; very severe renal impairment may require dosage adjustments)

THOSE INDICATING NEED FOR MEDICAL ATTENTION ONLY IF THEY CONTINUE OR ARE BOTHERSOME
Incidence more frequent Cats Lip smackingwith clindamycin oral solution{R-53}; salivationwith clindamycin oral solution{R-53} Incidence less frequent or rare Pigs Anal swelling{R-41; 42}; diarrhea{R-41; 42}transient; irritable behavior{R-41; 42}; skin reddening{R-41; 42} Note: Anal swelling, diarrhea, irritable behavior, and skin reddening are generally self-limiting within 5 to 8 days.

PATIENT MONITORING
The following may be especially important in patient monitoring (other tests may be warranted in some patients, depending on condition; = major clinical signicance): Culture and susceptibility, in vitro, and Minimum inhibitory concentration (MIC) (in vitro cultures and MIC tests should be done on samples collected prior to lincosamide administration to determine pathogen susceptibility) Note: The clindamycin disk is used for in vitro susceptibility testing to assess susceptibility to both clindamycin and lincomycin{R-31}.

HUMAN SIDE/ADVERSE EFFECTS{R-61}

In addition to the above side/adverse effects reported in animals, the following side/adverse effects have been reported in humans, and are included in the human monographs Clindamycin (Systemic) and Lincomycin (Systemic) in USP DI Volume I; these side/adverse effects are intended for informational purposes only and may or may not be applicable to the use of clindamycin and lincomycin in the treatment of animals: Incidence more frequent Gastrointestinal disturbances; pseudomembranous colitis Incidence less frequent Fungal overgrowth; hypersensitivity; neutropenia; thrombocytopenia Indicating possible pseudomembranous colitis and the need for medical attention if they occur after medication is discontinued Abdominal or stomach cramps and pain, severe; abdominal tenderness; diarrhea, watery and severe, which may also be bloody; fever

SIDE/ADVERSE EFFECTS
Note: The pseudomembranous colitis reported in people as an adverse reaction to lincosamides as well as the colitis and diarrhea side effects reported in chinchillas, guinea pigs, horses, rabbits, and ruminants are considered to be caused by overgrowth of resistant organisms. Resistant Clostridium species are suspected, but other organisms or even other mechanisms may also be involved.{R-811; 48} The following side/adverse effects have been selected on the basis of their potential clinical signicance (possible signs and, for humans, symptoms in parentheses where appropriate)not necessarily inclusive:

THOSE INDICATING NEED FOR MEDICAL ATTENTION

Incidence more frequent Chinchillas, guinea pigs, hamsters, horses, ponies, and rabbits{R-79; 11} Enterocolitis (anorexia; collapse; dehydration; diarrhea, watery and sometimes hemorrhagic) Incidence less frequent

OVERDOSE
For information in cases of overdose or unintentional ingestion, contact the American Society for the Prevention of Cruelty to Animals (ASPCA) National Animal Poison Control Center (888-426-4435 or 900-443-0000; a fee may be required for consultation) and/or the drug manufacturer.

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114 LINCOSAMIDES VeterinarySystemic

CLIENT CONSULTATION
Medication should be administered for the full length of time prescribed. Any signs of anorexia, diarrhea, or vomiting should be reported to the veterinarian.

Apparatus 1 at 100 rpm), Uniformity of dosage units, and Water (not more than 7.0%).{R-26}

CLINDAMYCIN HYDROCHLORIDE ORAL SOLUTION USP

Usual dose: Osteomyelitis; or [Skin infections]1Dogs: See Clindamycin Hydrochloride Capsules USP. Periodontal infections and soft tissue infections Cats: Oral, 11 to 33 mg (base) per kg of body weight every twentyfour hours{R-1}. Dogs: Oral, 5.5 to 33 mg (base) per kg of body weight every twelve hours{R-1}. Note: CatsBased on dosing studies, the following dosages have been used in cats for treatment of [osteomyelitis]1 and [skin infections]1: Staphylococcal infectionsOral, 5.5 mg (base) per kg of body weight every twelve hours.{R-53} Anaerobic bacterial infectionsOral, 11 mg (base) per kg of body weight every twelve hours or 22 mg per kg of body weight every twenty-four hours.{R-53} Based on clinical efcacy and pharmacokinetic studies, the following dose has been used in cats for the treatment of [toxoplasmosis]1Oral, 12.5 to 25 mg (base) per kg of body weight every twelve hours for two to four weeks.{R-17; 18; 53; 54; 57; 59} Strength(s) usually available: U.S.{R-6} Veterinary-labeled product(s): 25 mg (base) per mL (Rx) [AmTech Clindamycin Hydrochloride Oral Liquid; Antirobe Aquadrops; ClindaCure; Clinda-Guard; Clindrops; generic]. Canada{R-6} Veterinary-labeled product(s): 25 mg (base) per mL (Rx) [Antirobe Aquadrops]. Packaging and storage: Store below 40 C (104 F), preferably between 15 and 30 C (59 and 86 F), unless otherwise specied by manufacturer. Protect from freezing. USP requirements: Preserve in tight containers. Label oral solution to indicate that it is intended for veterinary use only. Contains the equivalent of the labeled amounts, within 10%. Meets the requirements for Identication, Uniformity of dosage units, Deliverable volume, and pH (3.05.5){R-26}.
1

CLINDAMYCIN SUMMARY OF DIFFERENCES

Indications: Has wider spectrum of activity than does lincomycin. Indicated in the treatment of osteomyelitis, periodontal infections, and soft tissue infections. Used in the treatment of skin infections. Pharmacology/pharmacokinetics: Highly absorbed after oral administration. Absorption is unaffected by the presence of food in the stomach.

ORAL DOSAGE FORMS

Note: Bracketed information in the Dosage Forms section refers to uses that either are not included in U.S. product labeling or are for products not commercially available in the U.S. The dosing and strengths of the dosage forms available are expressed in terms of the clindamycin base (not the hydrochloride salt).

CLINDAMYCIN HYDROCHLORIDE CAPSULES USP

Usual dose: OsteomyelitisDogs: Oral, 11 to 33 mg (base) per kg of body weight every twelve hours{R-1}. Periodontal infections and soft tissue infectionsDogs: Oral, 5.5 to 33 mg (base) per kg of body weight every twelve hours{R-1}. [Skin infections]1Dogs: Oral, 11 mg (base) per kg of body weight every twenty-four hours.{R-20} Note: The above dose for the treatment of skin infections in dogs is based upon a clinical comparative efcacy study of clindamycin and lincomycin{R-20}. Strength(s) usually available: U.S.{R-1; 6} Veterinary-labeled product(s): 25 mg (base) (Rx) [AmTech Clindamycin Hydrochloride Capsules; Antirobe; Clincaps; generic]. 75 mg (base) (Rx) [AmTech Clindamycin Hydrochloride Capsules; Antirobe; Clincaps; generic]. 150 mg (base) (Rx) [AmTech Clindamycin Hydrochloride Capsules; Antirobe; Clincaps; generic]. 300 mg (base) (Rx) [Antirobe]. Canada{R-2; 6} Veterinary-labeled product(s): 25 mg (base) (OTC) [Antirobe; nvClindamycin Capsules]. 75 mg (base) (OTC) [Antirobe; nvClindamycin Capsules]. 150 mg (base) (OTC) [Antirobe; nvClindamycin Capsules]. Packaging and storage: Store below 40 C (104 F), preferably between 15 and 30 C (59 and 86 F), unless otherwise specied by manufacturer. Preserve in tight containers. USP requirements: Preserve in tight containers. Contain an amount of clindamycin hydrochloride equivalent to the labeled amount of clindamycin, within 10% to +20%. Meet the requirements for Identication, Dissolution (80% in 30 minutes in phosphate buffer [pH 6.8] in 2003 Thomson MICROMEDEX

Not included in Canadian product labeling or product not commercially available in Canada.

LINCOMYCIN SUMMARY OF DIFFERENCES

Indications: Indicated in the treatment of swine dysentery; growth promotion and feed efciency in chickens and pigs; joint infections in pigs; metritis in dogs; pneumonia in pigs; respiratory tract infections in cats and dogs; skin infections in dogs; and soft tissue infections in cats and dogs. Indicated in the control of necrotic enteritis in chickens. Pharmacology/pharmacokinetics: Oral lincomycin is less well absorbed than intramuscular lincomycin; dosages are adjusted to compensate. Elimination of lincomycin is affected to a greater extent by severe renal All rights reserved

LINCOSAMIDES VeterinarySystemic 115 function impairment than is clindamycin. Absorption is reduced by the presence of food in the stomach.
Species Withdrawal time Meat (days) 0 0

ORAL DOSAGE FORMS

Note: The dosing and strengths of the dosage forms available are expressed in terms of lincomycin base (not the hydrochloride salt).

Chickens Pigs

LINCOMYCIN HYDROCHLORIDE FOR MEDICATED FEED

Usual dose: Growth promotion Chickens: Oral, 2 to 4 grams (base) per ton of feed, fed as the only ration.{R-38} Pigs1: Oral, 20 grams (base) per ton of feed, fed as the only ration.{R-38} Mycoplasma pneumoniaPigs: Oral, 200 grams (base) per ton of feed, fed as the only ration for twenty-one days.{R-38} Necrotic enteritis1Chickens: Oral, 2 grams (base) per ton of feed, fed as the only ration.{R-48} Porcine proliferative enteropathies (control)1Pigs: Oral, 100 grams (base) per ton of feed, fed as the only ration for twenty-one days or until signs of disease disappear. A dose of 40 grams (base) per ton of feed, fed as the only ration, may follow the above dose or be used in place of the 100-gram dose in animals that have not yet had symptoms{R-38}. Swine dysenteryPigs: ControlOral, 40 grams (base) per ton of feed, fed as the only ration.{R-38; 42} TreatmentOral, 100 grams (base) per ton of feed (approximately 4.4 to 8.8 mg [base] per kg of body weight), fed as the only ration for twenty-one days or until signs of disease disappear.{R-38; 42} Strength(s) usually available: U.S.{R-6} Veterinary-labeled product(s): 10 grams (base) per pound of premix (OTC) [Moormans LN 10]. 20 grams (base) per pound of premix (OTC) [Lincomix 20 Feed Medication]. 50 grams (base) per pound of premix (OTC) [Lincomix 50 Feed Medication]. Canada{R-6} Veterinary-labeled products: 44 grams (base) per kg of premix (OTC) [Lincomix 44 Premix; Lincomycin 44 Premix; Lincomycin 44G Premix]. 110 grams (base) per kg of premix (OTC) [Lincomix 110 Premix; Lincomycin 110 Premix; Lincomycin 110G Premix]. Withdrawal times: U.S.{R-38; 42}
Withdrawal time Species Chickens Pigs Meat (days) 0 0 or 6, depending on product

When mixed at 110 or 220 grams (base) of lincomycin per metric ton of feed for pigs:
Withdrawal time Species Pigs Meat (days) 2

Packaging and storage: Store below 40 C (104 F), preferably between 15 and 30 C (59 and 86 F), unless otherwise specied by manufacturer. Store in a dry place.{R-42} Preparation of dosage form: Premix should be mixed into the complete feed following manufacturers directions to produce 2, 3, 4, 20, 40, 100, or 200 grams of lincomycin (base) per ton of feed. Additional information: Not for use in breeding swine or laying chickens.{R-38; 42} In preparing feeds, appropriate cleanout procedures should be followed to prevent cross-contamination of other feeds.{R-42} USP requirements: Not in USP{R-26}.

LINCOMYCIN HYDROCHLORIDE SOLUBLE POWDER USP

Usual dose: Necrotic enteritisChickens: Oral, 64 mg (base) per gallon of water, administered as the only source of drinking water for seven days.{R-22;
28; 41; 56}

Swine dysenteryPigs: Oral, 250 mg (base) per gallon of water (approximately 8.4 mg [base] per kg of body weight) a day, administered as the only source of drinking water for ve to ten days{R-28; 41}. Strength(s) usually available: U.S.{R-6} Veterinary-labeled product(s): 400 mg (base) per gram of powder (OTC) [Lincomix Soluble Powder; Lincosol Soluble Powder; generic]. Canada{R-6} Veterinary-labeled product(s): 400 mg (base) per gram of powder (OTC) [Lincomix Soluble Powder; generic]. Withdrawal times: U.S.{R-41}
Withdrawal time Species Chickens Pigs Meat (days) 0 0 or 6, depending on product

Canada{R-63} When mixed at 2.2 grams of lincomycin (base) per metric ton (1000 kg) of feed for chickens and 44 grams (base) of lincomycin per metric ton of feed for pigs: 2003 Thomson MICROMEDEX

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116 LINCOSAMIDES VeterinarySystemic Canada{R-28} When mixed at concentrations of 16 mg of lincomycin (base) per liter of water (61 mg per gallon) for chickens or 33 mg of lincomycin (base) per liter of water (125 mg per gallon) for pigs:
Withdrawal time Species Chickens Pigs Meat (days) 0 1

LINCOMYCIN HYDROCHLORIDE TABLETS

Usual dose: Metritis1; or Skin infections1Dogs: Oral, 22 mg (base) per kg of body weight every twelve hours or 15.4 mg (base) per kg of body weight every eight hours.{R-3} Respiratory tract infections1Cats and dogs: Oral, 22 mg (base) per kg of body weight every twelve hours or 15.4 mg (base) per kg of body weight every eight hours{R-3}. Soft tissue infections1Cats and dogs: Oral, 22 mg (base) per kg of body weight every twelve hours or 15.4 mg (base) per kg of body weight every eight hours.{R-3} Strength(s) usually available: U.S.{R-3; 6} Veterinary-labeled product(s): 100 mg (base) (Rx) [Lincocin]. 200 mg (base) (Rx) [Lincocin]. 500 mg (base) (Rx) [Lincocin]. Canada{R-6} Veterinary-labeled product(s): Not commercially available. Packaging and storage: Store below 40 C (104 F), preferably between 15 and 30 C (59 and 86 F), unless otherwise specied by manufacturer. USP requirements: Not in USP{R-26}.
1

Packaging and storage: Store below 40 C (104 F), preferably between 15 and 30 C (59 and 86 F), unless otherwise specied by manufacturer. Preparation of dosage form: Powder should be mixed into the drinking water following manufacturers directions to produce 61, 64, 125, or 250 mg (base) per gallon. Fresh stock solutions should be prepared on the day of use and unused medicated water discarded after 2 days. USP requirements: Preserve in tight containers. Label it to indicate that it is for veterinary use only. Contains an amount of Lincomycin Hydrochloride equivalent to the labeled amount of lincomycin, within 10%. Meets the requirements for Identication, Water, and Minimum ll{R-26}.

LINCOMYCIN HYDROCHLORIDE SYRUP USP

Usual dose: Metritis1; or Skin infections1Dogs: Oral, 22 mg (base) per kg of body weight every twelve hours or 15.4 mg (base) per kg of body weight every eight hours.{R-3} Respiratory tract infections1Cats and dogs: Oral, 22 mg (base) per kg of body weight every twelve hours or 15.4 mg (base) per kg of body weight every eight hours{R-3}. Soft tissue infections1Cats and dogs: Oral, 22 mg (base) per kg of body weight every twelve hours or 15.4 mg (base) per kg of body weight every eight hours.{R-3} Strength(s) usually available: U.S.{R-3; 6} Veterinary-labeled product(s): 50 mg (base) per mL (Rx) [Lincocin Aquadrops]. Canada{R-6} Veterinary-labeled product(s): Not commercially available. Packaging and storage: Store between 15 and 30 C (59 and 86 F), unless otherwise specied by manufacturer.{R-33} Store in a tight container. USP requirements: Preserve in tight containers. Contains an amount of Lincomycin Hydrochloride equivalent to the labeled amount of lincomycin, within 10% to +20%, and one or more suitable colors, avors, preservatives, and sweeteners in water. Meets the requirements for Uniformity of dosage units (for syrup packaged in single-unit containers), Deliverable volume (for syrup packaged in multiple-unit containers), and pH (35.5).{R-26} 2003 Thomson MICROMEDEX

Not included in Canadian product labeling or product not commercially available in Canada.

PARENTERAL DOSAGE FORMS

Note: Bracketed information in the Dosage Forms section refers to uses that either are not included in U.S. product labeling or are for products not commercially available in the U.S. The dosing and strengths of the dosage forms available are expressed in terms of lincomycin base (not the hydrochloride salt).

LINCOMYCIN INJECTION USP

Usual dose: Joint infections; or Mycoplasma pneumonia1Pigs: Intramuscular, 11 mg (base) per kg of body weight every twenty-four hours for three to seven days.{R-4} Metritis1; or Skin infections1Dogs: Intramuscular or intravenous, 22 mg (base) per kg of body weight every twenty-four hours or 11 mg (base) per kg of body weight every twelve hours.{R-3} Respiratory tract infections1; or Soft tissue infections1Cats and dogs: Intramuscular or intravenous, 22 mg (base) per kg of body weight every twenty-four hours or 11 mg (base) per kg of body weight every twelve hours.{R-3} Note: For intravenous administration, the injection should be diluted with 5% glucose or normal saline and administered as a drip infusion.{R-3} Note: [Cattle]1Although the safety and efcacy have not been established for treatment of laryngeal abscesses, mastitis, or septic arthritis in cattle, a dose of 5 mg (base) lincomycin per kg of body All rights reserved

LINCOSAMIDES VeterinarySystemic 117 weight every twenty-four hours, administered intramuscularly for ve to seven days, has been used.{R-44; 45; 60} For deep-seated or severe infections, a dose of 10 mg (base) per kg of body weight every twelve hours has been recommended{R-46; 48}. [Sheep]1Although the safety and efcacy have not been established for treatment of septic arthritis in sheep, cases have been reported that responded to 5 mg (base) per kg of body weight, administered intramuscularly every twenty-four hours for three to ve days.{R-44} Strength(s) usually available: U.S.{R-6} Veterinary-labeled product(s): 25 mg (base) per mL (OTC) [Lincocin Injectable; Lincocin Sterile Solution; Lincomix Injectable]. 100 mg (base) per mL [Lincocin Sterile Solution [cats and dogs] (Rx); Lincocin Sterile Solution [pigs] (OTC); Lincomix Injectable (OTC)]. 300 mg (base) per mL (OTC) [Lincocin Injectable; Lincocin Sterile Solution; Lincomix Injectable]. Canada{R-6} Veterinary-labeled product(s): 100 mg (base) per mL (OTC) [Lincomix Injectable Solution]. Withdrawal times: Note: There are no established withdrawal times for cattle or sheep in the United States or Canada because lincomycin is not approved for use in these species. If lincomycin is administered to cattle at the dose of 5 mg (base) per kg of body weight for four days, evidence has been compiled by the Food Animal Residue Avoidance Databank (FARAD) that suggests a milk withholding time of 96 hours{R-45; 60} and a meat withdrawal time of 7 days{R-60} would be sufcient to avoid residues. There is no available information to make recommendations for withdrawal times when lincomycin is administered to cattle concurrently with other medications or when doses greater than 5 mg (base) per kg of body weight every twenty-four hours are administered. Also, no recommendations can be made for withdrawal times when lincomycin is administered to sheep. If it is necessary to administer these doses, extended withdrawal times are recommended. U.S.{R-4}
Withdrawal time Species Pigs Meat (days) 2
1

Not included in Canadian product labeling or product not commercially available in Canada.

Developed: 07/17/96 Interim revision: 05/07/97; 10/15/99; 09/30/02; 04/04/03

REFERENCES
1. Clindamycin package insert (Antirobe, Pharmacia Animal HealthUS), Rev 2/02. Downloaded from www.pharmaciaah.com on 8/9/02. 2. Clindamycin package insert (Antirobe, Pharmacia Animal HealthCanada). In: Arrioja-Dechert A, editor. Compendium of veterinary products, CD ed. Port Huron, MI: North American Compendiums, Inc. 2002. 3. Lincomycin package insert (Lincocin [cat and dog], Pharmacia Animal HealthUS), Rev 10/00. Downloaded from www.pharmaciaah.com on 8/9/02. 4. Lincomycin package insert (Lincomix [swine], Pharmacia Animal HealthUS), Rev 8/99. Downloaded from www.pharmaciaah.com on 8/9/02. 5. Lincomycin product overview for pigs (Lincomix 100, PharmaciaCanada). Downloaded 2/26/03 from www. pharmaciaah.ca. 6. Arrioja-Dechert A, editor. Compendium of veterinary products, CD ed. Port Huron, MI: North American Compendiums, Inc. 2002. 7. Thilstead JP, Newton WM, Crandell RA, et al. Fatal diarrhea in rabbits resulting from the feeding of antibiotic-contaminated feed. J Am Vet Med Assoc 1981; 179(4): 3602. 8. Raisbeck MF, Holt GR, Osweiler GD. Lincomycin-associated colitis in horses. J Am Vet Med Assoc 1981; 179(4): 3623. 9. Maiers JD, Mason SJ. Lincomycin-associated enterocolitis in rabbits. J Am Vet Med Assoc 1984 Sep 15; 185(6): 6702. 10. Bulgin MS. Losses related to the ingestion of lincomycin-medicated feed in a range sheep ock. J Am Vet Med Assoc 1988 Apr 15; 192(8): 10836. 11. Staempi JR, Prescott JF, Brash ML. Lincomycin-induced severe colitis in ponies: association with Clostridium cadaveris. Can J Vet Res 1992; 56(2): 1689. 12. Rice DA, McMurray CH. Ketosis in dairy cows caused by low levels of lincomycin in concentrated feed. Vet Rec 1983; 113: 4956. 13. Havari J, Lincoln J. Pharmacologic features of clindamycin in dogs and cats. J Am Vet Med Assoc 1989 Jul 1; 195(1): 1245. 14. Ziv G, Sulman FG. Penetration of lincomycin and clindamycin into milk in ewes. Br Vet J 1973; 129: 83. 15. Panel comment, 4/25/96. 16. Budsberg SC, Kemp DT, Wolski N. Pharmacokinetics of clindamycin phosphate in dogs after single intravenous and intramuscular administrations. Am J Vet Res 1992 Dec; 53(12): 23336. 17. Lappin MR, Greene CE, Winston S, et al. Clinical feline toxoplasmosis. J Vet Int Med 1989 Jul/Sep; 3(3): 13943. 18. Greene CE, Cook JR, Mahaffey EA. Clindamycin for treatment of Toxoplasma polymyositis in a dog. J Am Vet Med Assoc 1985 Sep 15; 187(6): 6314. 19. Dubey JP, Yeary RA. Anticoccidial activity of 2-sulfa-moyl-4,4-diaminophenylsulfone, sulfadiazine, pyrimethamine and clindamycin in cats infected with toxoplasma gondii. Can Vet J 1977 Mar; 18(3): 517. 20. Harvey RG, Noble WC, Ferguson EA. A comparison of lincomycin hydrochloride and clindamycin hydrochloride in the treatment of supercial pyoderma in dogs. Vet Rec 1993; 132: 3513. 21. Hamdy AH, Kratzer DD. Therapeutic effects of parenteral administration of lincomycin on experimentally transmitted swine dysentery. Am J Vet Res 1981 Feb; 42(2): 17882. 22. Hamdy AH, Thomas RW, Yancey RJ. Therapeutic effect of optimal lincomycin concentration in drinking water on necrotic enteritis in broilers. Poult Sci 1983 Apr; 62(4): 58991. 23. Swenson GH, Barbiers AR. The distribution and depletion of lincomycin in swine following parenteral administration. International Pig Veterinary Society Proceedings, 4th ed.; 1976: B.5. 24. Brown SA, Zaya MJ, Dieringer TM, et al. Tissue concentrations of clindamycin after multiple oral doses in normal cats. J Vet Pharm Ther 1990; 13(3): 2707. 25. USP dictionary of USAN and international drug names, 2002 ed. Rockville, MD: The United States Pharmacopeial Convention, Inc.; 2002. 26. The United States pharmacopeia. The national formulary. USP 26th revision (January 1, 2003). NF 21st ed (January 1, 2003). Rockville, MD: The United States Pharmacopeial Convention, Inc.; 2002. p. 471, 472, 1082, 1083, 2555, 2567.

Canada{R-6}
Withdrawal time Species Pigs Meat (days) 2

Packaging and storage: Store below 40 C (104 F), preferably between 15 and 30 C (59 and 86 F), unless otherwise specied by manufacturer. USP requirements: Preserve in single-dose or in multiple-dose containers, preferably of Type I glass. Contains benzyl alcohol as a preservative. Contains an amount of Lincomycin Hydrochloride in Water for Injection equivalent to the labeled amount of lincomycin, within 10% to +20%. Meets the requirements for Bacterial endotoxins, Sterility, pH (3.05.5), and Particulate matter, and for Injections.{R-26} 2003 Thomson MICROMEDEX

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118 LINCOSAMIDES VeterinarySystemic

27. Clindamycin package insert (Cleocin HCL, PharmaciaUS), Rev 9/02, Rec 1/14/03. 28. Lincomycin product overview for poultry and pigs (Lincomix Soluble Powder, PharmaciaCanada). Downloaded 2/26/03 from www. pharmaciaah.ca. 29. Veterinary Advisory Panel meeting, 2/1/96. 30. Telecommunication (UpjohnUS), 1/30/96. 31. National Committee for Clinical Laboratory Standards publication. Villanova, PA: NCCLS, 1983; 3(14): M2-T3, M31-P. 32. DSD comment, 8/91. 33. Blais J, Tardif C, Chamberland S. Effect of clindamycin on intracellular replication, protein synthesis, and infectivity of Toxoplasma gondii. Antimicrob Agents Chemother 1993 Dec; 37(12): 25717. 34. Peterson JL, Willard MD, Lees GE, et al. Toxoplasmosis in two cats with inammatory intestinal disease. J Am Vet Med Assoc 1991 Aug 15; 199(4): 4736. 35. Braden TD, Johnson CA, Wakerell P, et al. Efcacy of clindamycin in the treatment of Staphylococcus aureus osteomyelitis in dogs. J Am Vet Med Assoc 1988 Jun 15; 192(12): 17215. 36. Braden TD, Johnson CA, Gabel CL, et al. Posologic evaluation of clindamycin, using a canine model of post-traumatic osteomyelitis. Am J Vet Res 1987; 48(7): 11015. 37. Mann HJ, Townsend RJ, Fuhs DW, et al. Decreased hepatic clearance of clindamycin in critically ill patients with sepsis. Clin Pharm 1987 Feb; 6: 15460. 38. Lincomycin package insert (Lincomix 50, Pharmacia Animal HealthUS). Downloaded from www.pharmaciaah.com on 8/9/02. 39. Panel comment, 4/17/96. 40. Panel comment, 11/17/95. 41. Lincomycin package insert (Lincomix Soluble Powder, Pharmacia Animal HealthUS). Downloaded from www.pharmaciaah.com on 8/9/02. 42. Lincomycin package insert (Lincomix 44, Pharmacia Animal HealthCanada). In: Arrioja-Dechert A, editor. Compendium of veterinary products, CD ed. Port Huron, MI: North American Compendiums, Inc. 2002. 43. Barragry TB. Veterinary drug therapy. Baltimore: Lea & Febiger; 1994. p. 25162. 44. Plenderleith RWJ. Treatment of cattle, sheep, and horses with lincomycin: case studies. Vet Rec 1988; 122: 1123. 45. Pearson A. Determination of milk withholding time in cattle following use of intramuscular lincomycin. Vet Rec 1989; 125(24): 601. 46. Burrows GE, Barto PB, Weeks BR. Chloramphenicol, lincomycin and oxytetracycline disposition in calves with experimental pneumonic pasteurellosis. J Vet Pharm Ther 1986; 9: 21322. 47. Burrows GE, Barto PB, Martin B, et al. Comparative pharmacokinetics of antibiotics in newborn calves: chloramphenicol, lincomycin, and tylosin. Am J Vet Res 1983 Jun; 44(6): 10537. 48. Burrows GE. Pharmacotherapeutics of macrolides, lincomycins and spectinomycin. J Am Vet Med Assoc 1980 May 15; 176(10): 10727. 49. Hornish RE, Gosline RE, Nappier JM. Comparative metabolism of lincomycin in the swine, chicken and rat. Drug Metab Rev 1987; 18(2 & 3): 177214. 50. Brown RB, Barza M, Brusch JL, et al. Pharmacokinetics of lincomycin and clindamycin phosphate in a canine model. J Infect Dis 1975 Mar; 131(3): 25260. 51. Ziv G, Sulman FG. Binding of antibiotics to bovine and ovine serum. Antimicrob Agents Chemother 1972 Sep; 2(3): 20613. 52. Gyrd-Hansen N, Rasmussen F. Renal og mammaer ekskretion af lincomycin hos hoer. Nordisk Veterinaermedicin 1967; 19: 116. 53. Brown SA, Dieringer TM, Hunter RP, et al. Oral clindamycin disposition after single and multiple doses in normal cats. J Vet Pharm Ther 1989; 12: 20916. 54. Greene CE, Lappin MR, Marks A. Effect of clindamycin on clinical, hematological and biochemical parameters in clinically healthy cats. J Am Anim Hosp Assoc 1992 Jul/Aug; 28: 3236. 55. Vomand KC, Sumano H. Adverse drug reactions in cattle. J Am Vet Med Assoc 1990 Oct; 197(7): 899905. 56. Hamdy AH, Thomas RW, Kratzer DD, et al. Lincomycin dose response for treatment of necrotic enteritis in broilers. Poult Sci 1983; 62: 5858. 57. Jacobs G, Lappin M, Marks A, et al. Effect of clindamycin on Factor-VII activity in healthy cats. Am J Vet Res 1989 Mar; 50(3): 3935. 58. Brown MB, Scasserra AE. Antimicrobial resistance in streptococcal species isolated from bovine mammary glands. Am J Vet Res 1990 Dec; 51(12): 20158. 59. Lappin MR, Roberts SM, Davidson MG, et al. Enzyme-linked immunosorbent assays for the detection of Toxoplasma gondii-specic antibodies and antigens in the aqueous humor of cats. J Am Vet Med Assoc 1992 Oct 1; 201(7): 10104. 60. Panel comment, 11/28/95. 61. Klasco RK, editor. USP DI Drug information for the healthcare professional. Volume I. Greenwood Village, CO: MICROMEDEX, Inc.; 2003. 62. Clindamycin product overview for cats and dogs (Clindamycin, PharmaciaCanada). Downloaded 2/26/03 from www. pharmaciaah.ca. 63. Lincomycin product overview for poultry and pigs (Lincomix 44, PharmaciaCanada). Downloaded 2/26/03 from www. pharmaciaah.ca.

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MACROLIDES VeterinarySystemic 119

MACROLIDES VeterinarySystemic
This monograph includes information on the following: Azithromycin; Clarithromycin; Erythromycin; Tilmicosin; Tylosin. Some commonly used brand names are: For veterinary-labeled products
Erymycin-100 [Erythromycin Thiocyanate] Erythro-200 [Erythromycin Base] Gallimycin [Erythromycin Phosphate] Gallimycin-50 [Erythromycin Thiocyanate] Gallimycin-100 [Erythromycin Base] Gallimycin-200 [Erythromycin Base] Gallimycin PFC [Erythromycin Phosphate] Gallistat [Erythromycin Phosphate] Micotil [Tilmicosin Phosphate] Pulmotil 90 [Tilmicosin Phosphate] Pulmotil Premix [Tilmicosin Phosphate] Tylan 10 [Tylosin Phosphate] Tylan 40 [Tylosin Phosphate] Tylan 50 [Tylosin Base] Tylan 100 [Tylosin Phosphate] Tylan 200 [Tylosin Base] Tylan Soluble [Tylosin Tartrate] Tylocine 200 [Tylosin Base] Tylosin 10 Premix [Tylosin Phosphate] Tylosin 40 Premix [Tylosin Phosphate] Tyloved [Tylosin Base]

For human-labeled products

Apo-Erythro [Erythromycin Base] Apo-Erythro E-C [Erythromycin Base] Apo-Erythro-ES [Erythromycin Ethylsuccinate] Apo-Erythro-S [Erythromycin Stearate] Biaxin [Clarithromycin] Biaxin XL [Clarithromycin] E-Base [Erythromycin Base] E.E.S. [Erythromycin Ethylsuccinate] E-Mycin [Erythromycin Base] Erybid [Erythromycin Base] ERYC [Erythromycin Base] ERYC-250 [Erythromycin Base] ERYC-333 [Erythromycin Base] EryPed [Erythromycin Ethylsuccinate] Ery-Tab [Erythromycin Base] Erythro [Erythromycin Ethylsuccinate] Erythrocin [Erythromycin Lactobionate; Erythromycin Stearate] Erythrocot [Erythromycin Stearate] Erythromid [Erythromycin Base] Ilosone [Erythromycin Estolate] Ilotycin [Erythromycin Base; Erythromycin Gluceptate] My-E [Erythromycin Stearate] Novo-Rythro [Erythromycin Ethylsuccinate] Novo-rythro [Erythromycin Estolate; Erythromycin Stearate] Novo-rythro Encap [Erythromycin Base] PCE [Erythromycin Base] Wintrocin [Erythromycin Stearate] Zithromax [Azithromycin]

Note: For a listing of dosage forms and brand names by country availability, see the Dosage Forms section(s).

CATEGORY:
Antibacterial (systemic).

anaerobes, but Bacteroides fragilis is usually resistant. Some strains of Actinomyces and Chlamydia are inhibited by erythromycin.{R-1; 2} Most Pseudomonas, Escherichia coli, and Klebsiella strains are resistant to erythromycin{R-2}. Cross-resistance to the other macrolides can also occur{R-1}. Tilmicosin has in vitro activity against gram-positive organisms and mycoplasma and is active against certain gram-negative organisms{R-53}, such as Haemophilus somnus{R-89}, Mannheimia (Pasteurella) haemolytica, and Pasteurella multocida.{R-53} However, M. haemolytica is more sensitive than P. multocida to tilmicosin. Other gram-negative organisms tested{R-91}, including Enterobacter aerogenes, Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa, Salmonella{R-99}, and Serratia species, are very resistant to tilmicosin{R-91}. Some strains of Actinomyces also are extremely resistant to tilmicosin{R-99}. Tylosin has a spectrum of activity similar to that of erythromycin but is more active than erythromycin against certain mycoplasmas{R-51; 105} . Azithromycin, a macrolide labeled for human use, has some advantages over erythromycin in the treatment of infections in animals, including better oral absorption, a longer half-life, and a broader spectrum of activity than erythromycin{R-120; 122}. However, the activity of azithromycin against staphylococci is not as good as that of erythromycin. Azithromycin concentrates in tissues, particularly in leukocytes, macrophages and broblasts and is slowly released from leukocytes{R-119; 121}. The intracellular reservoir of azithromycin apparently produces effective drug concentrations in interstitial uids even after the plasma concentrations have declined below detectable levels; plasma pharmacokinetic parameters have little correlation to the in vivo efcacy of azithromycin. Azithromycin can be delivered to infected tissues and early abscesses via leukocytes.{R-119} Clarithromycin, also labeled for human use, is tolerated better than erythromycin by human patients, has a broader spectrum of activity than erythromycin, and, like azithromycin, it also concentrates in leukocytes. In dogs, clarithromycin has a shorter half-life than azithromycin{R-119; 124} and there is limited information for its clinical use in animals.

INDICATIONS
Note: Bracketed information in the Indications section refers to uses that either are not included in U.S. product labeling or are for products not commercially available in the U.S.

ACCEPTED
Abscesses, hepatic (prophylaxis)1Cattle, beef: Tylosin phosphate for medicated feed is indicated for reduction in incidence of hepatic abscesses caused by susceptible Fusobacterium necrophorum and Actinomyces pyogenes.{R-48; 49} Atrophic rhinitis (treatment)1Pigs: Tylosin phosphate for medicated feed is indicated for maintaining weight gain and feed efciency in the presence of atrophic rhinitis infections.{R-49} Arthritis, infectious (treatment)1Pigs: Tylosin injection is indicated in the treatment of swine arthritis caused by susceptible Mycoplasma hyosynoviae.{R-51; 52} Coryza, infectious (prophylaxis)Chickens: Erythromycin thiocyanate for medicated feed1 and [erythromycin phosphate powder for oral solution] are indicated as aids in the prevention of infectious coryza caused by susceptible organisms.{R-9; 54} Coryza, infectious (treatment)Chickens: Erythromycin phosphate powder for oral solution is indicated as an aid in the control of infectious

GENERAL CONSIDERATIONS
Macrolides are considered bacteriostatic at therapeutic concentrations but they can be slowly bactericidal, especially against streptococcal bacteria; their bactericidal action is described as time-dependent. The antimicrobial action of some macrolides is enhanced by a high pH and suppressed by low pH, making them less effective in abscesses, necrotic tissue, or acidic urine.{R-119} Erythromycin is an antibiotic with activity primarily against grampositive bacteria, such as Staphylococcus and Streptococcus species, including many that are resistant to penicillins by means of betalactamase production. Erythromycin is also active against mycoplasma and some gram-negative bacteria, including Campylobacter and Pasteurella species.{R-1; 1012} It has activity against some

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120 MACROLIDES VeterinarySystemic coryza caused by susceptible organisms, including Haemophilus gallinarum.{R-3; 9} Diphtheria (treatment)1Cattle, beef and nonlactating dairy: Tylosin injection is indicated in the treatment of diphtheria caused by susceptible Fusobacterium necrophorum.{R-51; 52} Dysentery, swine (prophylaxis)Pigs: Tylosin phosphate for medicated feed is indicated in the prevention of swine dysentery{R-48; 49}. Dysentery, swine (treatment)Pigs: Tylosin phosphate for medicated feed is indicated in the control of swine dysentery caused by susceptible organisms.{R-48; 49} Tylosin injection is indicated in the treatment of acute swine dysentery caused by susceptible Treponema hyodysenteriae, when followed by appropriate feed or water medication.{R-51; 52} Tylosin tartrate powder for oral solution is indicated in the control and treatment of swine dysentery{R-50; 66}. Enteritis (treatment) Piglets, one week of age or older: Erythromycin injection is indicated in the treatment of scours, caused by susceptible organisms, in young pigs{R-7; 111}. Turkeys: Erythromycin phosphate powder for oral solution is indicated in the control of enteritis (bluecomb) caused by susceptible organisms.{R-3; 9} Enterotoxemia (prophylaxis)Lambs, newborn: Erythromycin injection is indicated in the prevention of dysentery in lambs{R-7; 111}. Erysipelas (treatment)Pigs: Tylosin injection is indicated in the treatment of erysipelas caused by susceptible Erysipelothrix rhusiopathiae{R-51; 52}; however, penicillin is considered the primary treatment of choice for this indication{R-88}. Feed efciency, improvement of1; or Weight gain, increased rate1 Chickens, including laying chickens: Tylosin phosphate for medicated feed is indicated for increased rate of weight gain and improving feed efciency.{R-49} Pigs: Tylosin phosphate for medicated feed is indicated for improving feed efciency and growth promotion{R-48; 49}. LeptospirosisSows, farrowing: Erythromycin injection is indicated in the management of leptospirosis in sows at farrowing time{R-7; 111}. Metritis (treatment) Cattle, beef and nonlactating dairy: Erythromycin injection and tylosin injection are indicated in the treatment of metritis caused by susceptible organisms{R-7; 51; 52; 111}; however, therapeutic regimens often emphasize evacuation of uterine contents as the primary treatment. Sows, at farrowing time: Erythromycin injection is indicated in the treatment of metritis caused by susceptible organisms{R-7; 111}; however, therapeutic regimens often emphasize evacuation of uterine contents as the primary treatment. Pneumonia, bacterial (treatment) Cattle: Erythromycin injection is indicated in the treatment of pneumonia and bovine respiratory disease caused by susceptible bacteria, including Pasteurella multocida.{R-6; 7; 111} Tylosin injection is indicated in the treatment of pneumonia and bovine respiratory disease caused by susceptible bacteria, including Pasteurella multocida and Actinomyces pyogenes.{R-51} Tilmicosin injection is indicated in the control of bovine respiratory disease in cattle at high risk for infection and in the treatment of bovine respiratory disease caused by susceptible bacteria, including Mannheimia haemolytica{R-53}. In some regions, tilmicosin has been more effective than oxytetracycline{R-75} in clinical resolution of calf pneumonia. Pigs: Erythromycin injection is indicated in the treatment of respiratory syndrome (pneumonia, bronchitis, and rhinitis){R-7; 111} . Tilmicosin for medicated feed is indicated in the control of swine respiratory disease associated with Actinobacillus pleuropneumoniae and Pasteurella multocida{R-107}; however, parenteral tilmicosin should not be administered to pigs because of the risk of cardiovascular toxicity{R-53}. Tylosin injection is indicated in the treatment of pneumonia caused by susceptible bacteria, including P. multocida.{R-51; 52} [Calves]: Tilmicosin injection is indicated in Canadian product labeling for the treatment of bovine respiratory disease associated with susceptible M. haemolytica or Pasteurella multocida during the rst 30 days in the feedlot{R-65; 112}. [Foals]1: Erythromycin is used in the treatment of pneumonia caused by Rhodococcus equi{R-83}. Some clinicians recommend the use of rifampin in combination with erythromycin in the treatment of this infection{R-4; 13; 14}; however, comparative efcacy studies of erythromycin administered with and without rifampin have not been performed. See also Pneumonia under Acceptance not established below. [Lambs]: Tilmicosin injection is indicated in Canadian product labeling for the treatment of pneumonic pasteurellosis in lambs associated with susceptible M. haemolytica{R-65; 112}. Pododermatitis (treatment)1Cattle, beef and nonlactating dairy: Erythromycin injection and tylosin injection are indicated in the treatment of pododermatitis caused by susceptible organisms.{R-7; 51; 52; 111} Proliferative enteropathy, porcine (prophylaxis and treatment)1Pigs: Tylosin phosphate for medicated feed is indicated in the prevention and control of porcine proliferative enteropathy (ileitis) associated with susceptible Lawsonia intracellularis{R-49}. Respiratory disease, chronic (prophylaxis)1Chickens and turkeys: Erythromycin thiocyanate for medicated feed and [erythromycin phosphate powder for oral solution] are indicated as aids in the prevention of chronic respiratory disease.{R-54} Respiratory disease, chronic (treatment) Chickens, broiler and replacement: Erythromycin thiocyanate for medicated feed and erythromycin phosphate powder for oral solution are indicated in the control of chronic respiratory disease in chickens due to susceptible Mycoplasma gallisepticum.{R-3; 9; 54; 64} Tylosin tartrate powder for oral solution{R-50; 66} is indicated in the control of and as an aid in the treatment of chronic respiratory disease, and tylosin phosphate for medicated feed1 is indicated as an aid in the control of chronic respiratory disease caused by susceptible M. gallisepticum.{R-49} Turkeys: Erythromycin thiocyanate for medicated feed1 and [erythromycin phosphate powder for oral solution] are indicated for reduction of lesions and to decrease the severity of chronic respiratory disease.{R-9; 54; 64} Respiratory tract infections, bacterial (treatment) Pigs: Erythromycin injection is indicated in the treatment of respiratory syndrome (bronchitis, pneumonia, and rhinitis){R-7; 111}. Tilmicosin for medicated feed is indicated in the control of swine respiratory disease associated with Actinobacillus pleuropneumoniae and Pasteurella multocida{R-107}; however, parenteral tilmicosin should not be administered to pigs because of the risk of cardiovascular toxicity{R-53}. Sheep: Erythromycin injection is indicated in the treatment of upper respiratory tract infections{R-7; 111}.

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MACROLIDES VeterinarySystemic 121 Sinusitis, infectious (treatment)Turkeys: Tylosin tartrate powder for oral solution is indicated to maintain weight gain and feed efciency in the presence of infectious sinusitis caused by susceptible M. gallisepticum.{R-50} [Enteritis, Campylobacter (treatment)]1Dogs: Erythromycin stearate is used in the treatment of diarrhea believed to be caused by susceptible Campylobacter species. Erythromycin treatment stops the shedding of Campylobacter in the feces; however, shedding often recurs shortly after discontinuation of therapy.{R-1012} See also Enteritis, Campylobacter under Acceptance not established below. [Pyoderma (treatment)]1Dogs: Erythromycin tablets are used in the treatment of pyoderma caused by susceptible Staphylococcus species. However, because drug-induced vomiting is a common side effect of administration, erythromycin is not considered the treatment of choice.{R-4244} [Synovitis, infectious (prophylaxis)]Chickens and turkeys: Erythromycin phosphate powder for oral solution is indicated in the management of infectious synovitis{R-9}. Streptococcus species; however, studies have shown that erythromycin is distributed into milk at antimicrobial concentrations under certain pH conditions and may be clinically effective{R-4547}. [Pneumonia, bacterial, (treatment)]1Foals: Although there is insufcient evidence to establish efcacy, pharmacokinetic studies suggest that azithromycin may be as effective as erythromycin, with less frequent dosing and fewer side effects, in the treatment of pneumonia caused by Rhodococcus equi in foals{R-121; 122}. [Respiratory tract infections (treatment)]1, including, [Bronchitis (treatment)]1 [Laryngitis (treatment)]1 [Pneumonia (treatment)]1 [Tracheobronchitis (treatment)]1, or [Tracheitis (treatment)]1Cats and dogs: Although at one time Canadian tylosin tablets were available for the treatment of pneumonia and tracheobronchitis{R-56}, and the use of tylosin injection in the treatment of respiratory tract infections in cats and dogs has been approved by the U.S. Food and Drug Administration{R-108}, these uses are not included in United States or Canadian product labeling for tylosin. Studies performed during the original approval process showed that tylosin injection can be effective in the treatment of bronchitis, laryngitis, pneumonia, tracheobronchitis, or tracheitis in dogs and upper respiratory tract infections or pneumonitis in cats when the infection is caused by susceptible organisms{R-108}. [Rocky Mountain spotted fever]1Dogs: There are insufcient data at this time to establish the efcacy of azithromycin in the treatment of Rocky Mountain spotted fever in dogs. A comparative therapeutic study of induced Rocky Mountain spotted fever in dogs showed that azithromycin, when given for a 3-day treatment regimen, was effective in improving platelet counts, slowing vascular leakage, and reducing fever; however, retinal vascular lesions remained unchanged. Overall, the response was not as good as the administration of doxycycline for 7 days. If azithromycin is administered to dogs for the treatment of Rocky Mountain spotted fever, longer term treatment may be be more effective.{R-123125}
1

ACCEPTANCE NOT ESTABLISHED

[Chlamydial infections (treatment)]1Cats: There are no clinical studies to document the effectiveness of azithromycin in the treatment of chlamydial infections in cats. In vitro studies and clinical trials of azithromycin in urinary and respiratory tract chlamydial infections in human patients have demonstrated efcacy{R-3335; 113} and a pharmacokinetic study of azithromycin in cats allows for prediction of potentially effective dosing regimens{R-120}. [Colitis, chronic (treatment)]1Dogs: There are insufcient data to establish the efcacy of tylosin in the treatment of chronic colitis in dogs and there is no available information on the mechanism of action for alleviation of colitis. However, tylosin tartrate powder for oral solution has been used in the U.S. in the treatment of chronic colitis in dogs. The use of tylosin in the treatment of colitis is typically reserved for patients that are not responsive to other forms of therapy, such as diet change, and for patients with chronic colitis for which specic causes have been ruled out.{R-8486; 101; 102} [Cryptosporidiosis (treatment)]1Cats and dogs: There is no treatment that has been clearly demonstrated to eradicate Cryptosporidium species infection in human beings{R-32; 40} or animals; the zoonotic potential of this organism should be considered. Azithromycin can be administered to shorten the length of time oocysts are shed in cats and dogs; however, there are no clinical studies in these species to document efcacy in the treatment of cryptosporidiosis. There are studies of immunocompromised, human immunodeciency virus (HIV)-positive patients that show some evidence of the efcacy of azithromycin in prevention, remission, and possibly eradication of infection with long-term administration{R-41; 97}. Because of insufcient data, it is not possible at this time to recommend long-term dosing regimens that might be useful in the treatment of this infection in cats and dogs. [Enteritis, Campylobacter (treatment)]1Dogs: In vitro studies have demonstrated that azithromycin may have up to 6 times the activity of erythromycin against susceptible Campylobacter strains, making it a potential treatment for this type of enteritis in dogs; however, no clinical studies have been performed{R-57; 110}. [Mastitis (treatment)]1 Cattle: There are insufcient data to establish the efcacy of systemic erythromycin in the treatment of acute and peracute mastitis caused by susceptible Staphylococcus and 2003 Thomson MICROMEDEX

Not included in Canadian product labeling or product not commercially available in Canada.

REGULATORY CONSIDERATIONS
U.S. Erythromycin thiocyanate and tylosin tartrate are not labeled for use in chickens or turkeys producing eggs for human consumption.{R-8; 50; 54} Tilmicosin is not labeled for use in female dairy cattle 20 months of age or older{R-53}, veal calves, calves less than 1 month of age, or calves fed an all-milk diet. Tylosin injection is not labeled for use in lactating dairy cattle or preruminating calves.{R-51; 52} Withdrawal times have been established for erythromycin injection, erythromycin phosphate powder for oral solution, erythromycin thiocyanate, tilmicosin phosphate, tylosin injection, tylosin phosphate, and tylosin tartrate (see the Dosage Forms section). Azithromycin and clarithromycin are not labeled for use in animals. Canada Erythromycin phosphate, erythromycin thiocyanate, and tylosin tartrate are not labeled for use in chickens or turkeys producing eggs for human consumption.{R-8; 9} Neither tilmicosin nor tylosin base injection is labeled for use in lactating dairy cattle.{R-55; 65} All rights reserved

122 MACROLIDES VeterinarySystemic Withdrawal times have been established for erythromycin injection, erythromycin phosphate powder for oral solution, erythromycin thiocyanate, tilmicosin phosphate, tylosin injection, tylosin phosphate, and tylosin tartrate (see the Dosage Forms section). Azithromycin and clarithromycin are not labeled for use in animals. Clarithromycin747.95{R-16}. Erythromycin733.93{R-16}. Erythromycin estolate1056.39{R-16}. Erythromycin ethylsuccinate862.05{R-16}. Erythromycin gluceptate960.11{R-16}. Erythromycin lactobionate1092.22{R-16}. Erythromycin stearate1018.40{R-16}. Tilmicosin phosphate967.13{R-16}. Tylosin916.1{R-100}. Description: Azithromycin dihydrateWhite, crystalline powder{R-116}. Clarithromycin USPWhite to off-white, crystalline powder{R-22}. Erythromycin USPWhite or slightly yellow, crystalline powder. Is odorless or practically odorless{R-22}. Erythromycin Estolate USPWhite, crystalline powder. Is odorless or practically odorless{R-22}. Erythromycin Ethylsuccinate USPWhite or slightly yellow crystalline powder. Is odorless or practically odorless{R-22}. Erythromycin GluceptateWhite powder. Is odorless or practically odorless, and is slightly hygroscopic. Its solution (1 in 20) is neutral or slightly acid. Erythromycin Lactobionate for Injection USPWhite or slightly yellow crystals or powder, having a faint odor. Its solution (1 in 20) is neutral or slightly alkaline{R-22}. Erythromycin Stearate USPWhite or slightly yellow crystals or powder. Is odorless or may have a slight, earthy odor{R-22}. Tilmicosin USPWhite to off-white amorphous solid{R-22}. Tylosin USPWhite to buff-colored powder{R-22}. pKa: Erythromycin base8.8{R-18; 19}. Tilmicosin7.4; 8.6{R-94}. Tylosin7.1{R-5; 58}. Solubility: Azithromycin39 mg soluble per mL of water (pH 7.4 ) at 37 C{R-118}. Clarithromycin USPSoluble in acetone; slightly soluble in dehydrated alcohol, in methanol, and in acetonitrile; practically insoluble in water. Slightly soluble in phosphate buffer at pH values of 2 to 5{R-22}. Erythromycin USPSlightly soluble in water; soluble in alcohol, in chloroform, and in ether{R-22}. Erythromycin Estolate USPSoluble in alcohol, in acetone, and in chloroform; practically insoluble in water{R-22}. Erythromycin Ethylsuccinate USPVery slightly soluble in water; freely soluble in alcohol, in chloroform, and in polyethylene glycol 400{R-22}. Erythromycin GluceptateFreely soluble in water, in alcohol, and in methanol; slightly soluble in acetone and in chloroform; practically insoluble in ether. Erythromycin Lactobionate for Injection USPFreely soluble in water, in alcohol, and in methanol; slightly soluble in acetone and in chloroform; practically insoluble in ether{R-22}. Erythromycin Stearate USPPractically insoluble in water; soluble in alcohol, in chloroform, in methanol, and in ether{R-22}. Tilmicosin USPSlightly soluble in water and in n-hexane{R-22}. Tylosin USPFreely soluble in methanol; soluble in alcohol, in amyl acetate, in chloroform, and in dilute mineral acids; slightly soluble in water{R-22}. Tylosin tartrateReadily soluble in water, up to 600 mg per mL{R-61}.

CHEMISTRY
Source: Azithromycin and clarithromycinSemisynthetically derived from erythromycin{R-116; 119}. ErythromycinProduced from a strain of Saccharopolyspora erythraeus{R-7}. TilmicosinProduced semisynthetically{R-53} by chemical modications of desmycosin{R-1}. TylosinProduced by a strain of the actinomycete Streptomyces fradiae {R-55} . Chemical group: Azalide antibiotic, a subclass of macrolidesAzithromycin{R-116}. Macrolide antibiotics (macrocyclic lactones){R-1; 117}Clarithromycin, erythromycin, tilmicosin, and tylosin. Chemical name: Azithromycin1-Oxa-6-azacyclopentadecan-15-one, 13-[(2,6-dideoxy3-C-methyl-3-O-methyl-alpha-L-ribo-hexopyranosyl)oxy]-2-ethyl-3,4,10trihydroxy-3,5,6,8,10,12,14-heptamethyl-11-[[3,4,6-trideoxy-3-(dimethylamino)-beta-D-xylo-hexopyranosyl]oxy]-, dihydrate, [2R-(2R*, 3S*,4R*,5R*,8R*,10R*,11R*,12S*,13S*,14R*)]-{R-16}. ClarithromycinErythromycin, 6-O-methyl-{R-16}. ErythromycinErythromycin{R-16}. Erythromycin estolateErythromycin, 2-propanoate, dodecyl sulfate (salt){R-16}. Erythromycin ethylsuccinateErythromycin 2-(ethyl butanedioate){R-16}. Erythromycin gluceptateErythromycin monoglucoheptonate (salt){R-16}. Erythromycin lactobionateErythromycin mono(4-O-beta-D-galactopyranosyl-D-gluconate) (salt){R-16}. Erythromycin stearateErythromycin octadecanoate (salt){R-16}. Tilmicosin phosphateTylosin, 4A-O-de(2,6-dideoxy-3-C-methyl-alphaL-ribo-hexopyranosyl)-20-deoxo-20-(3,5-dimethyl-1-piperidinyl)-, [20(cis)]-, phosphate (1:1) (salt){R-16}. Tylosin(10E,12E)-(3R,4S,5S,6R,8R,14S,15R)-14-[(6-deoxy-2,3-diO-methyl-beta-D-allopyranosyl)oxymethyl]-5-[[3,6-dideoxy-4-O-(2,6dideoxy-3-C-methyl-alpha-L-ribo-hexopyranosyl)-3-dimethylaminobeta-D-glycopyranosyl]oxy]-6-formylmethyl-3-hydroxy-4,8,12-trimethyl-9-oxoheptadeca-10,12-dien-15-olide{R-100} . Molecular formula: AzithromycinC38H72N2O122H2O{R-16}. ClarithromycinC38H69NO13{R-16}. ErythromycinC37H67NO13{R-16}. Erythromycin estolateC40H71NO14C12H26O4S{R-16}. Erythromycin ethylsuccinateC43H75NO16{R-16}. Erythromycin gluceptateC37H67NO13C7H14O8{R-16}. Erythromycin lactobionateC37H67NO13C12H22O12{R-16}. Erythromycin stearateC37H67NO13C18H36O2{R-16}. Tilmicosin phosphateC46H80N2O13H3O4P{R-16}. TylosinC46H77NO17{R-100}. Molecular weight: Azithromycin785.02{R-16}.

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MACROLIDES VeterinarySystemic 123

PHARMACOLOGY/PHARMACOKINETICS
Note: See also Table 1. Pharmacology/Pharmacokinetics at the end of this monograph. Mechanism of action/effect: Bacteriostatic, with potential for a timedependent bactericidal action, particularly with high concentrations{R1; 5; 119} . The macrolides are thought to enter the cell and reversibly bind to the 50 S ribosomal subunit, inhibiting translocation of peptides, thereby inhibiting protein synthesis.{R-5} Bacterial resistance occurs by alteration of the ribosome receptor site and/or by prevention of the antibiotic from entering the cell. Although macrolides bind to mitochondrial ribosomes, as does chloramphenicol, macrolides are unable to cross the mitochondrial membrane and so do not produce bone marrow suppression in mammals{R-119}. Absorption: AzithromycinOral administration: Shown to be fairly well absorbed orally in cats (bioavailability of 58%), dogs (bioavailability of >90%), and foals (bioavailability of 39 to 56%){R-120123}. ErythromycinOral administration: Many oral erythromycin base preparations are coated to prevent degradation in the stomach. The higher pH of the intestine then permits absorption.{R-1; 2} However, absorption of enteric-coated and delayed-release dosage forms can be unpredictable in animals{R-21}. Erythromycin estolate and erythromycin ethylsuccinate are absorbed as inactive esters from the duodenum and then undergo hydrolysis to the free base. The stearate salt dissociates in the duodenum and is absorbed as the free base. It has been suggested that erythromycin phosphate also dissociates and is absorbed as the free base. Food in the stomach does not seem to affect signicantly the absorption of the base or salt. It is unclear whether any of the oral erythromycin preparations is absorbed more effectively than any other when administered to animals{R-1}; however, it does appear that oral absorption in horses may be different from human absorption. In horses, oral erythromycin stearate and erythromycin phosphate produced peak plasma concentrations more quickly than did the ester formulations; the effect is the opposite of that seen in human studies.{R-18} TylosinIntramuscular administration: BioavailabilityGoats: 72.6% (15 mg per kg of body weight [mg/kg] dose){R-72}. Distribution: Widely distributed in the body{R-1; 68}. Ion trapping and the high lipid solubility of the macrolides generally causes tissue concentrations to be higher (often many times higher) than serum concentrations.{R-1; 70} AzithromycinTissue concentrations can be as much as 100 times serum concentrations and concentrations in leukocytes can be 200 to 300 times serum concentrations{R-115; 119}. Cats: Azithromycin appears to distribute well, although sometimes slowly, into a variety of tissues. High tissue to plasma ratios are produced. In one study, lung, femur, eye, skin, and brain tissue concentrations of azithromycin were still rising when the last sample was taken, 72 hours after the dose{R-120}. Dogs: A single dose of azithromycin produced high tissue concentrations, often with a tissue to serum ratio of 100 to one; azithromycin concentrations in eye and brain tissue exceeded serum concentrations by 20- and 1.2-fold, respectively{R-123}.

Foals: Azithromycin peak concentration in polymorphonuclear leukocytes (PMN) was 27.3 mcg per mL (mcg/mL) while peak plasma concentration was 0.72 mcg/mL after a single 10 mg/kg oral dose. The drug persisted in PMNs for 120 hours while it was only detected in plasma for about 24 hours.{R-121} ClarithromycinWidely distributed into tissues and enters leukocytes and macrophages{R-115}. ErythromycinIn the calf, lung tissue erythromycin concentrations were found to be approximately three times higher than serum concentrations from 8 to 24 hours after intramuscular administration{R-28}. Tilmicosin and tylosinTylosin concentrations in lung tissue are many times higher than in serum from 2 to 36 hours after a single intramuscular administration{R-70}; tilmicosin concentrations in lung tissue are many times higher than in serum for at least 96 hours after a single subcutaneous administration{R-104}. Half-life: Azithromycin in leukocytes Foals: 49.2 hours{R-121}. Human data: 34 to 57 hours{R-115}. Elimination: Azithromycin Cats: More than 50% of the drug is eliminated unchanged in the bile. One major metabolite resulting from N-demethylation and two minor metabolites also appear in the bile{R-120}. Human information: More than 50% of the drug is eliminated unchanged through biliary excretion while 4 to 14%, depending on route of administration, is eliminated unchanged in the urine{R-115}. ClarithromycinHuman information: 20 to 40% is eliminated unchanged in the urine{R-115}. ErythromycinPrimarily hepatic; metabolite and a small amount of active drug are excreted to a large degree in the bile but are also excreted in urine and milk. After oral administration, high concentrations of erythromycin may be eliminated in the feces.{R-1; 29} TilmicosinCattle: Of the total subcutaneous dose administered, 24% has been recovered in the urine and 68% in the feces.{R-53} Duration of action: TilmicosinCattle, healthy or acutely pneumonic: 3 days, minimum (based on maintenance of >3.12 mcg/mL lung concentration [minimum inhibitory concentration 95% for M. haemolytica] with a subcutaneous dose of 10 mg/kg){R-53; 103; 104}. TylosinGoats: 12 hours (based on maintenance of >1 mcg/mL serum concentration with an intramuscular dose of 15 mg/kg).{R-72}

PRECAUTIONS TO CONSIDER SPECIES SENSITIVITY

Erythromycin: CattleOral administration of erythromycin phosphate or erythromycin stearate has caused severe diarrhea in ruminating calves.{R-28} Because of this adverse effect and poor absorption, oral erythromycin administration in cattle is not recommended. HorsesIn foals treated with erythromycin, mild self-limiting diarrhea may develop.{R-26} In adult horses, the risk of severe diarrhea makes the use of erythromycin controversial.{R-2}

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124 MACROLIDES VeterinarySystemic Tilmicosin: All speciesTo avoid cardiotoxicity, tilmicosin should not be administered intravenously{R-81}. HumanInjection of tilmicosin may be lethal. Although there is little information on the effects of tilmicosin in people, a variable susceptibility to cardiotoxic reactions in other species warrants caution with human exposure and close monitoring of the cardiovascular system, particularly after accidental injection{R-81}. A physician should be consulted immediately in cases of accidental injection.{R-53} DogsIn laboratory dogs, tachycardia and decreased cardiac contractility have been noted in response to tilmicosin injection{R-100}. GoatsAdministration of tilmicosin to goats at intramuscular or subcutaneous doses >10 mg per kg of body weight (mg/kg) is likely to lead to toxicity{R-81; 100}. HorsesAdministration of tilmicosin to horses at intramuscular or subcutaneous doses >10 mg/kg is likely to lead to toxicity{R-81; 100}. PigsInjection of tilmicosin into swine can be fatal as a result of cardiovascular toxicity. Administration of epinephrine to treat cardiovascular toxicity due to intravenous tilmicosin administration has been associated with an increased risk of death.{R-53; 100} Tylosin: HorsesInjection of tylosin has been fatal to horses.{R-51; 52} estolate has been associated with reversible hepatotoxicity in some women during pregnancy. Tilmicosin{R-53} and tylosin: Safety in breeding or pregnant animals has not been established.

LACTATION
Clarithromycin is excreted into milk{R-117}. The distribution of azithromycin into milk has not yet been demonstrated{R-116}. Erythromycin, tilmicosin, and tylosin concentrations in milk can be much higher than concentrations in serum.{R-26; 72; 74} In cattle, tilmicosin is distributed into milk at effective antibacterial concentrations for susceptible pathogens, but detectable concentrations in milk are maintained for many weeks (up to 42 days){R-87}. Tilmicosin should not be administered to lactating dairy cattle because of impractical withdrawal times.{R-74} In mastitis-free cattle, systemic tylosin is distributed into milk at concentrations that are therapeutic for some mastitis pathogens; however, tylosin is distributed into milk more readily as the pH of milk decreases. The pH of mastitic milk can approach 7.4 and decrease the diffusion of tylosin, interfering with the medications ability to reach therapeutic concentrations in milk against some organisms{R-79; 80}.

PEDIATRICS CROSS-SENSITIVITY AND/OR RELATED PROBLEMS

Patients that are hypersensitive to one macrolide may be hypersensitive to a different macrolide{R-116; 117}. In animals up to 1 month of age, the hepatic clearance of macrolides may be slower than in adult animals{R-1}.

PREGNANCY/REPRODUCTION
Azithromycin: Fertility and reproductionRats and mice given azithromycin at doses of up to 200 mg/kg a day have shown no evidence of impaired fertility or harm to the fetus{R-116}. FDA human pregnancy category B. Clarithromycin: Fertility and reproductionMale and female rats administered up to 160 mg/kg a day have shown no effect on estrous cycle, fertility, parturition, or viability of offspring{R-117}. PregnancyMonkeys administered oral doses of 150 mg/kg a day had embryonic loss, which was attributed to marked maternal toxicity at this dose. In utero fetal loss occurred in rabbits given intravenous doses of 33 mg per square meter of body surface area, which is equivalent to 17 times less than the maximum recommended human daily dose. Clarithromycin was not found to be teratogenic in four rat studies or in two rabbit studies. Two additional studies in a different rat strain demonstrated a low incidence of cardiovascular anomalies at oral doses of 150 mg/kg a day administered during gestation days 6 through 15. Cleft palate was seen at doses of 500 mg/kg a day. Fetal growth retardation was seen in monkeys given an oral dose of 70 mg/kg a day, which produced plasma concentrations that were equivalent to two times the human serum concentrations. FDA human pregnancy category C{R-115}. Erythromycin: Erythromycin crosses the placenta; however, there is no evidence of teratogenicity or other effects when female rats are fed erythromycin base during pregnancy.{R-17} In people, erythromycin

DRUG INTERACTIONS AND/OR RELATED PROBLEMS

The following drug interactions and/or related problems have been selected on the basis of their potential clinical signicance (possible mechanism in parentheses where appropriate)not necessarily inclusive ( = major clinical signicance): Note: Combinations containing any of the following medications, depending on the amount present, may also interact with this medication. Beta-adrenergic antagonists, such as Propranolol (propranolol and other beta-adrenergic antagonists exacerbate the negative inotrophy of tilmicosin-induced tachycardia in dogs{R-53}) Chloramphenicol or Florfenicol or Lincosamides or Macrolide antibiotics, other (chloramphenicol, orfenicol, and the lincosamides have mechanisms of action similar to the macrolides; they may be prevented from binding, or prevent a macrolide from binding, to the 50 S subunits of bacterial ribosomes; concurrent use is not recommended{R-1}) Epinephrine (in pigs, the intravenous administration of epinephrine potentiates the lethality of intravenously administered tilmicosin{R-53}) Phenobarbital or Medications metabolized by microsomal mixed-function oxidases, other (concurrent use with erythromycin may decrease the effects of these medications because of induction of hepatic microsomal enzymes{R-87})

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MACROLIDES VeterinarySystemic 125

HUMAN DRUG INTERACTIONS{R-115}

In addition to the above drug interactions reported in animals, the following drug interactions have been reported in humans, and are included in the human monographs Azithromycin (Systemic), Clarithromycin (Systemic), or Erythromycins (Systemic) in USP DI Volume I; these drug interactions are intended for informational purposes only and may or may not be applicable to the use of macrolides in the treatment of animals: Note: There are no tilmicosin or tylosin products labeled for use in people. Anticoagulants, coumarin- or indanedione-derivative or Warfarin (concurrent administration with macrolide antibiotics has been associated with increased anticoagulant effects; prothrombin time should be monitored carefully in patients receiving anticoagulants and macrolides concurrently) Carbamazepine or Cyclosporine or Digoxin or Hexobarbital or Phenytoin or Valproic acid (concurrent use with macrolide antibiotics has been associated with increased serum concentration of these medications; monitoring of serum concentrations of medications administered concurrently is recommended to avoid toxicity) (although no clinical cases of toxicity have been reported, concurrent use of oral antibiotics may increase serum digoxin concentrations in some individuals; in these individuals, alteration of gut ora by antibiotics may diminish digoxin conversion to inactive metabolites, resulting in increased serum digoxin concentrations; although limited data are available, this interaction has been reported with oral use of erythomycins, neomycin, and tetracyclines) Midazolam or Triazolam (concurrent use with macrolide antibiotics may decrease the clearance of these medications, increasing the pharmacologic effect of midazolam or triazolam) Penicillins (since bacteriostatic drugs may interfere with the bactericidal effect of penicillins in the treatment of meningitis or in other situations in which a rapid bactericidal effect is necessary, it is best to avoid concurrent therapy) Rifabutin or Rifampin (concurrent use of rifabutin with azithromycin causes a 15% decrease in serum concentration of rifabutin{R-116}) (concurrent use of rifabutin or rifampin with clarithromycin causes a decrease in the serum concentration of clarithromycin by greater than 50%) Xanthines, such as: Aminophylline Caffeine Oxtriphylline Theophylline (concurrent use of the xanthines [except dyphylline] with macrolides may decrease hepatic clearance of xanthines, resulting in increased serum concentrations and/or toxicity; dosage

adjustment of the xanthines may be necessary during and after therapy with macrolides) (concurrent administration of theophylline with clarithromycin has been shown to increase the area under the plasma concentrationtime curve [AUC] of theophylline by 17%; monitoring of theophylline serum concentrations is recommended in patients receiving high doses of theophylline or in patients with theophylline serum concentrations in the upper therapeutic range) (with erythromycin, this effect may be more likely to occur after 6 days of concurrent therapy because the magnitude of theophylline clearance reduction is proportional to the peak serum erythromycin concentrations) For azithromycin Antacids, aluminum- and magnesium-containing (concurrent use with antacids decreases the peak serum concentration [Cmax] of azithromycin by approximately 24%, but has no effect on the area under the plasma concentrationtime curve [AUC]; oral azithromycin should be administered at least 1 hour before or 2 hours after aluminum- and magnesium-containing antacids) For clarithromycin Pimozide (concurrent administration of pimozide with clarithromycin has resulted in cardiac arrhythmias, including QTc-interval prolongation, ventricular tachycardia, ventricular brillation, and torsades de pointes; fatalities have also occurred; the most likely cause is the inhibition of hepatic metabolism of pimozide by clarithromycin; concurrent use is contraindicated) Zidovudine (concurrent administration with clarithromycin causes a decrease in the steady state concentration of zidovudine; doses of clarithromycin and zidovudine should be taken at least 4 hours apart) For erythromycin Hepatotoxic medications, other (concurrent use of other hepatotoxic medications with erythromycin may increase the potential for hepatotoxicity) Ototoxic medications, other (concurrent use with high-dose erythromycin in patients with renal function impairment may increase the potential for ototoxicity)

LABORATORY VALUE ALTERATIONS

The following have been selected on the basis of their potential clinical signicance (possible effect in parentheses where appropriate)not necessarily inclusive ( = major clinical signicance): Note: Laboratory value alterations relating specically to use of macrolides in animals are rarely described. Human laboratory value alterations have been reported for erythromycin and are included in the following section.

HUMAN LABORATORY VALUE ALTERATIONS{R-115}

The following laboratory value alterations have been reported in humans, and are included in the human monographs Azithromycin (Systemic), Clarithromycin (Systemic), or Erythromycins (Systemic) in USP DI Volume I; these laboratory value alterations are intended for informational purposes only and may not be applicable to the use of macrolides in the treatment of animals: Note: There are no tilmicosin or tylosin products labeled for use in people. For azithromycin With physiology/laboratory test values

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126 MACROLIDES VeterinarySystemic Alanine aminotransferase (ALT [SGPT]) and Aspartate aminotransferase (AST [SGOT]) and Creatine kinase and Gamma-glutamyltransferase and Lactate dehydrogenase (serum values may be increased) Bilirubin, serum and Potassium, serum (concentrations may be increased) For clarithromycin With physiology/laboratory test values Alanine aminotransferase (ALT [SGPT]) and Aspartate aminotransferase (AST [SGOT]) (rarely, serum values may be increased) Blood urea nitrogen (BUN) (rarely, concentration may be elevated) For erythromycin With diagnostic test results Aspartate aminotransferase (AST [SGOT]) (use of erythromycin may interfere with AST [SGOT] determinations if azonefast violet B or diphenylhydrazine colorimetric tests are used) Catecholamines, urinary (erythromycin may produce false elevations of urinary catecholamines because of interference with the uorometric determination) With physiology/laboratory test values Alanine aminotransferase (ALT [SGPT]) and Alkaline phosphatase and Aspartate aminotransferase (AST [SGOT]) and Bilirubin, serum (values may be increased by all erythromycins, but more commonly by erythromycin estolate) Minimum inhibitory concentration (MIC) (in vitro cultures and MIC tests should be done on samples collected prior to macrolide administration to determine pathogen susceptibility)

SIDE/ADVERSE EFFECTS
The following side/adverse effects have been selected on the basis of their potential clinical signicance (possible signs and, for humans, symptoms in parentheses where appropriate)not necessarily inclusive:

THOSE INDICATING NEED FOR MEDICAL ATTENTION

Incidence unknown All species Allergic reactionsconsidered rare{R-1} Cats and dogs Gastrointestinal effects (anorexia, diarrhea, vomiting)particularly with erythromycin{R-1; 2; 96} Note: In dogs, it has been shown that intravenous erythromycin produces an increase in the electrical and motor activity of the stomach; this effect most likely occurs through cholinergic pathways. The effect produces an abrupt, powerful increase in gastric motility causing retrograde contractions leading to gastrointestinal effects, such as vomiting and retching.{R-59; 60} In one survey, 41% of pet owners reported that their dogs (19 of 46) vomited following administration of oral erythromycin stearate.{R-96} This increase in gastric motility has not been shown to occur in response to tylosin{R-67} and, although vomiting may occur in response to tylosin administration, it occurs infrequently. Cattle Diarrheaassociated with oral erythromycin dosage forms{R-28} Horses Diarrhea, severewith erythromycin; considered more likely in adult horses{R-2} Pigs Diarrhea, erythema, and pruritiswith tylosin;{R-51} edema, rectal, and partial anal prolapse{R-2; 51}with erythromycin and tylosin

MEDICAL CONSIDERATIONS/CONTRAINDICATIONS
The medical considerations/contraindications included have been selected on the basis of their potential clinical signicance (reasons given in parentheses where appropriate)not necessarily inclusive ( = major clinical signicance). Risk-benet should be considered when the following medical problems exist: Hepatic function impairment (macrolides are hepatically metabolized{R-29}; although hepatotoxicity has not been reported in animals, erythromycin estolate has, on uncommon occasions, been associated with hepatotoxicity in people; therefore, consideration of risk is recommended{R-1}) Renal function impairment, severe (clarithromycin elimination is reduced in human patients with renal function impairment, particularly those with a creatinine clearance < 30 mL per minute; it is recommended that the dose be reduced by one-half or that the dosage interval be doubled{R-115})

THOSE INDICATING NEED FOR MEDICAL ATTENTION ONLY IF THEY CONTINUE OR ARE BOTHERSOME
All species Pain and/or swelling at the site of injectionwith subcutaneous injection in cattle, swelling is transient and usually mild{R-2; 29; 53}

HUMAN SIDE/ADVERSE EFFECTS{R-115}

In addition to the above side/adverse effects reported in animals, the following side/adverse effects have been reported in humans, and are included in the human monographs Azithromycin (Systemic), Clarithromycin (Systemic), or Erythromycins (Systemic) in USP DI Volume I; these side/adverse effects are intended for informational purposes only and may or may not be applicable to the use of macrolides in the treatment of animals: Note: There are no tilmicosin or tylosin products labeled for use in people. For azithromycin Incidence more frequentfor injection form only

PATIENT MONITORING
The following may be especially important in patient monitoring (other tests may be warranted in some patients, depending on condition; = major clinical signicance): Culture and susceptibility in vitro and

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MACROLIDES VeterinarySystemic 127 Thrombophlebitis Incidence less frequent Gastrointestinal disturbances Incidence rare Acute interstitial nephritis; allergic reactions; dizziness; headache; pseudomembranous colitis For clarithromycin Incidence less frequent Abnormal sensation of taste; gastrointestinal disturbances; headache Incidence rare Hepatotoxicity; hypersensitivity reaction; pseudomembranous colitis; thrombocytopenia For erythromycin Incidence more frequent Gastrointestinal disturbances Incidence less frequent Hepatotoxicity; hypersensitivity; inammation or phlebitis at the injection sitewith parenteral erythromycins only; oral candidiasis; vaginal candidiasis Incidence rare Cardiac toxicity, especially QT prolongation and torsades de pointes; loss of hearing, usually reversible; pancreatitis Note: Hepatotoxicity has been associated rarely with all erythromycin salts, but more frequently with erythromycin estolate. Reports suggest that a hypersensitivity mechanism may be involved. Liver function tests often indicate cholestasis. Symptoms typically appear within a few days to 1 or 2 weeks after the start of continuous therapy and are reversible when erythromycin is discontinued. However, hepatotoxicity reappears promptly on readministration to sensitive patients. Loss of hearing is more likely to occur with administration of high doses ( 4 grams per day) in patients with renal or hepatic disease and/or in elderly patients. It appears to be related to high peak plasma concentrations, usually exceeding 12 mcg per mL. Hearing loss is usually reversible, although irreversible deafness has occurred. It occurs 36 hours to 8 days after treatment is started and begins to dissipate within 1 to 14 days after erythromycin is discontinued. the mild evidence of myocardial necrosis seen with three 50 mg/kg doses administered 72 hours apart{R-53} was not found with a 30 mg/ kg dosage regimen. Repeated subcutaneous doses of 150 mg/kg every 3 days resulted in one death following the third treatment and one death following the fourth treatment in cattle{R-53; 100}. In contrast, three of four pigs administered a 20 mg/kg intramuscular dose of tilmicosin and four of four pigs given a 30 mg/kg dose died. In goats and horses, subcutaneous or intramuscular doses above 10 mg/kg may cause signs of toxicosis{R-81; 100}. Oral tilmicosin caused no ill effects in pigs when they were administered 2000 parts per million (ppm) in the only ration for 42 days or 4000 ppm for 21 days{R-107}. Oral doses of 4 mg/kg a day administered to dogs for up to a year caused no observable adverse effects{R-107}. The median lethal dose of oral tilmicosin in fasted rats is 800 mg/kg and in nonfasted rats is 2250 mg/kg{R-107}.

CLINICAL EFFECTS OF OVERDOSE

The following effects have been selected on the basis of their potential clinical signicance (possible signs in parentheses where appropriate)not necessarily inclusive: For tilmicosinin order of their appearance Dogs Cardiovascular changes, including sinus tachycardia, myocardial depression, and reduced arterial pulse pressure (tremors, rapid respiration, convulsions, and in severe cases, death)noted with an intravenous dose of 2.5 mcg/kg{R-81}.

TREATMENT OF OVERDOSE
For tilmicosin: The treatment of tilmicosin-induced cardiotoxicosis is not yet well established. Tachycardia is believed to result in part from stimulation of cardiac beta-receptors. In dogs, this effect is partially blocked by propranolol; however, propranolol also potentiates the decreased cardiac contractility induced by tilmicosin{R-81}. Dobutamine may partially remedy the cardiac depression in dogs{R-81}. Epinephrine potentiated the lethality of intravenously administered tilmicosin in pigs{R-53}.

VETERINARY DOSING INFORMATION OVERDOSE

For more information in cases of overdose or unintentional ingestion, contact the American Society for the Prevention of Cruelty to Animals (ASPCA) National Animal Poison Control Center (888426-4435 or 900-443-0000; a fee may be required for consultation) and/or the drug manufacturer. For azithromycin: Mice and ratsThe LD50 for oral administration is 3000 to 4000 mg/kg{R-118}. For tilmicosin: Greater susceptibility to toxicity from parenterally administered tilmicosin has been shown in goats, horses, and pigs than in cattle.{R-81}. In all species tested, the primary toxic effect is cardiotoxicity{R-53; 81}. Intravenous administration of tilmicosin is not recommended for use in any species because an intravenous dose of 10 mg or less per kg of body weight (mg/kg) causes signs of toxicity and, in some cases, death in calves, cattle, goats, horses, and sheep{R-81}. Subcutaneous doses of up to 30 mg/kg every 3 days for a total of three doses in cattle have been specied as the highest nontoxic dose in healthy cattle because Activity of the macrolides is highest in tissues and in environments with elevated pH.{R-1} Organisms that develop resistance to one macrolide antibiotic may also be resistant to other macrolide antibiotics; this cross-resistance should be considered when alternative antibacterials are chosen{R-1}. Bacterial resistance to erythromycin seems to be more of a problem with repeated or continuous use; resistance decreases rapidly when medication is discontinued.{R-1}

FOR ORAL DOSAGE FORMS ONLY

Tylosin is more stable than erythromycin in acid environments and therefore can be administered orally without enteric coating.{R-58}

FOR PARENTERAL DOSAGE FORMS ONLY

Only the gluceptate and the lactobionate salts of erythromycin can be administered intravenously. Other parenteral dosage forms must be administered by the intramuscular route only.

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128 MACROLIDES VeterinarySystemic Cattle: The intramuscular route of administration for erythromycin is recommended to avoid the poor absorption and intestinal side effects associated with oral dosing and the poor absorption and more severe local reactions associated with subcutaneous administration{R-28}. Even with intramuscular injection, the effect of erythromycin on edible tissues should be considered before administration{R-95}. High-dose intravenous administration should be avoided unless the gluceptate or lactobionate forms are used{R-82} because immediate side effects have been reported with such administration. [Foals]1Although the safety and efcacy have not been established, an oral dose of 10 mg per kg of body weight every twenty-four hours for ve days, followed by 10 mg per kg of body weight every forty-eight hours has been recommended in the treatment of Rhodococcus equi pneumonia, based on pharmacokinetic data{R-121; 122}. Erythromycin has typically been used in combination with rifampin in the treatment of R. equi pneumonia and the same might be expected for azithromycin; however, many clinicians are administering azithromycin without rifampin in the treatment of this infection. Strength(s) usually available{R-116}: U.S. Veterinary-labeled product(s): Not commercially available. Human-labeled product(s): 20 mg per mL (when reconstituted according to manufacturers instruction) (available in 300-mg bottles) (Rx) [Zithromax (sucrose)]. 40 mg per mL (when reconstituted according to manufacturers instruction) (available in 600-, 900-, and 1200-mg bottles) (Rx) [Zithromax (sucrose)]. Canada Veterinary-labeled product(s): Not commercially available. Human-labeled product(s): 20 mg per mL (when reconstituted according to manufacturers instruction) (available in 300-mg bottles) (Rx) [Zithromax (sucrose)]. 40 mg per mL (when reconstituted according to manufacturers instruction) (available in 600- and 900-mg bottles) (Rx) [Zithromax (sucrose)]. Packaging and storage: Prior to reconstitution, store between 5 and 30 C (41 and 86 F) in a tight container. After reconstitution, the pediatric oral suspension should be stored between 5 and 30 C (41 and 86 F) and used within 10 days. Preparation of dosage form: For the pediatric suspension, add the volume of water indicated on manufacturers product labeling to the bottle and shake well. USP requirements: Preserve in tight containers. A dry mixture of Azithromycin and one or more buffers, sweeteners, diluents, anticaking agents, and avors. Contains the labeled amount, within 10%. Meets the requirements for Identication, Uniformity of dosage units (for solid packaged in single-unit containers), Deliverable volume, pH (9.011.0 [for solid packaged in single-unit containers], 8.511.0 [for solid packaged in multiple-unit containers], in the suspension constituted as directed in the labeling), and Water not more than 1.5%).{R-22}

FOR TREATMENT OF ADVERSE EFFECTS

For anaphylaxis Recommended treatment consists of the following: Parenteral epinephrine. Oxygen administration and breathing support. Parenteral uid administration as needed. Note: Parenteral epinephrine is not recommended treatment for tilmicosin toxicity because of adverse effects noted in pigs (see Overdose section); however,{R-53} epinephrine is not contraindicated for anaphylaxis due to tilmicosin{R-100}.

AZITHROMYCIN SUMMARY OF DIFFERENCES

Pharmacology/pharmacokinetics: DistributionAzithromycin concentrates in tissues, particularly in leukocytes, macrophages and broblasts and is slowly released from leukocytes{R-120; 121}. The intracellular reservoir of azithromycin produces effective drug concentrations in interstitial uids even after the plasma concentrations have declined below detectable levels{R-121}. Azithromycin can be delivered to infected tissues and early abscesses via leukocytes{R-119}.

ORAL DOSAGE FORMS

Note: Bracketed information in the Dosage Forms section refers to uses that either are not included in U.S. product labeling or are for products not commercially available in the U.S.

AZITHROMYCIN FOR ORAL SUSPENSION USP

Usual dose: Note: Dosing recommendations for the use of azithromycin in the treatment of animals are given with some caution advised. Unlike other antibiotics for which there is limited clinical efcacy and safety data, the ability of azithromycin to concentrate in tissues makes the typical dosing estimation based on pharmacokinetic data more challenging. The following are current recommendations for dosing; however, these may be supplanted as knowledge about azithromycin increases: [Cats]1 and [dogs]1Although the safety and efcacy have not been established, an oral dose of 3 to 5 mg per kg of body weight every twenty-four hours for three to four days has been used to treat susceptible bacterial infections, based on pharmacokinetic data{R-120; 123; 1257} . For infections that require longer-term treatment, azithromycin has been administered for a maximum of 3 or 4 days a week; this is done either by administering the 3 to 5 mg per kg dose every other day or by administering the same dose once on three subsequent days (Monday, Tuesday, and Wednesday) each week, with no treatment on the other four days of the week.

AZITHROMYCIN TABLETS
Usual dose: See Azithromycin For Oral Suspension USP. Strength(s) usually available{R-116}: U.S. Veterinary-labeled product(s): Not commercially available.

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MACROLIDES VeterinarySystemic 129 Human-labeled product(s): 250 mg (Rx) [Zithromax]. 500 mg (Rx) [Zithromax]. Canada Veterinary-labeled product(s): Not commercially available. Human-labeled product(s): 250 mg (Rx) [Zithromax]. 500 mg (Rx) [Zithromax]. Packaging and storage: Store below 40 C (104 F), preferably between 15 and 30 C (59 and 86 F), in a well-closed container. USP requirements: Not in USP{R-22}.
1

CLARITHROMYCIN ORAL DOSAGE FORMS

Note: Bracketed information in the Dosage Forms section refers to uses that either are not included in U.S. product labeling or are for products not commercially available in the U.S.

CLARITHROMYCIN FOR ORAL SUSPENSION USP

Usual dose: Note: Dosing recommendations for the use of clarithromycin in the treatment of animals are given with caution advised. Unlike other antibiotics for which there is limited clinical efcacy and safety data, the ability of clarithromycin to concentrate in tissues makes the typical dosing estimation based on pharmacokinetic data more challenging. One pharmacokinetic study suggested that 10 mg per kg a day may be an effective dose for [dogs]1, but did not attempt to recommend duration of therapy{R-124}. There are no reports of specic dosing regimens in common usage. Strength(s) usually available{R-115}: When reconstituted according to manufacturers instructions U.S.: Veterinary-labeled product(s) Not commercially available. Human-labeled product(s) 25 mg per mL (Rx) [Biaxin]. 50 mg per mL (Rx) [Biaxin]. Canada: Veterinary-labeled product(s) Not commercially available. Human-labeled product(s) 25 mg per mL (Rx) [Biaxin]. 50 mg per mL (Rx) [Biaxin]. Packaging and storage: Store between 15 and 30 C (59 and 86 F), in a well-closed container. Protect from light. Preparation of dosage form: Add the total volume of water indicated on manufacturers product labeling, in two portions, shaking well after each addition. Stability: After reconstitution, suspension retains its potency for 14 days. Do not refrigerate. USP requirements: Preserve in tight containers. A dry mixture of Clarithromycin, dispersing agents, diluents, preservatives, and avorings. Contains the labeled amount, within 10 to +15%, labeled amount being 25 mg or 50 mg per mL when constituted as directed in the labeling. Meets the requirements for Identication, pH (4.05.4, in the suspension constituted as directed in the labeling), Loss on drying (not more than 2.0%), and Deliverable volume.{R-22}

Not included in Canadian product labeling or product not commercially available in Canada.

PARENTERAL DOSAGE FORMS AZITHROMYCIN FOR INJECTION

Usual dose: Note: There are no data at this time to recommend dosing for parenteral azithromycin in animals. Strength(s) usually available{R-115}: U.S. Veterinary-labeled product(s): Not commercially available. Human-labeled product(s): 500 mg (Rx) [Zithromax]. Canada Veterinary-labeled product(s): Not commercially available. Human-labeled product(s): 500 mg (Rx) [Zithromax]. Packaging and storage: Store below 40 C (104 F), preferably between 15 and 30 C (59 and 86 F), unless otherwise specied by manufacturer.

Preparation of dosage form: To prepare the initial solution for intravenous infusion, add 4.8 mL of sterile water for injection to each 500-mg vial and shake until all of the medication is dissolved. Further dilute this solution by transferring it into 250 or 500 mL of a suitable diluent (see manufacturers package insert) to provide a nal concentration of 2 or 1 mg per mL, respectively.

Stability: After reconstitution with sterile water for injection, the solution is stable for 24 hours when stored below 30 C (86 F). After dilution to 1 or 2 mg per mL in suitable diluent, solutions are stable for 24 hours at or below room temperature (30 C [86 F]), or for 7 days if stored at 5 C (41 F). USP requirements: Not in USP{R-22}. 2003 Thomson MICROMEDEX

CLARITHROMYCIN TABLETS USP

Usual dose: See Clarithromycin for Oral Suspension USP. Strength(s) usually available{R-115}: U.S. Veterinary-labeled product(s): Not commercially available. All rights reserved

130 MACROLIDES VeterinarySystemic Human-labeled product(s): 250 mg (Rx) [Biaxin]. 500 mg (Rx) [Biaxin]. Canada Veterinary-labeled product(s): Not commercially available. Human-labeled product(s): 250 mg (Rx) [Biaxin]. 500 mg (Rx) [Biaxin]. Packaging and storage: Store between 15 and 30 C (59 and 86 F), unless otherwise specied by the manufacturer. Protect from light. Preserve in tight containers. USP requirements: Preserve in tight containers. Contain the labeled amount, within 10%. Meet the requirements for Identication, Dissolution (80% in 30 minutes in 0.1 M Sodium acetate buffer in Apparatus 2 at 50 rpm), Uniformity of dosage units, and Loss on drying (not more than 6.0%).{R-22} Strength(s) usually available: U.S. Veterinary-labeled product(s): Not commercially available. Human-labeled product(s): 250 mg (Rx) [ERYC; generic]. Canada Veterinary-labeled product(s): Not commercially available. Human-labeled product(s): 250 mg (Rx) [Apo-Erythro E-C; ERYC-250; Novo-rythro Encap]. 333 mg (Rx) [Apo-Erythro E-C; ERYC-333]. Packaging and storage: Store below 40 C (104 F), preferably between 15 and 30 C (59 and 86 F), unless otherwise specied by manufacturer. Store in a tight container. USP requirements: Preserve in tight containers. Contain the labeled amount, within 10% to +15%. Meet the requirements for Identication, Drug release (Method B: 80% in 60 minutes for Acid stage and 60 minutes for Buffer stage in Apparatus 1 at 50 rpm), and Water (not more than 7.5%).{R-22}

CLARITHROMYCIN EXTENDED-RELEASE TABLETS

Usual dose: Note: There is no specic evidence that human extended-release dosage forms are completely absorbed by animals; therefore, reliable dose recommendations cannot be made. Strength(s) usually available{R-115}: U.S. Veterinary-labeled product(s): Not commercially available. Human-labeled product(s): 500 mg (Rx) [Biaxin XL]. Canada Veterinary-labeled product(s): Not commercially available. Human-labeled product(s): 500 mg (Rx) [Biaxin XL]. Packaging and storage: Store between 15 and 30 C (59 and 86 F), unless otherwise specied by the manufacturer. Protect from light. USP requirements: Not in USP.{R-22}
1

ERYTHROMYCIN TABLETS USP

Usual dose: [Pyoderma]1Dogs: Oral, 10 to 20 mg per kg of body weight every eight to twelve hours.{R-30; 4244; 60} Note: The above dose recommendation is based on current clinical practice rather than specic canine pharmacokinetic data. The absorption of enteric-coated tablets in dogs can be unpredictable.{R-21} Strength(s) usually available: U.S. Veterinary-labeled product(s): Not commercially available. Human-labeled product(s): 250 mg (Rx) [generic]. 500 mg (Rx) [generic]. Canada Veterinary-labeled product(s): Not commercially available. Human-labeled product(s): 250 mg (Rx) [Apo-Erythro; Erythromid]. Packaging and storage: Store below 40 C (104 F), preferably between 15 and 30 C (59 and 86 F), unless otherwise specied by manufacturer. Store in a tight container. USP requirements: Preserve in tight containers. Contain the labeled amount, within 10% to +20%. Meet the requirements for Identication, Dissolution (70% in 60 minutes in 0.05 M phosphate buffer [pH 6.8] in Apparatus 2 at 50 rpm), Uniformity of dosage units, and Loss on drying (not more than 5.0%).{R-22} Note: Tablets that are enteric-coated meet the requirements for Erythromycin Delayed-release Tablets.{R-22}

Not included in Canadian product labeling or product not commercially available in Canada.

ERYTHROMYCIN BASE ORAL DOSAGE FORMS

Note: Bracketed information in the Dosage Forms section refers to uses that either are not included in U.S. product labeling or are for products not commercially available in the U.S.

ERYTHROMYCIN DELAYED-RELEASE CAPSULES USP

Usual dose: Note: There is no specic evidence that human delayed-release dosage forms are completely absorbed by animals; therefore, reliable dose recommendations cannot be made. 2003 Thomson MICROMEDEX

ERYTHROMYCIN DELAYED-RELEASE TABLETS USP

Usual dose: Note: There is no specic evidence that human delayed-release dosage forms are completely absorbed by animals; therefore, reliable dose recommendations cannot be made. All rights reserved

MACROLIDES VeterinarySystemic 131 Strength(s) usually available: U.S. Veterinary-labeled product(s): Not commercially available. Human-labeled product(s): 250 mg (Rx) [E-Mycin; Ery-Tab; Ilotycin; generic]. 333 mg (Rx) [E-Base; E-Mycin; Ery-Tab; PCE; generic]. 500 mg (Rx) [E-Base; Ery-Tab; PCE]. Canada Veterinary-labeled product(s): Not commercially available. Human-labeled product(s): 250 mg (Rx) [E-Mycin; generic]. 333 mg (Rx) [PCE]. 500 mg (Rx) [Erybid]. Packaging and storage: Store below 40 C (104 F), preferably between 15 and 30 C (59 and 86 F), unless otherwise specied by manufacturer. Store in a tight container. USP requirements: Preserve in tight containers. The label indicates that Erythromycin Delayed-release Tablets are enteric-coated. The labeling indicates the Drug Release Test with which the product complies. Contain the labeled amount, within 10% to +20%. Meet the requirements for Identication, Drug Release (Method B: 75% in 60 minutes for Acid stage and 60 minutes for Buffer stage in Apparatus 1 at 100 rpm for Test 1 and in Apparatus 2 at 75 rpm for Test 2), Uniformity of dosage units, and Water (not more than 6.0%).{R-22}
1

Note: The above dose is higher than those stated on U.S. or Canadian product labeling. Pigs (treatment of respiratory syndrome): Intramuscular, 1.1 to 3.3 mg per kg of body weight every twenty-four hours{R-111}. Note: Injections should be made deep into the muscle.{R-6} Erythromycin injection should not be administered intravenously or subcutaneously. PododermatitisCattle: Intramuscular, 1.1 to 2.2 mg per kg of body weight every twenty-four hours{R-111}. Respiratory tract infections, bacterial (treatment) Pigs (treatment of respiratory syndrome): Intramuscular, 1.1 to 3.3 mg per kg of body weight every twenty-four hours{R-111}. Sheep (treatment of upper respiratory tract infections): Intramuscular, 1.1 mg per kg of body weight every twenty-four hours{R-111}. Strength(s) usually available: U.S.{R-6; 8} Veterinary-labeled product(s): 100 mg per mL (OTC) [Gallimycin-100]. 200 mg per mL (OTC) [Gallimycin-200]. Canada{R-7; 8} Veterinary-labeled product(s): 200 mg per mL (OTC) [Erythro-200; Gallimycin-200]. Withdrawal times: U.S. For Gallimycin-200{R-6}:
Withdrawal time

Not included in Canadian product labeling or product not commercially available in Canada.

Species Cattle

Meat (days) 6

PARENTERAL DOSAGE FORMS

Note: Bracketed information in the Dosage Forms section refers to uses that either are not included in U.S. product labeling or are for products not commercially available in the U.S.

ERYTHROMYCIN INJECTION USP

Usual dose: Enteritis (scours)Piglets, one week of age or older: Intramuscular, 11 mg per kg of body weight every twenty-four hours{R-111}. Enterotoxemia (lamb dysentery) (prophylaxis)Lambs, newborn: Intramuscular, 5.5 mg per kg of body weight every twenty-four hours, as soon after birth as is practical{R-111}. LeptospirosisSows, farrowing: Intramuscular, 1.1 to 3.3 mg per kg of body weight every twenty-four hours{R-111}. Metritis Cattle: Intramuscular, 1.1 to 2.2 mg per kg of body weight every twenty-four hours{R-111}. Sows, farrowing: Intramuscular, 1.1 to 3.3 mg per kg of body weight every twenty-four hours{R-111}. Pneumonia, bacterial Cattle: Intramuscular, 2.2{R-111} to 8.8{R-6} mg per kg of body weight every twenty-four hours. Note: See product labeling for the above dosing recommendations with applicable withdrawal times. For pneumonic pasteurellosis[Intramuscular, 15 mg per kg of body weight every twelve hours.{R-24; 28}]1 2003 Thomson MICROMEDEX

Note: Product labeling listing the above withdrawal time states that it applies to a dose of 8.8 mg per kg of body weight every 24 hours and a course of therapy not exceeding 5 days. Higher doses or longer duration of treatment may increase withdrawal times. This product is not labeled for use in lactating dairy cattle. To avoid excessive trim, cattle should not be slaughtered for 21 days after the last injection. For Gallimycin-100{R-111}:
Withdrawal time Species Cattle Pigs Sheep Meat (day) 14 7 3 Milk (hours) 72

Note: Product labeling listing the above withdrawal times states that they apply to a dose of 1.1 to 2.2 mg per kg of body weight for cattle, 1.1 to 3.3 mg per kg of body weight for pigs, and 1.1 mg per kg of body weight for sheep. Canada{R-7}
Withdrawal time Species Cattle Pigs Sheep Meat (day) 14 7 3 Milk (hours) 72

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132 MACROLIDES VeterinarySystemic Note: Product labeling listing the above withdrawal times states that the recommended withdrawal times apply to doses of 2.2 to 4.4 mg per kg of body weight in cattle, 22 mg per kg of body weight in piglets, 2.2 to 6.6 mg per kg of body weight in pigs, 11 mg per kg of body weight in lambs, and 2.2 mg per kg of body weight in sheep; administered every 24 hours in each species. To avoid excessive trim, cattle should not be slaughtered for 21 days after the last injection; for pigs and sheep, the waiting period is 10 days. Packaging and storage: Store below 40 C (104 F), preferably between 15 and 30 C (59 and 86 F), unless otherwise specied by manufacturer. Protect from freezing. USP requirements: Preserve in multiple-dose containers. A sterile solution of Erythromycin in a polyethylene glycol vehicle. Label it to indicate that it is for veterinary use only. Label it to state that it is for intramuscular administration only. Contains the labeled amount, within 10% to +20%. Meets the requirements for Identication, Water (not more than 1.0%), and Sterility, and for Injections.{R-22}
1

Canada Veterinary-labeled product(s): Not commercially available. Human-labeled product(s): 250 mg (base) (Rx) [Ilosone; Novo-rythro]. Packaging and storage: Store below 40 C (104 F), preferably between 15 and 30 C (59 and 86 F), unless otherwise specied by manufacturer. Store in a tight container. USP requirements: Preserve in tight containers. Contain an amount of erythromycin estolate equivalent to the labeled amount of erythromycin, within 10% to +15%. Meet the requirements for Identication, Disintegration (30 minutes), Uniformity of dosage units, and Water (not more than 5.0%).{R-22}

ERYTHROMYCIN ESTOLATE ORAL SUSPENSION USP

Usual dose: See Erythromycin Estolate Capsules USP. Strength(s) usually available: U.S. Veterinary-labeled product(s): Not commercially available. Human-labeled product(s): 25 mg (base) per mL (Rx) [Ilosone; 50 mg (base) per mL (Rx) [Ilosone; Canada Veterinary-labeled product(s): Not commercially available. Human-labeled product(s): 25 mg (base) per mL (Rx) [Ilosone; 50 mg (base) per mL (Rx) [Ilosone;

Not included in Canadian product labeling or product not commercially available in Canada.

generic]. generic].

ERYTHROMYCIN ESTOLATE SUMMARY OF DIFFERENCES

Pharmacology/pharmacokinetics: AbsorptionErythromycin estolate is absorbed as the ester from the duodenum and is hydrolyzed to free base in the body.{R-1; 18} Side/adverse effects: In humans, erythromycin estolate has been associated with an increased risk of subclinical hepatotoxicity during pregnancy and an increased risk of cholestatic jaundice at any time. These effects have not been reported in animals; however, periodic liver function tests for animals receiving long-term erythromycin estolate therapy have been recommended.{R-2}

Novo-rythro]. Novo-rythro].

Packaging and storage: Store between 2 and 8 C (36 and 46 F). Store in a tight container. Auxiliary labeling: Refrigerate. Shake well. USP requirements: Preserve in tight containers, in a cold place. Contains one or more suitable buffers, colors, diluents, dispersants, and avors. Contains an amount of erythromycin estolate equivalent to the labeled amount of erythromycin, within 10% to +15%. Meets the requirements for Identication, Uniformity of dosage units (single-unit containers), Deliverable volume, and pH (3.56.5){R-22}.

ORAL DOSAGE FORMS

Note: Bracketed information in the Dosage Forms section refers to uses that either are not included in U.S. product labeling or are for products not commercially available in the U.S. The dosing and strengths of the dosage forms available are expressed in terms of erythromycin base (not the estolate salt).

ERYTHROMYCIN ESTOLATE CAPSULES USP

Usual dose: [Rhodococcus equi pneumonia]1Foals: Oral, 25 mg (base) per kg of body weight every six hours.{R-13; 14; 26} Note: The above dose has also been administered concurrently with 5 mg rifampin per kg of body weight.{R-13; 14} The doses recommended are based on pharmacokinetic and clinical efcacy studies in foals.{R-13; 14;
26}

ERYTHROMYCIN ESTOLATE TABLETS USP

Usual dose: See Erythromycin Estolate Capsules USP. Strength(s) usually available. U.S. Veterinary-labeled product(s): Not commercially available. Human-labeled product(s): 250 mg (base) (Rx) [generic]. 500 mg (base) (Rx) [Ilosone]. Canada Veterinary-labeled product(s): Not commercially available. All rights reserved

Strength(s) usually available: U.S. Veterinary-labeled product(s): Not commercially available. Human-labeled product(s): 250 mg (base) (Rx) [Ilosone; generic]. 2003 Thomson MICROMEDEX

MACROLIDES VeterinarySystemic 133 Human-labeled product(s): 500 mg (base) (Rx) [Ilosone]. Packaging and storage: Store below 40 C (104 F), preferably between 15 and 30 C (59 and 86 F), unless otherwise specied by the manufacturer. Store in a tight container. USP requirements: Preserve in tight containers. Label Tablets to indicate whether they are to be chewed before swallowing. Contain an amount of erythromycin estolate equivalent to the labeled amount of erythromycin, within 10% to +20% (+15%, if chewable). Meet the requirements for Identication, Disintegration (30 minutes [Note: Chewable tablets are exempt from this requirement]), Uniformity of dosage units, and Water (not more than 5.0%; if chewable, not more than 4.0%).{R-22}
1

USP requirements: Preserve in tight containers, and store in a cold place. A suspension of Erythromycin Ethylsuccinate containing one or more suitable buffers, colors, dispersants, avors, and preservatives. Contains an amount of erythromycin ethylsuccinate equivalent to the labeled amount of erythromycin, within 10% to +20%. Meets the requirements for Identication, Uniformity of dosage units (single-unit containers), Deliverable volume, and pH (6.58.5).{R-22}

ERYTHROMYCIN ETHYLSUCCINATE FOR ORAL SUSPENSION USP

Usual dose: See Erythromycin Ethylsuccinate Oral Suspension USP. Strength(s) usually available: When reconstituted according to manufacturers instructions U.S.: Veterinary-labeled product(s): Not commercially available. Human-labeled product(s): 40 mg per mL (Rx) [E.E.S.; EryPed; generic]. 80 mg per mL (Rx) [EryPed; generic]. Canada: Veterinary-labeled product(s): Not commercially available. Human-labeled product(s): 20 mg per mL (Rx) [Novo-Rythro]. 40 mg per mL (Rx) [E.E.S.; Novo-Rythro]. 80 mg per mL (Rx) [E.E.S.]. Packaging and storage: Prior to reconstitution, store below 40 C (104 F), preferably between 15 and 30 C (59 and 86 F), unless otherwise specied by manufacturer. Store in a tight container. Stability: After reconstitution, depending on the manufacturer or the specic product, suspensions do not require refrigeration if used within 14 days. USP requirements: Preserve in tight containers. A dry mixture of Erythromycin Ethylsuccinate with one or more suitable buffers, colors, diluents, dispersants, and avors. Contains an amount of erythromycin ethylsuccinate equivalent to the labeled amount of erythromycin, within 10% to +20%. Meets the requirements for Identication, Uniformity of dosage units (single-unit containers), Deliverable volume, pH (7.09.0, in the suspension constituted as directed in the labeling), and Loss on drying (not more than 1.0%).{R-22}

Not included in Canadian product labeling or product not commercially available in Canada.

ERYTHROMYCIN ETHYLSUCCINATE SUMMARY OF DIFFERENCES

Pharmacology/pharmacokinetics: Absorption Absorbed as the ester, then hydrolyzed to free base in the body.{R-1} Pigeons: Orally administered erythromycin ethylsuccinate has a relative bioavailability of less than 10%.{R-27}

ORAL DOSAGE FORMS

Note: The strengths of the dosage forms available are expressed in terms of the ethylsuccinate salt. In people, 400 mg of erythromycin ethylsuccinate produces approximately the same blood concentrations as 250 mg of erythromycin base. 1.17 grams of erythromycin ethylsuccinate equal 1 gram of erythromycin base{R-90}.

ERYTHROMYCIN ETHYLSUCCINATE ORAL SUSPENSION USP

Usual dose: Note: There are no dose recommendations specic to animals for this dosage form. Strength(s) usually available: U.S. Veterinary-labeled product(s): Not commercially available. Human-labeled product(s): 40 mg per mL (Rx) [E.E.S.; Erythro; generic]. 80 mg per mL (Rx) [E.E.S.; Erythro; generic]. Canada Not commercially available. Packaging and storage: Store between 2 and 8 C (36 and 46 F). Store in a tight container. Stability: After dispensing, suspensions do not require refrigeration if used within 14 days. Some manufacturers recommend storage in light-resistant containers to prevent discoloration.{R-36} 2003 Thomson MICROMEDEX

ERYTHROMYCIN ETHYLSUCCINATE TABLETS USP

Usual dose: See Erythromycin Ethylsuccinate Oral Suspension USP. Strength(s) usually available. U.S. Veterinary-labeled product(s): Not commercially available. Human-labeled product(s): 400 mg (Rx) [E.E.S.; generic]. Canada Veterinary-labeled product(s): Not commercially available. Human-labeled product(s): 600 mg (Rx) [Apo-Erythro-ES; E.E.S.]. All rights reserved

134 MACROLIDES VeterinarySystemic Packaging and storage: Store below 40 C (104 F), preferably between 15 and 30 C (59 and 86 F), unless otherwise specied by manufacturer. Store in a tight container. USP requirements: Preserve in tight containers. Label the chewable Tablets to indicate that they are to be chewed before swallowing. Contain an amount of erythromycin ethylsuccinate equivalent to the labeled amount of erythromycin, within 10% to +20%. Meet the requirements for Identication, Dissolution (75% in 45 minutes in 0.01 N hydrochloric acid in Apparatus 2 at 50 rpm for nonchewable tablets and 75% in 60 minutes in 0.1 M acetate buffer [pH 5.0] in Apparatus 2 at 75 rpm for Tablets labeled as chewable), Uniformity of dosage units, Loss on drying (not more than 4.0% [Note: Chewable Tablets are exempt from this requirement]), and Water (Chewable Tablets only, not more than 5.0%).{R-22}

STERILE ERYTHROMYCIN GLUCEPTATE USP

Usual dose: [Antibacterial]1Foals: Intravenous, 5 mg (base) per kg of body weight every four to six hours.{R-26} Size(s) usually available: U.S. Veterinary-labeled product(s): Not commercially available. Human-labeled product(s): 1 gram (base) (Rx) [Ilotycin]. Canada Veterinary-labeled product(s): Not commercially available. Human-labeled product(s): 500 mg (base) (Rx) [Ilotycin]. 1 gram (base) (Rx) [Ilotycin]. Packaging and storage: Prior to reconstitution, store below 40 C (104 F), preferably between 15 and 30 C (59 and 86 F), unless otherwise specied by manufacturer. Preparation of dosage form:{R-37} To prepare solution, add at least 10 mL of sterile water for injection to each 500-mg vial and at least 20 mL of diluent to each 1-gram vial. After initial dilution, solution may be further diluted to a concentration of 1 gram per L in 0.9% sodium chloride injection or 5% dextrose injection for slow, continuous infusion. Stability: After reconstitution, initial dilutions (25 to 50 mg per mL) retain their potency for 7 days if refrigerated.{R-37} USP requirements: Preserve in Containers for Sterile Solids. It is Erythromycin Gluceptate suitable for parenteral use. Has a potency equivalent to not less than 600 mcg of erythromycin per mg, calculated on the anhydrous basis. In addition, where packaged for dispensing, contains an amount of erythromycin gluceptate equivalent to the labeled amount of erythromycin, within 10% to +15%. Meets the requirements for Identication, Bacterial endotoxins, Sterility, pH (6.08.0, in a solution containing 25 mg per mL), Water (not more than 5.0%), and Particulate matter, and, where packaged for dispensing, Uniformity of dosage units, Constituted solutions, and Labeling under Injections.{R-22}
1

ERYTHROMYCIN ETHYLSUCCINATE TABLETS (CHEWABLE) USP

Usual dose: See Erythromycin Ethylsuccinate Oral Suspension USP. Strength(s) usually available: U.S. Veterinary-labeled product(s): Not commercially available. Human-labeled product(s): 200 mg (Rx) [EryPed]. 400 mg (Rx) [Erythro]. Canada Veterinary-labeled product(s): Not commercially available. Human-labeled product(s): 200 mg (Rx) [E.E.S. (scored); EryPed]. Packaging and storage: Store below 40 C (104 F), preferably between 15 and 30 C (59 and 86 F), unless otherwise specied by manufacturer. Store in a tight container. USP requirements: Preserve in tight containers. Label the chewable Tablets to indicate that they are to be chewed before swallowing. Contain an amount of erythromycin ethylsuccinate equivalent to the labeled amount of erythromycin, within 10% to +20%. Meet the requirements for Identication, Dissolution (75% in 45 minutes in 0.01 N hydrochloric acid in Apparatus 2 at 50 rpm for nonchewable tablets and 75% in 60 minutes in 0.1 M acetate buffer [pH 5.0] in Apparatus 2 at 75 rpm for Tablets labeled as chewable), Uniformity of dosage units, Loss on drying (not more than 4.0% [Note: Chewable Tablets are exempt from this requirement]), and Water (Chewable Tablets only, not more than 5.0%).{R-22}

Not included in Canadian product labeling or product not commercially available in Canada.

ERYTHROMYCIN LACTOBIONATE PARENTERAL DOSAGE FORMS

Note: The strengths of the dosage forms available are expressed in terms of erythromycin base (not the lactobionate salt).

ERYTHROMYCIN LACTOBIONATE FOR INJECTION USP ERYTHROMYCIN GLUCEPTATE PARENTERAL DOSAGE FORMS
Note: Bracketed information in the Dosage Forms section refers to uses that either are not included in U.S. product labeling or are for products not commercially available in the U.S. The dosing and strengths of the dosage forms available are expressed in terms of erythromycin base (not the gluceptate salt). 2003 Thomson MICROMEDEX Usual dose: Note: There are no dose recommendations specic to animals for this dosage form. Size(s) usually available: U.S.{R-39} Veterinary-labeled product(s): Not commercially available. All rights reserved

MACROLIDES VeterinarySystemic 135 Human-labeled product(s): 500 mg (base) (Rx) [Erythrocin; generic]. 1 gram (base) (Rx) [Erythrocin; generic]. Canada Veterinary-labeled product(s): Not commercially available. Human-labeled product(s): 500 mg (base) (Rx) [Erythrocin]. 1 gram (base) (Rx) [Erythrocin]. Packaging and storage: Prior to reconstitution, store below 40 C (104 F), preferably between 15 and 30 C (59 and 86 F), unless otherwise specied by manufacturer. Preparation of dosage form: See manufacturers product labeling. Stability: After reconstitution, initial dilutions (50 mg per mL) retain their potency for 14 days if refrigerated, or for 24 hours at room temperature. Infusions prepared in piggyback infusion bottles retain their potency for 8 hours at room temperature, for 24 hours if refrigerated, or for 30 days if frozen. Acidic infusions are unstable and lose potency rapidly. A pH of at least 5.5 is recommended for nal dilutions, which should be administered completely within 8 hours after dilution. USP requirements: Preserve in Containers for Sterile Solids. A sterile, dry mixture of erythromycin lactobionate and a suitable preservative. Contains an amount of erythromycin lactobionate equivalent to the labeled amount of erythromycin, within 10% to +20%. Meets the requirements for Constituted solution, Identication, Bacterial endotoxins, pH (6.5 7.5, in a solution containing the equivalent of 50 mg of erythromycin per mL), Water (not more than 5.0%), Particulate matter, and Heavy metals (not more than 0.005%), and for Injections.{R-22} EnteritisTurkeys: Oral, 500 mg per gallon of water, administered as the only source of drinking water for seven days.{R-3} Note: Dosage ranges for birds are approximate, based on variable water consumption and animal size. Strength(s) usually available: U.S.{R-3; 6; 8} Veterinary-labeled product(s): 260 mg (231.2 mg erythromycin base) per gram (OTC) [Gallimycin PFC]. Canada{R-8; 9} Veterinary-labeled product(s): 130 mg (115.6 mg base) per gram (OTC) [Gallimycin; Gallistat]. 260 mg (231.2 mg base) per gram (OTC) [Gallimycin PFC]. Withdrawal times: U.S. and Canada{R-3;
9}

Withdrawal time Species Chickens and turkeys Meat (days) 1

Note: Products are not labeled for use in birds producing eggs for human consumption or in replacement pullets over 16 weeks of age{R-3; 9}. Canadian product labeling lists the dose as 116 mg (base) per liter of water for chickens and turkeys. Packaging and storage: Store below 40 C (104 F), preferably between 15 and 30 C (59 and 86 F), unless otherwise specied by manufacturer. Stability: Solutions should be discarded after 3 days.{R-8} USP requirements: Not in USP{R-22}.

ERYTHROMYCIN STEARATE ERYTHROMYCIN PHOSPHATE SUMMARY OF DIFFERENCES

Pharmacology/pharmacokinetics: Absorption Erythromycin phosphate is presumed to dissociate in the duodenum and be absorbed as the free base.{R-18} Horses: Erythromycin phosphate is absorbed at least as well as erythromycin estolate when administered orally.{R-18}

SUMMARY OF DIFFERENCES
Pharmacology/pharmacokinetics: AbsorptionErythromycin stearate dissociates in the duodenum and is absorbed as the free base.{R-18}

ORAL DOSAGE FORMS

Note: Bracketed information in the Dosage Forms section refers to uses that either are not included in U.S. product labeling or are for products not commercially available in the U.S. The dosing and strengths of the dosage forms available are expressed in terms of erythromycin base (not the stearate salt).

ORAL DOSAGE FORMS

Note: The dosing and strengths of the dosage form available are expressed in terms of erythromycin phosphate (not erythromycin base). 1.12 grams of erythromycin phosphate equal 1 gram of erythromycin base{R-8}.

ERYTHROMYCIN STEARATE ORAL SUSPENSION

Usual dose: [Enteritis, Campylobacter]1Dogs: Oral, 10 mg (base) per kg of body weight every eight hours.{R-10} Strength(s) usually available: U.S. Not commercially available. Canada Veterinary-labeled product(s): Not commercially available. Human-labeled product(s): 25 mg (base) per mL (Rx) [Erythrocin; Novo-rythro]. 50 mg (base) per mL (Rx) [Erythrocin; Novo-rythro]. All rights reserved

ERYTHROMYCIN PHOSPHATE POWDER FOR ORAL SOLUTION

Usual dose: Chronic respiratory diseaseChickens: Oral, 500 mg per gallon of water, administered as the only source of drinking water every twenty-four hours for ve days{R-3}. Coryza, infectiousChickens: Oral, 500 mg per gallon of water, administered as the only source of drinking water for seven days.{R-3} 2003 Thomson MICROMEDEX

136 MACROLIDES VeterinarySystemic Packaging and storage: Store below 40 C (104 F), preferably between 15 and 30 C (59 and 86 F), unless otherwise specied by manufacturer. Store in a tight container. Auxiliary labeling: Refrigerate. Shake well. USP requirements: Not in USP.{R-22} Respiratory disease, chronic (treatment)Chickens and turkeys1: Oral, 200 grams (185 grams of base) per ton of feed, fed as the only ration.{R-54} Strength(s) usually available: U.S.{R-8; 54} Veterinary-labeled product(s): 220 grams (203 grams of base) per kg of premix (OTC) [Erymycin-100]. Canada{R-8; 64} Veterinary-labeled product(s): 110 grams (102 grams of base) per kg of premix (OTC) [Gallimycin-50]. Withdrawal times: U.S.{R-54} With a dose of 200 grams (185 grams of base) per ton of feed:
Withdrawal time Species Chickens Turkeys Meat (days) 2 0

ERYTHROMYCIN STEARATE TABLETS USP

Usual dose: See Erythromycin Stearate Oral Suspension. Strength(s) usually available: U.S. Veterinary-labeled product(s): Not commercially available. Human-labeled product(s): 250 mg (base) (Rx) [Erythrocin; Erythrocot; My-E; Wintrocin; generic]. 500 mg (base) (Rx) [Erythrocin; generic]. Canada Veterinary-labeled product(s): Not commercially available. Human-labeled product(s): 250 mg (base) (Rx) [Apo-Erythro-S; Erythrocin; Novo-rythro]. 500 mg (base) (Rx) [Apo-Erythro-S; Erythrocin]. Packaging and storage: Store below 40 C (104 F), preferably between 15 and 30 C (59 and 86 F), unless otherwise specied by manufacturer. Store in a tight container. Note: Some manufacturers recommend storage in light-resistant containers to prevent discoloration. USP requirements: Preserve in tight containers. Contain an amount of erythromycin stearate equivalent to the labeled amount of erythromycin, within 10% to +20%. Meet the requirements for Identication, Dissolution (75% in 120 minutes in 0.05 M phosphate buffer [pH 6.8] in Apparatus 2 at 100 rpm), Uniformity of dosage units, and Loss on drying (not more than 5.0%).{R-22}
1

Note: Product is not labeled for use in birds producing eggs for human consumption{R-54}. With a dose of 100 grams (93 grams of base) per ton of feed:
Withdrawal time Species Chickens Turkeys Meat (days) 1 0

Note: Product is not labeled for use in birds producing eggs for human consumption{R-54}. Canada
Withdrawal time Species Chickens Meat (days) 1

Not included in Canadian product labeling or product not commercially available in Canada.

Note: Product labeling listing the above withdrawal time states that it applies to a dose of 220 grams per metric ton (1000 kg) of feed, fed as the only ration, to chickens.{R-64} Not labeled for use in chickens producing eggs for human consumption. Packaging and storage: Store below 40 C (104 F), preferably between 15 and 30 C (59 and 86 F), unless otherwise specied by manufacturer. USP requirements: Not in USP.{R-22}
1

ERYTHROMYCIN THIOCYANATE ORAL DOSAGE FORMS

Note: 1.08 grams of thiocyanate salt equal 1 gram of erythromycin base{R-54}.

Not included in Canadian product labeling or product not commercially available in Canada.

ERYTHROMYCIN THIOCYANATE FOR MEDICATED FEED

Usual dose: Coryza, infectious (prophylaxis)1Chickens: Oral, 100 grams (93 grams of base) per ton of feed, fed as the only ration for seven to fourteen days.{R-54} Respiratory disease, chronic (prophylaxis)1Chickens and turkeys: Oral, 100 grams (93 grams of base) per ton of feed, fed as the only ration from two days before stress until three to six days after stress.{R-54}

TILMICOSIN PHOSPHATE ADDITIONAL DOSING INFORMATION

Tilmicosin injection should be given only by subcutaneous administration because intravenous administration is fatal with doses as low as 5 mg per kg of body weight.{R-53} Parenteral administration of tilmicosin to pigs by any route often is fatal.{R-53}

2003 Thomson MICROMEDEX

All rights reserved

MACROLIDES VeterinarySystemic 137

ORAL DOSAGE FORMS

Note: The dosing and strengths of the dosage form available are expressed in terms of tilmicosin base (not the phosphate salt).

Note: Tilmicosin should not be administered intravenously. Intramuscular administration should be avoided. No more than 15 mL should be administered per injection site.{R-53} Strength(s) usually available{R-8}: U.S. Veterinary-labeled product(s): 300 mg (base) per mL (Rx) [Micotil]. Canada Veterinary-labeled product(s): 300 mg (base) per mL (Rx) [Micotil]. Withdrawal times: U.S.
Withdrawal time Species Cattle Meat (days) 28

TILMICOSIN FOR MEDICATED FEED

Usual dose: Pneumonia, bacterialPigs: Oral, 181 to 383 grams per ton of feed, fed as the only ration for twenty-one days, beginning approximately seven days before an anticipated disease outbreak, if possible{R-107; 114}. Strength(s) usually available{R-8}: U.S. Veterinary-labeled product(s): 200 grams (base) per kg (90.7 grams [base] per pound) of premix (Rx) [Pulmotil 90]. Canada Veterinary-labeled product(s): 200 grams (base) per kg (OTC) [Pulmotil Premix]. Withdrawal times: U.S.{R-107}
Withdrawal time Species Pigs Meat (days) 7

Canada{R-114}
Withdrawal time Species Pigs Meat (days) 7

Note: Product labeling listing the above withdrawal time states that it applies to a dose of 10 mg (base) per kg of body weight administered once to cattle. Not labeled for use in lactating cattle. Tilmicosin should not be used in lactating dairy cows because of its extended antimicrobial activity in milk. A single subcutaneous tilmicosin dose of 10 mg per kg of body weight resulted in tilmicosin concentrations detectable in milk for 19 to 31 days when measured by high performance liquid chromatography or 14 to 21 days when measured by Bacillus stearothermophilus assay{R-74}. Canada
Withdrawal time

Packaging and storage: Store below 40 C (104 F), preferably between 15 and 30 C (59 and 86 F), unless otherwise specied by manufacturer. Preparation of dosage form: Tilmicosin should not be mixed in concentrates or feeds containing bentonite because bentonite may reduce the efcacy of tilmicosin{R-107}. Premix should be thoroughly mixed in feed before administration{R-107}. Caution: Inhalation, oral exposure, and direct contact with eyes should be avoided{R-107}. USP requirements: Not in USP.
{R-22}

Species Calves, cattle, lambs

Meat (days) 28

Note: Product labeling listing the above withdrawal time states that it applies to a dose of 10 mg (base) per kg of body weight administered once to cattle or lambs{R-112}. Not labeled for use in lactating dairy cattle, veal calves, calves weighing less than 70 kg, or lactating sheep{R-92}. Packaging and storage: Store at or below 30 C (86 F). Protect from light.{R-53} Caution: Injection of tilmicosin in humans may be fatal. Caution should be exercised to avoid self-injection. An automatically powered syringe should not be used for administration.{R-53} Auxiliary labeling: Keep out of the reach of children. Avoid contact with eyes. USP requirements: Preserve in light-resistant Containers for Injections. Store at or below 30. A sterile solution of Tilmicosin in a mixture of Propylene Glycol and Water for Injection, solubilized with the aid of Phosphoric Acid. Label the Injection to indicate that it is for veterinary use only. Contains the labeled amount, within 10%. Meets the requirements for Identication, Bacterial endotoxins, Sterility, pH All rights reserved

PARENTERAL DOSAGE FORMS

Note: Bracketed information in the Dosage Forms section refers to uses that either are not included in U.S. product labeling or are for products not commercially available in the U.S. The dosing and strengths of the dosage form available are expressed in terms of tilmicosin base (not the phosphate salt).

TILMICOSIN INJECTION USP

Usual dose: Pneumonia, bacterial Cattle: Subcutaneous, 10 mg (base) per kg of body weight as a single dose{R-53}. [Calves] and [lambs]: Subcutaneous, 10 mg (base) per kg of body weight as a single dose{R-65; 112}. 2003 Thomson MICROMEDEX

138 MACROLIDES VeterinarySystemic (5.56.5), Particulate matter, and Content of propylene glycol (within 20% of labeled amount){R-22}. If tylosin-medicated drinking water is used as a follow-up treatment for swine dysentery, feed containing 40 to 100 grams of tylosin phosphate for medicated feed per ton of feed is recommended to assure depletion of tissue residues.{R-51; 52} Canada{R-55}
Withdrawal time Species Cattle Pigs Meat (days) 21 14

TYLOSIN BASE SUMMARY OF DIFFERENCES

Pharmacology/pharmacokinetics: Tylosin is stable enough in acid environments to be administered orally without enteric coating.{R-58}

PARENTERAL DOSAGE FORMS

Note: Bracketed information in the Dosage Forms section refers to uses that either are not included in U.S. product labeling or are for products not commercially available in the U.S.

TYLOSIN INJECTION
Usual dose: Arthritis, infectious1; Erysipelas; or Swine dysenteryPigs: Intramuscular, 8.8 mg per kg of body weight every twelve hours{R-51}. Note: When used to treat swine dysentery, tylosin injection should be followed by administration of medication in feed or drinking water.{R-51} Diphtheria1; Metritis; or Pododermatitis1Cattle, beef and nonlactating dairy: Intramuscular, 17.6 mg per kg of body weight every twenty-four hours.{R-51; 52; 55}. Pneumonia, bacterial Cattle, beef and nonlactating dairy: Intramuscular, 17.6 mg per kg of body weight every twenty-four hours{R-51; 55}. Pigs: Intramuscular, 8.8 mg per kg of body weight every twelve hours{R-51}. Note: In pigs, no more than 5 mL per injection site is recommended; in cattle, no more than 10 mL per injection site.{R-51; 52} Note: [Cats]1 and [dogs]1A dose of 6.6 to 11 mg per kg of body weight every twelve to twenty-four hours has been used in the treatment of respiratory tract infections in cats and dogs{R-108}. Strength(s) usually available{R-8}: U.S. Veterinary-labeled product(s): 50 mg per mL (OTC) [Tylan 50]. 200 mg per mL (OTC) [Tylan 200; TyloVed; generic]. Canada{R-55} Veterinary-labeled product(s): 200 mg per mL (OTC) [Tylan 200; Tylocine 200]. Withdrawal times: U.S.{R-51; 52}
Withdrawal time Species Cattle Pigs Meat (days) 21 14

Note: Product labeling listing the above withdrawal times states that they apply to a dose of 17.6 mg per kg of body weight (mg/kg) for cattle and 2.2 to 8.8 mg/kg every 24 hours for pigs. Not for use in lactating dairy cattle. To avoid excessive trim, swine should not be slaughtered for 21 days after treatment; cattle should not be slaughtered for 42 days after treatment.{R-55} Packaging and storage: Store below 40 C (104 F), preferably between 15 and 30 C (59 and 86 F), unless otherwise specied by manufacturer. Incompatibilities: To avoid precipitation, tylosin injection should not be mixed with other injectables.{R-51} Caution: Contact with human skin should be avoided. Injection into pigs weighing less than 6.25 pounds should not be attempted unless the syringe is capable of accurately delivering 0.1 mL. Adverse reactions may occur from overdosage in piglets.{R-51; 52} USP requirements: Not in USP.{R-22}
1

Not included in Canadian product labeling or product not commercially available in Canada.

TYLOSIN PHOSPHATE ORAL DOSAGE FORMS TYLOSIN GRANULATED USP

Usual dose: Abscesses, hepatic (prophylaxis)1Cattle, beef: Oral, 8 to 10 grams per ton of feed (approximately 60 to 90 mg per animal a day), fed as the only ration{R-49}. Atrophic rhinitis1Pigs: Oral, 100 grams per ton of feed, fed as the only ration{R-49}. Dysentery, swinePigs: ProphylaxisOral, 100 grams per ton of feed, fed as the only ration for at least three weeks, followed by 40 grams per ton of feed, fed as the only ration{R-49}. TreatmentOral, 40 to 100 grams per ton of feed, fed as the only ration for two to six weeks{R-48; 49}. Note: The dose shown for treatment with tylosin phosphate for medicated feed should follow an initial treatment with tylosin powder for oral solution in the drinking water for three to ten days{R-49; 100}. All rights reserved

Note: Product labeling listing the above withdrawal times states that they apply to a maximum treatment period of 5 days in cattle and maximum treatment period of 3 days in pigs{R-51; 52}. Not for use in lactating dairy cattle{R-51} or preruminant calves. 2003 Thomson MICROMEDEX

MACROLIDES VeterinarySystemic 139 Feed efciency, improvement of1; or Increased weight gain1 Chickens: Oral, 4 to 50 grams per ton of feed, fed as the only ration{R49} . Chickens, laying: Oral, 20 to 50 grams per ton of feed, fed as the only ration{R-49}. Pigs: Oral, 10 to 40 grams per ton of feed, fed as the only ration{R-48; 49} . Proliferative enteropathy, porcine (prophylaxis and treatment)1Pigs: Oral, 100 grams per ton of feed, fed as the only ration for three weeks{R-49}. Respiratory disease, chronic1 Chickens, broiler: Oral, 800 to 1000 grams per ton of feed, fed as the only ration. Chickens, replacement: Oral, 1000 grams per ton of feed, fed as the only ration. Note: Medication should be administered in feed to chickens up to 5 days of age, then administered again for twenty-four to forty-eight hours to chickens 3 to 5 weeks of age. Strength(s) usually available{R-8}: U.S. Veterinary-labeled product(s): 22 grams per kg (10 grams per pound) of premix (OTC) [Tylan 10]. 88 grams per kg (40 grams per pound) of premix (OTC) [Tylan 40]. 220 grams per kg (100 grams per pound) of premix (OTC) [Tylan 100]. Canada Veterinary-labeled product(s): 22 grams per kg of premix (OTC) [Tylan 10; Tylosin 10 Premix]. 88 grams per kg of premix (OTC) [Tylan 40; Tylosin 40 Premix]. 220 grams per kg of premix (OTC) [Tylan 100]. Withdrawal times: U.S.{R-49; 100} When fed at doses of 10 to 100 grams of tylosin phosphate per ton of feed:
Withdrawal time Species Pigs Meat (days) 0

tartrate in drinking water, a withdrawal time of two days is necessary. Packaging and storage: Store below 40 C (104 F), preferably between 15 and 30 C (59 and 86 F), unless otherwise specied by manufacturer. Preparation of dosage form: Medication should be thoroughly mixed in feed before use. It should not be used in any feed containing more than 2% bentonite.{R-49} Caution: When handling and mixing medication, protective clothing and impervious gloves should be used. Contact with human skin should be avoided.{R-49} USP requirements: Preserve in well-closed, polyethylene-lined or polypropylene-lined containers, protected from moisture and excessive heat. Contains tylosin phosphate mixed with suitable carriers and inactive ingredients. Label it to indicate that it is for animal use only. Label it also to indicate that it is for manufacturing, processing, or repackaging. Contains the labeled amount, within 20%. Meets the requirement for Identication, Loss on drying (not more than 12.0%), Powder neness, and Content of tylosins.{R-22}
1

Not included in Canadian product labeling or product not commercially available in Canada.

TYLOSIN TARTRATE ORAL DOSAGE FORMS

Note: Bracketed information in the Dosage Forms section refers to uses that either are not included in U.S. product labeling or are for products not commercially available in the U.S. 1.1 grams of tylosin tartrate equals 1 gram of tylosin base{R-90}. The dosing and strengths of the dosage forms available are expressed in terms of the base.

TYLOSIN TARTRATE POWDER FOR ORAL SOLUTION

Usual dose: Dysentery, swinePigs: Oral, 250 mg per gallon of water, as the only source of drinking water for three to ten days.{R-50} Respiratory disease, chronicChickens: Oral, 2 grams (base) per gallon (approximately, 110 mg per kg of body weight a day) in the only source of drinking water for three to ve days.{R-50} Sinusitis, infectiousTurkeys: Oral, 2 grams per gallon (approximately 132 mg per kg of body weight a day) in the only source of drinking water for three to ve days.{R-50} Note: [Dogs]1There are insufcient data to establish the efcacy of tylosin in the treatment of chronic colitis in dogs; however, an oral dose of 11 mg per kg of body weight every eight hours has been recommended{R-84}. Note that reformulation is necessary for administration to dogs{R109} . Size(s) usually available{R-8; 50}: U.S. Veterinary-labeled product(s): 100 grams (base) of powder (OTC) [Tylan Soluble]. All rights reserved

When fed at doses of 800 to 1000 grams of tylosin phosphate per ton of feed:
Withdrawal time Species Chickens Meat (days) 5

Canada When fed at a dose of 110 grams of tylosin phosphate per metric ton (1000 kg) of feed:
Withdrawal time Species Pigs Meat (days) 0

Note: Product labeling listing the above withdrawal time states that when tylosin premix is administered concurrently with tylosin 2003 Thomson MICROMEDEX

140 MACROLIDES VeterinarySystemic Canada Veterinary-labeled product(s): 100 grams (base) of powder (OTC) [Tylan Soluble]. Withdrawal times{R-8}: U.S.
Withdrawal time Species Chickens Turkeys Meat (days) 1 5

Note: Product labeling listing the above withdrawal times states that they apply to a dose of 1 gram per 4 L (approximately 1 gallon) of drinking water for 3 to 10 days for pigs, 2 grams per 4 L of drinking water for 3 to 5 days for chickens, and 2 grams per 4 L of drinking water for 3 to 5 days for turkeys.{R-66} Packaging and storage: Store below 40 C (104 F), preferably between 15 and 30 C (59 and 86 F), unless otherwise specied by manufacturer. Preparation of dosage form: A fresh solution of tylosin tartrate should be prepared every 3 days. Water should be added to powder (not powder added to water) when preparing the solution.{R-50} Caution: Contact with human skin should be avoided. Protective clothing and impervious gloves should be worn when mixing and handling solutions.{R-50} USP requirements: Not in USP.{R-22}
1

Note: Product labeling listing the above withdrawal times states that they apply to a dose of 250 mg per gallon of drinking water for pigs and 2 grams per gallon of drinking water for chickens and turkeys. Product is not labeled for use in birds producing eggs for human consumption{R-50}. Canada
Withdrawal time Species Chickens Pigs Turkeys Meat (days) 1 2 3

Not included in Canadian product labeling or product not commercially available in Canada.

Developed: 07/22/97 Revised: 09/30/02 Interim revision: 11/21/99; 04/04/03

Table 1. Pharmacology/pharmacokinetics.
Protein binding (%) Elimination half-life (hr) Volume of distribution (L/kg)

Drug Azithromycin Cats{R-120} Dogs (beagles)

{R-123}

Clearance (mL/min/kg)

Route; Dose (mg/kg)

Tmax (hr)

Cmax (mcg/mL)

Bioavailablity (%)

Terminal: 35 1626* 29 16 Terminal: 16.3 20.3 750 1429* 11 to 14 32

Steady state: 23 Steady state: 12 Area: 12.4 Steady state: 11.6 Area: 22.3 Steady state: 18.6 Steady state: 33 Steady state: 84

10.7

Foals, 8- to 14weeks{R-121} Foals, 6- to 10weeks{R-122} Human data{R-115} Rats{R-123} Clarithromycin Dogs (crossbred beagles){R-124} Fed Fasted Erythromycin Calves{R-23} Cattle{R-21}
{R-25}

10 10.4

IV; 5 PO; 5 IV; 24 PO; 24 IV; 5 PO; 10 IV; 10 PO; 10 PO: 500 mg total dose IV; 20 PO; 20 IV; 10 PO; 10 PO; 10

0.85 0.33

0.97 4.2

58 97

1.4 1.8 2 to 3

0.72 0.57 0.4

39 56 37

2.0

0.29

46

Terminal: 3.9

Steady state: 1.4

4.3

1.6 1.7

3.3 3.5

70 79

2.2 18 3.2 1.7 1 0.7 0.9 0.7 0.7 23

Area: 1.5 Area: 0.79 Steady state: 2.7 Area: 2.3 to 7.2 Steady state: 3.6

7.8 2.9 21 77

Dogs{R-62} Horses, foals{R-26} Mice{R-62} Pigeons{R-27} Rabbits{R-62} Rats{R-62} Sheep{R-21}

Steady state: 6.8 Steady state: 9.3

53 73

IV; 15 IV/IM; 20 IV; 12.5 IV; 10 IV; 5 to 20 IV; 10 IV; 20 PO; 100 IV; 10 IV; 25 IV/IM; 20

10

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Table 1. (Contd.)
Protein Binding (%) Elimination Half-life (hr) Volume of Distribution (L/kg)

Drug Tilmicosin Cattle{R-91}

{R-104}

Clearance (mL/min/kg)

Route; Dose (mg/kg)

Tmax (hr)

Cmax (mcg/mL)

Bioavailablity (%)

SC; 10 SC; 10 2.3 1 to 15 1.2 30 33.5 1.6 2.1 0.9 38 38 3 2.1 Area: 1.1 Area: 1.7 Area: 1.7 7.8 22 6.8 Area: 4.4 Area: 3.6 to 4.4 Area: 2.5 24.5 32 to 48 23.7 IV; 10 IV: 10 IV; 10

1.8 1

0.13 0.71

Tylosin Calves, newborn{R-73} Calves, 1 week to 9 months Calves, 7 weeks{R-69} Chickens{R-71} Cattle{R-20}
{R-25; 80} {R-79}

Dogs{R-68} Goats Sheep{R-20}

{R-79} {R-72}

IV/IM; 20 IV; 12.5 IV; 20 IV; 10 IM; 10 IM; 15 IV/IM; 20 IV; 20

0.5 4.2

1.5 2.4

73

*Protein binding is concentration dependent, reported as increasing with decreasing concentration from 10 to 0.02 mg/L. Protein binding is concentration dependent, reported as increasing with decreasing concentration from 1 to 0.2 mcg/mL.

REFERENCES
1. Barragry TB. Veterinary drug therapy. Philadelphia: Lea & Febiger, 1994: 224-6, 25162. 2. Plumb DC. Veterinary drug handbook. White Bear Lake, MN: PharmaVet Publishing, 1991: 513. 3. Erythromycin phosphate product information (Gallimycin-PFC, BimedaUS), Rec 2/12/03. 4. Beech J. Drug therapy of respiratory disorders. Vet Clin North Am Equine Pract 1987; 3(1): 5980. 5. Prescott JF, Baggot JD, editors. Antimicrobial therapy in veterinary medicine. 2nd ed. Ames, IA: Iowa State University Press, 1993: 11926; 187203. 6. Erythromycin base package insert (Gallimycin-200, BimedaUS), Rec 7/01/ 02. 7. Erythromycin base package insert (Gallimycin-200, A.P.A. of VetoquinolCanada) In: Arrioja-Dechert A, editor. Compendium of veterinary products, CD ed. Port Huron, MI: North American Compendiums, Inc. 2002. 8. Arrioja-Dechert A, editor. Compendium of veterinary products, CD ed. Port Huron, MI: North American Compendiums, Inc. 2002. 9. Erythromycin phosphate package insert (Gallimycin PFC, A.P.A. of VetoquinolCanada) In: Arrioja-Dechert A, editor. Compendium of veterinary products, CD ed. Port Huron, MI: North American Compendiums, Inc. 2002. 10. Monfort JD, Donahoe JP, Stills HF, et al. Efcacies of erythromycin and chloramphenicol in extinguishing fecal shedding of Campylobacter jejuni in dogs. J Am Vet Med Assoc 1990; 196(7): 106972. 11. Smith JA, Isaac-Renton JL, Jellett JF, et al. Inhibitory and lethal activities of rosaramicin, erythromycin, and clindamycin against Campylobacter fetus susp jejuni and intestinalis. Am J Vet Res 1983; 44(8): 16056. 12. Fox JG, Moore R, Ackerman JI. Campylobacter jejuni-associated diarrhea in dogs. J Am Vet Med Assoc 1983; 183(12): 14303. 13. Hillidge CJ. Use of erythromycin-rifampin combination in treatment of Rhodococcus equi pneumonia. Vet Microbiol 1987; 14: 33742. 14. Sweeney CR, Sweeney RW, Divers TJ. Rhodococcus equi pneumonia in 48 foals: response to antimicrobial therapy. Vet Microbiol 1987; 14: 32936. 15. Kenney DG, Robbins SC, Prescott, et al. Development of reactive arthritis and resistance to erythromycin and rifampin in a foal during treatment for Rhodococcus equi pneumonia. Equine Vet J 1994; 25(3): 2468. 16. USP dictionary of USAN and international drug names, 2002 ed. Rockville, MD: The United States Pharmacopeial Convention, Inc.; 2002. 17. Erythromycin base (E-mycin, Boots). In: PDR Physicians desk reference. 49th ed. Montvale, NJ: Medical Economics Data Production Company, 1994: 6513.

18. Ewing PJ, Burrows G, Macallister C, et al. Comparison of oral erythromycin formulations in the horse using pharmacokinetic proles. J Vet Pharmacol Ther 1994; 17: 1723. 19. Clarke CR, Barron SJ, Ayalew S, et al. Response of Pasteurella haemolytica to erythromycin and dexamethasone in calves with established infection. Am J Vet Res 1992; 53(5): 6847. 20. Ziv G, Sulman FG. Binding of antibiotics to bovine and ovine serum. Antimicrobial Agents and Chemotherapy 1972 Sep: 20613. 21. Nap RC, Breen DJ, Lam TJGM, DeBruyne JJ. Gastric retention of enteric-coated aspirin tablets in beagle dogs. J Vet Pharmacol Ther 1990; 13: 14853. 22. The United States pharmacopeia. The national formulary. USP 26th revision (January 1, 2003). NF 21st ed (January 1, 2003). Rockville, MD: The United States Pharmacopeial Convention, Inc., 2002. p. 200, 201, 465, 466, 728, 729, 7314, 7379, 741, 1838, 2555, 2560, 2584, 2586. 23. Burrows GE. Effects of experimentally induced Pasteurella haemolytica pneumonia on the pharmacokinetics of erythromycin in the calf. Am J Vet Res 1985; 46(4): 798803. 24. Burrows GE, Griffen DD, Pippin A, et al. A comparison of the various routes of administration of erythromycin in cattle. J Vet Pharmacol Ther 1989; 12: 28995. 25. Baggot JD, Gingerich DA. Pharmacokinetic interpretation of erythromycin and tylosin activity in serum after intravenous administration of a single dose to cows. Res Vet Sci 1976; 21: 31823. 26. Prescott JF, Hoover DJ, Dohoo IR. Pharmacokinetics of erythromycin in foals and in adult horses. J Vet Pharmacol Ther 1983; 6: 6774. 27. Vanhaecke E, De Backer P, Remon JP, et al. Pharmacokinetics and bioavailability of erythromycin in pigeons (Columba livia). J Vet Pharmacol Ther 1990; 13: 35660. 28. Burrows GE, Gentry M, Ewing BS. Serum and tissue concentrations of erythromycin in calves with induced pneumonic pasteurellosis. Am J Vet Res 1989; 50(7): 11669. 29. Huber WB. In: Booth NH, McDonald LE. Veterinary pharmacology and therapeutics. 5th ed. Ames, IA: Iowa State University Press, 1968. 30. Kirk RW, Bonagura JD, editors. Current veterinary therapy small animal practice. Philadelphia: W.B. Saunders Company, 1992. p. 1238. 31. Erythromycin base (ERYC, PD). In: Krogh CME, editor. CPS Compendium of pharmaceuticals and specialties. 28th ed. Ottawa: Canadian Pharmaceutical Association, 1994: 4589. 32. Mead JR. Cryptosporidiosis and the challenges of chemotherapy. Drug Resist Updat 2002 Feb; 5(1): 4757.

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33. Fraser-Hurt N, Bailey RL, Cousens S, et al. Efcacy of oral azithromycin versus topical tetracycline in mass treatment of endemic trachoma. Bulletin of the World Health Organization 2001; 79: 63240. 34. Samra Z, Rosenberg S, Soffer Y, et al. In vitro susceptibility of recent clinical isolates of Chlamydia trachomatis to macrolides and tetracyclines. Diagnostic Microbiology and Infectious Disease 2001; 39: 1779. 35. Niki Y, Kimura M, Miyashita N, et al. In vitro and in vivo activities of azithromycin, a new azalide antibiotic, against chlamydia. Antimicrob Agents Chemo 1994 Oct; 38(10): 22969. 36. Erythromycin ethylsuccinate (E.E.S., Abbott). In: PDR Physicians desk reference. 49th ed. 1995. Montvale, NJ: Medical Economics Data Production Company, 1995. p. 4234. 37. Erythromycin gluceptate (Ilotycin, Dista). In: PDR Physicians desk reference. 49th ed. 1995. Montvale, NJ: Medical Economics Data Production Company, 1995. p. 9378. 38. Robinson NE, editor. 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Drug selection and use in mastitis: systemic vs local therapy. J Am Vet Med Assoc 1980 May 15; 176(10): 110915. 47. MacDiarmid SC. Antibacterial drugs used against mastitis in cattle by the systemic route. N Z Vet J 1978; 26: 2905. 48. Tylosin package insert (Tylosin 10 Premix, Bio-Agri-MixCanada), Rec 7/7/ 95. 49. Tylosin package insert (Tylan 40, ElancoUS), Rec 1/13/97. 50. Tylosin package insert (Tylan Soluble, ElancoUS), Rev 3/98. Downloaded 2/17/03 from www.elanco.com. 51. Tylosin package insert (Tylan 50, ElancoUS), Rev 11/4/93, Rec 8/4/95. 52. Tylosin package insert (Tylosin Injection, Boehringer-IngelheimUS). Downloaded 2/17/03 from www.bi-vetmedica.com. 53. Tilmicosin package insert (Micotil injection, ElancoUS), Rev 6/1/2000. Downloaded 2/12/03 from www.elanco.com. 54. Erythromycin package insert (Erymycin-100, BimedaUS), Rec 7/12/02. 55. Tylocine 200, Provel. In: Arrioja-Dechert A, editor. Compendium of veterinary products, CD ed. Port Huron, MI: North American Compendiums, Inc. 2002. 56. Tylosin base (Tylocine tablets, MTCCanada), Rev 5/91, Rec 12/10/96 [discontinued product]. 57. Taylor DE, Chang N. In vitro susceptibilites of campylobacter jejuni and campylobacter coli to azithromycin and erythromycin. Antimicrob Agents Chemo 1991 Sep; 35(9): 19178. 58. Riviere J, Craigmill AL, Sundlof SF. Handbook of comparative pharmacokinetics and residues of veterinary antimicrobials. CRC Press, Inc: Boca Raton, FL 1991. p. 22961. 59. Holle GE, Seinbach E, Forth W. Effects of erythromycin in the dog upper gastrointestinal tract. Am J Physiology 1992; 263 (1): G529. 60. Panel comment, Rec 6/16/95. 61. Brander GC, Pugh DM, Bywater RJ, Jenkins WL. Veterinary applied pharmacology & therapeutics, 5th ed. Philadelphia: Bailliere Tindall 1991. p. 4635. 62. Duthu GS. Interspecies correlation of the pharmacokinetics of erythromycin, oleandomycin, and tylosin. J Pharm Sci Sep 1985; 74 (9): 9436. 63. Christie PJ, Davidson JN, Novick RP, et al. Effects of tylosin feeding on the antibiotic resistance of selected gram-positive bacteria in pigs. Am J Vet Res Jan 1983; 44 (1): 1268. 64. Erythromycin thiocyanate (Gallimycin50, A.D.ACanada). In: ArriojaDechert A, editor. Compendium of veterinary products, CD ed. Port Huron, MI: North American Compendiums, Inc. 2002. 65. Tilmicosin phosphate (Micotil, ProvelCanada). In: ArriojaDechert A, editor. Compendium of veterinary products, CD ed. Port Huron, MI: North American Compendiums, Inc. 2002. 66. Tylosin package insert (Tylocine Soluble Powder, ElancoCanada). In: Arrioja-Dechert A, editor. Compendium of veterinary products, CD ed. Port Huron, MI: North American Compendiums, Inc. 2002. 67. Itoh Z, Suzuki T, Nayaka M, et al. Structure-activity relation among macrolide antibiotics in initiation of interdigestive migrating contractions in the canine gastrointestinal tract. Am J Physiol 1985 Mar; 248(3 Pt 1): G320 5. 68. Weisel MK, Powers JD, Powers TE, et al. A pharmacokinetic analysis of tylosin in the normal dog. Am J Vet Res 1977 Feb; 33: 2735. 69. Burrows GE, Barto PB, Martin B. Antibiotic disposition in experimental pneumonic pasteurellosis: gentamicin and tylosin. Can J Vet Res 1986; 50: 1939. 70. Van Duyn RL, Folkberts TM. Concentrations of tylosin in blood and lung tissue from calves given single and repeated daily intramuscular doses. Vet Med Small Anim Clin 1979 Mar: 3759. 71. Ziv G. Preliminary clinical pharmacological investigations of tylosin and tiamulin in chickens. Vet Q 1980 Oct; 2(4): 20610. 72. Atef M, Youssef AH, Atta AH, et al. Disposition of tylosin in goats. Br Vet J 1991; 147: 207. 73. Burrows GE, Barto PB, Martin B, et al. Comparative pharmacokinetics of antibiotics in newborn calves: chloramphenicol, lincomycin, and tylosin. Am J Vet Res 1983 Jun; 44 (6): 10537. 74. Helton-Groce SL, Thomson TD, Readnour RS. A study of tilmicosin residues in milk following subcutaneous administration to lactating dairy cows. Can Vet J 1993 Oct; 34: 61921. 75. Laven R, Andrews AH. Long-acting antibiotic formulations in the treatment of calf pneumonia: a comparative study of tilmicosin and oxytetracycline. Vet Rec 1991; 129: 10911. 76. Ose EE, Tonkinson LV. Single dose treatment of neonatal calf pneumonia with the new macrolide antibiotic tilmicosin. Vet Rec 1988 Oct; 123: 3679. 77. Scott PR. Field study of undifferentiated respiratory disease in housed beef calves. Vet Rec 1994 Mar; 134: 3257. 78. Picavet T, Muylle E, Devriese LA, et al. Efcacy of tilmicosin in treatment of pulmonary infections in calves. Vet Rec 1991; 129: 4003. 79. Ziv G, Sulman FG. Serum and milk concentrations of spectinomycin and tylosin in cows and ewes. Am J Vet Res 1973 Mar; 34 (3): 32933. 80. Gingerich DA, Baggot JD, Kowalski JJ. Tylosin antimicrobial activity and pharmacokinetics in cows. Can Vet J 1977 Apr; 18 (4): 96100. 81. Jordan WH, Byrd RA, Cochrane RI, et al. A review of the toxicity of the antibiotic Micotil 300. Vet Hum Toxicol 1993 Apr; 35(2): 1518. 82. Panel comment, Rec 3/26/96. 83. Panel comment, Rec 4/15/96. 84. Panel comment, Rec 4/1/96. 85. Panel comment, Rec 4/18/96. 86. Leib M, Matz ME. Diseases of the large intestine. In: Ettinger SJ, Feldman EC, editors. Textbook of veterinary internal medicine, 4th ed. Philadelphia, PA: W.B. Saunders, 1995. 87. Panel comment, Rec 4/2/96. 88. Panel comment, Rec 3/19/96. 89. Panel comment, Rec 4/1/96. 90. Reynolds JEF, editor. Martindale, the extra pharmacopeia. 30th ed. London: The Pharmaceutical Press, 1993: 2201. 91. Ziv G, Shem-Tov M, Glickman A, et al. Tilmicosin antibacterial activity and pharmacokinetics in cows. J Vet Pharmacol Ther 1995; 18: 3405. 92. Manufacturer comment, Rec 5/24/96. 93. Kunkle GA. New considerations for rational antibiotic therapy of cutaneous staphylococcal infection in the dog. Semin Vet Med Surg Small Anim 1987; 2: 21220. 94. Manufacturer comment, Rec 5/24/96. 95. Panel comment, Rec 5/24/96. 96. Kunkle GA, Sundlof S, Keisling K. Adverse side effects of oral antibacterial therapy in dogs and cats: an epidemiologic study of pet owners observations. J Am Anim Hosp Assoc 1995; 31: 4655. 97. Holmberg SD, Moorman AC, Von Bargen JC, et al. Possible effectiveness of clarithromycin and rifabutin for cryptosporidiosis chemoprophylaxis in HIV disease. J Am Med Assoc 1998 Feb; 279(5): 3846. 98. Panel comment, Rec 5/24/96. 99. Ose EE. In vitro antibacterial properties of EL-870, a new semisynthetic macrolide antibiotic. J Antibiot 1987 Feb; 40(2): 1904. 100. Manufacturer comment, Rec 10/30/96.

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101. Veterinary Supplemental New Drug Submission. Health and Welfare Canada. Health Protection Branch. The use of tylosin in the treatment of chronic colitis in dogs and cats. Provel. DIN 0919660. 102. Van Kruiningen HJ. Clinical efcacy of tylosin in canine inammatory bowel disease. J Am Anim Hosp Assoc 1976; 12(4): 498501. 103. Thomson TD, Laudert SB, Chamberland S, et al. Micotilpharmacokinetics of tilmicosin, a semisythetic macrolide antibiotic in acutely pneumonic cattle and primary bovine alveolar macrophages. In: European Association for Veterinary Pharmacology and Toxicology. Proceedings of the 6th International Congress; Aug 8, 1994. Edinburgh UK: Blackwell Scientic Publications. August 711, 1994; O12: 31. 104. Thomson TD, Lawrence K. Micotil: pharmacokinetics of tilmicosin, a semisynthetic macrolide antibiotic in cattle. In: European Association for Veterinary Pharmacology and Toxicology. Proceedings of the 6th International Congress. Edinburgh, UK: Blackwell Scientic Publications. August 711, 1994; P31; 55. 105. Kato H, Murakami T, Takase S, et al. Sensitivities in vitro to antibiotics of mycoplasma isolated from canine sources. Jap J Vet Sci 1972; 34: 197206. 106. Manufacturer comment, Rec 1/13/97. 107. Tilmicosin package insert (Pulmotil, ElancoUS). Downloaded 2/12/03 from www.elanco.com. 108. Tylosin injection (21 CFR 522.2640[a]). Federal Register. April 1, 1995. 109. Veterinary Medicine Advisory Panel meeting, 4/28/97. 110. Gomex-Garces JL, Cogollos R, Alos JI. Susceptibilities of uoroquinoloneresistant strains of Campylobacter jejuni to 11 oral antimicrobial agents. Antimicrob Agents Chemo 1995 Feb; 39(2): 5424. 111. Erythromycin package insert (Gallimycin-100, BimedaUS), Rec 7/18/02. 112. Tilmicosin package insert (Micotil, ProvelCanada), Rec 10/21/98. 113. Martin DH, Mroczkowski TF, Dalu ZA, et al. A controlled trial of a single dose of azithromycin for the treatment of chlamydial urethritis and cervicitis. New England J Med 1992 Sep; 327(13): 9215. 114. Tilmicosin package insert (Pulmotil Premix, ElancoCanada), In: ArriojaDechert A, editor. Compendium of veterinary products, CD ed. Port Huron, MI: North American Compendiums, Inc. 2002. 115. Klasco RK, editor. USP DI Drug information for the healthcare professional. Volume I. Greenwood Village, CO: MICROMEDEX, Inc.; 2003. 116. Azithromycin package insert (Zithromax, PzerUS). Downloaded from www.zithromax.com on 7/2/02. 117. Clarithromycin package insert (Biaxin, Abbott LaboratoriesUS). Downloaded from www.biaxin.com on 7/2/02. 118. McEvoy GK, editor. AHFS Drug Information. Bethesda: American Society of Health-System Pharmacists. 2001. p. 288312. 119. Adams HR, editor. Veterinary Pharmacology and Therapeutics, 8th ed. Ames: Iowa State University Press. 2001. p. 876882. 120. Hunter RP, Lynch MJ, Ericson JF, et al. Pharmacokinetics, oral bioavailability and tissue distribution of azithromycin in cats. J Vet Pharmacol Ther 1995; 18: 3846. 121. Davis JL, Gardner SY, Jones SL, et al. Pharmacokinetics of azithromycin in foals after i.v. and oral dose and disposition into phagocytes. J Vet Pharmacol Ther 2002; 25(2): 99104. 122. Jacks S, Giguere S, Gronwall RR, et al. Pharmacokinetics of azithromycin and concentration in body uids and bronchoalveolar cells in foals. Am J Vet Res 2001; 62(12): 18705. 123. Shepard RM, Falkner FC. Pharmacokinetics of azithromycin in rats and dogs. Antimicrob Chemother 1990; 25(Suppl A): 4960. 124. Vilmanyi E, Kung K, Riond JL, et al. Clarithromycin pharmacokinetics after oral administration with or without fasting in crossbred beagles. J Small Anim Pract 1996; 37(11): 5359. 125. Breitschwerdt EB, Papich MG, Hegarty BC, et al. Efcacy of doxycycline, azithromycin, or trovaoxacin for treatment of experimental Rocky Mountain spotted fever in dogs. Antimicrob Agents Chemo 1999 Apr; 43(4): 81321.

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METRONIDAZOLE VeterinarySystemic
Some commonly used brand names for human-labeled products are: ApoMetronidazole; Flagyl; Flagyl I.V.; Flagyl I.V. RTU; Metric 21; Metro I.V.; Novonidazol; Protostat; and Trikacide. Note: For a listing of dosage forms and brand names by country availability, see the Dosage Forms section(s). bacterial colitis caused by susceptible organisms, including Clostridium difcile{R-1012}. [Encephalopathy, hepatic (treatment)] Cats and dogs: Although there are insufcient data to establish efcacy, metronidazole is used to reduce gastrointestinal bacterial production of ammonia thought to contribute to clinical signs in hepatic encephalopathy. [Endometritis (treatment)]1Horses: Although there are insufcient data to establish efcacy, metronidazole is used in combination with other antibiotics in the treatment of endometritis, including infections caused by penicillinase-producing anaerobic bacteria{R-13}. [Helicobacter species infections (treatment)]1Cats and dogs: Although the treatment of Helicobacter pylori in human gastrointestinal disease has had major clinical impact, there is currently little evidence to suggest that these organisms signicantly affect gastrointestinal function in cats and dogs or that metronidazole, in combination with another antibiotic and bismuth subsalicylate or subcitrate, will produce long-term eradication of Helicobacter species in these species{R-2226}. [Infections, bacterial (treatment)]1, including [Bone and joint infections (treatment)]1; [Central nervous system infections (treatment)]1; [Intra-abdominal infections (treatment)]1; [Perioperative infections, colorectal (prophylaxis)]1; [Respiratory tract infections, lower (treatment)]1; [Septicemia, bacterial (treatment)]1; or [Skin and soft tissue infections (treatment)]1Cats, dogs, and horses: Although there are insufcient clinical research data to establish efcacy, metronidazole is used in the treatment of many types of anaerobic bacterial infections in animals. In human patients, metronidazole is indicated, usually in combination with other antibiotics, in the prevention of perioperative infections during colorectal surgery and in the treatment of bone and joint infections; central nervous system infections; intraoperative infections; lower respiratory tract infections, including pleuropneumonia and lung abscess; septicemia; and skin and soft tissue infections caused by susceptible species, including Bacteroides and Clostridium species{R-1; 4}. There are limited pharmacokinetic data and case reports available pertaining to the use of metronidazole in the treatment of these types of infections in animals{R-8; 9; 12; 14; 16; 1921; 28}. [Periodontal infections (treatment)]1Cats and dogs: Metronidazole is used in the treatment of periodontal infections in cats and dogs{R-15; 17; 18} It may be administered for destructive periodontal diseases as part of a treatment plan that also includes one or more of the following: dental scaling, gingival crevicular lavage, periodontal surgery, or regular teeth cleaning{R-17}.

CATEGORY:
Antibacterial (systemic); antiprotozoal.

INDICATIONS
Note: In other USP DI monographs, bracketed information in the Indications section refers to uses that are not included in U.S. product labeling, and superscript 1 refers to uses that are not included in Canadian product labeling. However, since metronidazole is not specically approved for veterinary use, there is no product labeling identifying approved indications.

GENERAL CONSIDERATIONS
Metronidazole is effective in the treatment of systemic and enteric obligate anaerobic bacterial infections, including Clostridium species, Fusobacterium species{R-1}, and penicillinase-producing strains of Bacteroides{R-2; 3}. Surgical therapy may be necessary to completely resolve isolated infections{R-3}. Metronidazole is not clinically effective against facultative anaerobes or obligate aerobes{R-1; 4}. However, it is often combined with another antibiotic or antibiotics effective against aerobes to treat mixed bacterial infections{R-2}. Metronidazole is considered effective in the treatment of some protozoal infections in animals.

ACCEPTED
[Giardiasis (treatment)]1Cats and dogs: Metronidazole is used to eliminate shedding of giardial cysts and treat associated diarrhea in cats and dogs{R-6; 7; 36}. Environmental eradication is necessary for effective treatment. The infection may not be completely cleared in all animals{R-7}.

ACCEPTANCE NOT ESTABLISHED

[Amebiasis, intestinal (treatment)]1; [Balantidiasis, intestinal (treatment)]1; or [Trichomoniasis, intestinal (treatment)]1Cats and dogs: In human patients, metronidazole is used in the treatment of susceptible Balantidium coli, Entamoeba histolytica, and Trichomonas species{R-1; 4; 5}. Metronidazole is also recommended in the treatment of enteric protozoal infections in cats and dogs, although the relationship between infection and clinical signs can be difcult to dene. [Bowel disease, inammatory (treatment)]1Cats and dogs: Although there are insufcient data to establish efcacy, metronidazole is used in the treatment of inammatory bowel disease. [Colitis, antibiotic-associated (treatment)]1; or [Colitis, clostridial (treatment)]1Horses: Although there are insufcient data to establish efcacy, metronidazole is used in the treatment of

REGULATORY CONSIDERATIONS
U.S. The Food and Drug Administration has not approved the use of metronidazole in animals. The use of nitroimidazoles in food animals is strictly prohibited.{R-27} Canada Metronidazole is not approved for use in food-producing animals. There are no established withdrawal times.

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CHEMISTRY
Chemical group: Nitroimidazoles. Chemical name: Metronidazole1H-Imidazole-1-ethanol, 2-methyl-5-nitro-.{R-29} Metronidazole hydrochloride1H-Imidazole-1-ethanol, 2-methyl-5nitro-, hydrochloride.{R-29} Molecular formula: MetronidazoleC6H9N3O3.{R-29} Metronidazole hydrochlorideC6H9N3O3 HCl.{R-29} Molecular weight: Metronidazole171.15.{R-29} Metronidazole hydrochloride207.61.{R-29} Description: Metronidazole USPWhite to pale yellow, odorless crystals or crystalline powder. Is stable in air, but darkens on exposure to light.{R-30} Solubility: Metronidazole USPSparingly soluble in water and in alcohol; slightly soluble in ether and in chloroform.{R-30}

PRECAUTIONS TO CONSIDER CARCINOGENICITY/MUTAGENICITY

Metronidazole has been shown to be a carcinogen in mice and rats with chronic oral administration. It has also been shown to be mutagenic in in vitro assays.{R-1; 4}

PREGNANCY/REPRODUCTION
PregnancyMetronidazole readily crosses the placenta and enters the fetal circulation{R-1}. No teratogenic effects were seen in the pups of rats that had received 250 mg per kg of body weight (mg/kg) a day for 1 to 12 days, or 100 mg/kg a day for 40 days. However, spermatogenesis in male rats was affected by the administration of 100 mg/kg a day.

LACTATION
Metronidazole is distributed into milk at concentrations similar to plasma concentrations{R-1; 4}. Risk-benet should be considered carefully when metronidazole is used in nursing animals.

PHARMACOLOGY/PHARMACOKINETICS
Mechanism of action/effect: Metronidazole is reduced as it enters the target cell where it interacts with bacterial or protozoal DNA, causing a loss of helical structure and strand breakage in the DNA; these effects inhibit nucleic acid synthesis and cause death of the cell. Absorption: Metronidazole is moderately well absorbed from the gastrointestinal tract.{R-21; 33; 37} Distribution: HorsesIn one pharmacokinetic study of horses, peak metronidazole concentrations in peritoneal uid, synovial uid, and cerebrospinal uid were 65%, 92%, and 30% of peak serum concentrations.{R-21} With an oral dose of 7.5 mg/kg every 6 hours, endometrial penetration was poor{R-21}. Biotransformation: Hepatic, metabolized primarily by side-chain oxidation and glucuronide synthesis. Pharmacokinetic data:

DRUG INTERACTIONS AND/OR RELATED PROBLEMS

The following drug interactions and/or related problems have been selected on the basis of their potential clinical signicance (possible mechanism in parentheses where appropriate)not necessarily inclusive: Note: Combinations containing any of the following medications, depending on the amount present, may also interact with metronidazole. Cimetidine (hepatic metabolism of metronidazole may be decreased when metronidazole and cimetidine are used concurrently, possibly resulting in delayed elimination and increased serum metronidazole concentrations{R-5}; dosage of metronidazole may need to be adjusted) Phenobarbital (phenobarbital may induce microsomal liver enzymes, increasing metronidazoles metabolism and resulting in a decrease in half-life and plasma concentration{R-5}; dosage of metronidazole may need to be adjusted)

SIDE/ADVERSE EFFECTS
The following side/adverse effects have been selected on the basis of their potential clinical signicance (possible signs and, for humans, symptoms in parentheses where appropriate)not necessarily inclusive:

Table 1. Intravenous administration.

Half-life of elimination (hours) 4.48 0.89 2.9 3.11 0.21 3.27 0.65 Volume of distribution (L/kg) Area: 0.95 0.10 Area: 1.70 0.24 Area: 0.74 0.01 Steady state: 0.69 0.01 Steady state: 0.68 0.16 Clearance (mL/kg/min) 2.49 0.54 6.67 0.83 2.8 0.18 2.8 0.8

Species Dogs{R-37} Horses{R-33}

{R-21}

THOSE INDICATING NEED FOR MEDICAL ATTENTION

Neurologic disturbances (ataxia, nystagmus, seizures, tremors, weakness)with high dosage in cats, dogs, and horses{R-31; 32}

{R-39}

Table 2. Oral administration.

Dose (mg/kg) 44 25 20 15 Cmax (mcg/mL) 42* 12.6 2.4 22 8 13.9 2.18 Tmax (hour) 1* 1 to 2 1.1 0.6 0.67 Bioavailability (%) 59 to 100 85.0 18.6 74 18 97 5.7

THOSE INDICATING NEED FOR MEDICAL ATTENTION ONLY IF THEY CONTINUE OR ARE BOTHERSOME
Anorexia; neutropenia; vomiting

Species Dogs{R-37} Horses{R-33}

{R-39} {R-21}

THOSE NOT INDICATING NEED FOR MEDICAL ATTENTION

Reddish brown urine

*Read from graph. Two horses with pleuropneumonia yielded similar kinetic results to that of healthy mares in this study.

HUMAN SIDE/ADVERSE EFFECTS{R-5}

In addition to the above side/adverse effects reported in animals, the following side/adverse effects have been reported in humans, and are All rights reserved

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146 METRONIDAZOLE VeterinarySystemic included in the human monograph Metronidazole (Systemic) in USP DI Volume I; these side/adverse effects are intended for informational purposes only and may or may not be applicable to the use of metronidazole in the treatment of animals: Incidence more frequent Central nervous system (CNS) effects; gastrointestinal disturbance Incidence less frequent or rare Change in taste sensation; CNS toxicity, including ataxia and encephalopathy; dark urine; dryness of mouth; hypersensitivity; leukopenia; pancreatitis; peripheral neuropathyusually with high doses or prolonged use; seizuresusually with high doses; thrombocytopeniareversible; thrombophlebitis; unpleasant or sharp metallic taste; urinary tract effects, including frequent or painful urination and inability to control urine ow; vaginal candidiasis Horses: Oral, 15 to 25 mg (base) per kg of body weight every six hours{R-33}. Note: Anorexia may occur in horses treated with the above dose; therefore, some clinicians recommend use of a lower oral dose of 10 mg per kg of body weight every twelve hours{R-40}. For susceptible gram-negative anaerobic infections in horses, one study recommended an alternative dosage regimen of 15 mg per kg of body weight as an initial dose, followed by 7.5 mg per kg of body weight every six hours{R-21}. Contents of the capsule can be mixed with molasses or administered via nasogastric tube.{R-31; 33; 34} [Hepatic encephalopathy]1; or [Inammatory bowel disease]1Cats and dogs: Oral, 7.5 mg (base) per kg of body weight every twelve hours. Strength(s) usually available: U.S. Veterinary product(s): Not commercially available. Human product(s): 375 mg (base) (Rx) [Flagyl]. Canada Veterinary-labeled product(s): Not commercially available. Human-labeled product(s): 500 mg (base) (Rx) [Flagyl; Trikacide]. Packaging and storage: Store below 40 C (104 F), preferably between 15 and 30 C (59 and 86 F), in a well-closed container, unless otherwise specied by manufacturer. Store in a light-resistant container. USP requirements: Not in USP{R-30}.

OVERDOSE
For information in cases of overdose or unintentional ingestion, contact the American Society for the Prevention of Cruelty to Animals (ASPCA) National Animal Poison Control Center (888-426-4435 or 900-443-0000; a fee may be required for consultation) and/or the drug manufacturer. Lethal doseDogs: 250 mg per kg of body weight (mg/kg) a day induced central nervous system dysfunction within 4 to 6 days and death within a week of onset of signs{R-32}.

CLINICAL EFFECTS OF OVERDOSE

The following effects have been selected on the basis of their potential clinical signicancenot necessarily inclusive: Dogs, with doses of 65 to 129 mg/kg a day.{R-32} Ataxia; head tilt; nystagmus (spontaneous, positional, vertical); seizures Note: Ataxia and nystagmus were noted consistently in a report on ve cases of toxicosis. Signs appeared within 7 to 12 days of initiating therapy. In dogs that survived complications of neurologic dysfunction, signs gradually resolved over 1 to 2 weeks after ending metronidazole administration{R-32}.

METRONIDAZOLE TABLETS USP

Usual dose: See Metronidazole Capsules. Note: CatsThe typical way to give 15 mg per kg of body weight to a nine-pound cat is to administer one-fourth of a 250-mg tablet. Strength(s) usually available: U.S. Veterinary-labeled product(s): Not commercially available. Human-labeled product(s): 250 mg (base) (Rx) [Flagyl; Metric 21; Protostat (scored; lactose)]. 500 mg (base) (Rx) [Flagyl; Protostat (scored; lactose)]. Canada Veterinary-labeled product(s): Not commercially available. Human-labeled product(s): 250 mg (base) (Rx) [Apo-Metronidazole; Flagyl; Novonidazol (scored); Trikacide]. Packaging and storage: Store below 40 C (104 F), preferably between 15 and 30 C (59 and 86 F), in a well-closed container, unless otherwise specied by manufacturer. Store in a light-resistant container. Additional information: For cats, tablets should not be crushed for administration, because metronidazole is bitter and often unpalatable.

ORAL DOSAGE FORMS

Note: In other USP DI monographs, bracketed uses in the Dosage Forms section refer to categories of use and/or indications that are not included in U.S. product labeling, and superscript 1 refers to categories of use and/or indications that are not included in Canadian product labeling. However, since metronidazole is not specically approved for veterinary use, there is no product labeling identifying approved indications. The dosing and strengths of the dosage forms available are expressed in terms of metronidazole base.

METRONIDAZOLE CAPSULES
Usual dose: [Bacterial infections, anaerobic]1; or [Protozoal infections]1 Cats and dogs: Oral, 15 mg (base) per kg of body weight every twelve hours{R-38}. 2003 Thomson MICROMEDEX

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METRONIDAZOLE VeterinarySystemic 147 USP requirements: Preserve in well-closed, light-resistant containers. Contain the labeled amount, within 10%. Meet the requirements for Identication, Dissolution (85% in 60 minutes in 0.1 N hydrochloric acid in Apparatus 1 at 100 rpm), and Uniformity of dosage units{R-30}.

METRONIDAZOLE HYDROCHLORIDE FOR INJECTION

Usual dose: See Metronidazole Injection USP. Size(s) usually available: U.S. Veterinary-labeled product(s): Not commercially available. Human-labeled product(s): 500 mg (base) (Rx) [Flagyl I.V.]. Canada Not commercially available. Packaging and storage: Prior to reconstitution, store below 30 C (86 F), in a light-resistant container, unless otherwise specied by manufacturer. Preparation of dosage form: Metronidazole hydrochloride for injection must not be given by direct intravenous injection, since the initial dilution has an extremely low pH (0.5 to 2.0). It must be diluted further and neutralized prior to administration.{R-35} To prepare initial dilution for intravenous infusion, add 4.4 mL of sterile water for injection, bacteriostatic water for injection, 0.9% sodium chloride injection, or bacteriostatic sodium chloride injection to each 500-mg vial, to provide a concentration of 100 mg per mL (pH 0.5 to 2.0). The resulting solution should be further diluted in 100 mL of 0.9% sodium chloride injection, 5% dextrose injection, or lactated Ringers injection. The nal dilution must be neutralized with approximately 5 mEq of sodium bicarbonate injection per 500 mg of metronidazole (nal pH 6 to 7). Since carbon dioxide gas is produced during neutralization, it may be necessary to relieve the pressure in the nal container. The nal concentration should not exceed 8 mg per mL, since neutralization decreases the solubility of metronidazole and precipitation may occur.{R-35} Stability: After reconstitution, solutions retain their potency for 96 hours if stored below 30 C (86 F) in room light. Diluted and neutralized solutions retain their potency for 24 hours. Neutralized solutions should not be refrigerated, because precipitation may occur. Incompatibilities:{R-35} Metronidazole should not be used with aluminum (needles or hubs) that would come into contact with the medication. Intravenous admixtures of metronidazole with other medications are not recommended. USP requirements: Not in USP{R-30}. Revised: 07/28/94; 09/30/02 Interim revision: 06/05/95; 06/20/96; 05/19/97; 7/21/98 04/05/03

PARENTERAL DOSAGE FORMS

Note: In other USP DI monographs, bracketed uses in the Dosage Forms section refer to categories of use and/or indications that are not included in U.S. product labeling, and superscript 1 refers to categories of use and/or indications that are not included in Canadian product labeling. However, since metronidazole is not specically approved for veterinary use, there is no product labeling identifying approved indications. The dosing and strengths of the dosage forms available are expressed in terms of metronidazole base.

METRONIDAZOLE INJECTION USP

Usual dose: Note: Reliable dosing information is not available for the use of parenteral metronidazole in animals. However, for situations in which oral administration is not a viable option, injectable forms are used by following dosing regimens similar to oral dosage forms. Strength(s) usually available: U.S. Veterinary-labeled product(s): Not commercially available. Human-labeled product(s): 500 mg (base) per 100 mL (Rx) [Flagyl I.V. RTU; Metro I.V.; generic]. Canada Veterinary-labeled product(s): Not commercially available. Human-labeled product(s): 500 mg (base) per 100 mL (Rx) [Flagyl; generic]. Withdrawal times: There are no established withdrawal times since metronidazole is not approved for use in food-producing animals. Packaging and storage: Store below 40 C (104 F), preferably between 15 and 30 C (59 and 86 F), unless otherwise specied by manufacturer. Protect from light. Protect from freezing. Incompatibilities: Intravenous admixtures of metronidazole and other medications are not recommended.{R-35} Additional information: Metronidazole Injection USP is an isotonic (297 to 310 mOsm per L), ready-to-use solution, requiring no dilution or buffering prior to administration.{R-35} USP requirements: Preserve in single-dose containers of Type I or Type II glass, or in suitable plastic containers, protected from light. A sterile, isotonic, buffered solution of Metronidazole in Water for Injection. Contains the labeled amount, within 10%. Meets the requirements for Identication, Bacterial endotoxins, pH (4.57.0), and Particulate matter, and for Injections{R-30}. 2003 Thomson MICROMEDEX

REFERENCES
1. Flagyl 375 (capsules) package insert (PharmaciaUS), Rev 9/01. Downloaded from www.pharmacia.com on 4/15/02. 2. Boothe DM. Anaerobic infections in small animals. Probl Vet Med 1990 Jun; 2(2): 33047.

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148 METRONIDAZOLE VeterinarySystemic

3. Dow SW. Management of anaerobic infections. Vet Clin North Am Small Anim Pract 1988 Nov; 18(6): 116782. 4. Flagyl tablets package insert (PharmaciaUS), Rev 9/01. Downloaded from www.pharmacia.com on 4/15/02. 5. Klasco RK, editor. USP DI Drug information for the healthcare professional. Volume I. Greenwood Village, CO: MICROMEDEX, Inc.; 2003. 6. Zimmer JF. Treatment of feline giardiasis with metronidazole. Cornell Vet 1987 Oct; 77(4): 3838. 7. Zimmer JF, Burrington DB. Comparison of four protocols for the treatment of canine giardiasis. J Am Anim Hosp Assoc 1986; 22: 16872. 8. Tisdall PL, Hunt GB, Beck JA, et al. Management of perianal stulae in ve dogs using azathioprine and metronidazole prior to surgery. Aust Vet J 1999 Jun; 77(6): 3748. 9. Carlson GP, OBrien MA. Anaerobic bacterial pneumonia with septicemia in two racehorses. J Am Vet Med Assoc 1990 Mar 15; 196(6): 9413. 10. Jones RL. Clostridial enterocolitis. Vet Clin North Am Equine Pract 2000 Dec; 16(3): 47185. 11. Weese JS, Parsons DA, Staempi HR. Association of Clostridium difcile with enterocolitis and lactose intolerance in a foal. J Am Vet Med Assoc 1999 Jan 15; 214(2): 22932, 205. 12. McGorum BC, Dixon PM, Smith DG. Use of metronidazole in equine acute idiopathic toxaemic colitis. Vet Rec 1998 Jun 6; 142(23): 6358. 13. Ricketts SW, Mackintosh ME. Role of anaerobic bacteria in equine endometritis. J Reprod Fertil Suppl 1987; 35(2): 34351. 14. Mair TS. The medical management of eight horses with grade 3 rectal tears. Equine Vet J Suppl 2000 Jun; 16(32): 1047. 15. Heijl L, Lindhe J. Effect of selective antimicrobial therapy on plaque and gingivitis in the dog. J Clin Periodontol 1980 Dec; 7(6): 46378. 16. Sweeney RW, Sweeney CR, Weiher J. Clinical use of metronidazole in horses: 200 cases (1984-1989). J Am Vet Med Assoc 1991 Mar 15; 198(6): 10458 17. Norris JM, Love DN. In vitro antimicrobial susceptibilities of three Porphyromonas spp and in vivo responses in the oral cavity of cats to selected antimicrobial agents. Aust Vet J 2000 Aug; 78(8): 5337. 18. Heijl L, Lindhe J. The effect of metronidazole on established gingivitis and plaque in beagle dogs. J Periodontol 1982 Mar; 53(3): 1807. 19. Chou S, Richards GK, Brown RA. A new approach to antibiotic therapy in colon surgery based on bioassay tissue concentrations. Can J Surg 1982 Sep; 25(5): 52731. 20. Piek CJ, Robben JH. Pyothorax in nine dogs. Vet Q 2000 Apr; 22(2): 10711. 21. Specht TE, Brown MP, Gronwall RR, et al. Pharmacokinetics of metronidazole and its concentration in body uids and endometrial tissues of mares. Am J Vet Res 1992 Oct; 53(10): 180712. 22. Neiger R, Seiler G, Schmassmann A. Use of a urea breath test to evaluate shortterm treatments for cats naturally infected with Helicobacter heilmannii. Am J Vet Res 1999 Jul; 60(7): 8803. 23. Perkins SE, Yan LL, Shen Z, et al. Use of PCR and culture to detect Helicobacter pylori in naturally infected cats following triple antimicrobial therapy. Antimicrob Agents Chemother 1996 Jun; 40(6): 148690. 24. Happonen I, Linden J, Westermarck EJ. Effect of triple therapy on eradication of canine gastric helicobacters and gastric disease. Small Anim Pract 2000 Jan; 41(1): 16. 25. Simpson KW, Strauss-Ayali D, McDonough PL, et al. Gastric function in dogs with naturally acquired gastric Helicobacter spp. infection. J Vet Intern Med 1999 Nov-Dec; 13(6): 50715. 26. Cornetta AM, Simpson KW, Strauss-Ayali D, et al. Use of a [13C]urea breath test for detection of gastric infection with Helicobacter spp in dogs. Am J Vet Res 1998 Nov; 59(11): 13649. 27. Extralabel drug use in animals. Fed Regist 1996 Nov 7; 61(217): 5773146. 28. Bartlett JG, Louie TJ, Gorbach SL, et al. Therapeutic efcacy of 29 antimicrobial regimens in experimental intra-abdominal sepsis. Rev Infect Dis 1981 MayJun; 313: 53542. 29. USP dictionary of USAN and international drug names, 2002 ed. Rockville, MD: The United States Pharmacopeial Convention, Inc., 2002. 30. The United States pharmacopeia. The national formulary. USP 26th revision (January 1, 2003). NF 21st ed (January 1, 2003). Rockville, MD: The United States Pharmacopeial Convention, Inc., 2002. p. 1227, 1228, 2570. 31. Panel comment, Rec. 5/93. 32. Dow SW, LeCouteur RA, Poss ML, et al. Central nervous system toxicosis associated with metronidazole treatment of dogs: ve cases (19841987). J Am Vet Med Assoc 1989; 195(3): 3658. 33. Sweeny RW, Sweeney CR, Soma LR, et al. Pharmacokinetics of metronidazole given to horses by intravenous and oral routes. Am J Vet Res 1986 Aug; 47(5): 17269. 34. Sweeny RW, Sweeney CR, Weiher J. Clinical use of metronidazole in horses: 200 cases (1984-1989). J Am Vet Med Assoc 1991; 198(6): 10458. 35. Flagyl IV and IV RTU package insert (SCS PharmaceuticalsUS), Rev 7/16/ 98. In: PDR Physicians Desk Reference. 54th ed. 2000. Montvale, NJ: Medical Economics Company, 2000. p. 287880. 36. Kirkpatrick CE, Farrell JP. Feline giardiasis: observations on natural and induced infections. Am J Vet Res 1984 Oct; 45(10): 21828. 37. Neff-Davis CA, Davis LE, Gillette EL. Metronidazole: a method for its determination in biological uids and its disposition kinetics in the dog. J Vet Pharmacol Ther 1981; 4: 1217. 38. Committee comment, Rec. 5/27/02. 39. Steinman A, Gips M, Lavy E, et al. Pharmacokinetics of metronidazole in horses after intravenous, rectal, and oral administration. J Vet Pharmacol Ther 2000; 23: 3537. 40. Panel comment, Rec. 11/29/94.

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PENICILLIN G VeterinaryIntramammary-Local 149

PENICILLIN G VeterinaryIntramammary-Local
Some commonly used brand names for veterinary-labeled products are Go-dry and Masti-Clear. Note: For a listing of dosage forms and brand names by country availability, see the Dosage Forms section(s). Not commercially available in Canada.

PHARMACOLOGY/PHARMACOKINETICS
Mechanism of action/effect: The penicillins produce their bactericidal effect by inhibiting cross-linkages during bacterial cell wall synthesis.{R-9} Pencillin G must penetrate the cell wall to attach to specic proteins on the inner surface of the bacterial cell membrane. In actively growing cells, the binding of penicillin within the cell wall leads to interference with production of cell wall peptidoglycans and subsequent lysis of the cell in a hypo- or iso-osmotic environment.{R-9; 13} Distribution: Medications infused into a teat are considered to be fairly evenly distributed in that quarter of the healthy mammary gland; however, in an udder affected by moderate to severe mastitis, the presence of edema, blockage of milk ducts, and reduced blood circulation causes uneven distribution.{R-14} After penicillin G procaine is infused into a mammary gland, it is also partially distributed into the other quarters of the gland,{R-4; 15} into the local lymph circulation, and to some degree into the plasma and other tissues.{R-16} Peak serum concentration: In healthy animals, after intramammary administration of 400 mg (404,000 Units) of penicillin G procaine in combination with the same amount of dihydrostreptomycin sulfate, the peak serum concentration of penicillin G is 0.07 mcg/mL at 4 hours.{R-16}

CATEGORY:
Antibacterial (intramammary-local).

INDICATIONS GENERAL CONSIDERATIONS

The spectrum of activity of penicillin G includes many aerobic and anaerobic gram-positive organisms. Penicillin G is highly susceptible to beta-lactamases and has little activity against organisms that can produce these enzymes. In addition, penicillin G is ineffective against bacteria that are resistant by certain other mechanisms, such as having a relatively impermeable cell wall. Therefore, penicillin G has little activity against many staphylococci and most gram-negative bacteria.

ACCEPTED
Mastitis (treatment)1Cattle: Penicillin G is indicated in the treatment of mastitis in cattle{R-1; 2; 7} caused by susceptible organisms such as Streptococcus agalactiae{R-7; 20}. Intramammary therapy alone is indicated only in the treatment of subacute mastitis manifested by mild inammatory changes in the milk or udder. Acute or peracute mastitis, in which gross inammatory changes in the milk or udder or systemic signs appear, requires administration of other medications also, which may include systemic antibiotics and/or supportive therapy.{R-5}
1

PRECAUTIONS TO CONSIDER PATIENT MONITORING

The following may be especially important in patient monitoring (other tests may be warranted in some patients, depending on condition; = major clinical signicance): Bacteriologic pathogen identication in milk (milk samples should be tested 3 weeks after the end of treatment; mastitis is not considered bacteriologically cured until samples show an absence of the mastitis-causing organisms{R-2}) Clinical signs (although a resolution of clinical signs of mastitis is not an indication that a bacteriologic cure has been achieved{R-18}, monitoring of the clinical condition of the mammary gland, teat, and milk produced can aid in diagnosis of a recurrence of mastitis or initial diagnosis of mastitis in another cow in the herd) Somatic cell count (somatic cell counts performed on milk to monitor the dairy herd are used primarily to maintain milk quality, but also to approximately assess the overall effectiveness of mastitis control programs that may include antibiotic treatment of cows){R-5}

Not included in Canadian product labeling or product not commercially available in Canada.

REGULATORY CONSIDERATIONS
U.S. Withdrawal times have been established for penicillin G procaine intramammary infusion (see the Dosage Forms section{R-1}).

CHEMISTRY
Source: Produced by the mold Penicillium.{R-8} Chemical group: Beta-lactam antibiotics.{R-8; 9} Chemical name: Penicillin G procaine4-Thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid, 3,3-dimethyl-7-oxo-6-[(phenylacetyl)amino]-, [2S-(2 alpha,5 alpha,6 beta)]-, compd. with 2-(diethylamino)ethyl 4-aminobenzoate (1:1) monohydrate.{R-10} Molecular formula: Penicillin G procaine C16H18N2O4S C13H20N2O2 H2O.{R-10} Molecular weight: Penicillin G procaine588.72.{R-10} Description: Penicillin G Procaine USPWhite crystals or white, very ne, microcrystalline powder. Is odorless or practically odorless, and is relatively stable in air. Its solutions are dextrorotary. Is rapidly inactivated by acids, by alkali hydroxides, and by oxidizing agents{R-17}. pKa: 2.7.{R-11; 12} Solubility: Penicillin G Procaine USPSlightly soluble in water; soluble in alcohol and in chloroform{R-17}. 2003 Thomson MICROMEDEX

SIDE/ADVERSE EFFECTS
The following side/adverse effects have been selected on the basis of their potential clinical signicance (possible signs and, for humans, symptoms in parentheses where appropriate)not necessarily inclusive:

THOSE INDICATING NEED FOR MEDICAL ATTENTION

Incidence unknown Cows Allergic reactionstheoretically possible locally or systemically All rights reserved

150 PENICILLIN G VeterinaryIntramammary-Local

OVERDOSE
For information in cases of overdose or unintentional ingestion, contact the American Society for the Prevention of Cruelty to Animals (ASPCA) National Animal Poison Control Center (888-426-4435 or 900-443-0000; a fee may be required for consultation) and/or the drug manufacturer.

Withdrawal times: U.S.{R-1; 2}

Withdrawal time Species Cows Nonlactating Lactating Meat (days) Milk (hours)

CLIENT CONSULTATION
Treatment of mastitis in dairy cattle is best achieved by a comprehensive mastitis control program in which herd management is the primary focus. The program should include good maintenance of milking equipment and constant evaluation of milking procedures and teat health as well as strategic treatment of clinical cases of mastitis.{R-7}

14 3

72 60

Packaging and storage: Store between 15 and 30 C (59 and 86 F), unless otherwise specied by manufacturer.{R-1; 2} USP requirements: Preserve in well-closed disposable syringes. A suspension of Penicillin G Procaine in a suitable vegetable oil vehicle. Label it to indicate that it is for veterinary use only. Contains an amount of penicillin G procaine equivalent to the labeled amount of penicillin G, within 10% to +15%. Meets the requirements for Identication and Water (not more than 1.4%).{R-17}
1

VETERINARY DOSING INFORMATION

Antibiotic therapy in the dry cow is measurably more effective than treatment during lactation.{R-7; 18} Choice of antibiotic for treatment of mastitis should be based on knowledge of culture and sensitivity of pathogens causing mastitis in the cow and the dairy herd.{R-19} Before administration of intramammary penicillin G procaine, the following steps should be performed:{R-1} The udder should be milked out completely and the teats washed with warm water and a disinfectant. Care should be taken to avoid washing excess dirt down from the udder onto the teat ends.{R-6} The area should be dried thoroughly. An effective germicidal teat dip should be applied for one minute and then each teat wiped with a separate cotton ball soaked with an antiseptic such as 70% alcohol. Persons performing the treatment should wash and dry their hands before each treatment. The tip of the syringe should be inserted into the teat end as little as possible{R-6} and the contents of the syringe should be injected into each streak canal while the teat is held rmly. The medication should then be gently massaged up the teat canal into the udder. An effective teat dip is recommended on all teats following treatment. For the lactating cow, treated quarters should not be milked for at least six hours after treatment but should be milked at regular intervals thereafter.{R-2}

Not included in Canadian product labeling or product not commercially available in Canada.

Developed: 03/08/95 Interim revision: 04/24/96; 05/19/97; 07/08/98; 10/15/99; 06/30/02 02/28/03

REFERENCES
1. Go-dry (G.C. Hanford Mfg. CoUS), Rev 10/92, Rec 7/22/94. 2. Masti-Clear (G.C. Hanford Mfg. CoUS), Rec 2/19/03. 3. Arrioja-Dechert A, editor. Compendium of veterinary products, CD edition. Port Huron, MI: North American Compendiums, Inc., 2002. 4. Hawkins GE, Cannon RY, Paar CF. Concentration of penicillin in milk from noninfused quarters following infusion of one quarter. J Dairy Sci 1962; 45: 10202. 5. Heath SE. Bovine mastitis. In: Howard JL. Current veterinary therapy 3 food animal practice. Philadelphia: W.B. Saunders, 1993. p. 7629. 6. Panel comment, Rec 12/6/94. 7. Hady PJ, Lloyd JW, Kaneene JB. Antibacterial use in lactating dairy cattle. J Am Vet Med Assoc 1993 Jul; 203(2): 21020. 8. Watson ADJ. Penicillin G and the alternatives. Vet Annu. 1985; 25: 27783. 9. Donowitz GR, Mandell GL. Beta-lactam antibiotics. N Engl J Med 1988; 318: 41926. 10. USP dictionary of USAN and international drug names, 2002 ed. Rockville, MD: The United States Pharmacopeial Convention, Inc.; 2002. 11. Prescott JF, Baggot JD. Antimicrobial therapy in veterinary medicine, 2nd ed. Ames, IA: Iowa State University Press, 1993. p. 819. 12. Ziv G, et al. Pharmacokinetic evaluation of penicillin and cephalosporin derivatives in serum and milk of lactating cows and ewes. Am J Vet Res 1973; 34(12): 15615. 13. Wright AJ, Wilkowski CJ. The penicillins. Mayo Clin Proc 1983: 58: 2132. 14. Jarp J, Bugge HP, Larsen S. Clinical trial of three therapeutic regimens for bovine mastitis. 1989; 124: 6304. 15. Anifantakis EM. Excretion rates of antibiotics in milk of sheep and their effect on yogurt production. J Dairy Sci 1982; 65: 4269. 16. Franklin A, Rantzien M, Obel N, et al. Concentrations of penicillin, streptomycin, and spiramycin in bovine udder tissue liquids. Am J Vet Res 1986 Apr; 47(4): 8047. 17. The United States pharmacopeia. The national formulary. USP 26th revision (January 1, 2003). NF 21st ed (January 1, 2003). Rockville, MD: The United States Pharmacopeial Convention, Inc., 2002. p. 1415, 2573. 18. Craven N. Efcacy and nancial value of antibiotic treatment of bovine clinical mastitis during lactationa review. Br Vet J 1987; 143: 41022. 19. Panel comment , Rec 11/18/94. 20. Panel comment, Rec 11/18/94.

INTRAMAMMARY DOSAGE FORMS PENICILLIN G PROCAINE INTRAMAMMARY INFUSION USP

Usual dose: Antibacterial1Cattle: Dry cow (nonlactating)Intramammary, 100,000 Units into each quarter of the udder at the time of drying-off.{R-1} Lactating cowIntramammary, 100,000 Units into each affected quarter of the udder every twelve hours for a maximum of three doses.{R-2} Strength(s) usually available: U.S.{R-1; 2} Veterinary-labeled product(s): 100,000 Units per 10 mL (OTC) [Go-dry (dry cow only); Masti-Clear (lactating cow only)]. Canada{R-3} Veterinary-labeled product(s): Not commercially available. 2003 Thomson MICROMEDEX

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PENICILLIN G VeterinarySystemic 151

PENICILLIN G VeterinarySystemic
Some commonly used brand names are: For veterinary-labeled productsAgri-cillin; Ambi-pen; Aquacillin; Benzapro; Combicillin; Combicillin AG; Depocillin; Derapen SQ/LA; Duo-Pen; Duplocillin LA; Durapen; Hi-Pencin 300; Longisil; Microcillin; PenAqueous; Pen G Injection; Penmed; Penpro; Pot-Pen; Propen LA; R-Pen; Twin-pen; and Ultrapen LA. For human-labeled productsPzerpen. which pathogens other than Actinomyces species are not yet involved.{R-6; 14} [Arthritis, septic (treatment)]Cattle, horses, pigs, and sheep:{R-6} Penicillin G is indicated in the treatment of septic arthritis caused by susceptible bacteria in cattle, horses, pigs, and sheep.{R-15; 16} [Leptospirosis (treatment)]Cattle,{R-6} dogs{R-6; 17}, horses1{R-18}, and pigs:{R-6} Penicillin G is indicated in the treatment of acute leptospirosis in cattle, dogs, horses, and pigs. The chronic shedding stage of leptospirosis is often treated with tetracycline; penicillin G administered alone will not clear the carrier state.{R-73; 85} [Malignant edema (treatment)]Cattle:{R-6} Penicillin G is indicated in the treatment of malignant edema caused by susceptible Clostridium septicum in cattle. [Metritis (treatment)]Cattle, horses, pigs, and sheep:{R-6} Penicillin G is indicated in the treatment of metritis caused by susceptible organisms in cattle, horses, pigs, and sheep{R-20; 21}; however, therapeutic regimens often emphasize evacuation of uterine contents as the primary treatment.{R-85} [Pyelonephritis (treatment)]Cattle: Penicillin G is indicated in the treatment of pyelonephritis caused by susceptible organisms such as Corynebacterium renale in cattle.{R-6; 22; 23} [Skin and soft tissue infections (treatment)] Cattle: Penicillin G is indicated in the treatment of skin and soft tissue infections caused by susceptible organisms, including those associated with calf diphtheria, foot rot, the umbilicus, and wounds.{R-10}. Horses: Penicillin G is indicated in the treatment of skin and soft tissue infections caused by susceptible organisms, including those associated with the umbilicus and with wounds.{R-6} Pigs: Penicillin G is indicated in the treatment of skin and soft tissue infections caused by susceptible organisms, including those associated with the umbilicus.{R-6} Sheep: Penicillin G is indicated in the treatment of skin and soft tissue infections caused by susceptible organisms, including those associated with post-surgical tail docking and castration site infections, and also those associated with the umbilicus.{R-6; 10} [Tetanus (treatment)]Cats, cattle, dogs, horses, and pigs1: Penicillin G is indicated in the treatment of Clostridium tetani in cats, cattle, dogs, horses, and pigs in conjunction with tetanus antitoxin and supportive therapy.{R-6}
1

CATEGORY:
Antibacterial (systemic).

INDICATIONS
Note: Bracketed information in the Indications section refers to uses that either are not included in U.S. product labeling or are for products not commercially available in the U.S.

GENERAL CONSIDERATIONS
The spectrum of activity of penicillin G includes many aerobic and anaerobic gram-positive organisms. Aerobes susceptible to penicillin G include most beta-hemolytic streptococci, beta-lactamase-negative staphylococci, Actinomyces species, some Bacillus anthracis, Corynebacterium species, and Erysipelothrix rhusiopathiae. Most species of anaerobes, including Clostridium species, but excluding beta-lactamase-producing Bacteroides species, are also susceptible to penicillin G. Penicillin G is easily inactivated by beta-lactamases and has little efcacy against organisms that can produce these enzymes. In addition, penicillin G is ineffective against those bacteria that are resistant by other mechanisms, such as having a relatively impermeable cell wall. Therefore, penicillin G has little activity against many staphylococci and most gram-negative bacteria.{R-3; 4}

ACCEPTED
Blackleg (treatment)Cattle and [sheep]: Penicillin G is indicated in the treatment of blackleg caused by susceptible organisms such as Clostridium chauvoei in cattle and sheep.{R-5; 6} Erysipelas (treatment)Pigs and turkeys: Penicillin G is indicated in the treatment of infections caused by Erysipelothrix rhusiopathiae (insidiosa) in pigs and turkeys.{R-69} Pharyngitis (treatment); or Rhinitis (treatment)Cattle: Penicillin G is indicated in the treatment of bacterial rhinitis or pharyngitis caused by susceptible organisms such as Actinomyces pyogenes.{R-5} Pneumonia, bacterial (treatment)Cattle,{R-6; 7} sheep{R-6; 7}, [horses]{R-6}, and [pigs]{R-10}: Penicillin G is indicated in the treatment of bacterial pneumonia caused by susceptible organisms in cattle, sheep, [horses], and [pigs]; however, for bacterial pneumonia in cattle, sheep, and pigs, penicillin G is not considered the drug of rst choice pending culture and sensitivity results.{R-85; 87} Strangles (treatment)Horses: Penicillin G is indicated in the treatment of strangles caused by Streptococcus equi;{R-7} however, it may be effective only during the acute phase of the infection.{R-13} [Actinomycosis (treatment)]Cattle: Penicillin G is indicated in the treatment of actinomycosis, and may be most effective for infections in

Not included in Canadian product labeling or product not commercially available in Canada.

REGULATORY CONSIDERATIONS
U.S. Administration of penicillin G procaine to animals may produce procaine concentrations in the blood and urine that violate equine and greyhound racing commission prohibitions.{R-91; 92} Penicillin G is not for use in turkeys producing eggs for human consumption or for use in horses intended for food.{R-7; 8} Penicillin G Benzathine and Penicillin G Procaine Injectable Suspension USP combination is not labeled for use in lactating cattle or preruminating calves.{R-5} Some brands of Penicillin G Procaine Injectable Suspension USP are not labeled for use in preruminating cattle.{R-53}

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152 PENICILLIN G VeterinarySystemic Withdrawal times have been established for Penicillin G Potassium USP, Penicillin G Benzathine and Penicillin G Procaine Injectable Suspension USP, and Penicillin G Procaine Injectable Suspension USP (see the Dosage Forms section).{R-5; 7; 8; 26} Canada Administration of penicillin G procaine to animals may produce procaine concentrations in the blood and urine that violate equine and greyhound racing commission prohibitions.{R-84} Penicillin G is not labeled for use in turkeys producing eggs for human consumption.{R-9} Penicillin G Benzathine and Penicillin G Procaine Injectable Suspension USP combination is not labeled for use in lactating cattle.{R-27; 28} Withdrawal times have been established for Penicillin G Potassium USP, Penicillin G Benzathine and Penicillin G Procaine Injectable Suspension USP, and Penicillin G Procaine Injectable Suspension USP (see the Dosage Forms section).{R-9; 27; 28} Penicillin G Sodium USPColorless or white crystals or white to slightly yellow, crystalline powder. Is odorless or practically odorless, and is moderately hygroscopic. Its solutions are dextrorotatory. Is relatively stable in air, but is inactivated by prolonged heating at about 100 C, especially in the presence of moisture. Its solutions lose potency fairly rapidly at room temperature, but retain substantially full potency for several days at temperatures below 15 C. Its solutions are rapidly inactivated by acids, alkali hydroxides, oxidizing agents, and penicillinase.{R-51} pKa: 2.7.{R-2; 32} Solubility: Penicillin G Benzathine USPVery slightly soluble in water; sparingly soluble in alcohol.{R-51} Penicillin G Potassium USPVery soluble in water, in saline TS, and in dextrose solutions; sparingly soluble in alcohol.{R-51} Penicillin G Procaine USPSlightly soluble in water; soluble in alcohol and in chloroform.{R-51}

CHEMISTRY
Source: Produced by the mold Penicillium.{R-1} Chemical group: Beta-lactam antibiotics.{R-1; 29} Chemical name: Penicillin G benzathine4-Thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid, 3,3-dimethyl-7-oxo-6-[(phenylacetyl)amino]-, [2S-(2alpha,5alpha, 6beta)]-, compd. with N,N-bis(phenylmethyl)-1,2-ethanediamine (2:1), tetrahydrate.{R-30} Penicillin G potassium4-Thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid, 3,3-dimethyl-7-oxo-6-[(phenylacetyl)amino]-, monopotassium salt, [2S-(2alpha,5alpha,6beta)]-.{R-30} Penicillin G procaine4-Thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid, 3,3-dimethyl-7-oxo-6-[(phenylacetyl)amino]-, [2S-(2alpha,5alpha, 6beta)]-, compd. with 2-(diethylamino)ethyl 4-aminobenzoate (1:1) monohydrate.{R-30} Penicillin G sodium4-Thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid, 3,3-dimethyl-7-oxo-6-[(phenylacetyl)amino]-, [2S-(2alpha, 5alpha,6beta)]-, monosodium salt.{R-30} Molecular formula: Penicillin G benzathine(C16H18N2)4S)2C16H20N24H2O.{R-30} Penicillin G potassiumC16H17KN2O4S.{R-30} Penicillin G procaineC16H18N2O4SC13H20N2O2H2O.{R-30} Penicillin G sodiumC16H17N2NaO4S.{R-30} Molecular weight: Penicillin G benzathine981.19.{R-30} Penicillin G potassium372.48.{R-30} Penicillin G procaine588.72.{R-30} Penicillin G sodium356.37.{R-30} Description: Penicillin G Benzathine USPWhite, odorless, crystalline powder.{R-51} Penicillin G Potassium USPColorless or white crystals, or white, crystalline powder. Is odorless or practically so, and is moderately hygroscopic. Its solutions are dextrorotatory. Its solutions retain substantially full potency for several days at temperatures below 15 C, but are rapidly inactivated by acids, by alkali hydroxides, by glycerin, and by oxidizing agents.{R-51} Penicillin G Procaine USPWhite crystals or white, very ne, microcrystalline powder. Is odorless or practically odorless, and is relatively stable in air. Its solutions are dextrorotatory. Is rapidly inactivated by acids, by alkali hydroxides, and by oxidizing agents.{R-51}

PHARMACOLOGY/PHARMACOKINETICS
See also Table 1. Pharmacokinetic Parameters at the end of this monograph. Note: With the exception of information in Table 1, pharmacokinetic data in this section are based on intravenous administration of potassium or sodium penicillin G. Mechanism of action/effect: The penicillins produce their bactericidal effect by inhibition of bacterial cell wall synthesis.{R-29} Pencillin G must penetrate the cell wall to attach to specic proteins on the inner surface of the bacterial cell membrane. In actively growing cells, the binding of penicillin within the cell wall leads to interference with production of cell wall peptidoglycans and subsequent lysis of the cell in a hypo- or iso-osmotic environment.{R-4; 29; 33} Absorption: Gastric absorption of penicillin G is poor in many species because it is rapidly hydrolyzed in the acid environment of the stomach or abomasum.{R-4} Only 15 to 30% of penicillin G may be absorbed by the oral route in a fasted animal and that percent decreases when there is food in the stomach.{R-34} The sodium and potassium salts of penicillin G are the only dosage forms that are suitable for intravenous administration. They are also the most quickly absorbed from intramuscular or subcutaneous sites of administration.{R-4; 34; 35} Procaine penicillin G is more slowly absorbed from intramuscular administration than are the sodium or potassium salts and so produces more sustained but lower plasma concentrations.{R-4; 35} Benzathine penicillin G is the least soluble of the dosage forms and so is the most slowly absorbed; the longest sustained but lowest plasma concentrations of penicillin G are produced.{R-4; 35} The rate of absorption from intramuscular injections of some penicillin dosage forms, such as procaine penicillin G, can vary depending on the injection site; injections into the neck muscle in cattle and horses produce more rapid absorption and higher plasma concentrations than do injections into the gluteal muscle. Also, procaine penicillin G is more completely absorbed in steers when injected intramuscularly than when administered subcutaneously. Distribution: Volume of distribution Dromedaries: 0.34 0.079 liter per kg (L/kg).{R-59}

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PENICILLIN G VeterinarySystemic 153 Horses: 0.72 0.16 L/kg.{R-44} Sheep: 0.604 0.205 L/kg.{R-59} Protein binding: CattleLow (28.5%).{R-38; 39} DogsModerate (60%).{R-40} HorsesModerate (5254%).{R-39; RabbitsLow (35%).{R-39; 42} SheepLow (30.4%).{R-38; 39}

PEDIATRICS
In neonates that have not yet developed full renal function, excretion of penicillin G occurs at a slower rate than it does in a mature animal.{R-60; 75}

41}

DRUG INTERACTIONS AND/OR RELATED PROBLEMS

The following drug interactions and/or related problems have been selected on the basis of their potential clinical signicance (possible mechanism in parentheses where appropriate)not necessarily inclusive ( = major clinical signicance): Note: Combinations containing any of the following medications, depending on the amount present, may also interact with this medication. Antibacterials, bacteriostatic, such as: Chloramphenicol or Tetracycline (because penicillin G acts only on cells that are actively reproducing, bacteriostatic antibiotics such as chloramphenicol or tetracycline may decrease the efcacy of penicillin G by depressing the activity of target cells{R-43}; however, the clinical signicance of this interference is not well documented{R-66}) Phenylbutazone (the concomitant administration of phenylbutazone with penicillin G may cause higher plasma concentrations of penicillin G, resulting in lower distribution of penicillin G to the tissues{R-44})

Half-life: Elimination Calves, newborn to 15 days: 26.6 minutes.{R-60} Dogs: 30 minutes.{R-39} Dromedaries: 49 minutes.{R-59} Horses: 48 to 53 minutes.{R-41; 57} Sheep: 42 minutes.{R-59} Turkeys: 30 minutes.{R-62} Elimination: Primarily renal{R-2; 4}; active renal tubular secretion occurs.{R-89} From 60 to 100% of the dose is recoverable from urine following injection of an aqueous solution of penicillin G.{R-43} Total clearance Dromedaries: 4.87 0.63 mL/min/kg.{R-59} Horses: 8.5 1.33 mL/min/kg.{R-44} Sheep: 9.17 1.39 mL/min/kg.{R-59} Calves: Newborn2.98 0.52 mL/min/kg.{R-60} Five days4.83 1.45 mL/min/kg.{R-60} Ten days3.11 1 mL/min/kg.{R-60} Fifteen days4.65 1.18 mL/min/kg.{R-60}

MEDICAL CONSIDERATIONS/CONTRAINDICATIONS
The medical considerations/contraindications included have been selected on the basis of their potential clinical signicance (reasons given in parentheses where appropriate)not necessarily inclusive ( = major clinical signicance). Except under special circumstances, this medication should not be used when the following medical problems exist: Hypersensitivity to penicillin (some reactions, such as hemolytic anemia in horses{R-49}, may be much more likely to occur in an animal that has had a previous reaction to penicillin G) Hypersensitivity to procaine{R-6} (some sources recommend intradermal procaine testing of animals suspected of procaine sensitivity before administering procaine penicillin G{R-6})

PRECAUTIONS TO CONSIDER CROSS-SENSITIVITY AND/OR RELATED PROBLEMS

In humans, patients allergic to other penicillins may also be allergic to penicillin G; in addition, patients allergic to cephalosporins may be allergic to penicillin G.{R-52} The incidence of these occurrences in animals is unknown, but it is recommended that penicillin use be avoided in animals that have had a previous severe reaction.{R-2} Animals allergic to procaine or other ester-type local anesthetics may also be allergic to penicillin G procaine.{R-6; 75}

PREGNANCY/REPRODUCTION
Penicillins have been shown to cross the placenta; however, no teratogenic problems have been associated with the use of penicillin G during pregnancy in studies of mice, rabbits, and rats, or during clinical use in many species. No well-controlled studies have been performed for most species.{R-75} Risk-benet should be considered when the following medical problems exist: Erysipelas in pigs (administration of procaine penicillin has caused recurrence or exacerbation of signs of erysipelas including abortion, cyanotic ears, fever of 39.5 to 41 C, inappetance, lassitude, vomiting, and shivering{R-50}) Renal function impairment (because penicillin G is primarily excreted by the kidneys, unnecessary accumulation of medication in the plasma and tissues may occur{R-45}; also, the sodium or potassium content of intravenous penicillin G dosage forms should be considered)

LACTATION
Penicillin G is distributed into milk{R-2}; in food animals the distribution is sufcient to cause violative residues. However, the concentrations of penicillin produced in milk are subtherapeutic for most bacteria.{R-85} In sheep, 0.11% of an intramuscular injection of sodium penicillin G was distributed into the milk.{R-31}

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154 PENICILLIN G VeterinarySystemic

PATIENT MONITORING
The following may be especially important in patient monitoring (other tests may be warranted in some patients, depending on condition; = major clinical signicance): Culture and susceptibility, in vitro, and Minimum inhibitory concentration (MIC) (in vitro cultures and MIC test should be done on samples collected prior to penicillin administration to determine pathogen susceptibility) Potassium or sodium, serum (determination of concentrations of serum sodium or potassium may be necessary in animals receiving high doses or long-term therapy with potassium or sodium penicillin G, particularly in those patients with severe renal function impairment, other pre-existing electrolyte imbalance, or congestive heart failure{R-75})

SIDE/ADVERSE EFFECTS
The following side/adverse effects have been selected on the basis of their potential clinical signicance (possible signs and, for humans, symptoms in parentheses where appropriate)not necessarily inclusive:

Gastrointestinal reactions; headache; oral candidiasis; vaginal candidiasis Incidence less frequent Allergic reactions, specically anaphylaxis; exfoliative dermatitis; serum sicknesslike reactions; skin rash, hives, or itching Incidence rare Clostridium difcile colitis; hepatotoxicity; interstitial nephritis; leukopenia or neutropenia; mental disturbances; pain at site of injection; platelet dysfunction or thrombocytopenia; seizures Note: Clostridium difcile colitis may occur up to several weeks after discontinuation of these medications. Interstitial nephritis is seen primarily with methicillin, and to a lesser degree with nafcillin and oxacillin, but may occur with any penicillin. Mental disturbances are toxic reactions to the procaine content of penicillin G procaine; this reaction may be seen in patients who receive a large single dose of the medication, as in the treatment of gonorrhea. Seizures are more likely to occur in patients receiving high doses of a penicillin and/or patients with severe renal function impairment.

OVERDOSE
For information in cases of overdose or unintentional ingestion, contact the American Society for the Prevention of Cruelty to Animals (ASPCA) National Animal Poison Control Center (888-426-4435 or 900-443-0000; a fee may be required for consultation) and/or the drug manufacturer.

THOSE INDICATING NEED FOR MEDICAL ATTENTION

Incidence unknown All species Allergic reactions, specically anaphylaxis,{R-6} contact dermatitis,{R-6} serum sicknesslike syndromes,{R-6} and urticaria{R-6}; overgrowth of nonsusceptible organisms{R-7}; procaine toxicitywith procaine-containing dosage forms only Note: Multiple cases of procaine toxicity have been reported in pig herds being treated for erysipelas{R-50; 77}. Signs included abortion, cyanotic ears, fever of 39.5 to 41 C, inappetance, lassitude, vomiting, and shivering. Horses Allergic reactions, specically anaphylaxis{R-6; 48} (hemorrhagic enterocolitis, progressive respiratory distress from coughing to dyspnea to apnea);{R-48} immune-mediated hemolytic anemia (icterus, inappetance, listlessness, paleness of mucous membranes, red-brown urine, splenomegaly, tachycardia);{R-49} procaine toxicity (signs in reported order of occurrence: fright, sudden backing, aimless galloping, loss of coordination, muscle tremors, apnea, cardiac arrest)with high doses of procaine-containing dosage forms{R-48}

VETERINARY DOSING INFORMATION FOR PARENTERAL DOSAGE FORMS ONLY

To prevent procaine toxicity, keeping procaine penicillin at proper storage temperature and following shelf life recommendations are recommended to avoid any degradation of the product.{R-48}

FOR TREATMENT OF ADVERSE EFFECTS

Recommended treatment consists of the following: For anaphylaxis {R-6} Parenteral epinephrine. Oxygen administration and respiratory support. For procaine toxicity{R-76} {R-48} If seizures occur, sedation with diazepam and/or barbitu{R-6} . rates Oxygen administration and respiratory support as needed. Treatment for cardiovascular collapse if necessary.

THOSE INDICATING NEED FOR MEDICAL ATTENTION ONLY IF THEY CONTINUE OR ARE BOTHERSOME
Incidence more frequent All species Pain at site of injectionwith higher doses{R-69}

ORAL DOSAGE FORMS PENICILLIN G POTASSIUM FOR ORAL SOLUTION USP

Usual dose: AntibacterialTurkeys: Oral, administered as the sole source of drinking water at a concentration of 1,500,000 Units per gallon (395,000 Units per L) for ve days.{R-8} Size(s) usually available{R-46}: U.S.{R-8} Veterinary-labeled product(s): 384,000,000 Units (OTC) [R-Pen]. 500,000,000 Units (OTC) [R-Pen; generic]. All rights reserved

HUMAN SIDE/ADVERSE EFFECTS{R-47}

In addition to the above side/adverse effects reported in animals, the following side/adverse effects have been reported in humans, and are included in the human monograph Penicillins (Systemic) in USP DI Volume I; these side/adverse effects are intended for informational purposes only and may or may not be applicable to the use of penicillin G in the treatment of animals: Incidence more frequent 2003 Thomson MICROMEDEX

PENICILLIN G VeterinarySystemic 155 Canada{R-9} Veterinary-labeled product(s): 100,000,000 Units (OTC) [Pot-Pen]. 500,000,000 Units (OTC) [Pot-Pen; generic]. 15,000,000,000 Units (OTC) [generic]. Withdrawal times: U.S.{R-8; 26} and Canada{R-9}
Withdrawal time Species Turkeys Meat (days) 1

Strength(s) usually available{R-46}: U.S. Veterinary-labeled product(s): 150,000 Units of penicillin G benzathine and 150,000 Units of penicillin G procaine per mL (Rx) [Ambi-pen; Combicillin; Combicillin AG; Duo-Pen; Durapen; Twin-Pen; generic]. Canada Veterinary-labeled product(s): 150,000 Units of penicillin G benzathine and 150,000 Units of penicillin G procaine per mL (Rx) [Benzapro; Duplocillin LA; Longisil]. Withdrawal times: U.S.{R-26}

Packaging and storage: Store below 40 C (104 F), preferably between 15 and 30 C (59 and 86 F), unless otherwise specied by the manufacturer. Store in a tight container. Preparation of dosage form: U.S.Dissolve 384,000,000 Units in 256 Gallons (969 L) to produce the nal 1,500,000 Units per Gallon (3.8 L) solution.{R-8} CanadaDissolve 100,000,000 Units in 88.7 Gallons (337 L) to produce the nal 1,128,600 Units per Gallon (3.8 L) solution.{R-9} Stability: Gravity ow water systems require preparation of fresh solutions every 12 hours. Automatic watering systems require fresh solution preparation every 24 hours.{R-8} USP requirements: Preserve in tight containers. A dry mixture of Penicillin G Potassium and one or more suitable buffers, colors, diluents, avors, and preservatives. Contains the labeled number of Penicillin G Units when constituted as directed in the labeling, within 10% to +30%. Meets the requirements for Identication, Uniformity of dosage units (single-unit containers), Deliverable volume (multipleunit containers), pH (5.57.5, in the solution constituted as directed in the labeling), and Water (not more than 1.0%).{R-51}

Withdrawal time Species Cattle, beef Meat (days) 30

Note: Products bearing labeling listing the above withdrawal time state that it is based on a dose of 4400 Units of penicillin G benzathine and 4400 Units of penicillin G procaine per kg (2000 Units of each per pound) of body weight administered subcutaneously every 48 hours for two treatments and is not applicable to higher doses or longer administration.{R-5} Canada{R-27;
28}

Withdrawal time Species Cattle, beef Meat (days) 14

Note: Products bearing labeling listing the above withdrawal time state that it is based on a dose of 4286 to 4500 Units of penicillin G benzathine and 4286 to 4500 Units of penicillin G procaine per kg of body weight administered intramuscularly and is not applicable to higher doses or longer administration.{R-27; 28; 63} Packaging and storage: Store between 2 and 8 C (36 and 46 F). Protect from freezing.{R-5} Preparation of dosage form: The vial should be warmed to room temperature and shaken well to insure a uniform suspension.{R-5} USP requirements: Preserve in single-dose or in multiple-dose containers, preferably of Type I or Type III glass. A sterile suspension of Penicillin G Benzathine and Penicillin G Procaine or when labeled for veterinary use only, of Penicillin G Benzathine and Penicillin G Procaine, in Water for Injection. Where it is intended for veterinary use only, it is so labeled. May contain one or more suitable buffers, preservatives, and suspending agents. Contains the labeled amounts, within 10% to +15%. Meets the requirements for Identication, Crystallinity, pH (5.07.5), Limit of soluble penicillin G and procaine (where it is prepared from penicillin G procaine and is labeled for veterinary use only, not more than 1%), and for Bacterial endotoxins, and Sterility under Penicillin G Procaine Suspension, and for Injections.{R-51}

PARENTERAL DOSAGE FORMS

Note: Bracketed information in the Dosage Forms section refers to uses that either are not included in U.S. product labeling or are for products not commercially available in the U.S.

PENICILLIN G BENZATHINE AND PENICILLIN G PROCAINE INJECTABLE SUSPENSION USP

Note: Penicillin G benzathine and penicillin G procaine combination has been replaced by other more effective medications. Although products containing penicillin G procaine and penicillin G benzathine combined may be effective in the treatment of extremely sensitive organisms, the plasma concentration of penicillin G produced by the administration of recommended doses of penicillin G benzathine drops to such a low level after 12 to 48 hours that it becomes ineffective in the treatment of most systemic infections.{R-78; 79} No dosage of these penicillin G procaine and penicillin G benzathine combinations can be recommended as likely to be effective for many infections caused by penicillin-sensitive organisms.{R-88} Even when administered at label doses, the risk exists for residues, which are 30 to 60 times the maximum limit, to occur at the injection site.{R-80}

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156 PENICILLIN G VeterinarySystemic

PENICILLIN G POTASSIUM FOR INJECTION USP

Usual dose: [Antibacterial]1 Cats and dogs: Intravenous or intramuscular, 20,000 to 40,000 Units per kg of body weight every six to eight hours.{R-54} Horses: Intravenous or intramuscular, 20,000 Units per kg of body weight every six to eight hours.{R-57; 65} Size(s) usually available: U.S.{R-66; 67} Veterinary-labeled product(s): Not commercially available. Human-labeled product(s): 1,000,000 Units (Rx) [generic]. 5,000,000 Units (Rx) [Pzerpen; generic]. 10,000,000 Units (Rx) [generic]. 20,000,000 Units (Rx) [Pzerpen; generic]. Canada{R-68} Veterinary-labeled product(s): Not commercially available. Human-labeled product(s): 1,000,000 Units (Rx) [generic]. 5,000,000 Units (Rx) [generic]. 10,000,000 Units (Rx) [generic]. Packaging and storage: Prior to reconstitution, store below 40 C (104 F), preferably between 15 and 30 C (59 and 86 F), unless otherwise specied by manufacturer. Preparation of dosage form: To prepare initial dilution for intramuscular or intravenous use, see manufacturers labeling. To prepare for further dilution for intravenous use, see manufacturers labeling. Stability: After reconstitution, solutions retain their potency for 24 hours at room temperature or for 7 days if refrigerated.{R-66; 68} Incompatibilities: Penicillin G potassium is rapidly inactivated by oxidizing and reducing agents, such as alcohols and glycols.{R-68} Extemporaneous admixtures of beta-lactam antibacterials (penicillins and cephalosporins) and aminoglycosides may result in substantial mutual inactivation. Do not mix these antibacterial agents in the same intravenous bag, bottle, or tubing.{R-69} Additional information: Human guidelines recommend that daily doses of 10,000,000 Units or more should be administered by slow intravenous infusion or by intermittent piggyback infusion to avoid causing or exacerbating possible electrolyte imbalance.{R-68} The potassium content and sodium content (derived from sodium citrate buffer) of penicillin G potassium for injection are approximately 1.7 mEq (66.3 mg) and 0.3 mEq (6.9 mg), respectively, per 1,000,000 Units of penicillin G.{R-66} USP requirements: Preserve in Containers for Sterile Solids. It is sterile Penicillin G Potassium or a sterile, dry mixture of Penicillin G Potassium with not less than 4.0% and not more than 5.0% of Sodium 2003 Thomson MICROMEDEX

Citrate, of which not more than 0.15% may be replaced by Citric Acid. Has a potency of the labeled number of Penicillin G Units, within 10% to +20%. In addition, where it contains Sodium Citrate it has a potency of not less than 1335 and not more than 1595 Penicillin G Units per mg. Meets the requirements for Constituted solution, Identication, Crystallinity, Bacterial endotoxins, Sterility, pH (6.08.5, in a solution containing 60 mg per mL or, where packaged for dispensing, in the solution constituted as directed in the labeling), Loss on drying (not more than 1.5%), and Particulate matter, and for Uniformity of dosage units and Labeling under Injections.{R-51}

PENICILLIN G PROCAINE INJECTABLE SUSPENSION USP

Usual dose: Antibacterial [Cats] and [dogs]: Intramuscular, 20,000 to 40,000 Units per kg of body weight every twelve to twenty-four hours.{R-54} Cattle, pigs, and sheep: Intramuscular, [24,000 to 66,000{R-36; 79} Units per kg of body weight every twenty-four hours]. Horses: Intramuscular, [20,000 Units per kg of body weight every twelve to twenty-four hours.{R-56; 58; 65; 69}] Note: Penicillin G procaine should not be administered subcutaneously at high doses{R-80} because doing so produces signicant local inammation and hemorrhage, as well as medication deposits{R-82} that can contribute to residue problems. The maximum dose per injection site of penicillin G procaine should be 3,000,000 Units (10 mL); injection sites should be different for each succeeding treatment.{R-7; 53} Penicillin G procaine should never be administered intravenously. Strength(s) usually available{R-46}: U.S. Veterinary-labeled product(s): 300,000 Units per mL (OTC) [Agri-cillin; Aquacillin; Microcillin; PenAqueous; generic]. Canada Veterinary-labeled product(s): 300,000 Units per mL (OTC) [Depocillin; Derapen SQ/LA; Hi-Pencin 300; Pen-Aqueous; Pen G Injection; Penmed; Penpro; Propen LA; Ultrapen LA; generic]. Note: Some Canadian products, such as Derapen SQ/LA, Propen LA, and Ultrapen LA, list their strengths and dosing in terms of milligrams rather than international units (IU){R-46}; procaine penicillin G contains 1009 penicillin G IU per mg{R-25}. Withdrawal times: U.S.{R-7; 26; 53}
Withdrawal time Species Cattle Calves (nonruminating) Sheep Swine Meat (days) 4 7 8 6 Milk (hours) 48

Note: Products bearing labeling with the above withdrawal times list a dose of 6600 Units per kg of body weight administered intramuscularly once every 24 hours. Treatment should not exceed ve days in lactating cattle or seven days in sheep, swine, or nonlactating cattle for these withdrawal times to apply.{R-7; 26} All rights reserved

PENICILLIN G VeterinarySystemic 157

Withdrawal time Species Cattle Sheep Swine Meat (days) 10 9 7 Milk (hours) 48

dose in cattle or a single intramusuclar dose in pigs. The dose may be repeated in seventy-two hours. Packaging and storage: Store between 2 and 8 C (36 and 46 F). Protect from freezing.{R-53; 70} Preparation of dosage form: The vial should be warmed to room temperature and shaken well to insure a uniform suspension.{R-53} Additional information: Some animals may develop procaine toxicity, which can result in acute neurologic signs{R-48}. Administration of penicillin G procaine to racing horses may produce violative procaine concentrations in urine for more than two weeks.{R-91; 92} USP requirements: Preserve in single-dose or in multiple-dose containers, preferably of Type I or Type III glass, in a refrigerator. A sterile suspension of Penicillin G Procaine or, where labeled for veterinary use only, of sterile penicillin G procaine, in Water for Injection and contains one or more suitable buffers, dispersants, or suspending agents, and a suitable preservative. It may contain procaine hydrochloride in a concentration not exceeding 2.0%. Where it is intended for veterinary use, the label so states. Contains an amount of penicillin G procaine equivalent to the labeled amount of penicillin G, within 10% to +15%, the labeled amount being not less than 300,000 Penicillin G Units per mL or per container. Meets the requirements for Identication, Crystallinity, Bacterial endotoxins, Sterility, pH (5.07.5), and Penicillin G and procaine contents, and for Injections.{R-51}

Note: Products bearing labeling with the above withdrawal times list a dose of 6600 Units per kg of body weight administered intramuscularly once every 24 hours. Treatment should not exceed four days for these withdrawal times to apply. These products are not labeled for use in pre-ruminating calves.{R-26; 53; 70} Canada{R-6; 81} When administered at a dose of 6670 Units per kg of body weight every twenty-four hours{R-81}:
Withdrawal time Species Cattle Meat (days) 5 Milk (hours) 72

When administered at a dose of 15,000 Units per kg of body weight every twenty-four hours{R-93}:
Withdrawal time Species Pigs Meat (days) 8

When administered at a dose of 21,000 Units per kg of body weight every twenty-four hours{R-93}:
Withdrawal time Species Cattle Sheep Meat (days) 10 10 Milk (hours) 96

PENICILLIN G SODIUM FOR INJECTION USP

Usual dose: [Antibacterial]1See Penicillin G Potassium for Injection USP. Strength(s) usually available: U.S. Veterinary-labeled product(s): Not commercially available. Human-labeled product(s): 5,000,000 Units (Rx) [generic]. Canada Veterinary-labeled product(s): Not commercially available. Human-labeled product(s): 1,000,000 Units (Rx) [generic]. 5,000,000 Units (Rx) [generic]. 10,000,000 Units (Rx) [generic]. Packaging and storage: Prior to reconstitution, store below 40 C (104 F), preferably between 15 and 30 C (59 and 86 F), unless otherwise specied by the manufacturer. Preparation of dosage form: To prepare initial dilution for intramuscular or intravenous use, see manufacturers labeling for instructions. Stability: After reconstitution, solutions retain their potency for 24 hours at room temperature or for 7 days if refrigerated.{R-68}

Note: The Canadian Bureau of Veterinary Drugs has published results of tissue residue studies and calculated withdrawal times for use of penicillin G procaine administered at doses that are higher than U.S. label doses{R-80; 82; 83}. Some of these withdrawal times are now listed in the labeling of Canadian products, as shown above, with the exception of the withdrawal calculated for the highest dose. If penicillin G is administered at the extra-label dose of 60,000 Units per kg of body weight every 24 hours, there is some evidence to suggest that a withdrawal time of 21 days would be sufcient to avoid residues in sheep and non-lactating cattle and that a withdrawal time of 15 days would be sufcient for pigs. For Derapen SQ/LA, Propen LA, and Ultrapen LA:
Withdrawal time Species Cattle Intramuscular dose Subcutaneous dose Pigs Meat (days)

21 14 10

Note: Products bearing labeling with the above withdrawal times list 20 mg per kg of body weight as a single intramusuclar or subcutaneous

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158 PENICILLIN G VeterinarySystemic Incompatibilities: Penicillin G sodium is rapidly inactivated by acids, alkalies, and oxidizing agents and in carbohydrate solutions at alkaline pH. Extemporaneous admixtures of beta-lactam antibacterials (penicillins and cephalosporins) and aminoglycosides may result in substantial mutual inactivation. Do not mix these antibacterials in the same intravenous bag, bottle, or tubing.{R-29; 71} Additional information:{R-68} Human guidelines recommend that daily doses of 10,000,000 Units or more should be administered by slow intravenous infusion to avoid causing or exacerbating electrolyte imbalance. The sodium content is approximately 2 mEq (2 mmol) per 1,000,000 Units of penicillin G. This should be considered in patients on a restricted sodium intake. USP requirements: Preserve in Containers for Sterile Solids. It is sterile Penicillin G Sodium or a sterile mixture of penicillin G sodium and not less than 4.0% and not more than 5.0% of Sodium Citrate, of which not more than 0.15% may be replaced by Citric Acid. Contains the labeled amount of Penicillin G, within 10% to +20%, and where it contains Sodium Citrate it has a potency of not less than 1420 and not more than 1667 Penicillin G Units per mg. Meets the requirements for Constituted solution, Identication, Crystallinity, Bacterial endotoxins, Sterility, pH (6.07.5, in a solution containing 60 mg per mL), Loss on drying (not more than 1.5%), and Particulate matter, and for Uniformity of dosage units and Labeling under Injections.{R-51}
1

Not included in Canadian product labeling or product not commercially available in Canada.

Developed: 04/27/95 Interim revision: 07/19/95; 07/11/96; 7/15/98; 11/5/99; 09/30/02; 04/05/03

Table 1. Pharmacokinetic parameters.

Disappearance rate constant (hour1) 0.08 0.03 0.04 0.01 0.04 0.01 0.04 0.00

Species Calves (69 mo.) Cattle After 5-day administration During 7-day administration: Horses

Penicillin G dosage form Potassium{R-55} Procaine{R-55} Procaine{R-36} Procaine{R-36}

Dose (Units/kg) 10,000 30,000 66,000 66,000 24,000 66,000 11,000 10,000 20,000 40,000 10,000 20,000 40,000 22,000 22,000

Route/site of administration* IM/neck IM/neck IM/neck SC/neck IM/gluteal IM/gluteal IM/not stated IV/jugular IV/jugular IV/jugular IM/gluteal IM/gluteal IM/gluteal IM/gluteal IM/semimembranous

Cmax (mcg/mL) 4.71 3.86 1.55 0.33 4.24 1.08 1.85 0.27 0.99 0.04 2.63 0.27 0.72

Tmax (hours) 1 to 1.5 1.5 to 6 6.00 0.00 5.33 0.67 5.33 0.67 6.00 0.00 2

Duration of action (hours)

Target minimum serum conc.(mcg/mL)

Benzathine with Procaine{R-69} Sodium{R-57}

Procaine{R-57}

1.68 2.92 3.90 4.90 18.75 >24 1.42 0.22 2.17 0.27 3 2

0.5 0.5 0.5 0.5 0.5 0.5

Procaine{R-56} Foals (07 days) Procaine{R-58}

*Legend: IM = intramuscular; IV = intravenous; SC = subcutaneous. The durations of action in this study were based on a specic minimum target serum concentration considered by that researcher to be a value high enough to treat penicillin-susceptible organisms. This study gave the stated dose once every 24 hours and monitored serum concentrations for 7 days. The Cmax shown here was the highest measured; values stayed below 0.31 after the rst day and went as low as 0.12 mcg/mL.

REFERENCES
1. Watson ADJ. Penicillin G and the alternatives. Vet Annu 1985; 25: 27783. 2. Prescott JF, Baggot JD. Antimicrobial therapy in veterinary medicine. 2nd ed. Ames, IA: Iowa State University Press, 1993: 819. 3. Barragry TB. Veterinary drug therapy. Baltimore, MD: Lea & Febiger, 1994: 2246, 70110. 4. Papich MG. The beta-lactam antibiotics: clinical pharmacology and recent developments. Compend Contin Educ Pract Vet 1987; 9(1): 6874. 5. Sterile penicillin G benzathine and penicillin G procaine in aqueous suspension package insert (G.C. Hanford Manufacturing CompanyUS), Rev 12/93, Rec 9/7/94. 6. Penpro package insert (Sano Sante AnimaleCanada), Rec 7/22/94. 7. Microcillin product information (AnthonyUS). In: Arrioja-Dechert A, editor. Compendium of veterinary products, CD ed. Port Huron, MI: North American Compendiums, Inc. 2002.

8. Penicillin G Potassium USP package labeling (Solvay Animal HealthUS), Rec 8/1/94. 9. Pot-Pen package labeling (Sano Sante AnimaleCanada), Rec 7/22/94. 10. Penicillin procaine G package insert (Pzer Sante AnimaleCanada), Rec 8/2/ 94. 11. Bateman KG, et al. An evaluation of antimicrobial therapy for undifferentiated bovine respiratory disease. Can Vet J 1990 Oct; 31: 68996. 12. Mechor GD, Jim GK, Janzen ED. Comparison of penicillin, oxytetracycline, and trimethoprim-sulfadoxine in the treatment of acute undifferentiated bovine respiratory disease. Can Vet J 1988 May; 29: 43843. 13. Taylor FGR. Strangles. In: Robinson NE. Current therapy in equine medicine 3. Philadelphia: W.B. Saunders, 1992: 3246. 14. Walker RD. Actinobacillosis and Actinomycosis. In: Howard JL. Current veterinary therapy 3 food animal practice. Philadelphia: W.B. Saunders Company, 1993: 5347.

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PENICILLIN G VeterinarySystemic 159

15. Wagner PC, Watrous BJ, Darien BJ. Septic arthritis and osteomyelitis. In: Robinson NE. Current therapy in equine medicine 3. Philadelphia: W.B. Saunders, 1992: 460. 16. St. Jean G. Septic arthritis. In: Howard JL. Current veterinary therapy 3 food animal practice. Philadelphia: W.B. Saunders Company, 1993: 8734. 17. Rentko VT, Ross LA. Canine leptospirosis. In: Kirk RW, Bonagura JD. Current veterinary therapy XI small animal practice. Philadelphia: W.B. Saunders, 1992: 2603. 18. Bernard WV. Leptospirosis. Vet Clin North Am Equine Pract 1993 Aug; 9(2): 43544. 19. Jarp J, Bugge HP, Larsen S. Clinical trial of three therapeutic regimens for bovine mastitis. Vet Rec 1989; 124: 6304. 20. Richarson GF. Metritis and endometritis. In: Howard JL. Current veterinary therapy 3 food animal practice. Philadelphia: W.B. Saunders Company, 1993: 7702. 21. Timoney PJ. Contagious equine metritis. In: Robinson NE. Current therapy in equine medicine 3. Philadelphia: W.B. Saunders, 1992: 75760. 22. Muckle CA, Menzies PI. Corynebacterium species infections in food animals. In: Howard JL. Current veterinary therapy 3 food animal practice. Philadelphia: W.B. Saunders Company, 1993: 53741. 23. Rebhun WC, et al. Pyelonephritis in cows: 15 cases (19821986). J Am Vet Med Assoc 1989 Apr; 194(7): 9535. 24. Ettinger SJ. Textbook of veterinary internal medicine. 2nd ed. Philadelphia: W.B. Saunders, 1983; 350, 359. 25. Hardman JG, Limbird LE, Gilman AG, editors. Goodman & Gilmans The Pharmacological Basis of Therapeutics, 10th ed. McGraw-Hill Professional Publishing. August 13, 2001. 26. Code of federal regulations. Washington, D.C.: Ofce of the Federal Register. April 1, 1993; 21(parts 500 to 599). 27. Derapen package insert (Ayerst LaboratoriesCanada), Rev 94, Rec 8/17/ 94. 28. Longisil package labeling (Sano Sante AnimaleCanada), Rec 8/17/94. 29. Donowitz GR, Mandell GL. Beta-lactam antibiotics. N Engl J Med 1988; 318: 41926. 30. USP dictionary of USAN and international drug names, 2002 ed. Rockville, MD: The United States Pharmacopeial Convention, Inc., 2002. 31. Anifantakis EM. Excretion rates of antibiotics in milk of sheep and their effect on yogurt production. J Dairy Sci 1982; 65: 4269. 32. Ziv G, et al. Pharmacokinetic evaluation of penicillin and cephalosporin derivatives in serum and milk of lactating cows and ewes. Am J Vet Res 1973; 34(12): 15615. 33. Wright AJ, Wilkowski CJ. The penicillins. Mayo Clin Proc 1983: 58: 2132. 34. Plumb DC. Veterinary drug handbook. White Bear Lake, MN: PharmaVet Publishing, 1991: 4701. 35. Watson ADJ. Penicillin G and the alternatives. Vet Ann 1985; 25: 27783. 36. Papich MG, et al. A study of the disposition of procaine penicillin G in feedlot steers following intramuscular and subcutaneous injection. J Vet Pharmacol Ther 1993; 16: 31727. 37. Firth EC. Effect of the injection site on the pharmacokinetics of procaine penicillin G in horses. Am J Vet Res 1986 Nov; 47(11): 23804. 38. Ziv G, Sulman FG. Binding of antibiotics to bovine and ovine serum. Antimicrob Agents Chemother 1972 Sep: 20613. 39. Powers TE, Garg RC. Pharmacotherapeutics of newer penicillins and cephalosporins. J Am Vet Med Assoc 1980 May; 176(10): 105460. 40. Peterson LR, et al. Prediction of peak penicillin and cephalosporin concentrations in canine serum as derived from in vitro serum and tissue quantitative protein binding. J Antimicrobial Chemotherapy 1979; 5: 21927. 41. Durr A. Comparison of the pharmacokinetics of penicillin G and ampicillin in the horse. Res Vet Sci 1976; 20: 249. 42. Rolinson GN, Sutherland R. The binding of antibiotics to serum proteins. Br J Pharmacol 1965; 25: 63850. 43. Huber WG. Penicillins. In: Booth NH, McDonald LE. Veterinary pharmacology and therapeutics. 5th ed. Ames, IA: Iowa State University Press, 1988: 796 812. 44. Firth EC, et al. The effect of phenylbutazone on the plasma disposition of penicillin G in the horse. J Vet Pharmacol Ther 1990; 13: 17985. 45. Riviere JE, Coppoc GL. Dosage of antimicrobial drugs in patients with renal insufciency. J Am Vet Med Assoc 1981 Jan; 178(1): 702. 46. Arrioja-Dechert A, editor. Compendium of veterinary products, CD ed. Port Huron, MI: North American Compendiums, Inc. 2002. 47. Klasco RK, editor. USP DI Drug information for the healthcare professional. Volume I. Greenwood Village, CO: MICROMEDEX, Inc.; 2003. 48. Nielsen IL, et al. Adverse reaction to procaine penicillin G in horses. Aust Vet J 1988 Jun; 65(6): 1814. 49. Blue JT, Dinsmore RP, Anderson KL. Immune-mediated hemolytic anemia induced by penicillin in horses. Cornell Vet 1987; 77: 26376. 50. Embrechts E. Procaine penicillin toxicity in pigs. Vet Rec 1982 Oct; 111: 314. 51. The United States pharmacopeia. The national formulary. USP 26th revision (January 1, 2003). NF 21st ed (January 1, 2003). Rockville, MD: The United States Pharmacopeial Convention, Inc., 2002. p. 1409, 1410, 1412, 1415, 1421, 2573. 52. Amoxicillin package insert (Trimox, ApotheconUS), Rev 4/90, Rec 7/93. 53. Agri-cillin package insert (Agri Laboritories Ltd.US), Rec 8/28/94. 54. Kirk RW, Bonagura JD, editors. Current veterinary therapy XI small animal practice. Philadelphia: W.B. Saunders, 1992: 1244. 55. Bengtsson AF, Luthman J, Jacobsson O. Concentrations of sulphadimidine, oxytetracycline and penicillin G in serum, synovial uid and tissue cage uid after parenteral administration to calves. J Vet Pharmacol Ther 1989; 12: 37 45. 56. Stover SM, et al. Aqueous procaine penicillin G in the horse: serum, synovial, peritoneal, and urine concentrations after single-dose intramuscular administration. Am J Vet Res 1981; 42: 62931. 57. Love DN, et al. Serum concentrations of penicillin in the horse after administration of a variety of penicillin preparations. Equine Vet J 1983; 15(1): 438. 58. Brown MP, et al. Aqueous procaine penicillin G in foals: Serum concentrations and pharmacokinetics after a single intramuscular dose. Equine Vet J 1984; 16(4): 3745. 59. Oukessou M, et al. Comparative benzylpenicillin pharmacokinetics in the dromedary Camelus dromedarius and in sheep. J Vet Pharmacol Ther 1990; 13: 298303. 60. Short CR, et al. Clearance of penicillin G in the newborn calf. J Vet Pharmacol Ther 1984; 7: 458. 61. Ziv G, Shani J, Sulman FG. Pharmacokinetic evaluation of penicillin and cephalosporin derivatives in serum and milk of lactating cows and ewes. Am J Vet Res 1973; 34(12): 15615. 62. Hirsh, et al. Pharmacokinetics of penicillin G in the turkey. Am J Vet Res 1978; 39(7): 121921. 63. Penlong XL. In: Bennett K, editor. Compendium of veterinary products. 2nd ed. Port Huron, MI: North American Compendiums Inc., 1993: 398. 64. Howard JL. Current veterinary therapy 3 food animal practice. Philadelphia: W.B. Saunders Company, 1993: 932. 65. Wilcke J, editor. Practice formulary. In: Veterinary values. 2nd ed. U.S.: AgResources, Inc. 1985: 1967. 66. Penicillin G potassium (Pzerpen, Roerig). In: PDR Physicians desk reference. 48th ed. 1994. Montvale, NJ: Medical Economics Data Production Company, 1994: 19857. 67. Penicillin G potassium, Apothecon. Red Book 1994. Montvale, NJ: Medical Economics Data, 1994: 311. 68. Penicillin G (generic, Wyeth-Ayerst). In: Krogh CME, editor. CPS Compendium of pharmaceuticals and specialties. 29th ed. Ottawa: Canadian Pharmaceutical Association, 1994: 9978. 69. Sullins KE, Messer NT, Nelson L. Serum concentration of penicillin in the horse after repeated intramuscular injections of procaine penicillin G alone or in combination with benzathine penicillin and/or phenylbutazone. Am J Vet Res 1984 May; 45(5): 10037. 70. Penicillin G Procaine Aqueous Suspension (G.C. Hanford Mfg. CoUS), Rev 9/93, Rec 8/1/94. 71. St Peter WL, Redic-Kill KA, Halstenson CE. Clinical pharmacokinetics of antibiotics in patients with impaired renal function. Clin Pharmacokinet 1992; 22(3): 169210. 72. English PB. Serum penicillin concentrations in the bovine with fortied benzathine. Aust Vet J 1959 Aug; 35: 3538. 73. Prescott JF. Leptospirosis. In: Howard JL. Current veterinary therapy 3 food animal practice. Philadelphia: W.B. Saunders, 1993. p. 5416. 74. Smith MC, Sherman DM. Goat medicine. Philadelphia, PA: Lea & Febiger, 1994. p. 2068. 75. Penicillin G procaine (Pzerpen-AS, Roerig). In: PDR Physicians desk reference. 48th ed. 1994. Montvale, NJ: Medical Economics Data Production Company, 1994. p. 19879. 76. Kirk RW, Bistner SI. Handbook of veterinary procedures and emergency treatment. 3rd ed. Philadelphia: W.B. Saunders, 1981. p. 1556. 77. Nurmio P. Penicillin G procaine: a possible cause of embryonic death in swine. Vet Rec 1980 Feb; 106 (5): 978. 78. Papich MG. Disposition of penicillin G after administration of benzathine penicillin G, or a combination of benzathine penicillin G and procaine penicillin G in cattle. Am J Vet Res 1994; 55(6): 82530. 79. Panel comment, 11/4/94.

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160 PENICILLIN G VeterinarySystemic

80. Korsrud GO, et al. Depletion of penicillin G residues in tissues and injection sites of yearling beef steers dosed with benzathine penicillin G alone or in combination with procaine penicillin G. Food additives and contaminants 1994; 11(1): 16. 81. Penmed product information (MedprodexCanada). In: Arrioja-Dechert A, editor. Compendium of veterinary products, CD ed. Port Huron, MI: North American Compendiums, Inc. 2002. 82. Bureau of Veterinary Drugs Overview 199394. Food Directorate/Health Protection Branch/Health Canada. Minister of National Health and Welfare: Minister of Supplies and Services Canada 1994. 83. Ritter L. Withholding times for procaine penicillin G in cattle [letter]. Can Vet J 1991; 32: 647. 84. Race track division schedule of drugs 1991. Agriculture Canada. 85. Panel comment, 11/21/94. 86. Heath SE. Bovine mastitis. In: Howard JL. Current veterinary therapy 3 food animal practice. Philadelphia: W.B. Saunders, 1993. p. 7628. 87. Panel comment, 11/15/94. 88. Panel comment, 11/29/94. 89. Panel comment, 11/17/94. 90. Bengtsson B, et al. Distribution of penicillin-G and spiramycin to tissue cages and subcutaneous tissue uid in calves. Res Vet Sci 1991; 50: 3017. 91. Panel comment, 11/15/94. 92. Tobin T. Drugs and the performance horse. Charles Thomas, Publishers, 1981. p. 2702. 93. Depocillin product information (IntervetCanada). In: Arrioja-Dechert A, editor. Compendium of veterinary products, CD ed. Port Huron, MI: North American Compendiums, Inc. 2002.

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PIRLIMYCIN VeterinaryIntramammary-Local 161

PIRLIMYCIN VeterinaryIntramammary-Local
Some commonly used brand names are Pirsue Aqueous Gel and Pirsue Sterile Solution{R-1}. Note: For a listing of dosage forms and brand names by country availability, see the Dosage Forms section(s). Absorption: Almost one half of the dose is absorbed systemically after intramammary administration.{R-5} Distribution: Pirlimycin is lipophilic and diffuses readily across tissue membranes.{R-3} Biotransformation: Pirlimycin is eliminated primarily as parent drug when administered by the intramammary route; however, 4% of the dose is oxidized by the liver to pirlimycin sulfoxide{R-5}. Peak concentrations: Based on two intramammary doses of 50 mg each, given 24 hours apart Blood: 0.025 mcg per mL (mcg/mL) 2 and 6 hours after the second 50-mg intramammary dose{R-14; 15}. Mammary tissue: 10 mcg per gram (mcg/gram) 10 hours after the second dose{R-4}. Milk: > 150 mcg/mL in the rst assay sample, taken 4 hours after each dose{R-4}. Liver concentration: TotalThe concentration of pirlimycin and metabolites (primarily pirlimycin sulfoxide) in the liver 4 days after the second 50-mg intramammary dose is 2.18 mcg/gram{R-11; 13; 14}. Parent compound (marker residue)The concentration of pirlimycin in the liver 2 days after the second 50-mg intramammary dose is 2.33 mcg/gram; the concentration falls below 0.5 mcg/gram by 21 days after the second dose{R-11; 14}. Mammary tissue concentration: Based on two intramammary doses of 50 mg each, given 24 hours apartThe mammary tissue concentration 4 days after the second dose is 0.927 mcg/ gram{R-14; 15}. Milk concentration: Based on a 50-mg intramammary dose at 0 and 24 hours, the milk pirlimycin concentration 12 hours after the second infusion of medication is measured to be 8 to 18 mcg/mL and by 36 hours the concentration is less than 1 mcg/mL{R-11}. Elimination: When pirlimycin is administered by the intramammary route, approximately 51% of the original dose is distributed into the milk, 10% into the urine, and 24% into the feces.{R-5} Of the total dose, 68% is recovered as unchanged pirlimycin.{R-5}

CATEGORY:
Antibacterial (intramammary-local).

INDICATIONS GENERAL CONSIDERATIONS

Pirlimycin is a lincosamide antibiotic with activity primarily against gram-positive organisms, including Staphylococcus and Streptococcus species.{R-1} It is considered more active than clindamycin against Staphylococcus aureus.{R-5} Pirlimycin is not active against gramnegative bacteria, such as Escherichia coli.{R-10}

ACCEPTED
Mastitis (treatment)Cows, lactating: Pirlimycin is indicated in the treatment of clinical and subclinical mastitis caused by Staphylococcus aureus, Streptococcus agalactiae, Streptococcus dysgalactiae, and Streptococcus uberis.{R-1} In refractory cases of chronic Staphylococcus aureus mastitis, administration of intramammary pirlimycin at recommended doses is sufcient to control but not eliminate the pathogen.{R-4} Intramammary therapy alone is indicated only in the treatment of subacute or subclinical mastitis manifested by mild changes in the milk or udder. Cows with acute or peracute mastitis, which involves gross changes in the milk or udder or systemic signs, should be given other medications also, which may include systemic antibiotics and/or supportive therapy.{R-6}

REGULATORY CONSIDERATIONS
U.S. and Canada Withdrawal times have been established for cattle. See the Dosage Forms section.{R-1}

CHEMISTRY
Source: Semisynthetic derivative of lincomycin.{R-3} Chemical group: Lincosamide antibiotic. Chemical name: Pirlimycin hydrochlorideL-threo-alpha-D-galactoOctopyranoside, methyl 7-chloro-6,7,8-trideoxy-6-[[(4-ethyl-2-piperidinyl)carbonyl]amino]-1-thio-, monohydrochloride, monohydrate, (2S-cis).{R-2} Molecular formula: Pirlimycin hydrochloride C17H31ClN2O5S HCl H2O.{R-2} Molecular weight: Pirlimycin hydrochloride465.43{R-2}. pKa: 8.5.{R-3}

PRECAUTIONS TO CONSIDER PATIENT MONITORING

The following may be especially important in patient monitoring (other tests may be warranted in some patients, depending on condition; = major clinical signicance): Bacteriologic pathogens in milk (milk samples should be tested three weeks after treatment with pirlimycin is discontinued; mastitis is not considered bacteriologically cured until samples show an absence of the mastitiscausing organism; for refractory Staphylococcus aureus mastitis, in which control, but not elimination, is achieved, S. aureus All rights reserved

PHARMACOLOGY/PHARMACOKINETICS
Mechanism of action/effect: Pirlimycin is bacteriostatic at therapeutic concentrations.{R-3} The lincosamides inhibit protein synthesis in susceptible bacteria by binding to the 50 S ribosomal subunits of bacterial ribosomes and preventing peptide bond formation.{R-7} 2003 Thomson MICROMEDEX

162 PIRLIMYCIN VeterinaryIntramammary-Local can reappear in milk cultures by 10 hours after the second treatment{R-4}) Strength(s) usually available: U.S.{R-1; 18; 19} Veterinary-labeled product(s): 5 mg per mL (Rx) [Pirsue Sterile Solution]. Canada{R-12; 18} Veterinary-labeled product(s): 5 mg per mL (Rx) [Pirsue Aqueous Gel]. Withdrawal times: U.S.{R-1719}
Withdrawal time Species Meat (days) 9
18}

SIDE/ADVERSE EFFECTS
Note: All clinical efcacy and toxicity studies performed with intramammary pirlimycin in cows have shown it to be nonirritating{R-11}. No serious adverse effects associated with the use of pirlimycin in cows have been documented. The Food and Drug Administration Adverse Drug Experience reporting program has received only one report of urticaria, possibly drug-related, in three cows that responded well to treatment for the urticaria{R-16}.

Milk (hours) 36

OVERDOSE
For information in cases of overdose or unintentional ingestion, contact the American Society for the Prevention of Cruelty to Animals (ASPCA) National Animal Poison Control Center (888-426-4435 or 900-443-0000; a fee may be required for consultation) and/or the drug manufacturer.

Cows

Canada{R-12;

Withdrawal time Species Cows Meat (days) 28 Milk (hours) 48

CLIENT CONSULTATION
Treatment of mastitis in dairy cattle is best achieved by a comprehensive mastitis control program in which herd management is the primary focus. The program should include good maintenance of milking equipment and constant evaluation of milking procedures and teat health as well as strategic treatment of clinical cases of mastitis.{R-9} Packaging and storage: Store at 25 C (77 F) or less, unless otherwise specied by manufacturer. Protect from freezing.{R-1} USP requirements: Not in USP{R-20}. Developed: 07/09/96 Revised: 02/27/98 Interim revision: 06/30/02; 02/28/03

VETERINARY DOSING INFORMATION

The choice of antibiotic for the treatment of mastitis should be based on knowledge of the culture and sensitivity of the pathogens causing mastitis in the cow and the dairy herd. Before administration of intramammary pirlimycin, the following steps should be performed: The udder should be milked out completely and the teats washed with warm water and a disinfectant. Care should be taken to avoid washing excess dirt down from the udder onto the teat ends. The area should be dried thoroughly. An effective germicidal teat dip should be applied for one minute and then each teat wiped with a separate cotton ball soaked with an antiseptic such as 70% isopropyl alcohol. Persons performing the treatment should wash and dry their hands before each treatment. To administer pirlimycin, the tip of the syringe should be inserted into the teat end as little as possible and the contents of the syringe should be injected into each streak canal while the teat is held rmly. The medication should then be gently massaged up the teat canal into the gland cistern. Following treatment, an effective teat dip is recommended on all teats.

REFERENCES
1. Pirsue Sterile Solution (PharmaciaUS), Rev 1/03. Downloaded 2/17/03 from www.pharmaciaah.com. 2. USP dictionary of USAN and international drug names, 2002 ed. Rockville, MD: The United States Pharmacopeial Convention Inc; 2002. 3. Henke CL, Chester ST, Dame KJ, et al. New developments in lactating cow preparationsthe efcacy of three blind labeled intramammary infusion formulae in the treatment of clinical mastitis. Proceedings of the 31st annual meeting of the National Mastitis Council, Inc.; 1992 Feb 1012; Arlington, Virginia. Arlington, VA: National Mastitis Council; 1992. 4. Owens WE, Nickerson SC, Watts JL, et al. Milk, serum, and mammary tissue concentration of pirlimycin following intramuscular, intramammary or combination therapy of chronic Staphyloccus aureus mastitis. Agri-Practice 1994 Mar; 15(3): 1923. 5. Hornish RE, Arnold TS, Baczynskyj L, et al. Pirlimycin in the dairy cow: metabolism and residues. Proceedings of the 202nd national meeting of the American Chemical Society; 1991 Aug 2530; New York. Washington, DC: American Chemical Society; 1992. 6. Heath SE. Bovine mastitis. In: Howard JL, editor. Current veterinary therapy 3. Food animal practice. Philadelphia: WB Saunders Co; 1993. p. 7629. 7. Barragry TB. Veterinary drug therapy. Baltimore: Lea & Febiger; 1994. p. 25162. 8. Jarp J, Bugge JP, Larsen S. Clinical trial of three therapeutic regimens for bovine mastitis. Vet Rec 1989; 124: 6304. 9. Hady PJ, Lloyd JW, Kaneene JB. Antibacterial use in lactating dairy cattle. J Am Vet Med Assoc 1993; 203(2): 21920. 10. Thornsberry C, Marler JK, Watts JL, et al. Activity of pirlimycin against pathogens from cows with mastitis and recommendations for disk diffusion tests. Antimicrob Agents Chemother 1993; 37: 11226. 11. Freedom of Information Summary. Pirlimycin hydrochloride for intramammary treatment of clinical or subclinical mastitis in lactating dairy cattle. NADA 141036. The Upjohn Company. Ofce of Consumer Affairs, Food and Drug Administration, Rockville, MD. 12. Pirsue Aqueous Gel package insert (PharmaciaCanada), Rev 1/01, Rec 1/30/02.

INTRAMAMMARY DOSAGE FORMS PIRLIMYCIN INTRAMAMMARY INFUSION

Usual dose: MastitisCows, lactating: Intramammary, 50 mg administered into each affected quarter, followed by a second dose administered twenty-four hours later.{R-1; 17} 2003 Thomson MICROMEDEX

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PIRLIMYCIN VeterinaryIntramammary-Local 163

13. Manufacturer comment, Rec 6/25/96. 14. Manufacturer comment, Rec 7/22/96. 15. Upjohn Technical Report (TR) 782-7926-92-002. Metabolism study 2. In: Freedom of Information Report. Pirlimycin hydrochloride for intramammary treatment of clinical or subclinical mastitis in lactating dairy cattle. NADA 141-036. The Upjohn Company. Ofce of Consumer Affairs, Food and Drug Administration, Rockville, MD. 16. The Food and Drug Administration Center for Veterinary Medicine Adverse Drug Experience Summaries, Center for Veterinary Medicine, Food and Drug Administration, Rockville, MD. 10/18/96. 17. Freedom of Information Summary. Pirsue Sterile Solution (new formulation and withdrawal period). NADA 141-036. Sponsor: Pharmacia & Upjohn Company. September 7, 2000. 18. Arrioja-Dechert A, editor. Compendium of veterinary products, CD edition. Port Huron, MI: North American Compendiums, Inc., 2002. 19. Entriken TL, editor. Veterinary pharmaceuticals and biologicals, 12th ed. Lenexa, KS: Veterinary Healthcare Communications, 2001. p. 18923. 20. The United States pharmacopeia. The national formulary. USP 26th revision (January 1, 2003). NF 21st ed (January 1, 2003). Rockville, MD: The United States Pharmacopeial Convention, Inc., 2002.

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164 POTENTIATED SULFONAMIDES VeterinarySystemic

POTENTIATED SULFONAMIDES VeterinarySystemic

This monograph includes information on the following: Ormetoprim and Sulfadimethoxine; Pyrimethamine and Sulfaquinoxaline*; Sulfadiazine and Trimethoprim; Sulfadoxine and Trimethoprim*; Sulfamethoxazole and Trimethoprim. Some commonly used brand names are: For veterinary-labeled products
Bimotrim [Sulfadoxine and Trimethoprim] Borgal [Sulfadoxine and Trimethoprim] Potensulf [Sulfadoxine and Trimethoprim] Primor 120 [Ormetoprim and Sulfadimethoxine] Primor 240 [Ormetoprim and Sulfadimethoxine] Primor 600 [Ormetoprim and Sulfadimethoxine] Primor 1200 [Ormetoprim and Sulfadimethoxine] Quinnoxine-S [Ormetoprim and Sulfadimethoxine] Rofenaid 40 [Ormetoprim and Sulfadimethoxine] Romet 30 [Ormetoprim and Sulfadimethoxine] Romet-30 [Ormetoprim and Sulfadimethoxine] Sulfaquinoxaline-S [Pyrimethamine and Sulfadimethoxine] Tribrissen 30 [Sulfadiazine and Trimethoprim] Tribrissen 120 [Sulfadiazine and Trimethoprim] Tribrissen 480 [Sulfadiazine and Trimethoprim] Tribrissen 960 [Sulfadiazine and Trimethoprim] Tribrissen 24% [Sulfadiazine and Trimethoprim] Tribrissen 48% [Sulfadiazine and Trimethoprim] Tribrissen 400 Oral Paste [Sulfadiazine and Trimethoprim] Tribrissen Piglet Suspension [Sulfadiazine and Trimethoprim] Tribrissen 40% Powder [Sulfadiazine and Trimethoprim] Trimidox [Sulfadoxine and Trimethoprim] Trivetrin [Sulfadoxine and Trimethoprim] Tucoprim Powder [Sulfadiazine and Trimethoprim] Uniprim Powder [Sulfadiazine and Trimethoprim]

CATEGORY:
Antibacterial (systemic); antiprotozoal (systemic).

INDICATIONS
Note: Bracketed information in the Indications section refers to uses that are either not included in U.S. product labeling or are for products not commercially available in the U.S. Information identied by a superscript 1 refers to uses that are either not included in Canadian product labeling or are for products not commercially available in Canada.

GENERAL CONSIDERATIONS
The combined and synergistic activities of the two agents in each type of potentiated sulfonamide produce antibacterial activity against a wide range of infections caused by gram-positive and gram-negative bacteria, some protozoa{R-3}, and some anaerobes under certain conditions{R-44}. The minimum inhibitory concentrations against specic susceptible bacteria for each antibiotic are generally lowered when the antibiotics are administered in the potentiated sulfonamide combination. The resistance developed to the potentiated sulfonamides is lower than that to each individual agent{R-20; 23}; this is an important benet because of the common resistance to sulfonamides and rapid development of resistance to diaminopyrimidines when used alone.{R-20} Cross-resistance between sulfonamides is considered complete{R-94} and often occurs between pyrimidines{R-25}.

For human-labeled products

Apo-Sulfatrim [Sulfamethoxazole and Trimethoprim] Apo-Sulfatrim DS [Sulfamethoxazole and Trimethoprim] Bactrim [Sulfamethoxazole and Trimethoprim] Bactrim DS [Sulfamethoxazole and Trimethoprim] Bactrim I.V. [Sulfamethoxazole and Trimethoprim] Bactrim Pediatric [Sulfamethoxazole and Trimethoprim] Cofatrim Forte [Sulfamethoxazole and Trimethoprim] Cotrim [Sulfamethoxazole and Trimethoprim] Cotrim DS [Sulfamethoxazole and Trimethoprim] Cotrim Pediatric [Sulfamethoxazole and Trimethoprim] Novo-Trimel [Sulfamethoxazole and Trimethoprim] Novo-Trimel D.S. [Sulfamethoxazole and Trimethoprim] Nu-Cotrimox [Sulfamethoxazole and Trimethoprim] Nu-Cotrimox DS [Sulfamethoxazole and Trimethoprim] Roubac [Sulfamethoxazole and Trimethoprim] Septra [Sulfamethoxazole and Trimethoprim] Septra DS [Sulfamethoxazole and Trimethoprim] Septra Grape Suspension [Sulfamethoxazole and Trimethoprim] Septra I.V. [Sulfamethoxazole and Trimethoprim] Septra Suspension [Sulfamethoxazole and Trimethoprim] Sulfatrim [Sulfamethoxazole and Trimethoprim] Sulfatrim DS [Sulfamethoxazole and Trimethoprim] Sulfatrim Pediatric [Sulfamethoxazole and Trimethoprim] Sulfatrim S/S [Sulfamethoxazole and Trimethoprim] Sulfatrim Suspension [Sulfamethoxazole and Trimethoprim]

ACCEPTED
Coccidiosis (prophylaxis) Chickens: Ormetoprim and sulfadimethoxine premix1{R-6} is indicated in the prevention of coccidiosis caused by susceptible Eimeria acervulina, E. brunetti, E. maxima, E. mivati, E. necatrix, and E. tenella. [Pyrimethamine and sulfaquinoxaline combination{R-17} is indicated in the prevention of coccidiosis, caused by susceptible organisms.] Potentiated sulfonamides may be more effective in the treatment of E. acervulina than of E. tenella{R-71}. Partridges, chukar1: Ormetoprim and sulfadimethoxine premix is indicated in the prevention of coccidiosis caused by susceptible Eimeria kofoidi and E. legionensis {R-6; 125}. Turkeys: Ormetoprim and sulfadimethoxine premix1{R-6} is indicated in the prevention of coccidiosis caused by susceptible Eimeria adenoeides, E. gallopavonis, and E. meleagridis. [Pyrimethamine and sulfaquinoxaline combination{R-17} is indicated in the prevention of coccidiosis caused by susceptible organisms.] [Coccidiosis (treatment)]Chickens and turkeys: Pyrimethamine and sulfaquinoxaline oral solution{R-17} is indicated to aid in the treatment of susceptible coccidia. Colibacillosis (prophylaxis)1Chickens, broiler and replacement, and ducks: Ormetoprim and sulfadimethoxine premix{R-6} is indicated in the prevention of colibacillosis caused by susceptible Escherichia coli. Colibacillosis (treatment) Ducks1: Ormetoprim and sulfadimethoxine premix{R-6} is indicated in the control of colibacillosis caused by susceptible E. coli. [Cattle]: Sulfadoxine and trimethoprim injection{R-13; 14} is indicated in the treatment of colibacillosis caused by susceptible organisms. All rights reserved

Note: For a listing of dosage forms and brand names by country availability, see the Dosage Forms section(s).

*Not commercially available in the U.S. 2003 Thomson MICROMEDEX

POTENTIATED SULFONAMIDES VeterinarySystemic 165 [Pigs]: Sulfadiazine and trimethoprim oral suspension{R-10} and sulfadoxine and trimethoprim injection{R-13} are indicated in the treatment of neonatal colibacillosis caused by susceptible E. coli {R-10} . Enteric septicemia (treatment)1Catsh: Ormetoprim and sulfadimethoxine premix{R-7; 16} is indicated in the control of enteric septicemia caused by susceptible Edwardsiella ictaluri. Fowl cholera (prophylaxis)1Chickens and turkeys: Ormetoprim and sulfadimethoxine premix{R-6} is indicated in the prevention of fowl cholera caused by susceptible Pasteurella multocida. Fowl cholera (treatment)1Ducks: Ormetoprim and sulfadimethoxine premix{R-6} is indicated in the control of fowl cholera caused by susceptible Pasteurella multocida. Furunculosis (treatment)Salmon and trout: Ormetoprim and sulfadimethoxine premix{R-7; 16} is indicated in the control of furunculosis caused by susceptible Aeromonas salmonicida. Gastrointestinal tract infections, bacterial (treatment)Treatment of gastroenteritis with antimicrobials should rely on a specic diagnosis and knowledge of pathogen susceptibility. Dogs: Sulfadiazine and trimethoprim [injection]{R-8; 95} and tablets1{R2; 11} are indicated in the treatment of acute gastrointestinal tract infections. [Cats]: Sulfadiazine and trimethoprim injection{R-8} and tablets1{R-11} are indicated in the treatment of acute gastrointestinal tract infections. Infectious coryza (prophylaxis)1Chickens: Ormetoprim and sulfadimethoxine premix{R-6} is indicated in the prevention of infectious coryza caused by susceptible Haemophilus gallinarum. New duck disease (treatment)1Ducks: Ormetoprim and sulfadimethoxine premix{R-6} is indicated in the control of new duck disease (infectious serositis) caused by susceptible Riemerella anatipestifer. Respiratory tract infections, bacterial (treatment) Dogs: Sulfadiazine and trimethoprim [injection{R-8; 95}] and tablets1{R2} are indicated in the treatment of acute bacterial respiratory tract infections caused by susceptible organisms. Horses: Sulfadiazine and trimethoprim injection{R-9; 96; 146}, oral paste{R-3; 18}, and oral powder1{R-4} are indicated in the treatment of respiratory tract infections caused by susceptible organisms. [Cats]: Sulfadiazine and trimethoprim injection{R-8} and tablets1{R-11} are indicated in the treatment of respiratory tract infections caused by susceptible organisms. Skin and soft tissue infections (treatment) Dogs: Ormetoprim and sulfadimethoxine tablets1{R-5} are indicated in the treatment of skin and soft tissue infections caused by susceptible E. coli and Staphylococcus intermedius. Sulfadiazine and trimethoprim [injection]{R-8} and tablets1{R-2; 11} are indicated in the treatment of abscesses and infected wounds caused by susceptible organisms. Horses: Sulfadiazine and trimethoprim injection{R-9; 96; 146}, oral paste{R-3; 18}, and oral powder1{R-4} are indicated in the treatment of abscesses and infected wounds caused by susceptible organisms. [Cats]: Sulfadiazine and trimethoprim injection{R-8} and tablets1{R-11} are indicated in the treatment of bacterial infections, such as abscesses and wounds, caused by susceptible organisms. Strangles (treatment)Horses: Sulfadiazine and trimethoprim injection{R-9; 96; 146}, oral paste{R-3; 18}, and oral powder1{R-4} are indicated in the treatment of acute strangles caused by susceptible organisms. Urinary tract infections (treatment)Dogs: Ormetoprim and sulfadimethoxine tablets{R-126} and sulfadiazine and trimethoprim tablets1{R-2} are indicated in the treatment of acute urinary tract infections caused by susceptible organisms. Urogenital tract infections (treatment)1Horses: Sulfadiazine and trimethoprim injection{R-96; 146}, oral paste, and oral powder{R-4} are indicated in the treatment of acute urogenital tract infections{R-3}. [Arthritis, bacterial (treatment)]Pigs: Sulfadoxine and trimethoprim injection{R-1315} is indicated in the treatment of bacterial arthritis caused by susceptible organisms. [Enteritis, bacterial (treatment)] Cattle: Sulfadoxine and trimethoprim injection{R-13; 14} is indicated in the treatment of enteritis caused by susceptible E. coli or Salmonella. Pigs: Sulfadiazine and trimethoprim oral suspension{R-10} and sulfadoxine and trimethoprim injection{R-13; 14} are indicated in the treatment of post-weaning scours caused by susceptible E. coli. [Mastitis (treatment)]; or [Metritis (treatment)]Sows: Sulfadoxine and trimethoprim injection{R-1315} is indicated in the treatment of mastitis-metritis-agalactia syndrome caused by susceptible organisms. [Perioperative infections (treatment)]Horses: Sulfadiazine and trimethoprim oral paste{R-18} and injection{R-9} are indicated in the treatment of postoperative bacterial infections caused by susceptible organisms. [Pneumonia, bacterial (treatment)] Cattle: Sulfadoxine and trimethoprim injection{R-13; 14} is indicated in the treatment of bacterial pneumonia, including bovine pneumonic pasteurellosis (shipping fever), caused by susceptible organisms. Pigs: Sulfadoxine and trimethoprim combination{R-14; 15} is indicated in the treatment of bacterial pneumonia caused by susceptible organisms. [Pododermatitis (treatment)]Cattle: Sulfadoxine and trimethoprim injection{R-13; 14} is indicated in the treatment of pododermatitis caused by susceptible organisms. [Septicemia (treatment)] Cattle: Sulfadoxine and trimethoprim injection{R-13; 14} is indicated in the treatment of septicemia caused by susceptible organisms. Dogs: Sulfadiazine and trimethoprim injection1{R-95} is used in the treatment of septicemia caused by susceptible organisms. [Vibrio anguillarum infection]Salmon: Sulfadiazine and trimethoprim combination oral powder{R-22} is indicated in the treatment of infections caused by susceptible Vibrio anguillarum{R-64}.

ACCEPTANCE NOT ESTABLISHED

Distemper, canine (treatment)Dogs: Although U.S. product labeling includes the use of sulfadiazine and trimethoprim in the treatment of secondary bacterial infections associated with canine distemper{R-2}, and this use may be appropriate in bacterial infections that are susceptible to this medication, the use of these antimicrobials in the treatment of distemper-associated infections is not considered more appropriate or more generally accepted than in the treatment of bacterial infections associated with other viral infections. Bacterial infections (treatment)Horses: There are insufcient controlled studies to support the efcacy and safety of [sulfamethoxazole and trimethoprim combination]1 in the treatment of bacterial infections in foals and horses; however, based on pharmacokinetic data, the combination is used in the treatment of susceptible infections{R-3133}.

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166 POTENTIATED SULFONAMIDES VeterinarySystemic [Coccidiosis (treatment)]1Cats and dogs: There are insufcient data to support the efcacy of sulfadiazine and trimethoprim or ormetoprim and sulfadimethoxine{R-136} in the treatment of enteric coccidiosis in cats and dogs; however, these medications are used to reduce the shedding of oocysts and may aid in the natural elimination of Isospora species. [Equine infectious arthritis (treatment)]1Horses: There are insufcient data to support the efcacy and safety of sulfadiazine and trimethoprim combination in the treatment of equine infectious arthritis; however, pharmacokinetic and clinical studies do lend support to its efcacy in the treatment of experimentally-induced Staphylococcus aureus joint infections{R-41; 42}. [Equine protozoal myeloencephalitis (treatment)]1; or [Protozoal infections (treatment)]1Horses: There are insufcient controlled studies to support the efcacy and safety of sulfamethoxazole and trimethoprim combination in the treatment of protozoal infections in foals and horses; however, based on pharmacokinetic data, the combination is used in the treatment of susceptible infections {R-3133} . Prior to the availability of approved products (ponazuril, toltrazuril) to treat equine protozoal myeloencephalitis, administration of sulfamethoxazole and trimethoprim in combination with pyrimethamine was clinically useful in treating horses with this disease{R-147}. In vitro studies also show efcacy of potentiated sulfonamides against Sarcocystis neurona{R-148}. [Meningitis, bacterial (treatment)]1Dogs: There are insufcient data to support the efcacy of sulfadiazine and trimethoprim combination in the treatment of bacterial meningitis in dogs; however, it has been used for this indication{R-38}. [Nocardiosis (treatment)]1Cats and dogs: There are insufcient data to support the efcacy of sulfadiazine and trimethoprim or sulfamethoxazole and trimethoprim in the treatment of nocardiosis in cats and dogs; however, these medications are used in the treatment of nocardial infections. Sulfonamides have been considered the treatment of choice and there is some evidence{R-128133} to suggest that sulfadiazine and trimethoprim or sulfamethoxazole and trimethoprim are efcacious in the treatment of these infections{R-128; 131; 133}. Ormetoprim and sulfadimethoxine combination could also be effective in the treatment of nocardiosis, based on a pharmacokinetic prole similar to that of trimethoprim with sulfadiazine or sulfamethoxazole{R-138}. Because of a variability in the susceptibility of Nocardia species, culture and sensitivity tests should be performed, if possible. Surgical drainage should be provided for any abscesses or draining tracts{R-130; 131}. Sulfonamide and trimethoprim combination administered alone may not be effective in the treatment of cerebral nocardiosis{R-132}. [Pneumonia (treatment)]1Calves, nonruminating: Until recently, Canadian sulfadiazine and trimethoprim boluses were labeled for use in the treatment of bacterial pneumonia in calves{R-12}. Such a product has not been available in the United States. Although there are no sulfadiazine and trimethoprim products labeled for use in calves in the United States or Canada at this time, oral sulfadiazine and trimethoprim tablets might be used in the treatment of susceptible infections, such as bacterial pneumonia, in calves. For more information, see Sulfadiazine and Trimethoprim Tablets in the Dosage Forms section of this monograph. [Prostate infection (treatment)]1Dogs: There are insufcient data to support the efcacy of trimethoprim in combination with sulfadiazine or sulfamethoxazole in the treatment of prostate infections caused by susceptible organisms in dogs; however, pharmacokinetic studies show that these trimethoprim and sulfonamide combinations are distributed into prostate uid at therapeutic concentrations{R-48}. Ormetoprim and sulfadimethoxine combination also could be effective in the treatment of prostatitis, based on a pharmacokinetic prole similar to that of trimethoprim with sulfadiazine or sulfamethoxazole{R-138}.
1

Not included in Canadian product labeling or product not commercially available in Canada.

REGULATORY CONSIDERATIONS
U.S. Withdrawal times have been established for ormetoprim and sulfadimethoxine for medicated feed (see the Dosage Forms section). Canada Withdrawal times have been established for ormetoprim and sulfadimethoxine for medicated feed; pyrimethamine and sulfaquinoxaline oral solution; sulfadiazine and trimethoprim boluses, oral paste, oral powder, and oral suspension; and sulfadoxine and trimethoprim injection (see the Dosage Forms section).

CHEMISTRY
Chemical group: Ormetoprim, pyrimethamine, and trimethoprimDiaminopyrimidines. Sulfadiazine, sulfadimethoxine, sulfadoxine, sulfamethoxazole, and sulfaquinoxalineSulfonamides. Chemical name: Ormetoprim2,4-Pyrimidinediamine,5-[(4,5-dimethoxy-2-methylphenyl) methyl]-{R-1}. Pyrimethamine2,4-Pyrimidinediamine, 5-(4-chlorophenyl)-6-ethyl-{R-1}. SulfadiazineBenzenesulfonamide, 4-amino-N-2-pyrimidinyl-{R-1}. SulfadimethoxineBenzenesulfonamide, 4-amino-N-(2,6-dimethoxy-4pyrimidinyl)-{R-1}. SulfadoxineBenzenesulfonamide, 4-amino-N-(5,6-dimethyoxy-4-pyrimidinyl)-{R-1}. SulfamethoxazoleBenzenesulfonamide, 4-amino-N-(5-methyl-3-isoxazolyl)-{R-1}. SulfaquinoxalineN1-2-Quinoxalinylsulfanilamide{R-1}. Trimethoprim2,4-Pyrimidinediamine, 5-[(3,4,5-trimethoxyphenyl) methyl]-{R-1}. Molecular formula: OrmetoprimC16H18N4O2{R-1}. PyrimethamineC12H13ClN4{R-1}. SulfadiazineC10H10N4O2S{R-1}. SulfadimethoxineC12H14N4O4S{R-1}. SulfadoxineC12H14N4O4{R-1}. SulfamethoxazoleC10H11N3O3S{R-1}. SulfaquinoxalineC14H12N4O2S{R-1}. TrimethoprimC14H18N4O3{R-1}. Molecular weight: Ormetoprim274.32{R-1}. Pyrimethamine248.71{R-1}. Sulfadiazine250.28{R-1}. Sulfadimethoxine310.34{R-1}. Sulfadoxine310.33{R-1}. Sulfamethoxazole253.28{R-1}. Sulfaquinoxaline300.34{R-1}. Trimethoprim290.32{R-1}.

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POTENTIATED SULFONAMIDES VeterinarySystemic 167 Description: OrmetoprimWhite powder{R-5}. Pyrimethamine USPWhite, odorless, crystalline powder{R-117}. Sulfadiazine USPWhite or slightly yellow powder. Odorless or nearly odorless and stable in air, but slowly darkens on exposure to light{R-117}. Sulfadimethoxine USPPractically white, crystalline powder{R-117}. SulfadoxineWhite or yellowish-white crystalline powder, melting at 197200 C{R-118}. Sulfamethoxazole USPWhite to off-white, practically odorless, crystalline powder{R-117}. SulfaquinoxalineYellow, odorless powder{R-118}. Trimethoprim USPWhite to cream-colored, odorless crystals, or crystalline powder{R-117}. pKa: Sulfadiazine6.4{R-25}. Sulfadimethoxine6.2{R-97; 98}. Sulfadoxine6.3{R-25}. Sulfamethoxasole5.7{R-25}. Sulfaquinoxaline5.5{R-99; 100}. Trimethoprim7.6{R-73; 90}. Solubility: Pyrimethamine USPPractically insoluble in water; slightly soluble in acetone, in alcohol, and in chloroform{R-117}. Sulfadiazine USPPractically insoluble in water; freely soluble in dilute mineral acids, in solutions of potassium and sodium hydroxides, and in ammonia TS; sparingly soluble in alcohol and in acetone; slightly soluble in human serum at 37 C{R-117}. Sulfadimethoxine USPSoluble in 2 N sodium hydroxide; sparingly soluble in 2 N hydrochloric acid; slightly soluble in alcohol, in ether, in chloroform, and in hexane; practically insoluble in water{R-117}. SulfadoxineVery slightly soluble in water; slightly soluble in alcohol and in methyl alcohol; practically insoluble in ether. Dissolves in solutions of alkali hydroxides and in dilute mineral acids{R-118}. Sulfamethoxazole USPPractically insoluble in water, in ether, and in chloroform; freely soluble in acetone and in dilute solutions of sodium hydroxide; sparingly soluble in alcohol{R-117}. SulfaquinoxalinePractically insoluble in water; very slightly soluble in alcohol; practically insoluble in ether; freely soluble in aqueous solutions of alkalis{R-118}. Trimethoprim USPVery slightly soluble in water; soluble in benzyl alcohol; sparingly soluble in chloroform and in methanol; slightly soluble in alcohol and in acetone; practically insoluble in ether and in carbon tetrachloride{R-117}. compete with para-aminobenzoic acid (PABA) for incorporation into dihydrofolic acid{R-20}. By replacing the PABA molecule in dihydrofolic acid, they prevent formation of folic acid required for nucleic acid synthesis and multiplication of the bacterial cell{R-94; 101}. Sulfonamides are effective only in cells that must produce their own folic acid; mammalian cells do not synthesize folic acid, but get it from outside sources. DiaminopyrimidinesOrmetoprim{R-5} and trimethoprim{R-23} are bacteriostatic antimicrobials that block a step in folate production just subsequent to that affected by the sulfonamides. Bacterial production of tetrahydrofolic acid from dihydrofolate is interrupted by the diaminopyrimidine as it reversibly binds and inhibits dihydrofolate reductase. Because the conversion of dihydrofolic acid to tetrahydrofolic acid is blocked, folate cannot be produced. Pyrimethamine causes the same inhibition of dihydrofolate reductase in protozoa{R-20}. Like bacteria and protozoa, animal cells also reduce folic acid to tetrahydrofolic acid; however, bacterial and protozoal dihydrofolate reductase is signicantly more tightly bound by trimethoprim than is human dihydrofolate reductase{R-2}. Potentiated sulfonamidesBecause the diaminopyrimidines exert their effect on folate biosynthesis at a step immediately subsequent to the one at which the sulfonamides act, the combination of a sulfonamide and diaminopyrimidine produces a synergistic effect that deprives the cell of essential nucleic acids and proteins. The potentiated sulfonamide combination produces an antimicrobial effect that is bacteriostatic and sometimes bactericidal against certain bacteria under optimum conditions.{R-2; 23; 24} The minimal effective ratio of sulfonamide to diaminopyrimidine in the target tissue is 20 to 1 for synergism. At equimolar quantities, other ratios are equally effective, depending on the strain of organism and the minimum inhibitory concentration (MIC) for each drug. Therefore, 16 to 1, 10 to 1, and other ratios may be effective, but combinations are formulated to achieve at least 20 to 1 in vivo{R-20}. Absorption: Oral Ormetoprim and sulfadimethoxine: Calves, 6 weeks of ageThe bioavailability of oral ormetoprim is very poor in ruminating calves{R-86}; the bioavailability of oral sulfadimethoxine in calves is slow but complete and unaffected by ruminant status{R-81}. DogsOrmetoprim and sulfadimethoxine are rapidly and well absorbed after oral administration{R-5}. HorsesOral absorption of ormetoprim and sulfadimethoxine is variable. Sulfadimethoxine appears to be more efciently absorbed than ormetoprim{R-35; 36}. Sulfadimethoxine administered alone: Bioavailability Catsh, channel: 40 mg/kg dose{R-68} Free base: 31%. Sodium salt: 34%. Trout, rainbow: 42 mg/kg dose{R-67} Free base: 34%. Sodium salt: 63%. 126 mg/kg doseSodium salt: 50%{R-67}. Sulfadiazine and trimethoprim: Calves, 6 weeks of ageThe bioavailability of oral trimethoprim is greatly reduced in ruminating calves as compared to preruminating calves. Therapeutic serum concentrations (> 0.1 mcg/mL) were not

PHARMACOLOGY/PHARMACOKINETICS
Note: Unless otherwise noted, pharmacokinetic values are based on administration of a single intravenous dose and concurrent administration of a diaminopyrimidine and a sulfonamide. When sulfamethoxazole and trimethoprim are administered concurrently to horses, the pharmacokinetics of each drug appears to be unaffected by the presence of the other{R-30; 32}.

Mechanism of action/effect: SulfonamidesThe sulfonamides are bacteriostatic antimicrobials that interfere with the biosynthesis of folic acid in bacterial cells; they

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168 POTENTIATED SULFONAMIDES VeterinarySystemic achieved with oral administration of 25 mg of sulfadiazine and 5 mg of trimethoprim in combination to ruminating calves{R-81}. The bioavailability of oral sulfadiazine in calves is slow but complete and unaffected by rumen status{R-81}. DogsSulfadiazine and trimethoprim are rapidly and well absorbed following oral administration{R-76}. However, absorption can be variable among dogs and between different doses given to the same dog{R-46}. HorsesThe absorption of trimethoprim is delayed when a horse has free access to feed{R-27}. Initial serum concentrations will be lower in a fed horse than in a fasted horse; however, the effect is greatly decreased by the third day of treatment{R-27}. PigsBioavailability: Dose of 40 mg of sulfadiazine and 4 mg of trimethoprim per kgFasted or fed: Sulfadiazine85 to 89%{R-91}. Trimethoprim90 to 92%{R-91}. SheepAbsorption of sulfadiazine in sheep is comparable to that in dogs; however, trimethoprim is not as well absorbed orally in sheep as in dogs{R-76}. Sulfamethoxazole and trimethoprim: BioavailabilityQuail: Dose of 50 mg of sulfamethoxazole and 10 mg of trimethoprim per kg of body weight Sulfamethoxazole: 81%{R-93}. Trimethoprim: 41%{R-93}. Distribution: Potentiated sulfonamides are widely distributed throughout body tissues{R-2; 3}. In general, the diaminopyrimidine concentration in plasma peaks early and is quickly found in high concentrations in tissues{R-76}; therefore, concentrations are generally higher in the tissues than in the serum{R-25}. The sulfonamide component generally is found at higher concentrations in plasma for a much longer time and tissue distribution is slower{R-76}. Initial concentrations of sulfonamides in tissues are generally lower than those in plasma{R-25}. Calves, preruminatingSulfadiazine and trimethoprim are distributed well into cerebrospinal uid (CSF){R-79} and synovial uid{R-80}. DogsPotentiated sulfonamides are rapidly and widely distributed in the tissues. Trimethoprim and sulfadiazine are distributed into the aqueous and vitreous humors of the eye at concentrations that are 30 to 50% of serum concentrations{R-45}. Trimethoprim is distributed into prostatic uid at concentrations that are up to three times the serum concentration and are higher when trimethoprim is administered concurrently with sulfadiazine or sulfamethoxazole{R-48}. Sulfadiazine and sulfamethoxazole are distributed into prostatic uid at about 10% of the concurrent serum concentration{R-48}. HorsesDistribution of potentiated sulfonamides has been broadly investigated in the horse. Ormetoprim and sulfadimethoxine{R-35}, sulfadiazine and trimethoprim{R-29}, and sulfamethoxazole and trimethoprim{R-31; 33} are all well distributed into peritoneal uid, CSF, synovial uid, and urine. Ormetoprim and sulfadimethoxine also have been shown to be well distributed into the endometrium{R-35}. Inammation in the meninges or synovium does not signicantly affect distribution into the respective uids{R-31}. Ormetoprim and sulfadimethoxine: Equine endometrial tissue and synovial and peritoneal uid concentrations of ormetoprim were similar to concurrent serum concentrations and concentrations of sulfadimethoxine in those uids were 25 to 30% of serum concentration{R-35}. Sulfadimethoxine and trimethoprim: After 4-day dosing in mares, trimethoprim was measured in CSF at 50% of serum concentrations, but sulfadimethoxine was measured at 2.7% of serum concentrations{R-35}. Sulfamethoxazole and trimethoprim: A single dose of 36 mg of sulfamethoxazole and 7.5 mg of trimethoprim per kg of body weight, administered intravenously to mares, reached concentrations in serum sufcient to exceed the minimum inhibitory concentrations (MICs) of common bacterial and protozoal pathogens{R-33}. After repeated doses, sulfamethoxazole, unlike trimethoprim, accumulated in the CSF{R-31}. FishSulfadimethoxine administered alone: In channel catsh, sulfadimethoxine is distributed into the muscle at the highest concentration immediately after administration, but within 48 to 96 hours the highest concentrations are in the bile{R-68}. At any point in time there can be wide variation in tissue residues among sh{R-69}. In rainbow trout, sulfadimethoxine is distributed at the highest concentrations into the bile, followed by the intestine, liver, blood, skin, kidney, spleen, gill, muscle, and fat.{R-67} Volume of distribution (VolD): Ormetoprim and sulfadimethoxineHorses:{R-35} Ormetoprim Area: 1.7 Liters per kg (L/kg). Steady state: 1.2 L/kg. Sulfadimethoxine Area: 0.28 L/kg. Steady state: 0.27 L/kg. Sulfadiazine and trimethoprim Calves: Area Sulfadiazine: 1 day of age0.72 L/kg{R-79}. 1 week of age0.66 L/kg{R-79; 80}. 6 weeks of age0.58 L/kg{R-79}. Ruminating0.85 L/kg{R-77}. Trimethoprim: 1 day of age1.69 L/kg{R-79}. 1 week of age2.2 to 2.5 L/kg{R-79; 80}. 6 weeks of age2.27 L/kg{R-79}. Ruminating1.97 L/kg{R-77}. Horses: Steady state Sulfadiazine: 0.58 L/kg{R-43}. Trimethoprim: 1.68 L/kg{R-43}. Pigs: Steady state Sulfadiazine: 0.54 L/kg{R-91}. Trimethoprim: 1.8 L/kg{R-91}. Sulfadimethoxine administered aloneSteady state: Catsh, channel0.66 L/kg{R-68}. Trout, rainbow0.42 to 0.5 L/kg{R-67; 70}. Sulfadoxine and trimethoprim Cows: Apparent Sulfadoxine: 0.37 L/kg{R-82}. Trimethoprim: 1.14 L/kg{R-82}. Goats: Apparent Sulfadoxine: 0.27 L/kg{R-72}. Trimethoprim: 1.2 L/kg{R-72}. Horses: Apparent Sulfadoxine: 0.39 L/kg{R-30}.

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POTENTIATED SULFONAMIDES VeterinarySystemic 169 Trimethoprim: 1.5 L/kg{R-30}. Sulfamethoxazole and trimethoprim Foals: SulfamethoxazoleArea and steady state: 0.73 L/kg{R-32}. TrimethoprimArea and steady state: 2.2 L/kg{R-32}. Horses: Sulfamethoxazole Area: 0.36 L/kg{R-31}. Steady state: 0.33 L/kg{R-31}; 0.5 L/kg{R-33}. Trimethoprim Area: 2.27 L/kg{R-31}. Steady state: 1.62 L/kg{R-31}; 2.79 L/kg{R-33}. Quail: SulfamethoxazoleArea: 0.48 L/kg{R-93}. TrimethoprimArea: 3.9 L/kg{R-93}. Protein binding: In general, the binding of sulfonamides to proteins is concentration-dependent{R-25; 30} and, in general, trimethoprim protein binding is independent of plasma concentration{R-25; 30}. There appears to be no interference in protein binding between sulfadoxine and trimethoprim{R-30}; this may also be true for other potentiated sulfonamides. Sulfadiazine Cattle: Moderate (50%) (concentration not specied){R-75}. Sulfadimethoxine Cats: High (87.5%) (50 mcg/mL plasma concentration){R-102}. Catsh, channel: Low (18%), not concentration-dependent{R-68}. Chickens: Average binding over a range of concentrations Moderate (40%), at serum concentrations of 2 to 10 mcg/ mL{R-103}. Dogs: High (> 75%), at plasma concentrations of 50 to 150 mcg/mL{R-104}. Goats: Very high (94%), at plasma concentration of 100 micromole/ L{R-98}. Trout, rainbow: Low (17%), not concentration-dependent{R-67}. Sulfadoxine Horses: High (72%), at serum concentration of 50 mcg/mL{R-30}. Moderate (40%), at serum concentration of 150 mcg/mL{R-30}. Low (14%), at serum concentration of 450 mcg/mL{R-30}. Cows: High (65 to 80%), at serum concentration of 100 mcg/mL or below{R-82; 83}. Moderate (44 to 51%), at serum concentration of 150 mcg/mL or more{R-82; 83}. Trimethoprim Cows: Moderate (57%){R-83}. Goats: Moderate (48%){R-73}. Horses: Moderate (50%){R-30}. Pigs: Moderate (33 to 54%){R-90}. Biotransformation: SulfonamidesSulfonamides are metabolized primarily in the liver, but metabolism also occurs in other tissues. Biotransformation occurs by acetylation, glucuronide conjugation, and aromatic hydroxylation in many species{R-94}. The types of metabolites formed and the amount of each varies depending on the specic sulfonamide administered; the species, age, diet, and environment of the animal; the presence of disease; and, with the exception of pigs and ruminants, the gender of the animal{R-105108}. N4-acetyl metabolites have no antimicrobial activity and hydroxymetabolites have 2.5 to 39.5% of the activity of the parent compound{R-109}. Metabolites may compete with the parent drug for involvement in folic acid synthesis. They have little detrimental effect on the bacterial cell, so their presence could decrease the activity of the remaining parent drug{R-109}. SulfadiazineCalves: Sulfadiazine is excreted primarily as unchanged drug in the urine; the percentage of unchanged drug excreted increases from 1 day of age to 42 days of age, changing from 22 to 50%{R-79}. Sulfadimethoxine: Catsh, channelMetabolized primarily by the liver; acetylation is the major pathway{R-68}. DogsSulfadimethoxine is not acetylated in the dog as it is in other species, and it is excreted primarily as unchanged drug{R-5}. SalmonMetabolism occurs primarily in the liver{R-66}. DiaminopyrimidinesTrimethoprim: In many species, including cows{R-79}, goats, and pigs, trimethoprim is extensively metabolized{R-25}. Half-life: AbsorptionHorses: OralSulfadiazine and trimethoprim: Dose of 25 mg of sulfadiazine and 5 mg of trimethoprim per kg of body weight (mg/kg){R-43} Sulfadiazine: 0.35 hour. Trimethoprim: 0.44 hour. DistributionHorses: OralSulfadiazine and trimethoprim: Dose of 25 mg of sulfadiazine and 5 mg of trimethoprim per kg of body weight{R-43} Sulfadiazine: 0.27 hour. Trimethoprim: 0.15 hour. Elimination Ormetoprim and sulfadimethoxine: Horses Ormetoprim: 1.7 hours{R-35}. Sulfadimethoxine: 7.9 hours{R-35}. Sulfadiazine and trimethoprim: Calves 1 day of age: Sulfadiazine5.7 hours{R-79}. Trimethoprim8.4 hours{R-79}. 1 week of age: Sulfadiazine4.4 hours{R-79; 80}. Trimethoprim2.1 hours{R-79; 80}. 6 weeks of age: Sulfadiazine3.6 hours{R-79}. Trimethoprim0.9 hour{R-79}. Calves, ruminating Sulfadiazine: 3.25 hours{R-77}; 4 hours{R-78}. Trimethoprim: 1 hour{R-78}; 3.44 hours{R-77}. Horses Sulfadiazine: 2.7 hours{R-29}; 4.65 hours{R-43}; 7 hours{R-3}. Trimethoprim: 2 to 3 hours{R-3; 29; 32; 43}. Sulfadoxine and trimethoprim: Cows, lactating Sulfadoxine: Alpha phase (up to 4 hours postadministration)0.9 hour{R-82}. Beta phase (between 4 and 48 hours postadministration)10.8 hours{R-82}.

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170 POTENTIATED SULFONAMIDES VeterinarySystemic Trimethoprim: 1.18 hours{R-82}. Goats 2 days of age: Sulfadoxine16.5 hours{R-72}. Trimethoprim3 hours{R-72}. 40 days of age to adult: Sulfadoxine11.7 hours{R-72}. Trimethoprim0.8 hour{R-72}. Horses Sulfadoxine: 14 hours{R-30}; 9.7 hours{R-37}. Trimethoprim: 3.2 hours{R-30}; 1.9 hours{R-37}. Sheep 1 week of age: Sulfadoxine15.3 hours{R-84}. Trimethoprim2.5 hours{R-84}. 4 months of age to adult: Sulfadoxine11.5 hours{R-84}. Trimethoprim0.75 hour{R-74; 84}. Sulfamethoxazole and trimethoprim: Horses Sulfamethoxazole: 3.5 hours{R-31}; 4.8 hours{R-33}. Trimethoprim: 1.9 hours{R-31}; 3.4 hours{R-33}. Horse foals Sulfamethoxazole: 9.9 hours{R-32}. Trimethoprim: 1.6 hours{R-32}. Pony foals Sulfamethoxazole: 5.8 hours{R-32}. Trimethoprim: 2.8 hours{R-32}. Quail: Sulfamethoxazole2.9 hours{R-93}. Trimethoprim2.38 hours{R-93}. Sulfadiazine: Administered alone orallyDogs: 9.84 hours{R-49}. Sulfadimethoxine: Administered alone Cats: 10.2 hours{R-102}. Dogs: 13.1 hours{R-104}. Trout, rainbow: 16 hours{R-67; 70}. Trimethoprim: Administered alone Dogs: Based on oral dosing2.5 hours{R-30; 49}. Pigs: 2.4 hours{R-89}. Sulfadiazine and trimethoprimOral: Calves 1 week of age: 11.9 mcg of sulfadiazine per mL at 12 hours and 0.41 mcg of trimethoprim per mL at 3 hours (dose of 25 mg of sulfadiazine and 5 mg of trimethoprim per kg){R-81}. 6 weeks of age: Milk-fed17.3 mcg of sulfadiazine per mL at 3 hours and 0.43 mcg of trimethoprim per mL at 1.5 hours (dose of 25 mg sulfadiazine and 5 mg of trimethoprim per kg of body weight){R-81}. Grain and berfed14.9 mcg of sulfadiazine per mL at 8 hours and < 0.1 mcg of trimethoprim per mL (below test limit) for entire trial (dose of 25 mg of sulfadiazine and 5 mg of trimethoprim per kg of body weight){R-81}. Dogs 12.4 mcg of sulfadiazine per mL at 4 hours and 1.7 mcg of trimethoprim per mL at 1 hour (dose of 20 mg of sulfadiazine and 4 mg of trimethoprim per kg of body weight){R-49}. 30.1 mcg of sulfadiazine per mL{R-19} and 1.52 mcg of trimethoprim per mL{R-2; 19} at 3 hours (dose of 25 mg of sulfadiazine and 5 mg of trimethoprim per kg of body weight). After 2 days of dosing every 12 hours: 67.4 mcg of sulfadiazine per mL and 2.98 mcg of trimethoprim per mL at 2 hours{R-46} (dose of 25 mg of sulfadiazine and 5 mg of trimethoprim per kg). After 4 days of dosing every 24 hours: 84.7 mcg of sulfadiazine at 3 hours and 2.55 mcg of trimethoprim per mL at 2 hours{R-46} (dose of 25 mg of sulfadiazine and 5 mg of trimethoprim per kg). Horses Fasted: 9 to 13 mcg of sulfadiazine per mL at 3 hours and 1 to 1.5 mcg of trimethoprim per mL at 1 to 2 hours (dose of 25 to 29 mg of sulfadiazine and 5 to 6 mg of trimethoprim per kg of body weight){R-2729} Fed: 10 mcg of sulfadiazine per mL and 0.5 mcg of trimethoprim per mL at 6 hours (dose of 29.2 mg of sulfadiazine and 5.8 mg of trimethoprim per kg of body weight){R-27}. Pigs Fasted: 32 mcg of sulfadiazine per mL at 4.3 hours and 1.9 mcg of trimethoprim per mL at 2.1 hours (oral dose of 40 mg of sulfadiazine and 8 mg of trimethoprim per kg of body weight){R-91}. Fed: 25 mcg of sulfadiazine per mL at 3.2 hours and 1.5 mcg of trimethoprim per mL at 3.4 hours (oral dose of 40 mg of sulfadiazine and 8 mg of trimethoprim per kg of body weight){R-91}. Salmon20.3 mcg of sulfadiazine per mL at 24 hours and 3.25 mcg of trimethoprim per mL at 12 hours (oral dose of 83.3 mg of sulfadiazine and 16.7 mg of trimethoprim per kg of body weight of sh at 8 C){R-63}. Sulfadoxine and trimethoprimCattle: Intramuscular administration30.3 mcg of sulfadoxine per mL at 2 hours and 0.7 mcg of trimethoprim per mL at 0.75 to 1 hour (dose of 13.3 mg of sulfadoxine and 2.7 mg of trimethoprim per kg of body weight){R-85}. Sulfamethoxazole and trimethoprimHorses: Oral administration0.26 mcg/mL of trimethoprim at 0.75 hour and 13.7 mcg/mL of sulfamethoxazole at 1.5 hours (dose of 12.5 mg of sulfamethoxazole and 2.5 mg of trimethoprim per kg of body weight){R-31}. Duration of action: Duration of action may be estimated by the length of time target serum concentrations are maintained; however, duration of action for the potentiated sulfonamides is difcult to estimate from target serum concentrations{R-78} because of the rapid movement of the

Peak serum concentration: SulfadimethoxineAdministered alone: Oral Catsh, channel: 7.83 to 11 mcg/mL at 3 to 6 hours (after 5 days of dosing 40 to 42 mg/kg every 24 hours){R-68; 69}. Chickens: 106.3 mcg/mL at 12 hours (single dose of 100 mg/kg).{R103}

Cows: 114 10 mcg/mL at 10 hours (dose of 107 mg/kg).{R-111} Dogs: 67 16 mcg/mL at 3.75 hours (dose of 55 mg/kg).{R-104} Ormetoprim and sulfadimethoxineOral: Foals, 1 to 3 days of age0.65 mcg of ormetoprim per mL at 2 hours and 54.6 mcg of sulfadimethoxine per mL at 8 hours (dose of 3.5 mg of ormetoprim and 17.5 mg of sulfadimethoxine per kg of body weight){R-36}. Horses80 mcg of sulfadimethoxine per mL at 8 hours and 0.92 mcg of ormetoprim per mL at 0.5 hour postadministration (loading dose of 9.2 mg of ormetoprim and 45.8 mg of sulfadimethoxine per kg of body weight){R-25}.

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POTENTIATED SULFONAMIDES VeterinarySystemic 171 diaminopyrimidines into the tissues and the possibly wide range of local sulfonamide to diaminopyrimidine concentration ratios believed to be effective and synergistic. Target concentrations should be viewed as estimates only, and clinical response should be considered one of the measurements of activity of the medication. Some sources consider bacteria susceptible if their minimum inhibitory concentration (MIC) is 0.5 mcg/mL for trimethoprim and 9.5 mcg/mL for sulfonamide{R-25}. However, the National Committee for Clinical Laboratory Standards (NCCLS) in the U.S. lists MIC breakpoints for animal isolates and trimethoprim/sulfamethoxazole as 2 mcg per mL/38 mcg per mL for susceptible organisms and 4 mcg per mL/76 mcg per mL for resistant organisms{R-141}. Organisms testing between these values are considered intermediate and may or may not be inhibited in certain body sites or with certain antimicrobials with low toxicity in which high concentrations can be achieved{R-141}. These breakpoints are also used to test for susceptibility to sulfadiazine and trimethoprim or ormetoprim and sulfadimethoxine combination{R-141}. Sulfadiazine and trimethoprimCalves: 1 day of ageA single intravenous dose of 25 mg of sulfadiazine and 5 mg of trimethoprim produced therapeutic serum concentrations > 2 mcg of sulfadiazine per mL of serum for 24 hours and > 0.1 mcg of trimethoprim per mL for 15 hours{R-79}. 7 to 42 days of ageA single intravenous dose of 25 mg of sulfadiazine and 5 mg of trimethoprim produced therapeutic serum concentrations of > 2 mcg of sulfadiazine per mL of serum for 15 hours and > 0.1 mcg/mL of trimethoprim for 6 to 8 hours{R-79}. Sulfadoxine and trimethoprimCattle: Sulfadoxine serum concentrations exceeded 9.5 mcg/mL from 12 minutes to 10 hours postinjection and trimethoprim serum concentrations exceeded 0.5 mcg/mL from 15 minutes to 2 hours (intramuscular dose of 13.3 mg of sulfadoxine and 2.7 mg of trimethoprim per kg of body weight) postinjection{R-85}. azine and trimethoprim are administered concurrently, neither antibiotic interferes with the excretion of the other{R-3; 4}. Dogs: Two-thirds of the total dose is eliminated in the urine as parent drug in the rst 24 hours{R-19}. Total clearance Ormetoprim and sulfadimethoxine: Horses Ormetoprim: 11.1 mL per minute per kg (mL/min/kg){R-35}. Sulfadimethoxine: 0.42 mL/min/kg{R-35}. Sulfadiazine and trimethoprim: Calves Sulfadiazine: 1 day of age1.43 mL/min/kg{R-79}. 1 week of age1.7 mL/min/kg{R-79; 80}. 6 weeks of age1.88 mL/min/kg{R-79}. Trimethoprim: 1 day of age2.8 mL/min/kg{R-79}. 1 week of age12 mL/min/kg{R-79; 80}. 6 weeks of age28.9 mL/min/kg{R-79}. Calves, ruminating Sulfadiazine: 3.15 mL/min/kg{R-77}. Trimethoprim: 6.6 mL/min/kg{R-77}. Horses Sulfadiazine: 1.92 mL/min/kg{R-43}. Trimethoprim: 8.49 mL/min/kg{R-43}. Pigs Sulfadiazine: 2.3 mL/min/kg{R-91}. Trimethoprim: 9.1 mL/min/kg{R-91}. Sulfamethoxazole and trimethoprim: Horses Sulfamethoxazole: 1.3 mL/min/kg{R-31; 33}. Trimethoprim: 11.3 mL/min/kg{R-33}; 14.8 mL/min/kg{R-31}. Horse foals Sulfamethoxazole: 0.83 mL/min/kg{R-32}. Trimethoprim: 17.1 mL/min/kg{R-32}. Pony foals Sulfamethoxazole: 1.1 mL/min/kg{R-32}. Trimethoprim: 11.7 mL/min/kg{R-32}. Sulfadimethoxine: Administered alone Cats: 0.32 mL/min/kg{R-102}. Dogs: 0.36 mL/min/kg{R-104}. Trout, rainbow: 0.36 mL/min/kg{R-70}.

Elimination: SulfonamidesRenal excretion is the primary route of elimination for most nonenteric sulfonamides and it occurs by glomerular ltration of parent drug, tubular excretion of unchanged drug and metabolites, and passive reabsorption of nonionized drug.{R-94; 110} Alkalization of the urine increases the fraction of the dose that is eliminated in the urine.{R-110} In general, the metabolites of the parent drug are more quickly eliminated by the kidney than is the original sulfonamide{R-75}, but the proportions of metabolites formed can vary depending on many factors. Sulfadimethoxine: CattleSulfadimethoxine is metabolized to a great degree, so that 40 to 60% of the administered dose is excreted as metabolites in the urine{R-111}. DogsSulfadimethoxine is slowly excreted renally because of a high degree of tubular reabsorption{R-5}. Sulfadoxine: HorsesSulfadoxine is excreted by glomerular ltration and reabsorption{R-34}. The clearance of sulfadoxine increases with increasing pH{R-34}. TrimethoprimRenal excretion occurs by glomerular ltration, active tubular secretion, and reabsorption{R-25; 89}. Horses: It is believed that a large percentage of trimethoprim is metabolized before elimination in urine (46%) and feces (52%){R-25; 26; 30} . The clearance of trimethoprim is affected by urine pH, plasma concentration, and extent of diuresis{R-34}; however, when sulfadi 2003 Thomson MICROMEDEX

PRECAUTIONS TO CONSIDER SPECIES SENSITIVITY

Dogs: An idiosyncratic sulfonamide toxicosis can occur in any breed of dog, but this reaction has been reported more frequently in the Doberman Pinscher than in other breeds. This specic type of drug reaction includes blood dyscrasias, nonseptic polyarthritis, and skin rash{R-53; 54}. See also the Side Adverse Effects section in this monograph. Horses: Trimethoprim with sulfadiazine or with sulfadoxine infused into the uterus of horses can cause endometrial inammation, straining, and expulsion of the medication. Conception rates may be lowered. Because there is good distribution of these medications when administered by systemic routes, intrauterine administration is not recommended.{R-27}.

CROSS-SENSITIVITY AND/OR RELATED PROBLEMS

Patients allergic to one sulfonamide may be allergic to other sulfonamides also. All rights reserved

172 POTENTIATED SULFONAMIDES VeterinarySystemic

PREGNANCY/REPRODUCTION
Sulfonamides and diaminopyrimidines cross the placenta in pregnant animals{R-110} and some teratogenic effects have been seen with very high doses given to pregnant mice and rats{R-110}. Ormetoprim and sulfadimethoxine: DogsSafety in breeding or pregnant animals has not been established{R-5}. Sulfadiazine and trimethoprim: DogsThe recommended dose of 25 mg of sulfadiazine and 5 mg of trimethoprim per kg of body weight administered during pregnancy had no apparent effect on offspring{R-2; 19}. HorsesSafety in pregnant animals has not been established{R-4}. With administration of recommended doses, no changes in spermatogenesis in stallions were apparent{R-4}.

LACTATION
Sulfonamides are distributed into milk, with 0.5 to 2% of the total dose found in the milk{R-114; 115}. For example, the milk-to-plasma concentration ratio for sulfadiazine and sulfadoxine was measured to be 0.5 in cows{R-75; 82}. Trimethoprim is distributed into milk{R-35}. Trimethoprim concentrations in milk were found to be 1.3 to 3.5 times the plasma concentration measured at the same time in goats{R-73}. The concentration of trimethoprim in the milk of cows is 1 to 3 times higher than in plasma{R-82; 83} and the concentration of trimethoprim in the milk of pigs is 1.3 to 3.5 times higher than in plasma{R-90}.

DRUG INTERACTIONS AND/OR RELATED PROBLEMS

The following drug interactions and/or related problems have been selected on the basis of their potential clinical signicance (possible mechanism in parentheses where appropriate)not necessarily inclusive ( = major clinical signicance): Note: Combinations containing the following medication, depending on the amount present, may also interact with this medication. Detomidine (a trimethoprim and sulfonamide combination administered to a detomidine-anesthetized horse can lead to arrhythmias, hypotension, and death; it is suspected that the antimicrobial potentiates the cardiac changes reported with detomidine{R-25; 120}).

HUMAN DRUG INTERACTIONS{R-149}

In addition to the above drug interactions reported in animals, the following drug interactions have been reported in humans and are included in the human monographs Sulfonamides (Systemic) and Trimethoprim (Systemic) in USP DI Volume I; these drug interactions are intended for informational purposes only and may or may not be applicable to the use of sulfonamides in the treatment of animals: Note: Combinations containing any of the following medications, depending on the amount present, may also interact with this medication. Anticoagulants, coumarin- or indandione-derivative, or Anticonvulsants, hydantoin, or Antidiabetic agents, oral (these medications may be displaced from protein binding sites and/ or their metabolism may be inhibited by some sulfonamides, resulting in increased or prolonged effects and/or toxicity; dosage adjustments may be necessary during and after sulfonamide therapy) Bone marrow depressants (concurrent use of bone marrow depressants with sulfonamides or aminopyrimidines may increase the leukopenic and/or 2003 Thomson MICROMEDEX

thrombocytopenic effects; if concurrent use is required, close observation for myelotoxic effects should be considered) Cyclosporine (concurrent use with sulfonamides or trimethoprim may increase the metabolism of cyclosporine, resulting in decreased plasma concentrations and potential transplant rejection, and additive nephrotoxicity; plasma cyclosporine concentrations and renal function should be monitored) Dapsone (concurrent use with trimethoprim will usually increase the plasma concentrations of both dapsone and trimethoprim, possibly due to an inhibition in dapsone metabolism, and/or competition for renal secretion between the two medications; increased serum dapsone concentrations may increase the number and severity of side effects, especially methemoglobinemia) Folate antagonists, other (concurrent use with trimethoprim or use of trimethoprim between courses of other folic acid antagonists is not recommended because of the possibility of an increased risk of megaloblastic anemia) Hemolytics, other (concurrent use with sulfonamides may increase the potential for toxic side effects) Hepatotoxic medications, other (concurrent use with sulfonamides may result in an increased incidence of hepatotoxicity; patients, especially those on prolonged administration or those with a history of liver disease, should be carefully monitored) Methenamine (in acid urine, methenamine breaks down into formaldehyde, which may form an insoluble precipitate with certain sulfonamides, especially those that are less soluble in urine, and may also increase the danger of crystalluria; concurrent use is not recommended) Methotrexate or Phenylbutazone or Sulnpyrazone (the effects of methotrexate may be potentiated during concurrent use with sulfonamides because of displacement from plasma protein binding sites; phenylbutazone and sulnpyrazone may displace sulfonamides from plasma protein binding sites, increasing sulfonamide concentrations) Phenytoin (trimethoprim may inhibit the hepatic metabolism of phenytoin, increasing the half-life of phenytoin by up to 50% and decreasing its clearance by 30%) Procainamide (concurrent use with trimethoprim may increase the plasma concentration of both procainamide and its metabolite NAPA by decreasing their renal clearance) Rifampin (concurrent use may signicantly increase the elimination and shorten the elimination half-life of trimethoprim) Warfarin (trimethoprim may potentiate the anticoagulant activity of warfarin by inhibiting its metabolism)

LABORATORY VALUE ALTERATIONS

The following have been selected on the basis of their potential clinical signicance (possible effect in parentheses where appropriate)not necessarily inclusive ( = major clinical signicance): All rights reserved

POTENTIATED SULFONAMIDES VeterinarySystemic 173 With diagnostic test results Thyrotropin stimulation tests or Total serum thyroxine (T4) (thyroid function tests may be lowered in dogs with administration of sulfamethoxazole and trimethoprim combination at high doses [25 mg of sulfamethoxazole and 5 mg of trimethoprim per kg of body weight every 12 hours for 6 weeks]{R-62} or ormetoprim and sulfadimethoxine{R-21} [8 weeks of medication with the labeled dose or with three to ve times the labeled dose]; the T4 and thyrotropin stimulation tests, but not T3, may be signicantly reduced{R-61}; this effect was not shown with labeled doses of sulfadiazine and trimethoprim{R-62}) With physiology/laboratory test values Cholesterol, serum (cholesterol concentrations can be elevated with administration of sulfonamides, including ormetoprim and sulfadimethoxine combination; however, this effect is reversible{R-5}) (slight to moderate reduction in hematopoietic activity has been reported with long-term high dosing of potentiated sulfonamides{R-99}) Hypersensitivity to diaminopyrimidines or sulfonamides{R-5; 10; 18; 19} (animals that have had a previous reaction may be much more likely to react on subsequent administration) Risk-benet should be considered when the following medical problems exist: Hepatic function impairment{R-5; 10; 18; 19; 25} (delayed biotransformation may increase the risk of adverse effects) Renal function impairment{R-25} (delayed elimination could cause accumulation of sulfonamide and metabolites, increasing the risk of adverse effects) Urolithiasis{R-25} (sulfonamides can crystallize in the renal system under certain conditions{R-25})

PATIENT MONITORING HUMAN LABORATORY VALUE ALTERATIONS{R-149}

In addition to the above laboratory value alterations reported in animals, the following laboratory value alterations have been reported in humans, and are included in the human monographs Sulfonamides (Systemic) and Trimethoprim (Systemic) in USP DI Volume I; these laboratory value alterations are intended for informational purposes only and may or may not be applicable to the use of sulfonamides in the treatment of animals: With diagnostic test results Benedicts test (sulfonamides may produce a false-positive Benedicts test for urine glucose) Creatinine determinations (sulfamethoxazole or trimethoprim may interfere with the Jaffe alkaline picrate reaction assay for creatinine, resulting in creatinine values that are approximately 10% higher than actual values) Sulfosalicylic acid test (sulfonamides may produce a false-positive sulfosalicylic acid test for urine protein) Urine urobilinogen test strip (e.g., Urobilistix) (sulfonamides may interfere with the Urobilistix test for urinary urobilinogen) With physiology/laboratory test values Alanine aminotransferase (ALT [SGPT]), serum, and Aspartate aminotransferase (AST [SGOT]), serum (values may be increased) Bilirubin, serum, and Blood urea nitrogen (BUN) and Creatinine, serum (concentrations may be increased) The following may be especially important in patient monitoring (other tests may be warranted in some patients, depending on condition; = major clinical signicance): Complete blood count (CBC), including platelet count (some animals have had reductions in hematopoietic activity when administered potentiated sulfonamides; periodic CBC and platelet counts are recommended if it is necessary to administer long-term treatment with potentiated sulfonamides{R-3; 19}) Culture and susceptibility, in vitro, and Minimum inhibitory concentration (MIC) (in vitro cultures and MIC test should be done on samples collected prior to potentiated sulfonamide administration to determine pathogen susceptibility) Schirmers tear test (periodic Schirmers tear tests during potentiated sulfonamide therapy in dogs may be warranted to monitor for early keratoconjunctivitis sicca{R-124})

SIDE/ADVERSE EFFECTS
The following side/adverse effects have been selected on the basis of their potential clinical signicance (possible signs and, for humans, symptoms in parentheses where appropriate)not necessarily inclusive:

THOSE INDICATING NEED FOR MEDICAL ATTENTION

Incidence unknown For all species Crystallization in the urinary tract{R-5}; hypersensitivity, specically anaphylaxis{R-4; 5} Note: Crystallization of sulfonamides is theoretically possible with administration of potentiated sulfonamides; however, the lower doses of sulfonamide used in the potentiated sulfonamide combination makes crystallization less likely to occur than with sulfonamide administered alone. Sulfonamides can crystallize in the kidneys or urine in animals with aciduria, with high doses of sulfonamide, or with dehydration. The amount of drug in the acetylated metabolite form also can affect solubility. Because dogs do not produce acetylated metabolites, they may be less susceptible to this adverse effect{R-123}. Crystallization also can be minimized in susceptible animals by maintaining a high urine ow and, if necessary, alkalinizing the urine. All rights reserved

MEDICAL CONSIDERATIONS/CONTRAINDICATIONS
The medical considerations/contraindications included have been selected on the basis of their potential clinical signicance (reasons given in parentheses where appropriate)not necessarily inclusive ( = major clinical signicance). Except under special circumstances, this medication should not be used when the following medical problems exist: Blood dyscrasias{R-25; 99} 2003 Thomson MICROMEDEX

174 POTENTIATED SULFONAMIDES VeterinarySystemic Dogs Anemia, hemolytic{R-5; 19}; anemia, nonregenerative{R-23; 51}; anorexia{R-5; 19}; cutaneous drug eruption, including erythema multiforme, perforating folliculitis, and pustular dermatitides{R-54; 60}; diarrhea{R-5; 19}; facial swelling{R-5; 19}; fever{R-5; 19} ; hepatitis{R-5; 19; 52; 54}; hypothyroidism{R-21; 61; 62}; idiosyncratic toxicosis{R-53; 54; 5760} (blood dyscrasias, including anemia, leukopenia, or thrombocytopenia; fever; focal retinitis; lymphadenopathy; nonseptic polyarthritis; polymyositis; skin rash); keratoconjunctivitis sicca{R-5; 19; 55; 56}; neurologic disorders{R-19} (aggression, ataxia, behavioral changes, hyperexcitability, seizures); polyarthritis{R-5; 19}; polydipsia/polyuria{R-5; 19}; thrombocytopeniaone case reported without other blood lines affected{R-116}; urticaria{R-5; 19}; vomiting{R-5; 19}. Note: Idiosyncratic toxicosis can occur 8 to 20 days after starting treatment and is believed to be caused by either an immune-mediated syndrome or by an idiosyncratic reaction in dogs, perhaps due to toxic metabolites of the sulfonamide. Of 22 reported cases compiled in one study, 7 were Doberman Pinschers and it has been theorized that they are more susceptible than other breeds to this toxicosis{R-53; 54}. A large majority of the animals in which idiosyncratic toxicosis occurs have had a previous exposure to a sulfonamide{R-54}. When sulfonamide therapy is discontinued, recovery generally occurs within 2 to 5 days.{R-54; 60} Keratoconjunctivitis sicca is considered a possible side/adverse effect in any dog administered sulfonamides; it can occur at any time after therapy is initiated. The most frequent reports have been with sulfasalazine or trimethoprim and sulfonamide combination{R-55; 56} , perhaps because these medications are most commonly used for long-term therapy in dogs. As many as 15% (5 out of 33 in one study) of dogs treated with sulfadiazine and trimethoprim may develop keratoconjunctivitis sicca{R-124}. While increased risk has not been linked to higher dose or longer treatment, dogs weighing less than 12 kg may be at increased risk{R-124}. Lacrimation may return to normal after discontinuation of sulfonamide treatment. The nonregenerative anemias seen in response to long-term administration of sulfadiazine and trimethoprim combination are, in some cases, believed to be related to folate reduction with long-term, highdose administration (60 to 120 mg/kg a day for many weeks{R-23}) of potentiated sulfonamide{R-23; 50}; these anemias generally respond well to withdrawal of the medication{R-23}. In the event an animal does not respond to medication withdrawal, folinic or folic acid supplementation may be necessary{R-137; 138}. Iatrogenic hypothyroidism may occur and thyroid function test results may be lowered with administration of sulfamethoxazole and trimethoprim combination at high doses (25 mg of sulfamethoxazole and 5 mg of trimethoprim per kg every 12 hours for 6 weeks){R-62} or ormetoprim and sulfadimethoxine{R-21} (8-week medication with the labeled dose or with three to ve times the labeled dose). Results of the T4 and thyrotropin stimulation tests, but not T3, may show signicant reduction{R-61}; this effect was not shown with labeled doses of sulfadiazine and trimethoprim (12.5 mg of sulfadiazine and 2.5 mg of trimethoprim per kg every 12 hours for 4 weeks){R-62}. Horses Diarrhea, transientapproximately 3% of horses treated in one study{R-3; 139}; hypersensitivity reactions (anorexia; decreased hematopoiesis{R-3}; loose stool; or muscle tremors)with intravenous administration of potentiated sulfonamides{R-25; 26; 35} Pigs Thyroid hyperplasiain gilts, sows and piglets; believed to be in response to the sulfadimethoxine component of ormetoprim and sulfadimethoxine combination{R-92} For sulfaquinoxaline Chickens and dogs Hemorrhagic syndrome (anorexia, epistaxis, hemoptysis, lethargy, pale mucous membranes, death){R-100; 112; 113; 121; 122} Note: Hemorrhagic syndrome has been reported in chickens and dogs but may occur in other species. It is most often reported with the addition of sulfaquinoxaline to feed for chickens, but in dogs, reports follow administration of products labeled for poultry but administered to dogs in the water supply.{R-112; 113; 121; 122} Sulfaquinoxaline is a vitamin K antagonist that inhibits vitamin K epoxide and vitamin K quinone reductase and causes an effect similar to that of coumarin anticoagulants.{R-100} Rapid hypoprothrombinemia occurs in dogs and an additional adverse effect of sulfaquinoxaline on specic cell types may explain why supplementation of chicken feeds with vitamin K has not always prevented the syndrome in chickens.{R-100; 112} Rapid discontinuation of medication and initiation of therapy with vitamin K1 may reverse the effects.

THOSE INDICATING NEED FOR MEDICAL ATTENTION ONLY IF THEY CONTINUE OR ARE BOTHERSOME
Incidence more frequent Cats Salivationwith uncoated tablets or broken tablets{R-11}; thyroid function changeswith prolonged dosages{R-11}; vomiting, transientup to 1 hour after administration of sulfadiazine and trimethoprim combination{R-23} Cattle, horses, or pigs Local pain and swellingwith intramuscular injection of sulfonamide and trimethoprim{R-9; 13; 14} Pigs Irritant reactionswith intramuscular injections{R-14}; vomitingwith oral suspension of sulfadiazine and trimethoprim combination{R-10}

HUMAN SIDE/ADVERSE EFFECTS{R-149}

In addition to the above side/adverse effects reported in animals, the following side/adverse effects have been reported in humans and are included in the human monographs Sulfonamides (Systemic) and Trimethoprim (Systemic) in USP DI Volume I; these side/adverse effects are intended for informational purposes only and may or may not be applicable to the use of potentiated sulfonamides in the treatment of animals: For sulfonamides Incidence more frequent Central nervous system (CNS) effects; gastrointestinal disturbances; hypersensitivity; photosensitivity Incidence less frequent Blood dyscrasias; hepatitis; Lyells syndrome (difculty in swallowing; redness, blistering, peeling, or loosening of skin); Stevens-Johnson syndrome (aching joints and muscles; redness, blistering, peeling, or loosening of skin; unusual tiredness or weakness) All rights reserved

2003 Thomson MICROMEDEX

POTENTIATED SULFONAMIDES VeterinarySystemic 175 Incidence rare CNS toxicity; Clostridium difcile colitis; crystalluria or hematuria; goiter or thyroid function disturbance; interstitial nephritis or tubular necrosis Note: Fatalities have occurred, although rarely, due to severe reactions such as Stevens-Johnson syndrome, fulminant hepatic necrosis, agranulocytosis, aplastic anemia, and other blood dyscrasias. Therapy should be discontinued at the rst appearance of skin rash or any serious side/adverse effects or if signs of folic acid deciency occur. Crystalluria is more likely to occur with a less soluble sulfonamide, such as sulfadiazine. It occurs most often with the administration of high doses, and can be minimized by maintaining a high urine ow and alkalinizing the urine. C. difcile colitis may occur up to several weeks after discontinuation of these medications. For trimethoprim Incidence less frequent Gastrointestinal disturbances; headache; pruritis; skin rash Incidence rare Anaphylaxis; aseptic meningitis; blood dyscrasias, such as leukopenia or neutropenia, megaloblastic anemia, and thrombocytopenia; glossitis; methemoglobinemia; phototoxicity; severe skin reactions, such as erythema multiforme, exfoliative dermatitis, Stevens-Johnson syndrome, and toxic epidermal necrolysis [Lyells syndrome]

VETERINARY DOSING INFORMATION

Although the minimum inhibitory concentrations (MICs) of potentiated sulfonamides are important in determining therapeutic regimens, they can be misleading because the actual concentrations of drugs at the therapeutic site can be difcult to pinpoint at any one time. Trimethoprim goes rapidly into tissues, and sulfonamides often have measurable serum concentrations for longer periods. The ratio of sulfonamide to trimethoprim concentrations necessary at the site for efcacy may vary from the goal of 20 to 1, depending on the tissue and the local concentrations of other factors, such as thymidine.{R-24}. Clinical efcacy also should be considered, once pathogen susceptibility has been determined{R-24; 31}. The National Committee for Clinical Laboratory Standards (NCCLS) in the U.S. lists MIC breakpoints for animal isolates and trimethoprim/ sulfamethoxazole as 2 mcg per mL/38 mcg per mL for susceptible organisms and 4 mcg per mL/76 mcg per mL for resistant organisms{R-141}. Organisms testing between these values are considered intermediate and may or may not be inhibited in certain body sites in which high concentrations can be achieved or with certain antimicrobial agents with low toxicity{R-141}. These breakpoints are also used to test for susceptibility to sulfadiazine and trimethoprim or ormetoprim and sulfadimethoxine combination{R-141}.

FOR ORAL DOSAGE FORMS ONLY

Horses: The oral administration of 25 to 100 mg of sulfadiazine and 5 to 20 mg of trimethoprim per kg of body weight a day for 5 days does not cause the increase in coliform bacteria and Clostridium perfringens type A associated with induced colitis. Healthy horses do not appear to develop watery stools within this dosage range. At the highest dose, a slight decrease in coliform count is noted in healthy horses.{R-40} Having free access to feed does not signicantly affect the horses ability to absorb sulfadiazine during administration of oral sulfadiazine and trimethoprim combination. The absorption of trimethoprim is delayed so initial serum concentrations will be lower in a fed horse than in a fasted horse; however, this effect is greatly decreased by the third day of treatment{R-27}.

OVERDOSE
For more information in cases of overdose or unintentional ingestion, contact the American Society for the Prevention of Cruelty to Animals (ASPCA) National Animal Poison Control Center (888426-4435 or 900-443-0000; a fee may be required for consultation) and/or the drug manufacturer. Acute toxicities appear to be difcult to induce; those reported below are in response to a dose ve times the loading dose and ten times the maintenance dose on the product label.

CLINICAL EFFECTS OF OVERDOSE

The following effects have been selected on the basis of their potential clinical signicance (possible signs in parentheses where appropriate)not necessarily inclusive: For ormetoprim and sulfadimethoxine{R-21} Dogs (53 mg ormetoprim and 267 mg sulfadimethoxine per kg of body weight dose or 160 mg ormetoprim per kg administered alone) Convulsions; hyperglycemia, mild

FOR TREATMENT OF ADVERSE EFFECTS

Recommended treatment consists of the following: For anaphylaxis Parenteral epinephrine. Oxygen administration and respiratory support.

ORMETOPRIM AND SULFADIMETHOXINE TREATMENT OF OVERDOSE

Recommended treatment consists of the following: Discontinuing medication. Administering intravenous diazepam or other acute antiseizure medication as needed. Providing uid replacement therapy as required.

ORAL DOSAGE FORMS

Note: Bracketed information in the Dosage Forms section refers to uses that either are not included in U.S. product labeling or are for products not commercially available in the U.S.

ORMETOPRIM AND SULFADIMETHOXINE FOR MEDICATED FEED

Usual dose: Coccidiosis (prophylaxis)1 Chickens and partridges, chukar: Oral, 68.1 grams of ormetoprim and 113.5 grams of sulfadimethoxine per ton of feed, fed as the only ration{R-6; 125}. All rights reserved

CLIENT CONSULTATION
Dosage and length of treatment recommendations should be followed. High doses or long-term use can increase the risk of side effects. Animals should have a good water supply and should be monitored to insure their adequate water consumption during treatment. 2003 Thomson MICROMEDEX

176 POTENTIATED SULFONAMIDES VeterinarySystemic Turkeys: Oral, 34 grams of ormetoprim and 56.8 grams of sulfadimethoxine per ton of feed, fed as the only ration{R-6}. Colibacillosis (prophylaxis)1Chickens: Oral, 68.1 grams of ormetoprim and 113.5 grams of sulfadimethoxine per ton of feed, fed as the only ration{R-6}. Colibacillosis (treatment)1Ducks: Oral, 272.4 grams of ormetoprim and 454 grams of sulfadimethoxine per ton of feed, fed as the only ration for seven days{R-6}. Enteric septicemia1Catsh: Oral, 8 mg of ormetoprim and 42 mg of sulfadimethoxine per kg of body weight a day, administered in the feed and fed as the only ration for ve days{R-7; 16}. Fowl cholera (prophylaxis)1 Chickens: Oral, 68.1 grams of ormetoprim and 113.5 grams of sulfadimethoxine per ton of feed, fed as the only ration{R-6}. Turkeys: Oral, 34 grams of ormetoprim and 56.8 grams of sulfadimethoxine per ton of feed, fed as the only ration{R-6}. Fowl cholera (treatment)1Ducks: RoutineOral, 136.2 grams of ormetoprim and 227 grams of sulfadimethoxine per ton of feed, fed as the only ration for seven days{R-6}. SevereOral, 272.4 grams of ormetoprim and 454 grams of sulfadimethoxine per ton of feed, fed as the only ration for seven days{R-6}. FurunculosisSalmon and trout: Oral, 8 mg of ormetoprim and 42 mg of sulfadimethoxine per kg of body weight a day, administered in the feed, and fed as the only ration for ve days{R-7; 16}. Infectious coryza (prophylaxis)1Chickens: Oral, 68.1 grams of ormetoprim and 113.5 grams of sulfadimethoxine per ton of feed, fed as the only ration{R-6}. New duck disease1Ducks: Oral, 272.4 grams of ormetoprim and 454 grams of sulfadimethoxine per ton of feed, fed as the only ration for seven days{R-6}.
Withdrawal time Species Catsh Salmon, trout Meat (days) 3 42

Canada{R-16}
Withdrawal time Species Salmon, trout Meat (days) 42

Note: Product labeling with the above withdrawal time states that it applies to a dose of 15 mg per kg of body weight a day when the water temperature is 10 C. Packaging and storage: Store below 40 C (104 F), preferably between 15 and 30 C (59 and 86 F), unless otherwise specied by the manufacturer. Additional information: Canadian labeling states that the product should not be used when the water temperature is below 10 C{R-16}. USP requirements: Not in USP.

ORMETOPRIM AND SULFADIMETHOXINE TABLETS

Usual dose: Skin and soft tissue infections1; or Urinary tract infections1Dogs: Oral, 9.2 mg of ormetoprim and 45.8 mg of sulfadimethoxine per kg of body weight as an initial dose, followed by 4.6 mg of ormetoprim and 22.9 mg of trimethoprim per kg of body weight every twenty-four hours{R-5}. Administration for more than twenty-one days is not recommended{R-5}. Note: DogsAlthough the efcacy has not been established, a dose of 11 mg of ormetoprim and 55 mg of sulfadimethoxine a day has been used in the treatment of [enteric coccidiosis]1 in dogs. This therapy may reduce shedding of oocysts and relieve symptoms{R-136}. Strength(s) usually available{R-150}: U.S.{R-5} Veterinary-labeled product(s): 20 mg of ormetoprim and 100 mg of sulfadimethoxine (Rx) [Primor 120]. 40 mg of ormetoprim and 200 mg of sulfadimethoxine (Rx) [Primor 240]. 100 mg of ormetoprim and 500 mg of sulfadimethoxine (Rx) [Primor 600]. 200 mg of ormetoprim and 1000 mg of sulfadimethoxine (Rx) [Primor 1200]. Canada Veterinary-labeled product(s): Not commercially available. Packaging and storage: Store below 40 C (104 F), preferably between 15 and 30 C (59 and 86 F), unless otherwise specied by the manufacturer.

Strength(s) usually available{R-150}: U.S. Veterinary-labeled product(s): 50 grams of ormetoprim and 250 grams of sulfadimethoxine per kg of premix (OTC) [Romet 30 (catsh and salmonids)]. 150 grams of ormetoprim and 250 grams of sulfadimethoxine per kg of premix (OTC) [Rofenaid 40 (chickens, ducks, partridges, and turkeys)]. Canada Veterinary-labeled product(s): 50 grams of ormetoprim and 250 grams of sulfadimethoxine per kg of premix (Rx) [Romet-30 (salmonids)]. Withdrawal times: U.S.{R-6; 7}
Withdrawal time Species Chickens, ducks, partridges, turkeys Meat (days) 5

Note: Product labeling with the above withdrawal times states that this combination is not for use in birds producing eggs for food or for chickens over 16 weeks of age{R-6}. 2003 Thomson MICROMEDEX

All rights reserved

POTENTIATED SULFONAMIDES VeterinarySystemic 177 USP requirements: Not in USP.

1

Not included in Canadian product labeling or product not commercially available in Canada

PYRIMETHAMINE AND SULFAQUINOXALINE ORAL DOSAGE FORMS

Note: Bracketed information in the Dosage Forms section refers to uses that either are not included in U.S. product labeling or are for products not commercially available in the U.S.

PYRIMETHAMINE AND SULFAQUINOXALINE ORAL SOLUTION

Usual dose: [Coccidiosis (prophylaxis and treatment)]Chickens and turkeys: Oral, 14.7 mg of pyrimethamine and 48.8 mg of sulfaquinoxaline per liter of water, administered as the only source of drinking water for two days. Treatment is stopped for three days and then repeated as necessary to control infection. For existing infection, treatment should be repeated until symptoms of disease have disappeared{R-17}. Strength(s) usually available{R-150}: U.S. Veterinary-labeled product(s): Not commercially available. Canada{R-17} Veterinary-labeled product(s): 9.8 grams of pyrimethamine and 32.5 grams of sulfaquinoxaline per liter of solution (OTC) [Quinnoxine-S; Sulfaquinoxaline-S]. Withdrawal times: Canada{R-17}
Withdrawal time Species Chickens, turkeys Meat (days) 4

Note: HorsesBased on pharmacokinetic studies, disease models of infectious arthritis, and the relatively short half-life of trimethoprim in the horse, an [oral dose of 25 mg of sulfadiazine and 5 mg of trimethoprim per kg of body weight every twelve hours has been used to treat susceptible infections in horses{R-25}, including equine infectious arthritis]1, in which case the dose is administered for three to six weeks{R-41; 42}. The administration of oral sulfadiazine and trimethoprim combination while a horse has free access to feed does not signicantly affect the absorption of the sulfadiazine{R-25; 27; 28}; however, the absorption of trimethoprim is delayed so that initial serum concentrations will be lower in a fed horse than in a fasted horse. This effect is greatly decreased by the third day of treatment{R-27}. For horses being treated for less severe, susceptible infections, allowing free access to food is recommended to decrease the risk of diarrhea{R-25}. Strength(s) usually available{R-150}: U.S.{R-3} Veterinary-labeled product(s): 333 mg of sulfadiazine and 67 mg of trimethoprim per gram of paste (Rx) [Tribrissen 400 Oral Paste]. Canada{R-18} Veterinary-labeled product(s): Not commercially available. Withdrawal times: U.S.Sulfadiazine and trimethoprim oral paste is not labeled for use in food-producing animals, including horses intended for food production. See Sulfadiazine and Trimethoprim Tablets for more information. Packaging and storage: Store between 15 and 30 C (59 and 86 F), unless otherwise specied by the manufacturer{R-3}. USP requirements: Not in USP.

SULFADIAZINE AND TRIMETHOPRIM ORAL POWDER

Usual dose: Respiratory tract infections1; Skin and soft tissue infections1; Strangles1; or Urogenital infections1Horses: Oral, 25 mg of sulfadiazine and 5 mg of trimethoprim per kg of body weight every twenty-four hours{R-4}. Note: Based on pharmacokinetic studies, an [oral dose of 25 mg of sulfadiazine and 5 mg of trimethoprim per kg of body weight every twelve hours]1 has also been used in horses{R-25}. The administration of oral sulfadiazine and trimethoprim combination while a horse has free access to feed does not signicantly affect the absorption of the sulfadiazine{R-25; 27; 28}; however, the absorption of trimethoprim is delayed so initial serum concentrations will be lower in a fed horse than in a fasted horse. This effect is greatly decreased by the third day of treatment{R-27}. For horses being treated for less severe, susceptible infections, allowing free access to food is recommended to decrease the risk of diarrhea{R-25}. [Vibrio anguillarum infection]Salmon: Oral, 25 mg of sulfadiazine and 5 mg of trimethoprim per kg of body weight a day, administered in the feed, and fed as the only ration for seven to ten days{R-22}. All rights reserved

Packaging and storage: Store below 23 C (73 F), unless otherwise specied by the manufacturer. Protect from freezing{R-17}. USP requirements: Not in USP.

SULFADIAZINE AND TRIMETHOPRIM ORAL DOSAGE FORMS

Note: Bracketed information in the Dosage Forms section refers to uses that either are not included in U.S. product labeling or are for products not commercially available in the U.S.

SULFADIAZINE AND TRIMETHOPRIM ORAL PASTE

Usual dose: Respiratory tract infections; Skin and soft tissue infections; Strangles; Urogenital infections1; or [Perioperative infections]Horses: Oral, 25 mg of sulfadiazine and 5 mg of trimethoprim per kg of body weight every twenty-four hours{R-3; 18}. 2003 Thomson MICROMEDEX

178 POTENTIATED SULFONAMIDES VeterinarySystemic Strength(s) usually available{R-150}: U.S. Veterinary-labeled product(s): 333 mg of sulfadiazine and 67 mg of trimethoprim per gram of powder (Rx) [Tucoprim Powder; Uniprim Powder (horses)]. Canada Veterinary-labeled product(s): 333 mg of sulfadiazine and 67 mg of trimethoprim per gram of powder (Rx) [Tribrissen 40% Powder (salmon)]. Withdrawal times: U.S.Sulfadiazine and trimethoprim oral powder is not labeled for use in food-producing animals, including horses intended for food production. See Sulfadiazine and Trimethoprim Tablets for more information. Canada{R-22}
Withdrawal time Species Salmon Meat (days) 80

SULFADIAZINE AND TRIMETHOPRIM TABLETS

Usual dose: Gastrointestinal tract infections1; Respiratory tract infections1; or Skin and soft tissue infections1{R-46}Dogs and [cats]: Oral, 12.5 mg of sulfadiazine and 2.5 mg of trimethoprim per kg of body weight every twelve hours{R-2; 11; 19} or, less commonly, 25 mg of sulfadiazine and 5 mg of trimethoprim per kg of body weight every twenty-four hours. Note: Only intact tablets should be administered to cats, to avoid excessive salivation caused by contact of the medication with oral mucosa{R-11}. Urinary tract infections1Dogs: Oral, 12.5 mg of sulfadiazine and 2.5 mg of trimethoprim per kg of body weight every twelve hours or, less commonly, 25 mg of sulfadiazine and 5 mg of trimethoprim per kg of body weight every twenty-four hours{R-11}. Note: For [bacterial prostatitis in dogs, 25 mg of sulfadiazine and 5 mg of trimethoprim per kg of body weight every twelve hours for two to four weeks]1 is recommended{R-23; 47; 48}, based on pharmacokinetic data. Product labeling states that administration for more than fourteen days is not recommended{R-2; 11; 19}. Note: Although the efcacy has not been established, doses up to [37.5 to 50 mg of sulfadiazine and 7.5 to 10 mg of trimethoprim per kg of body weight every twelve hours for three to six months have been used in the treatment of nocardiosis]1 in cats and dogs{R-23; 130; 132}. For organisms susceptible to both sulfadiazine and trimethoprim, once-daily dosing is likely to be efcacious for cats and dogs. However, for organisms that may be resistant to one of the antimicrobials, twice-daily dosing as above is recommended. For infections for which susceptibility is unknown or when life-threatening infections are present, 25 mg of sulfadiazine and 5 mg of trimethoprim per kg of body weight every twelve hours has been used, based on current information about the pharmacokinetics of this medication in the dog{R-23}. Note: [Calves, nonruminating]1Until recently, Canadian sulfadiazine and trimethoprim boluses were labeled for use in the treatment of bacterial pneumonia in calves{R-12}. Although there are no sulfadiazine and trimethoprim products labeled for use in calves in the United States or Canada at this time, oral sulfadiazine and trimethoprim tablets might be used in the treatment of susceptible infections, such as pneumonia, in calves. Tablets are not recommended for use in ruminating animals because of poor bioavailability{R-81} and subsequent lack of efcacy as calves progress to the ruminant state{R-12}. In ruminating calves, therapeutic serum concentrations of trimethoprim have not been reached with oral administration{R-81}. Increased rate of elimination and decreased absorption of the medication as calves mature lead to a decrease in resulting serum antibiotic concentration that is measurable at 6 weeks of age in milk-fed calves and becomes so pronounced with onset of rumination that this medication cannot be administered effectively{R-79; 81; 143}. According to some researchers{R-24; 81; 143}, many pathogens important in calfhood diseases, including Escherichia coli, Salmonella species, and Haemophilus species, have minimum inhibitory concentrations (MICs) that range from 3 to 10 mcg per mL (mcg/mL) for sulfonamides and 0.1 to 0.5 mcg/mL for trimethoprim. Researchers have suggested that, in calves less than 1 week of age, oral

Note: The half-lives of sulfadiazine and trimethoprim in the deepest layer of marine sediments can be ninety days or longer{R-65}. Packaging and storage: Store below 40 C (104 F), preferably between 15 and 30 C (59 and 86 F), in a tight container, unless otherwise specied by the manufacturer. Protect from light{R-22}. USP requirements: Not in USP.

SULFADIAZINE AND TRIMETHOPRIM ORAL SUSPENSION

Usual dose: [Colibacillosis]; or [Enteritis, bacterial]Piglets: Oral, 22.8 mg of sulfadiazine and 4.6 mg of trimethoprim per kg of body weight every twenty-four hours{R-10}. Strength(s) usually available{R-150}: U.S. Veterinary-labeled product(s): Not commercially available. Canada Veterinary-labeled product(s): 45.5 mg of sulfadiazine and 9.1 mg of trimethoprim per mL (Rx) [Tribrissen Piglet Suspension]. Withdrawal times: Canada{R-10}
Withdrawal time Species Piglets Meat (days) 5

Packaging and storage: Store below 40 C (104 F), preferably between 15 and 30 C (59 and 86 F), unless otherwise specied by the manufacturer. Protect from freezing. USP requirements: Not in USP.

2003 Thomson MICROMEDEX

All rights reserved

POTENTIATED SULFONAMIDES VeterinarySystemic 179 administration of 12.5 mg of sulfadiazine and 2.5 mg of trimethoprim per kg of body weight every 24 hours would be appropriate in the treatment of infections caused by these organisms{R-81}. They note that in animals older than 1 week of age, an oral dose of 25 mg of sulfadiazine and 5 mg of trimethoprim per kg of body weight, administered every 12 hours, has been necessary to maintain therapeutic concentrations{R-81}. However, the National Committee for Clinical Laboratory Standards (NCCLS) lists the breakpoints as 38/2 mcg/mL for sulfonamide and trimethoprim, respectively{R-141}. It is possible for an organism to be classied as sensitive yet have MICs above the plasma concentration achieved by the above dosages{R-145}. Based on pharmacokinetic calculations, an oral dosage of 37.5 mg of sulfadiazine and 7.5 mg of trimethoprim per kg of body weight every 12 hours in calves older than 1 week of age but younger than 6 weeks of age may be needed to consistently maintain concentrations greater than or equal to the NCCLS breakpoints, but the safety and efcacy of such a dose has not been tested in calves{R-144; 145}. Strength(s) usually available{R-150}: U.S. Veterinary-labeled product(s): 25 mg of sulfadiazine and 5 mg of trimethoprim (Rx) [Tribrissen 30]. 100 mg of sulfadiazine and 20 mg of trimethoprim (Rx) [Tribrissen 120]. 400 mg of sulfadiazine and 80 mg of trimethoprim (Rx) [Tribrissen 480]. 800 mg of sulfadiazine and 160 mg of trimethoprim (Rx) [Tribrissen 960]. Canada Veterinary-labeled product(s): Not commercially available. Withdrawal times: U.S. and CanadaSulfadiazine and trimethoprim tablets are not labeled for use in food-producing animals. There is no established withdrawal time for calves in the U.S. and, in Canada, where a sulfadiazine and trimethoprim bolus was once available, there is no longer any product labeled for use in calves. If a sulfadiazine and trimethoprim combination product available in the U.S. is administered to 1-week-old calves at a dose of 12.5 mg of sulfadiazine and 2.5 mg of trimethoprim every twelve hours, there is some evidence to suggest that a meat withdrawal time of 10 days, the discontinued Canadian product label withdrawal time, would be sufcient to avoid residues that would violate U.S. standards{R-12; 79; 80; 81; 140; 142} . Estimates for a withdrawal time for dosages larger than 12.5 mg of sulfadiazine and 2.5 mg of trimethoprim every twelve hours are not available. It should be considered that substitution of one oral dosage form for another may result in differences in pharmacokinetic results. Available residue studies{R-140} and pharmacokinetic{R81} studies for oral products were performed in calves using boluses and tablets, respectively. Packaging and storage: Store below 40 C (104 F), preferably between 15 and 30 C (59 and 86 F), unless otherwise specied by the manufacturer.

PARENTERAL DOSAGE FORMS

Note: Bracketed information in the Dosage Forms section refers to uses that either are not included in U.S. product labeling or are for products not commercially available in the U.S.

SULFADIAZINE AND TRIMETHOPRIM INJECTION

Usual dose: Respiratory tract infections; or Skin and soft tissue infections [Cats] and [dogs]: Subcutaneous, 12.5 mg of sulfadiazine and 2.5 mg of trimethoprim per kg of body weight every twelve hours or, less commonly, 25 mg of sulfadiazine and 5 mg of trimethoprim per kg of body weight every twenty-four hours{R-8; 95}. Horses: Intramuscular or intravenous, 20 mg of sulfadazine and 4 mg of trimethoprim per kg of body weight every twenty-four hours{R-9}. Strangles; or Urogenital tract infections1Horses: Intramuscular or intravenous, 20 mg of sulfadiazine and 4 mg of trimethoprim per kg of body weight every twenty-four hours{R-9}. [Gastrointestional tract infections]Cats and dogs: Subcutaneous, 12.5 mg of sulfadiazine and 2.5 mg of trimethoprim per kg of body weight every twelve hours or, less commonly, 25 mg of sulfadiazine and 5 mg of trimethoprim per kg of body weight every twenty-four hours{R-8}. Note: Although Canadian labeling recommends intramuscular or intravenous administration of sulfadiazine and trimethoprim combination and there are few reports in the literature of adverse reactions to intravenous administration of this combination, some sources recommend caution when administering these medications intravenously to horses{R-25}. Product labeling states that administration for more than fourteen days in cats and dogs and more than seven days in horses is not recommended{R-8; 9}. Strength(s) usually available{R-150}: U.S. Veterinary-labeled product(s): 400 mg of sulfadiazine and 80 mg of trimethoprim per mL (Rx) [Tribrissen 48% (horses)]. Canada Veterinary-labeled product(s): 200 mg of sulfadiazine and 40 mg of trimethoprim per mL (Rx) [Tribrissen 24% (cats and dogs)]. 400 mg of sulfadiazine and 80 mg of trimethoprim per mL (Rx) [Tribrissen 48% (horses)]. Withdrawal times: U.S. and CanadaProducts are not labeled for use in horses to be used for food production{R-9}. Packaging and storage: Store below 40 C (104 F), preferably between 15 and 30 C (59 and 86 F), unless otherwise specied by the manufacturer. USP requirements: Not in USP.
1

USP requirements: Not in USP.

1

Not included in Canadian product labeling or product not commercially available in Canada.

Not included in Canadian product labeling or product not commercially available in Canada. All rights reserved

2003 Thomson MICROMEDEX

180 POTENTIATED SULFONAMIDES VeterinarySystemic

SULFADOXINE AND TRIMETHOPRIM PARENTERAL DOSAGE FORMS

Note: Bracketed information in the Dosage Forms section refers to uses that either are not included in U.S. product labeling or are for products not commercially available in the U.S.

SULFAMETHOXAZOLE AND TRIMETHOPRIM ORAL SUSPENSION USP

Usual dose: Note: [Dogs]1Although the safety and efcacy have not been established, an oral dose of 25 mg of sulfamethoxazole and 5 mg of trimethoprim per kg of body weight every twelve hours for two to four weeks has been used in the treatment of bacterial prostatitis in dogs, based on pharmacokinetic data{R-47; 48}. [Horses]1Although the safety and efcacy have not been established, an oral dose of 25 mg of sulfamethoxazole and 5 mg of trimethoprim per kg of body weight every twelve hours has been used in the treatment of bacterial infections, based on pharmacokinetic studies{R-31}. Strength(s) usually available: U.S. Veterinary-labeled product(s): Not commercially available. Human-labeled product(s):{R-119} 40 mg of sulfamethoxazole and 8 mg of trimethoprim per mL (Rx) [Bactrim Pediatric; Cotrim Pediatric; Septra Grape Suspension; Septra Suspension; Sulfatrim Pediatric; Sulfatrim Suspension; generic]. Canada Veterinary-labeled product(s): Not commercially available. Human-labeled product(s): 40 mg of sulfamethoxazole and 8 mg of trimethoprim per mL (Rx) [Apo-Sulfatrim; Bactrim; Novo-Trimel; Nu-Cotrimox; Septra]. Packaging and storage: Store below 40 C (104 F), preferably between 15 and 30 C (59 and 86 F), unless otherwise specied by the manufacturer. Store in a tight, light-resistant container. Protect from freezing. USP requirements: Preserve in tight, light-resistant containers. Contains the labeled amounts, within 10%. Meets the requirements for Identication, pH (5.06.5), Chromatographic purity, and Alcohol content (not more than 0.5%){R-117}.

SULFADOXINE AND TRIMETHOPRIM INJECTION

Usual dose: [Bacterial enteritis]; [Bacterial pneumonia]; or [Colibacillosis]Cattle and pigs: Intramuscular or slow intravenous, 13.3 mg of sulfadoxime and 2.7 mg of trimethoprim per kg of body weight, every twenty-four hours for ve days{R-1315}. Note: [Cattle]Based on pharmacokinetic studies, a dose of 13.3 mg of sulfadoxine and 2.7 mg of trimethoprim per kg of body weight every twelve hours1 may be necessary to treat infections in cattle caused by organisms that are less than very sensitive to sulfadoxine and trimethoprim{R-85}. [Bacterial arthritis]; [Mastitis]; or [Metritis]Pigs: Intramuscular or slow intravenous, 13.3 mg of sulfadoxine and 2.7 mg of trimethoprim per kg of body weight every twenty-four hours for ve days{R-1315}. [Pododermatitis]; or [Septicemia]Cattle: Intramuscular or slow intravenous, 13.3 mg of sulfadoxine and 2.7 mg of trimethoprim per kg of body weight, every twenty-four hours for ve days{R-1315}. Strength(s) usually available{R-150}: U.S. Veterinary-labeled product(s): Not commercially available. Canada Veterinary-labeled product(s): 200 mg of sulfadoxine and 40 mg of trimethoprim per mL (Rx) [Bimotrim; Borgal; Potensulf; Trimidox; Trivetrin]. Withdrawal times: Canada{R-1315}
Withdrawal time Species Cattle Pigs Meat (days) 10 10 Milk (hours) 96

SULFAMETHOXAZOLE AND TRIMETHOPRIM TABLETS USP

Usual dose: See Sulfamethoxazole and Trimethoprim Oral Suspension USP. Strength(s) usually available: U.S. Veterinary-labeled product(s): Not commercially available. Human-labeled product(s):{R-119} 400 mg of sulfamethoxazole and 80 mg of trimethoprim (Rx) [Bactrim; Cotrim; Septra; Sulfatrim; Sulfatrim S/S]. 800 mg of sulfamethoxazole and 160 mg of trimethoprim (Rx) [Bactrim DS; Cofatrim Forte; Cotrim DS; Septra DS; Sulfatrim DS]. Canada Veterinary-labeled product(s): Not commercially available. Human-labeled product(s): 100 mg of sulfamethoxazole and 20 mg of trimethoprim (Rx) [ApoSulfatrim]. All rights reserved

Packaging and storage: Store below 40 C (104 F), preferably between 15 and 30 C (59 and 86 F), unless otherwise specied by the manufacturer. Protect from freezing. USP requirements: Not in USP.
1

Not included in Canadian product labeling or product not commercially available in Canada.

SULFAMETHOXAZOLE AND TRIMETHOPRIM ORAL DOSAGE FORMS

Note: Bracketed information in the Dosage Forms section refers to uses that either are not included in U.S. product labeling or are for products not commercially available in the U.S. 2003 Thomson MICROMEDEX

POTENTIATED SULFONAMIDES VeterinarySystemic 181 400 mg of sulfamethoxazole and 80 mg of trimethoprim (Rx) [ApoSulfatrim; Bactrim; Novo-Trimel; Nu-Cotrimox; Septra]. 800 mg of sulfamethoxazole and 160 mg of trimethoprim (Rx) [ApoSulfatrim DS; Bactrim DS; Novo-Trimel D.S.; Nu-Cotrimox DS; Roubac; Septra DS]. Packaging and storage: Store below 40 C (104 F), preferably between 15 and 30 C (59 and 86 F), unless otherwise specied by the manufacturer. Store in a well-closed, light-resistant container. USP requirements: Preserve in well-closed, light-resistant containers. Contain the labeled amounts, within 7%. Meet the requirements for Identication, Dissolution (70% of each active ingredient in 60 minutes in 0.1 N hydrochloride acid in Apparatus 2 at 75 rpm), and Uniformity of dosage units{R-117}. Preparation of dosage form: The contents of each vial (5 mL) must be diluted to 75 to 125 mL with 5% dextrose injection prior to administration by intravenous infusion. The resulting solution should be administered by intravenous infusion over a sixty- to ninety-minute period. Stability: After initial dilution with 75 or 125 mL of 5% dextrose injection, infusion should be administered within two or six hours, respectively. The solution should not be used if it is cloudy or contains a precipitate. The solution should not be mixed with other medications or solutions. USP requirements: Preserve in single-dose, light-resistant containers, preferably of Type I glass. May be packaged in 50-mL multiple-dose containers. A sterile solution of Sulfamethoxazole and Trimethoprim in Water for Injection which, when diluted with Dextrose Injection, is suitable for intravenous infusion. Label it to indicate that it is to be diluted with 5% Dextrose Injection prior to administration. Contains the labeled amounts, within 10%. Meets the requirements for Identication, Pyrogen, pH (9.510.5), Particulate matter, and Related compounds, and for Injections.{R-117}

Not included in Canadian product labeling or product not commercially available in Canada.

PARENTERAL DOSAGE FORMS

Note: Bracketed information in the Dosage Forms section refers to uses that either are not included in U.S. product labeling or are for products not commercially available in the U.S.

Not included in Canadian product labeling or product not commercially available in Canada.

SULFAMETHOXAZOLE AND TRIMETHOPRIM INJECTION USP

Usual dose: Note: [Foals]1 and [horses]1Although the efcacy and safety have not been established, a slow intravenous dose of 12.5 mg of sulfamethoxasole and 2.5 mg of trimethoprim per kg of body weight every twelve hours has been used in the treatment of susceptible bacterial and protozoal infections in foals and horses, based on pharmacokinetic data{R-31; 32}. However, to reach effective concentrations in the cerebrospinal uid (CSF) for bacterial and protozoal infections, higher doses are required; distribution studies show that an intravenous dose of 36 mg of sulfamethoxazole and 7.5 mg of trimethoprim per kg of body weight will produce CSF concentrations sufcient to treat susceptible bacterial and protozoal infections{R-31; 33}. Intravenous doses should be administered slowly. Strength(s) usually available: U.S. Veterinary-labeled product(s): Not commercially available. Human-labeled product(s):{R-119} 80 mg of sulfamethoxazole and 16 mg of trimethoprim per mL (Rx) [Bactrim I.V.; Septra I.V.]. Canada Veterinary-labeled product(s): Not commercially available. Human-labeled product(s): 80 mg of sulfamethoxazole and 16 mg of trimethoprim per mL (Rx) [Septra]. Packaging and storage: Store below 40 C (104 F), preferably between 15 and 30 C (59 and 86 F), unless otherwise specied by the manufacturer. Store in a light-resistant container. Should not be refrigerated. 2003 Thomson MICROMEDEX

Developed: 6/10/98 Revised: 6/30/02 Interim revision: 11/10/99; 4/10/03

REFERENCES
1. USP dictionary of USAN and international drug names, 2002 ed. Rockville, MD: The United States Pharmacopeial Convention, Inc. 2002. 2. Sulfadiazine and trimethoprim product information (Tribrissen tablets, Schering-PloughUS). Downloaded from www.spah.com on 2/21/03. 3. Sulfadiazine and trimethoprim product information (Tribrissen 400 Oral Paste, Schering-PloughUS). Downloaded from www.spah.com on 2/21/03. 4. Sulfadiazine and trimethoprim package insert (Tucoprim, PharmaciaUS), Rev 4/01. Downloaded from www.pharmaciaah.com on 2/21/03. 5. Ormetoprim and sulfadimethoxine package insert (Primor, PzerUS), Rev 3/94. Downloaded from www.pzer.com on 2/21/03. 6. Ormetoprim and sulfadimethoxine package insert (Rofenaid 40 Premix, RocheUS), Rev 92, Rec 10/30/95. 7. Ormetoprim and sulfadimethoxine package insert (Romet B, RocheUS), Rev 87, Rec 10/30/95. 8. Sulfadiazine and trimethoprim product information (Tribrissen 24% Injection, Schering-PloughCanada). Downloaded from Schering-Plough Animal Health Product Label Retrieval Service on 2/21/03. 9. Sulfadiazine and trimethoprim product information (Tribrissen 48% Injection, Schering-PloughCanada). Downloaded from Schering-Plough Animal Health Product Label Retrieval Service on 2/21/03. 10. Sulfadiazine and trimethoprim package insert (Tribrissen Piglet Suspension, MallinckrodtCanada), Rec 6/1/95. 11. Sulfadiazine and trimethoprim package insert (Tribrissen Tablets, MallinckrodtCanada), Rec 6/1/95 [discontinued product]. 12. Sulfadiazine and trimethoprim package insert (Tribrissen Boluses, MallinckrodtCanada), Rec 6/1/95 [discontinued product]. 13. Sulfadoxine and trimethoprim product information (Trivetrin Injection, Schering-PloughCanada). Downloaded from Schering-Plough Animal Health Product Label Retrieval Service on 2/21/03. 14. Sulfadoxine and trimethoprim package insert (Borgal Injection, HoeschstCanada), Rec 7/5/95. 15. Sulfadoxine and trimethoprim package insert (Trimidox, SanoCanada), Rec 5/19/95.

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182 POTENTIATED SULFONAMIDES VeterinarySystemic

16. Romet-30, Hoffman-LaRoche. In: Bennett K, editor. Compendium of veterinary products. 4th ed. Hensall, Ontario: North American Compendiums, Ltd.; 1995. p. 572. 17. Pyrimethamine and sulfaquinoxaline product label (Quinnoxine-S, A.P.A./ SanoCanada), Rec 10/27/95. 18. Sulfadiazine and trimethoprim package insert (Tribrissen Oral Paste, MallinckrodtCanada), Rec 6/1/95. 19. Sulfadiazine and trimethoprim package insert (Ditrim, SyntexUS), Rev 5/ 93, Rec 3/1/96. 20. Van Miert ASGPAM. The sulfonamide-diaminopyridine story. J Vet Pharmacol Ther 1994; 17: 30916. 21. Freedom of information summary. Primor tablets. New Animal Drug Application (NADA) 100929. Hoffman-LaRoche Inc. 22. Sulfadiazine and trimethoprim product information (Tribrissen 40% Powder, Schering-PloughCanada). Downloaded from Schering-Plough Animal Health Product Label Retrieval Service on 2/21/03. 23. Wilcke JR. Therapeutic application of sulfadiazine/trimethoprim in dogs and cats: a review. Companion Anim Pract 1988 Sep: 38. 24. Bushby SRM. Sulfonamide and trimethoprim combinations. J Am Vet Med Assoc 1980 May; 176(10): 104953. 25. Van Duijkeren E, Vulto AG, Van Miert ASGPAM. Trimethoprim/sulfonamide combinations in the horse: a review. J Vet Pharmacol Ther 1994; 17: 6473. 26. Alexander F, Collett RA. Trimethoprim in the horse. Equine Vet J 1975 Oct; 7(4): 2036. 27. Sigel CW, Byars TD, Divers TJ, et al. Serum concentrations of trimethoprim and sulfadiazine following oral paste administration to the horse. Am J Vet Res 1981 Nov; 42 (11): 20025. 28. Bogan JA, Galbraith A, Baxter NM, et al. Effect of feeding on the fate of orally administered phenylbutazone, trimethoprim and sulphadiazine in the horse. Vet Rec 1984; 115: 599600. 29. Brown MP, Kelly RH, Stover SM, et al. Trimethoprim-sulfadiazine in the horse: serum, synovial, peritoneal, and urine concentrations after single-dose intravenous administration. Am J Vet Res 1983 Apr; 44(4): 5403. 30. Rasmussen F, Gelsa H, Nielsen P. Pharmacokinetics of sulphadoxine and trimethoprim in horses. Half-life and volume of distribution of sulphadoxine and trimethoprim and cumulative excretion of [14C]-trimethoprim. J Vet Pharmacol Ther 1979; 2: 24555. 31. Brown MP, Gronwall R, Castro L. Pharmacokinetics and body uid and endometrial concentrations of trimethoprim-sulfamethoxazole in mares. Am J Vet Res 1988 Jun; 49(6): 91822. 32. Brown MP, McCartney JH, Gronwall R, et al. Pharmacokinetics of trimethoprim-sulphamethoxazole in two-day-old foals after a single intravenous injection. Equine Vet J 1990; 22(1): 513. 33. Green SL, Mayhew IG, Brown MP, et al. Concentrations of trimethoprim and sulfamethoxazole in cerebrospinal uid and serum in mares with and without a dimethyl sulfoxide pretreatment. Can J Vet Res 1990 Apr; 54(2): 21522. 34. Gelsa J. The renal clearance of inulin, creatinine, trimethoprim and sulphadoxine in horses. J Vet Pharmacol Ther 1979; 2: 25764. 35. Brown MP, Gronwall RR, Houston AE. Pharmacokinetics and body uid and endometrial concentrations of ormetoprim-sulfadimethoxine in mares. Can J Vet Res 1989; 53: 126. 36. Brown MP, Gronwall RR, Cook LK, et al. Serum concentrations of ormetoprim/sulphadimethoxine in 13-day-old foals after a single dose of oral paste combination. Equine Vet J 1993; 25: 734. 37. Boyd EH, Allen WE. Absorption of two trimethoprim/sulphonamide combinations from the uterus of pony mares. J Vet Pharmacol Ther 1989 Dec; 12(4): 43843. 38. Carli S, Sonzogni O, Villa R. Pharmacokinetic prole of sulphamonomethoxine-trimethoprim in horses after intravenous, intramuscular and oral administration. Res Vet Sci 1993; 54: 1848. 39. Van Duijkeren E, Vulto AG, Sloet Van Oldruitenborgh-Oosterbaan MM, et al. Pharmacokinetics of trimethoprim/sulphachlorpyridazine in horses after oral, nasogastric and intravenous administration. J Vet Pharmacol Ther 1995; 18: 4753. 40. White G, Prior SD. Comparative effects of oral administration of trimethoprim/sulphadiazine or oxytetracycline on the faecal ora of horses. Vet Rec 1982; 111: 3168. 41. Bertone AL, McIlwraith CW, Jones RL, et al. Comparison of various treatments for experimentally induced equine arthritis. Am J Vet Res 1987 Mar; 48(3): 51929. 42. Bertone AL, Jones RL, McIlwraith CW. Serum and synovial uid steadystate concentrations of trimethoprim and sulfadiazine in horses with experimentally induced infectious arthritis. Am J Vet Res 1988 Oct; 49(10): 16817. Van Duijkeren E, Vulto AG, Sloet Van Oldruitenborgh-Oosterbaan MM, et al. A comparative study of the pharmacokinetics of intravenous and oral trimethoprim/sulfadiazine formulations in the horse. J Vet Pharmacol Ther 1994; 17: 4406. Indiveri MC, Hirsh DC. Susceptibility of obligate anaerobes to trimethoprimsulfamethoxazole. J Am Vet Med Assoc 1986 Jan; 188(1): 468. Sigel CW, Macklin AW, Grace ME, et al. Trimethoprim and sulfadiazine concentrations in aqueous and vitreous humors of the dog. Vet Med Small Anim Clin 1981 Jul; 76(7): 9913. Pohlenz-Zertuche HO, Brown MP, Gronwall R, et al. Serum and skin concentrations after multiple-dose oral administration of trimethoprimsulfadiazine in dogs. Am J Vet Res 1992 Jul; 53(7): 12736. Rogers KS, Lees GE, Simpson RB. Effects of single-dose and three-day trimethoprim-sulfadiazine and amikacin treatment of induced Escherichia coli urinary tract infections in dogs. Am J Vet Res 1988; 49(3): 3459. Robb CA, Carroll PT, Tippett LO, et al. The diffusion of selected sulfonamides, trimethoprim, and diaveridine into prostatic uid of dogs. Invest Urol 1971; 8(6): 67985. Sigel CW, Ling GV, Bushbuy SRM, et al. Pharmacokinetics of trimethoprim and sulfadiazine in the dog: urine concentrations after oral administration. Am J Vet Res 1981 Jun; 42(6): 9961001. Fox LE, Ford S, Alleman AR, et al. Aplastic anemia associated with prolonged high-dose trimethoprim-sulfadiazine administration in two dogs. Vet Clin Path 1993 Sep; 22(3): 8992. Weiss DJ, Klausner JS. Drug-associated aplastic anemia in dogs: eight cases (19841988). J Am Vet Med Assoc 1990 Feb; 196(3): 4725. Rowland PH, Center SA, Dougherty SA. Presumptive trimethoprim-sulfadiazine-related hepatotoxicosis in a dog. J Am Vet Med Assoc 1992 Feb; 200(3): 34850. Cribb AE, Spielberg SP. An in vitro investigation of predisposition to sulphonamide idiosyncratic toxicity in dogs. Vet Res Commun 1990; 14: 24152. Cribb AE. Idiosyncratic reactions to sulfonamides in dogs. J Am Vet Med Assoc 1989 Dec; 195(11): 1615. Collins BK, Moore CP, Hagee JH. Sulfonamide-associated keratoconjunctivitis sicca and corneal ulceration in a dysuric dog. J Am Vet Med Assoc 1986 Oct; 189(8): 9246. Morgan RV, Bachrach A. Keratoconjunctivitis sicca associated with sulfonamide therapy in dogs. J Am Vet Med Assoc 1982; 180: 4324. Giger U, Werner LL, Millichamp NJ, et al. Sulfadiazine-induced allergy in six Doberman Pinschers. J Am Vet Med Assoc 1995 Mar; 186(5): 47984. Werner LL, Bright JM. Drug-induced hypersensitivity disorders in two dogs treated with trimethoprim sulfadiazine: case reports and drug challenge studies. J Am Anim Hosp Assoc 1983 Sep/Oct; 19(5): 78390. Lees GE, Rogers KS, Troy GC. Polyarthritis associated with sulfadiazine administration in a Labrador retriever dog. Southwest Vet 1986; 37(1): 147. Medleau L, Shanley KJ, Rakich PM, et al. Trimethoprim-sulfonamideassociated drug eruptions in dogs. J Am Anim Hosp Assoc 1990 May/Jun; 26(3): 30511. Hall IA, Campbell KL, Chambers MD, et al. Effect of trimethoprim/sulfamethoxazole on thyroid function in dogs with pyoderma. J Am Vet Med Assoc 1993 Jun; 202(12): 195962. Panciera DL, Post K. Effect of oral administration of sulfadiazine and trimethoprim in combination on thyroid function in dogs. Can J Vet Res 1992; 56: 34952. Hormazabal V, Rogstad A. Simultaneous determination of sulphadiazine and trimethoprim in plasma and tissues of cultured sh for residual and pharmacokinetic studies. J Chromatogr 1992 Dec; 583(2): 2017. Kimura T, Yoshimizu M, Wada M. In vitro antibacterial activity of the combination of sulphadiazine and trimethoprim on bacterial sh pathogens. J Fish Dis 1983 Nov; 6(6): 52532. Hektoen H, Berge JA, Hormazabal V, et al. Persistence of antibacterial agents in marine sediments. Aquaculture 1995 Jun; 133(34): 17584. Zheng M, Liu H, Hall SF, et al. High-performance liquid chromatographic analysis of Romet-30 in Chinook salmon (Oncorhynchus tshawytscha): wash-out time, tissue distribution in muscle, liver and skin, and metabolism of sulfadimethoxine. J Chromatogr 1994; 670: 7788. Kleinow KM, Lech JJ. A review of the pharmacokinetics and metabolism of sulfadimethoxine in the rainbow trout (Salmo gairdneri). Vet Hum Toxicol 1988; 30 (Suppl. 1): 2630.

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54. 55.

56. 57. 58.

59.

60.

61.

62.

63.

64.

65. 66.

67.

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POTENTIATED SULFONAMIDES VeterinarySystemic 183

68. Squibb KS, Michel CMF, Zelikoff JT, et al. Sulfadimethoxine pharmacokinetics and metabolism in the channel catsh (Ictalurus punctatus). Vet Hum Toxicol 1988; 30 (Suppl. 1): 315. 69. Walker CC, Thune RL, Barker SA. Plasma/muscle ratios of sulfadimethoxine residues in channel catsh (Ictalurus punctatus). J Vet Pharmacol Ther 1995; 18: 30610. 70. Kleinow KM, James MO, Lech JJ. Drug pharmacokinetics and metabolism in food-producing sh and crustaceans: methods and examples. In: Hutson DH, Hawkins DR, Paulson GD, et al, editors. Xenobiotics and food-producing animals: metabolism and residues. Proceedings of the American Chemical Society. American Chemical Society, New York, NY, 1991; Aug 2530; 1992. p. 98130. 71. Mathis GF, McDougald LR, McMurray B. Effectiveness of therapeutic anticoccidial drugs against recently isolated coccidia. Poult Sci 1984; 63: 114953. 72. Nielsen P, Rasmussen F. Inuence of age on half-life of trimethoprim and sulphadoxine in goats. Acta Pharmacol Toxicol 1976; 38: 1139. 73. Rasmussen F. Renal and mammary excretion of trimethoprim in goats. Vet Rec 1970 Jul; 87(1): 148. 74. Atef M, Al-Khayyat AA, Fahd K. Pharmacokinetics and tissue distribution of trimethoprim in sheep. Zentralbl Veterinarmed Reine A 1978 Sep; 25(7): 57984. 75. Nouws JFM, Mevius D, Vree TB, et al. Pharmacokinetics, metabolism, and renal clearance of sulfadiazine, sulfamerazine, and sulfamethazine and of their N4-acetyl and hydroxy metabolites in calves and cows. Am J Vet Res 1988 Jul; 49(7): 105965. 76. Piercy DWT. Distribution of trimethoprim/sulphadiazine in plasma, tissue and synovial uids. Vet Rec 1978 Jun; 102(24): 5234. 77. Clarke CR, Short CR, Corstvet RE, et al. Effect of pasteurella haemolytica infection on the distribution of sulfadiazine and trimethoprim into tissue chambers implanted subcutaneously in cattle. Am J Vet Res 1989 Sep; 50(9): 15516. 78. White G, Piercy WT, Gibbs HA. Use of a calf salmonellosis model to evaluate the therapeutic properties of trimethoprim and sulphadiazine and their mutual potentiation in vivo. Res Vet Sci 1981; 31: 2731. 79. Shoaf SE, Schwark WS, Guard CL. Pharmacokinetics of sulfadiazine/trimethoprim in neonatal male calves: effect of age and penetration into cerebrospinal uid. Am J Vet Res 1989 Mar; 50(3): 396403. 80. Shoaf SE, Schwark WS, Guard CL, et al. Pharmacokinetics of trimethoprim/ sulfadiazine in neonatal calves: inuence of synovitis. J Vet Pharmacol Ther 1986 Dec; 9(4): 44654. 81. Shoaf SE, Schwark WS, Guard CL. The effect of age and diet on sulfadiazine/ trimethoprim disposition following oral and subcutaneous administration to calves. J Vet Pharmacol Ther 1987 Dec; 10(4): 33145. 82. Davitiyananda D, Rasmussen F. Half-lives of sulphadoxine and trimethoprim after a single intravenous infusion in cows. Acta Vet Scand 1974; 15: 35665. 83. Davitiyananda D, Rasmussen F. Mammary and renal excretion of sulphadoxine and trimethoprim in cows. Acta Vet Scand 1974; 15: 34055. 84. Atef M, Al-Samarrae SA, Abdel Hamid YM. Half-life and volume of distribution of trimethoprim and sulphadoxine in sheep and its relation to age and weight. Zentralbl Veterinarmed A 1979; 26: 316. 85. Conlon PD, Butler DG, Burger JP, et al. Evaluation of route and frequency of administration of three antimicrobial drugs in cattle. Can Vet J 1993 Oct; 34: 60610. 86. Wilson WD, George LW, Baggot JD, et al. Ormetoprim-sulfadimethoxine in cattle: pharmacokinetics, bioavailability, distribution to the tears, and in vitro activity against Moraxella bovis. Am J Vet Res 1987 Mar; 48(3): 407 14. 87. Bateman KG, Martin SW, Shewen PE, et al. An evaluation of antimicrobial therapy for undifferentiated bovine respiratory disease. Can Vet J 1990 Oct; 31: 68996. 88. Kee Jim G, Booker CW, Guichon PT. A comparison of trimethoprimsulfadoxine and ceftiofur sodium for the treatment of respiratory disease in feedlot calves. Can Vet J 1992 Apr; 33: 24550. 89. Nielsen P, Rasmussen F. Half-life and renal excretion of trimethoprim in swine. Acta Pharmacol Toxicol 1975; 36: 12331. 90. Atef M. Trimethoprim in sheep: inuence of pH and protein binding on mammary and renal excretion. Zentralbl Veterinarmed Reine A 1979 Jan; 26(1): 3743. 91. Nielsen P, Gyrd-Hansen N. Oral bioavailability of sulphadiazine and trimethoprim in fed and fasted pigs. Res Vet Sci 1994; 56: 4852. 92. Blackwell TE, Werdin RE, Eisenmenger MC, et al. Goitrogenic effects in offspring of swine fed sulfadimethoxine and ormetoprim in late gestation. J Am Vet Med Assoc 1989 Feb; 194(4): 51923. 93. Lashev LD, Mihailov R. Pharmacokinetics of sulphamethoxazole and trimethoprim administered intravenously and orally to Japanese quails. J Vet Pharmacol Ther 1994; 17: 32730. 94. Prescott JF, Baggott JD, editors. Antimicrobial therapy in veterinary medicine, 2nd ed. Ames, Iowa: Iowa State University Press; 1993. p. 11926. 95. Tribrissen 24% Injection. In: Code of Federal Regulations 522.2610 Trimethoprim and sulfadiazine sterile suspension. NADA 105093. 96. Tribrissen 48% Injection. In: Code of Federal Regulations 522.2610 Trimethoprim and sulfadiazine sterile suspension. New Animal Drug Application (NADA) 105965. 97. Van Gogh H, Van Deurzen JM, Van Duin CTM, et al. Inuence of gestation on the pharmacokinetics of four sulphonamides in goats. Res Vet Sci 1990; 48: 1527. 98. Van Gogh H. Pharmacokinetics of nine sulphonamides in goats. J Vet Pharmacol Ther 1980; 3: 6981. 99. Riviere J, Craigmill AL, Sundlof SF. Handbook of comparative pharmacokinetics and residues of veterinary antimicrobials. Boca Raton, FL: CRC Press, Inc.; 1991. p. 339407. 100. Preusch PC, Hazelett SE, Lemasters KK. Sulfaquinoxaline inhibition of vitamin K epoxide and quinone reductase. Arch Biochem Biophys 1989 Feb 15; 269(1): 1824. 101. Appelgate J. Clinical pharmacology of sulfonamides. Mod Vet Pract 1983: 6679. 102. Baggot JD. Pharmacokinetics of sulfadimethoxine in cats. Aust J Exp Biol Med Sci 1977; 55(6): 66370. 103. Bajwa RS, Singh J. Studies on the levels of sulphadimethoxine and sulphamethoxypyridazine in blood of poultry. Indian J Anim Sci 1977 Sep; 47(9): 54953. 104. Baggot JD, Ludden TM, Powers TE. The bioavailability, disposition kinetics and dosage of sulphadimethoxine in dogs. Can J Comp Med 1976 Jul; 40: 3107. 105. Witkamp RF, Yun HI, vant Klooster GAE, et al. Comparative aspects and sex differentiation of plasma sulfamethazine elimination and metabolite formation in rats, rabbits, dwarf goats, and cattle. Am J Vet Res 1992 Oct; 53(10): 18305. 106. Paulson GD. The effect of dietary nitrite and nitrate on the metabolism of sulphamethazine in the rat. Xenobiotica 1986; 16(1): 5361. 107. Struble LB, Paulson GD. The metabolism and deamination of [14C]-sulphamethazine in a germ-free pig: the inuence of nitrate and nitrite. Food Chem Toxicol 1988 May; 26: 797801. 108. Nouws JFM, Vree TB, Baakman M, et al. Age and dosage dependency in the plasma disposition and the renal clearance of sulfamethazine and its N4-acetyl and hydroxy metabolites in calves and cows. Am J Vet Res 1986 Mar; 47(3): 6429. 109. Nouws JFM, Firth EC, Vree TB, et al. Pharmacokinetics and renal clearance of sulfamethazine, sulfamerazine, and sulfadiazine and their N4-acetyl and hydroxy metabolites in horses. Am J Vet Res 1987 Mar; 48(3): 392 402. 110. Plumb DC. Veterinary drug handbook. White Bear Lake, MN: PharmaVet Publishing; 1991. p. 5209. 111. Bourne DWA, Bialer M, Dittert LW, et al. Disposition of sulfadimethoxine in cattle: inclusion of protein binding factors in a pharmacokinetic model. J Pharm Sci 1981 Sep; 79(9): 106872. 112. Daft BM, Bickford AA, Hammarlund MA. Experimental and eld sulfaquinoxaline toxicosis in leghorn chickens. Avian Dis 1989; 33: 304. 113. Brown MJ. Adverse reactions to sulfaquinoxaline in coyote pups. J Am Vet Med Assoc 1982; 181(11): 141920. 114. Roudaut B, Moretain JP. Sulphonamide residues in milk of dairy cows following intravenous injection. Food Addit Contam 1990; 7(4): 52733. 115. Paulson GD, Feil VJ, Giddings JM, et al. Lactose conjugation of sulphonamide drugs in the lactating dairy cow. Xenobiotica 1992; 22(8): 92539. 116. Sullivan PS, Arrington K, West R, et al. Thrombocytopenia associated with administration of trimethoprim/sulfadiazine in a dog. J Am Vet Med Assoc 1992 Dec; 201(11): 17414. 117. The United States pharmacopeia. The national formulary. USP 26th revision (Jan 1, 2003). NF 21st ed (Jan 1, 2003). Rockville, MD: The United States Pharmacopeial Convention, Inc.; 2002. p. 173840, 2579, 2582, 2585. 118. USP DI Drug information for the healthcare professional. Volume III. Greenwood Village, CO: MICROMEDEX, Inc.; 2003. 119. Bactrim (Roche). In: PDR Physicians desk reference. 49th ed. 1995. Montvale, NJ: Medical Economics Company, 1995. p. 202630. 120. Taylor PM, Rest RJ, Duckham TN, et al. Possible potentiated sulphonamide and detomidine interactions. Vet Rec 1988; 122: 143.

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121. Osweiler GD, Green RA. Canine hypoprothrombinemia resulting from sulfaquinoxaline administration. Vet Hum Tox 1978 Jun; 20(3): 1902. 122. Neer TM, Savant RL. Hypoprothrombinemia secondary to administration of sulfaquinoxaline to dogs in a kennel setting. J Am Vet Med Assoc 1992 May; 200(9): 13445. 123. Panel comment on Sulfonamides (Veterinary-Systemic), 6/96. 124. Berger SL, Scagliotti RH, Lund EM. A quantitative study of the effects of Tribrissen on canine tear production. J Am Anim Hosp Assoc 1995 May/Jun; 31: 23641. 125. FDA. Sulfadimethoxine and ormetoprim. Freedom of Information Summary. Public Master File Number 5157. 126. Ormetoprim and sulfadimethoxine package insert (Primor tablets, PzerUS), Rev 5/96, Rec 12/20/96. 127. Bushby SRM. Sulfonamide and trimethoprim combinations. J Am Vet Med Assoc 1980 May 15; 10(2): 104953. 128. Itkin RJ, Krawiec DR, Cloran JA, et al. Ulcerative urocystitis in a dog. J Am Anim Hosp 1994; 30(3): 2969. 129. Buoro IBJ, Mande JD, Nyamwange SB. Isolation of Nocardia asteroides from a dog with haemorrhagic cystitis. J Small Anim Pract 1993; 34: 99 102. 130. Marino DJ, Jaggy A. Nocardiosis: a literature review with selected case reports in two dogs. J Vet Intern Med 1993 JanFeb; 7(1): 411. 131. Kirpensteijn J, Fingland RB. Cutaneous actinomycosis and nocardiosis in dogs: 48 cases (19801990). J Am Vet Med Assoc 1992 Sep 15; 201(6): 91720. 132. Gombert ME, duBouchet L, Aulicino TM, et al. Antimicrobial synergism in the therapy of experimental cerebral nocardiosis. J Antimicrob Chemother 1989; 23: 3943. 133. Davenport DJ, Johnson GC. Cutaneous nocardiosis in a cat. J Am Vet Med Assoc 1986; 188(7): 7289. 134. Meric SM. Canine meningitis: a changing emphasis. J Vet Intern Med 1988 JanMar; 2(1): 2635. 135. Fenner WR. Treatment of central nervous system infections in small animals. J Am Vet Med Assoc 1989 Nov 15; 185(10): 117680. 136. Dunbar MR, Foreyt WJ. Prevention of coccidiosis in domestic dogs and captive coyotes (Canis latrans) with sulfadimethoxine-ormetoprim combination. Am J Vet Res 1985 Se; 46(9): 1899902. 137. Castles TR, Kintner LD, Lee C. The effects of folic or folinic acid on the toxicity of pyrimethamine in dogs. Toxicol Appl Pharmacol 1971; 20: 44759. 138. Panel consensus, 4/28/97. 139. Wilson DA, MacFadden KE, Green EM, et al. Case control and historical cohort study of diarrhea associated with administration of trimethoprimpotentiated sulfonamides to horses and ponies. J Vet Intern Med 1996; 10(4): 25864. 140. Bennett EE, Craig GR, Piteld N, et al. The persistence and elimination of residues of trimethoprim and sulphadiazine in the tissues of calves treated with Tribrissen Boluses. Mallinkrodt Canada product report series. June 14, 1972. 141. National Committee for Clinical Laboratory Standards. Performance standards for antimicrobial disk and dilution susceptibility tests for bacteria isolated from animals; proposed standards. NCCLS document M31-P (ISBN 156238-258-6). Villanova, PA: National Committee for Clinical Laboratory Standards; 1994. p. 56, 347. 142. Code of Federal Regulation. 21 CFR Chapter 1. Washington, D.C.: U.S. Government Printing Ofce 1994 Apr 1. 556.490, 556.630, 556.640, 556.650, 556.660, 556.670, 556.680, 556.690. 143. Guard CL, Schwark WS, Friedman DS, et al. Age-related alterations in trimethoprim-sulfadiazine disposition following oral or parenteral administration in calves. Can J Vet Res 1986; 50: 3426. 144. Panel comment, 10/97. 145. Panel comment, 10/97. 146. Sulfadiazine and trimethoprim product information (Tribrissen 48%, Schering-PloughUS). Downloaded from www.spah.com on 2/17/03. 147. Fenger CK, Granstrom DE, Langemeir JL. Epizootic of equine protozoal myeloencephalomyelitis on a farm. J Am Vet Med Assoc 1997, 210(7): 923 927. 148. Lindsaya DS, Dubeyb JP. Determination of the activity of pyrimethamine, trimethoprim, sulfonamides, and combinations of pyrimethamine and sulfonamides against Sarcocystis neurona in cell cultures. Vet Parasit April 1999, 82(3): 205210. 149. Klasco RK, editor. USP DI Drug information for the healthcare professional. Volume I. Greenwood Village, CO: MICROMEDEX, Inc.; 2003. 150. Arrioja-Dechert A, editor. Compendium of veterinary products, CD edition. Port Huron, MI: North American Compendiums, Inc., 2002.

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PYRIMETHAMINE VeterinarySystemic 185

PYRIMETHAMINE VeterinarySystemic
A commonly used brand name for a human-labeled product is Daraprim. Note: For a listing of dosage forms and brand names by country availability, see the Dosage Forms section(s). in which clinical signs of the infection had not yet progressed to rigid hindlimb paralysis{R-12; 14; 15}. [Toxoplasmosis (treatment)]1Cats: Although the efcacy and safety have not been established, pyrimethamine is used in combination with sulfadiazine in the treatment of toxoplasmosis in cats{R-1820}. Side effects associated with the administration of pyrimethamine and sulfadiazine have led clinicians to search for other treatments. However, this therapy may have some value in the treatment of infection with nonencysted organisms in cats that can tolerate the medications.

CATEGORY:
Antiprotozoal (systemic).

INDICATIONS
Note: In other USP DI monographs, bracketed information in the Indications section refers to uses that are not included in U.S. product labeling, and superscript 1 refers to uses that are not included in Canadian product labeling. However, since pyrimethamine is not specically approved for veterinary use, there is no product labeling identifying approved indications.

REGULATORY CONSIDERATIONS
U.S. and CanadaPyrimethamine is not labeled for use in animals, including food-producing animals; therefore, there are no established withdrawal times.

GENERAL CONSIDERATIONS
Pyrimethamine is a folic acid antagonist{R-1}, active against protozoal dihydrofolate reductase. It is considered most effective against pathogenic protozoa when administered in combination with a sulfonamide{R-11; 16; 20}. The ready availability of combination products containing trimethoprim and sulfadiazine or trimethoprim and sulfamethoxazole may have contributed to the frequency of their concurrent administration with pyrimethamine. While trimethoprim does not increase the efcacy of therapy against protozoa{R-30}, it is suspected to increase the incidence of side effects due to folate reduction{R-1; 21}. Whenever possible, pyrimethamine should be administered in combination with a sulfonamide alone in the treatment of susceptible infections. The development of resistant organisms has been stimulated in in vitro experiments, and cross-resistance by these cultures to other dihydrofolate inhibitors has been shown. However, when pyrimethamine was combined with a sulfonamide in the treatment of pyrimethamineresistant Neospora cultures, the combination was completely effective{R-11}. In the case of equine protozoal myeloencephalitis, resistance may occur within an individual horse if inadequate treatment is administered; however, transmission of resistance to the Sarcocystis neurona population outside the individual is not considered a problem because the horse is an aberrant host and does not shed infectious organisms{R-21; 29}.

CHEMISTRY
Chemical group: A diaminopyrimidine; structurally related to trimethoprim{R-6}. Chemical name: 2,4-Pyrimidinediamine, 5-(4-chlorophenyl)-6ethyl-{R-2}. Molecular formula: C12H13ClN4{R-2}. Molecular weight: 248.71{R-2}. Description: Pyrimethamine USPWhite, odorless, crystalline powder{R-3}. pka: 7.34{R-5}. Solubility: Pyrimethamine USPPractically insoluble in water; slightly soluble in acetone, in alcohol, and in chloroform{R-3}.

PHARMACOLOGY/PHARMACOKINETICS
Mechanism of action/effect: Pyrimethamine reversibly binds to and inhibits the enzyme dihydrofolate reductase in protozoa. This inhibition prevents the production of tetrahydrofolic acid from dihydrofolate and thereby prevents the metabolism of folate{R-6}. Like protozoa, mammalian cells reduce folic acid to tetrahydrofolic acid; however, the therapeutic action of pyrimethamine relies on a greater selectivity for protozoal dihydrofolate reductase than for the mammalian enzyme{R-1; 16} . Pyrimethamine is generally administered in conjunction with a sulfonamide to take advantage of the sequential inhibition of enzymatic steps in folate synthesis provided by the combination{R-1}. Absorption: OralHuman beings: Pyrimethamine is well absorbed orally{R-1}. Bioavailability: OralHorses: Average, 56% (range, 39 to 78%){R-5}. Distribution: Rapidly and extensively distributed after intravenous administration{R-5}. HorsesCerebrospinal uid (CSF) concentrations reached 25 to 50% of the serum concentrations but did not appear to accumulate in horses administered daily oral doses of 1 mg per kg of body weight (mg/kg) for 10 days{R-6}. PigsDistribution occurs in two phases after a 10 mg/kg intravenous dose; the fast phase has a half-life of 0.11 hour, and the slow phase has a half-life of 1.6 hours{R-10}.

ACCEPTED
[Equine protozoal myeloencephalitis (treatment)]1Horses: Pyrimethamine is used in combination with a sulfonamide, such as sulfadiazine or sulfamethoxazole{R-9}, in the treatment of protozoal myeloencephalitis{R-7; 8; 21}.

ACCEPTANCE NOT ESTABLISHED

[Neospora caninum infection (treatment)]1Dogs: Although the efcacy and safety have not been established, pyrimethamine is used in combination with sulfonamides, most typically sulfadiazine, in the treatment of Neospora caninum infection. This use is based on evidence of in vitro pathogen susceptibility{R-11; 13} and case reports of successful treatment outcomes in some dogs, particularly in puppies

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186 PYRIMETHAMINE VeterinarySystemic RatsMean CSF concentration was 27% of the plasma concentration during the rst 48 hours after a single oral dose of 2.9 mg/kg (1 mg per rat){R-24}. Volume of distributionIntravenous administration: HorsesSteady-state: 1.52 liters per kg (L/kg){R-5}. PigsArea: 12.1 2 L/kg{R-10}. Protein binding: DogsHigh (85%){R-24}. Human beingsHigh (87%){R-24}. MiceHigh (78%){R-24}. PigsHigh (85%), independent of serum concentration{R-10}. RatsHigh (78%){R-6}. Biotransformation: Less than 5% of administered doses are excreted as unchanged drug in the urine in pigs{R-10} and rats{R-24}; ve hours after administration of radiolabeled pyrimethamine to a rat, less than 50% of radioactivity in the blood was intact parent drug{R-24}. Therefore, it is believed that pyrimethamine is extensively metabolized, although metabolites have not been identied in animals. In human beings, pyrimethamine is believed to be hepatically metabolized{R-24; 28}. Half-life: EliminationIntravenous administration: Horses12 3.7 hours{R-5}. Pigs13.3 4.9 hours{R-10}. Concentrations: Peak serum concentrationOral administration: Horses Single dose: 0.18 0.03 mcg per mL of serum (mcg/mL) with administration of 1 mg/kg{R-5}. Multiple doses: 0.32 0.11 mcg/mL after the 5th dose and 0.26 0.07 mcg/mL after the 10th dose of 10 daily doses of 1 mg/kg{R-6}. Time to peak concentrationOral administration: Horses Single dose: 2.9 2.1 hours after administration of 1 mg/kg{R-5}. Multiple doses: 2.2 hours after the 5th dose and 2.7 hours after the 10th dose of 10 daily doses of 1 mg/kg{R-6}. Serum concentrations, otherOral administration: Horses Single dose: 0.09 mcg/mL 24 hours after administration of 1 mg/kg{R-5}. Multiple doses: Plasma steady state was reached at the 5th day of 10 daily doses of 1 mg/kg; at that time the serum concentrations uctuated approximately 65% over each 24-hour period, with the peak at approximately 0.32 mcg/mL{R-6}. Elimination: PigsOnly about 3% of an intravenous dose of pyrimethamine is excreted in the urine as unchanged drug, although up to 90% of the dose is eliminated in that time{R-10}. Total clearance Horses: 1.6 0.32 mL per minute per kg (mL/min/kg){R-5}. Pigs: 0.68 0.16 mL/min/kg{R-10}.

PREGNANCY/REPRODUCTION
Reproduction: RatsThe fertility index of rats treated with pyrimethamine is lowered only by the highest doses administered. This suggests a toxic effect on the whole animal or the conceptus{R-1}. Pregnancy: HamstersSingle doses of 20 mg per pregnant hamster caused malformation or death in less than 10% of fetuses{R-1}. HorsesIn a group of horses treated with oral pyrimethamine at 1 mg per kg of body weight (mg/kg) a day, sulfadiazine at 16.7 mg/kg every twelve hours, and trimethoprim at 3.3 mg/kg every twelve hours, the three horses that were pregnant during therapy aborted during the second or third month of treatment{R-21}. Each of the aborted fetuses was in the fth month of gestation{R-21}. It is not certain which of the medications might have caused the abortions. The horses diets had not been supplemented with folate at the time of the abortions{R-21}. The administration of oral folic acid to pregnant mares being treated for equine protozoal myeloencephalitis may not protect the fetus from the effects of folate deciency. Reports have been made of mares delivering foals with congenital defects after oral administration during pregnancy of pyrimethamine, 0.5 to 1 mg/kg a day, with sulfadiazine, 25 mg/kg a day; or sulfamethoxazole, 12.5 mg/ kg day, and trimethoprim, 2.5 mg/kg{R-35}. Two of the three reported mares had been treated in the last 3 months of gestation and one for 2 years before foaling. These mares had also been supplemented with oral folic acid, 40 mg as a total daily dose, and vitamin E, 8000 Units as a total daily dose, during the period of antibiotic treatment. Each of three mares on this dosage regimen produced a foal with renal hypoplasia or nephrosis and bone marrow aplasia or hypoplasia{R-35}. In both mares and foals, serum folate concentrations were below the laboratory reference range and in two foals, folate was less than 30% of the minimum reference range{R-35}. The risk of congenital defects should be considered when treating pregnant mares with pyrimethamine and sulfonamide. Miniature pigsA high incidence of malformations (70%), such as cleft palate, club foot, and micrognathia, was seen in offspring when pregnant sows were administered pyrimethamine, 3.6 mg/kg a day, from days 11 to 35 of gestation; however, no abnormalities were noted in the offspring of sows administered 0.9 to 1.8 mg/kg a day during the same period of gestation{R-1; 4}. RatsFetal resorption and stunted growth in fetuses have been seen in pregnant rats given pyrimethamine{R-1}. Rats administered 12.5 mg/ kg from days 7 to 9 of gestation had 66% of fetuses resorbed and 33% stunted, while a dose of 0.5 to 1 mg/kg from days 4 to 13 of gestation caused resorption of 8 to 15% of fetuses and stunted growth in 7 to 17% of fetuses{R-1}.

LACTATION
Pyrimethamine is distributed into human milk{R-1}. Distribution into milk in lactating animals has not been determined.

PRECAUTIONS TO CONSIDER CARCINOGENICITY

Mice: A signicant increase in the number of lung tumors per mouse has been reported with doses of 25 mg per kg of body weight (mg/kg), administered intraperitoneally{R-1}. 2003 Thomson MICROMEDEX

PEDIATRICS
Dogs: Pyrimethamine has been administered at a dose of 1 mg per kg of body weight a day for 4 weeks in 8- to 17-week-old puppies, without any apparent harmful effects{R-14}. All rights reserved

PYRIMETHAMINE VeterinarySystemic 187

DRUG INTERACTIONS AND/OR RELATED PROBLEMS

The following drug interactions and/or related problems have been selected on the basis of their potential clinical signicance (possible mechanism in parentheses where appropriate)not necessarily inclusive ( = major clinical signicance): Note: Drug interactions relating specically to the use of pyrimethamine in animals are rarely reported in veterinary literature. Human drug interactions have been reported and are included in the following section.

Complete blood counts (CBCs){R-19; 21; 23} and Platelet counts (should be performed on a regular basis, particularly with long-term or high-dose therapy; periodic packed cell volume evaluation is recommended in horses being treated for equine protozoal myeloencephalitis to monitor for anemia{R-29})

SIDE/ADVERSE EFFECTS
The following side/adverse effects have been selected on the basis of their potential clinical signicance (possible signs and, for humans, symptoms in parentheses where appropriate)not necessarily inclusive: Note: It is assumed that animals have the same tendency as people to develop signs of folate deciency with long-term use or high doses of folic acid antagonists such as pyrimethamine. Signs of folate deciency have been reported frequently in the human literature and include agranulocytosis, megaloblastic anemia, and thrombocytopenia{R-16}. Similar signs have been noted in cats, dogs, and horses{R-19; 21; 26}. It should be considered that signs of folate deciency may occur in any species administered pyrimethamine. When administering pyrimethamine with a sulfonamide, the risk of sulfonamide-related side effects should be considered. See the Sulfonamides (Veterinary Systemic) monograph for further information.

HUMAN DRUG INTERACTIONS AND/OR RELATED PROBLEMS{R-37}

The following drug interactions have been reported in humans, and are included in the human monograph Pyrimethamine (Systemic) in USP DI Volume I; these drug interactions are intended for informational purposes only and may or may not be applicable to the use of pyrimethamine in the treatment of animals: Note: Combinations containing any of the following medications, depending on the amount present, may also interact with this medication. Bone marrow depressants (concurrent use of pyrimethamine with bone marrow depressants may increase the leukopenic and/or thrombocytopenic effects; if concurrent use is required, the possibility of increased myelotoxic effects should be considered, especially when pyrimethamine is used in large doses, such as those required in the treatment of toxoplasmosis) Folate antagonists, other (concurrent use of other folate antagonists with pyrimethamine or use of pyrimethamine between courses of other folate antagonists is not recommended because of the possible development of megaloblastic anemia)

THOSE INDICATING NEED FOR MEDICAL ATTENTION

Incidence unknown Cats Leukopeniaseen with a dose of 1 mg per kg of body weight (mg/ kg) a day for 6 days{R-19} Horses Anemia{R-21}; congenital defects in offspring (bone marrow aplasia or hypoplasia; renal nephrosis or hypoplasia; skin lesions){R-35}; diarrhea{R-21}; leukopenia{R-21}

MEDICAL CONSIDERATIONS/CONTRAINDICATIONS
The medical considerations/contraindications included have been selected on the basis of their potential clinical signicance (reasons given in parentheses where appropriate)not necessarily inclusive ( = major clinical signicance). Except under special circumstances, this medication should not be used when the following medical problems exist: Anemia or Bone marrow suppression (pyrimethamine may cause folate deciency, resulting in megaloblastic anemia and blood dyscrasias, including agranulocytosis and thrombocytopenia{R-19; 21; 26}) Hepatic function impairment, severe (in human beings, pyrimethamine is metabolized in the liver) Risk-benet should be considered when the following medical problem exists: Pregnancy (the risk of teratogenesis should be considered in planning treatment with pyrimethamine{R-35})

HUMAN SIDE/ADVERSE EFFECTS{R-37}

In addition to the above side/adverse effects reported in animals, the following side/adverse effects have been reported in humans, and are included in the human monograph Pyrimethamine (Systemic) in USP DI Volume I; these side/adverse effects are intended for informational purposes only, and may or may not be applicable to the use of pyrimethamine in the treatment of animals: Incidence less frequent Agranulocytosis, leukopenia, or thrombocytopenia; atrophic glossitis; gastrointestinal disturbances (anorexia, diarrhea, nausea, and vomiting) Incidence rare Erythema multiforme and/or Stevens-Johnson syndrome; hypersensitivity

OVERDOSE
For more information in cases of overdose or unintentional ingestion, contact the American Society for the Prevention of Cruelty to Animals (ASPCA) National Animal Poison Control Center (888-426-4435 or 900-443-0000; a fee may be required for consultation) and/or the drug manufacturer. All rights reserved

PATIENT MONITORING
The following may be especially important in patient monitoring (other tests may be warranted in some patients, depending on condition; = major clinical signicance): 2003 Thomson MICROMEDEX

188 PYRIMETHAMINE VeterinarySystemic

CLINICAL EFFECTS OF OVERDOSE

The following effects have been selected on the basis of their potential clinical signicance (possible signs in parentheses where appropriate)not necessarily inclusive: Dogswith a dose of 5 to 10 mg per kg of body weight (mg/kg) a day for 10 to 21 days{R-26} Chronic effects Anorexia and/or decreased appetite; ataxia; bone marrow suppression, including leukopenia and reticulocytopenia; dehydration; gastrointestinal toxicity (diarrhea, occasionally bloody; vomiting); weakness; weight loss Note: Bone marrow suppression has been demonstrated by biopsy in a few dogs receiving extremely high doses of pyrimethamine (6 mg/kg a day for 10 to 15 days){R-26}. Three of eight dogs treated had bone marrow suppression, particularly of the erythroid elements{R-26}. In dogs, vomiting was reported to be common within 2 to 5 hours of administration of 7.5 to 10 mg/kg, but vomiting was seen only occasionally in dogs receiving 5 mg/kg a day for 10 to 21 days{R-26}. Intestinal lesions, including inammation, mucoid degeneration, shortened villi and mucosal atrophy, are visible on histopathologic examination after administration of 6.2 mg/kg a day for 10 days to dogs{R-26}. Respiratory depression and circulatory collapse, as well as neurotoxicity leading to seizures, have been reported in people receiving total doses of 250 to 300 mg of pyrimethamine{R-1}. These specic signs have not been reported in animals; however, one of four dogs administered 5 mg/kg a day died on the 17th day of therapy; the specic cause of death was not reported{R-26}.

TREATMENT OF OVERDOSE{R-1}
Gastric lavage. Control of central nervous system stimulation by administration of benzodiazepines or short-acting barbiturates, if necessary. Respiratory assistance, if necessary. Administration of folate to prevent hematopoietic changes (see Veterinary Dosing Information).

mechanism of action of the drug{R-9; 21}; however, neither oral supplement has been clearly proven to be effective. Only limited information on the effectiveness of folic acid or folinic acid in the prevention of folate deciency caused by pyrimethamine is available. Cats and dogs: No denitive studies are available to conrm that folic acid or folinic acid supplementation should be used to prevent signs of folate deciency that may occur during treatment with pyrimethamine{R-36}. Monitoring animals for signs of folate deciency is recommended during treatment with pyrimethamine (see the Patient monitoring and Side/Adverse Effects sections){R-36}. Horses: An oral folic acid dose of 0.09 to 0.18 mg per kg of body weight mg/kg) (40 to 80 mg per horse) every twenty-four hours has been used{R-29; 31}; however, case reports have shown that a total dose of 40 mg of folic acid a day given to pregnant mares being treated with pyrimethamine and sulfonamide is sometimes not effective in preventing congenital defects in foals caused by folate deciency{R-35}. Fresh grass has more than twice the total folacin concentration of hay{R-32}, and serum folate concentrations tend to be much higher in pastured horses than in permanently stabled horses or horses in training{R-33; 34}. It has been recommended that horses be maintained on feeds containing high folacin concentrations during pyrimethamine therapy{R-29}. Rather than supplementing horses with folic acid, some clinicians recommend monitoring the packed-cell volume to detect developing anemias. Some clinicians have used the in vitro minimum inhibitory concentration (MIC) of pyrimethamine considered necessary to inhibit Toxoplasma gondii{R-5; 21} or the MIC of pyrimethamine necessary to inhibit Neospora caninum{R-11} as guidelines for target cerebrospinal uid concentrations for control of the Sarcocystis species responsible for equine protozoal myeloencephalitis.{R-5}

DIET/NUTRITION
Horses: Pyrimethamine should be administered 1 hour prior to feeding hay{R-9}. Human beings: Information from human product labeling includes the statement that anorexia and vomiting induced by pyrimethamine may be minimized by administering it with food{R-1}.

CLIENT CONSULTATION
Clients should be advised to watch for signs such as loss of appetite, weakness, pale mucous membranes or pinpoint blood spots in membranes, or noticeable bruising.

ORAL DOSAGE FORMS

Note: In other USP DI monographs, bracketed information in the Dosage Forms section refers to categories of use and/or indications that are not included in U.S. product labeling, and superscript 1 refers to categories of use and/or indications that are not included in Canadian product labeling. However, since pyrimethamine is not specically approved for veterinary use, there is no product labeling identifying approved indications.

VETERINARY DOSING INFORMATION

The administration of sulfadiazine and trimethoprim products labeled for use in animals in combination with human-labeled pyrimethamine tablets is commonly discussed in veterinary literature. However, the low afnity of protozoal dihydrofolate for trimethoprim suggests poor efcacy of trimethoprim in the treatment of protozoal infections{R-30}. The concurrent administration of trimethoprim with pyrimethamine offers no known benet and may increase the risk of adverse effects associated with these dihydrofolate reductase inhibitors{R-1; 9; 21}. Whenever possible, pyrimethamine should be administered in combination with a sulfonamide alone in the treatment of susceptible infections. The administration of folic acid or folinic acid supplements during treatment with pyrimethamine may help to prevent adverse effects associated with folate deciency, which occur as an extension of the 2003 Thomson MICROMEDEX

PYRIMETHAMINE TABLETS USP

Usual dose: [Equine protozoal myeloencephalitis]1Horses: Oral, 1 mg per kg of body weight every twenty-four hours{R-5} in combination with 16.7 mg of sulfadiazine or sulfamethoxazole per kg of body weight every twelve hours{R-5; 8; 9; 21} has been used. The average duration of treatment necessary to clear the organism may be as long as 130 days All rights reserved

PYRIMETHAMINE VeterinarySystemic 189 or more{R-21}. Testing cerebrospinal uid for Sarcocystis neurona antibodies may help determine when to discontinue treatment{R-21}. Note: The above dose is based on clinical case reports with successful outcomes that also included the concurrent administration of 3.3 mg of trimethoprim per kg of body weight. However, the administration of pyrimethamine concurrently with trimethoprim generally is not recommended. To decrease the risk of toxicity, the administration of pyrimethamine with sulfadiazine alone is preferred, but there are no specic reports of the efcacy of this combination. [Neospora caninum infection]1Dogs: Although the efcacy and safety have not been established, an oral dose of 1 mg of pyrimethamine per kg of body weight every twenty-four hours{R-14} in combination with 12.5 mg of sulfadiazine per kg of body weight every twelve hours{R-14} for four weeks has been used. Note: The above dose is based on clinical case reports with successful outcomes that also included the concurrent administration of 2.5 mg of trimethoprim per kg of body weight. However, the administration of pyrimethamine concurrently with trimethoprim generally is not recommended. To decrease the risk of toxicity, the administration of pyrimethamine with sulfadiazine alone is preferred, but there are no reports of the efcacy of this combination. [Toxoplasmosis]1Cats: Although the efcacy and safety have not been established, an oral dose of 1 mg of pyrimethamine per kg of body weight every twenty-four hours{R-18} in combination with 25 mg of sulfadiazine per kg of body weight every twelve hours{R-18} for fourteen to twenty-eight days has been used. Note: The above dose was extrapolated from studies evaluating the efcacy of pyrimethamine and sulfadiazine in ending or reducing shedding of oocysts{R-18; 19} as well as preventing tissue infection{R-19}. Because pyrimethamine is only available in 25-mg tablets, some clinicians will arrange for capsules to be formulated in smaller strengths for easier administration of the unpalatable medication to cats. Consultation with an experienced pharmacist is recommended. Strength(s) usually available: U.S. Veterinary-labeled product(s): Not commercially available. Human-labeled product(s){R-1}: 25 mg (Rx) [Daraprim (scored)]. Canada Veterinary-labeled product(s): Not commercially available. Human-labeled product(s): 25 mg (Rx) [Daraprim (scored)]. Withdrawal times: U.S. and CanadaPyrimethamine is not labeled for use in animals, including food-producing animals; therefore, there are no established withdrawal times. Packaging and storage: Store below 40 C (104 F), preferably between 15 and 30 C (59 and 86 F), unless otherwise specied by manufacturer. Store in a tight, light-resistant container. Auxiliary labeling: Keep out of the reach of children{R-1}. Caution: Potential danger of accidental overdose{R-1}. USP requirements: Preserve in tight, light-resistant containers. Contain the labeled amount, within 7%. Meet the requirements for Identication, Dissolution (75% in 45 minutes in 0.01 N hydrochloric acid in Apparatus 2 at 50 rpm), and Uniformity of dosage units{R-3}. Developed: 07/01/98 Interim revision: 10/14/99; 9/30/02; 03/28/03

REFERENCES
1. Pyrimethamine package insert (Daraprim, Burroughs WellcomeUS), Rev 4/94, Rec 10/13/94. 2. USP dictionary of USAN and international drug names, 2002 ed. Rockville, MD: The United States Pharmacopeial Convention, Inc., 2002. 3. The United States pharmacopeia. The national formulary. USP 26th revision (January 1, 2003). NF 21st ed (January 1, 2003). Rockville, MD: The United States Pharmacopeial Convention, Inc., 2002. p. 1602, 2579. 4. Misawa J, Kanda S, Kokue E, et al. Teratogenic activity of pyrimethamine in Gottingen minipig. Toxicol Lett 1982; 10(1): 514. 5. Clarke CR, Burrows GE, MacAllister CG, et al. Pharmacokinetics of intravenously and orally administered pyrimethamine in horses. Am J Vet Res 1992 Dec; 53(12): 22925. 6. Clarke CR, Burrows GE, MacAllister CG, et al. Pharmacokinetics, penetration into cerebrospinal uid, and hematologic effects after multiple oral administrations of pyrimethamine to horses. Am J Vet Res 1992 Dec; 53(12): 22969. 7. Boy MG, Galligan DT, Divers TJ. Protozoal encephalomyelitis in horses: 82 cases (1972-1986). J Am Vet Med Assoc 1990 Feb; 196(4): 6324. 8. Brewer B, Mayhew IG. Multifocal neurologic disease in a horse. J Equine Vet Sci 1988 Jul/Aug; 8(4): 3024. 9. Bertone JJ. Update on equine protozoal myeloencephalitis. FDA Vet 1996 May/Jun; XI(III): 79. 10. Shimoda M, Kokue E, Kurebayashi Y, et al. Three-compartment model for pyrimethamine disposition in the pig. J Vet Pharmacol Ther 1981 Jun; 4(2): 16570. 11. Lindsay DS, Butler JM, Rippey NS, et al. Demonstration of synergistic effects of sulfonamides and dihydrofolate reductase/thymidylate synthase inhibitors against Neospora caninum tachyzoites in cultured cells, and characterization of mutants resistant to pyrimethamine. Am J Vet Res 1996 Jan; 57(1): 6872. 12. Knowler C, Wheeler SJ. Neospora caninum infection in three dogs. J Small Anim Pract 1995; 36: 1727. 13. Lindsay DS, Rippey NS, Cole RA, et al. Examination of the activities of 43 chemotherapeutic agents against Neospora caninum tachyzoites in cultured cells. Am J Vet Res 1994 Jul; 55(7): 97681. 14. Mayhew IG, Smith KC, Dubey JP, et al. Treatment of encephalomyelitis due to Neospora caninum in a litter of puppies. J Small Anim Pract 1991; 32: 609 12. 15. Hay WH, Shell LG, Lindsay DS, et al. Diagnosis and treatment of Neospora caninum infection in a dog. J Am Vet Med Assoc 1990 Jul 1; 197(1): 878. 16. St. Georgiev V. Opportunistic/nosocomial infections. Treatment and developmental therapeutics. Toxoplasmosis. Med Res Rev 1993 Sep; 13(5): 52968. 17. Davidson MG, Lappin MR, Rottman JR, et al. Paradoxical effect of clindamycin in experimental, acute toxoplasmosis in cats. Antimicrob Agents Chemother 1996 Jun; 40(6): 13529. 18. Shefeld HG, Melton ML. Effects of pyrimethamine and sulfadiazine on the intestinal development of Toxoplasma gondii in cats. Am J Trop Med Hyg 1976 May; 25(3): 37983. 19. Dubey JP, Yeary RA. Anticoccidial activity of 2-sulfa-moyl-4,4-diaminodiphenylsulfone, sulfadiazine, pyrimethamine and clindamycin in cats infected with Toxoplasma gondii. Can Vet J 1977 Mar; 18(3): 517. 20. Mack DG, McLeod R. New micromethod to study the effect of antimicrobial agents on Toxoplasma gondii: comparison of sulfadoxine and sulfadiazine individually and in combination with pyrimethamine and study of clindamycin, metronidazole, and cyclosporin A. Antimicrob Agents Chemother 1984 Jul; 26(1): 2630. 21. Fenger CK, Granstom DE, Langemeier JL, et al. An epizootic of equine protozoal myeloencephalitis on a farm. J Am Vet Med Assoc 1997 Apr 1; 210(7): 9237. 22. McCabe RE, Oster S. Current recommendations and future prospects in the treatment of toxoplasmosis. Drugs 1989 Dec; 38(6): 97387. 23. Peterson JL, Willard MD, Lees GE, et al. Toxoplasmosis in two cats with inammatory intestinal disease. J Am Vet Med Assoc 1991 Aug; 199(4): 4736. 24. Cavallito JC, Nichol CA, Brenckman WD, et al. Lipid-soluble inhibitors of dihydrofolate reductase. I. Kinetics, tissue distribution, and extent of

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190 PYRIMETHAMINE VeterinarySystemic

metabolism of pyrimethamine, metoprine, and etoprine in the rat, dog, and man. Drug Metab Dispos 1978; 6: 32937. Bygbjerg IC, Lund JT, Hording M. Effect of folic and folinic acid on cytopenia occurring during cotrimoxazole treatment of pneumocystis carinii pneumonia. Scand J Infect Dis 1988; 20: 6856. Castles TR, Kintner LD, Lee C. The effects of folic or folinic acid on the toxicity of pyrmethamine in dogs. Toxicol Appl Pharmacol 1971; 20: 44759. Plumb DC. Veterinary drug handbook, 2nd ed. Ames, IA: Iowa University Press, 1995. p. 5413. Weiss LM, Harris C, Berger M, et al. Pyrimethamine concentrations in serum and cerebrospinal uid during treatment of acute toxoplasma encephalitis in patients with AIDS. J Infect Dis 1988 Mar; 157(3): 5803. Reviewer comment, Rec 7/11/97. Panel comment, Rec 6/22/97. 31. Reviewer comment, Rec 6/18/97. 32. National Research Council. Nutrient requirements of horses. Washington, D.C.: National Academy Press, 1989. p. 2930. 33. Roberts MC. Serum and red cell folate and serum levels in horses. Aust Vet J 1983 Apr; 60(4): 10611. 34. Allen BV. Serum folate levels in horses, with particular reference to the English thoroughbred. Vet Rec 1978; 103: 2579. 35. Toribio RE, Bain FT, Mrad OR, et al. Congenital defects in newborn foals of mares treated for equine protozoal myeloencephalitis during pregnancy. J Am Vet Med Assoc 1998 Mar 1; 212(5): 697701. 36. Panel consensus, 5/5/98. 37. Klasco RK, editor. USP DI Drug information for the healthcare professional. Volume I. Greenwood Village, CO: MICROMEDEX, Inc.; 2003.

25.

26. 27. 28.

29. 30.

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RIFAMPIN VeterinarySystemic 191

RIFAMPIN VeterinarySystemic
Some commonly used brand names for human-labeled products are: Rifadin; Rifadin IV; Rimactane; and Rofact. antimicrobial was not very effective{R-51} and in vivo efcacy against induced infections in mice was only weakly signicant{R-52}. Resistance to rifampin can develop quickly; therefore, it is most often used in combination with other antimicrobials{R-2; 11; 54}. Resistant mutants may be concentration-sensitive and contain RNA polymerases with one of a variety of sensitivities to rifampin{R-12}. Resistance may occur as a single-step mutation of the DNA-dependent RNA polymerase; therefore, initial susceptibility can rapidly diminish as small populations of resistant cells soon outnumber susceptible cells{R-2}. This effect is diminished when combination antibiotic treatment is administered{R-2; 4} . One case of the development of resistant Rhodococcus equi in a foal treated with erythromycin and rifampin has been reported{R-39}. Crossresistance to other antibiotics{R-2} or transfer of resistance to other local microorganisms has not been reported{R-4}.

CATEGORY:
Antibacterial (systemic).

INDICATIONS
Note: In other USP DI monographs, bracketed information in the Indications section refers to uses that are not included in U.S. product labeling, and superscript 1 refers to uses that are not included in Canadian product labeling. However, since rifampin is not specically approved for veterinary use, there is no product labeling identifying approved indications.

GENERAL CONSIDERATIONS
Rifampin is a broad-spectrum antibiotic, with activity against many gram-positive and some gram-negative aerobic bacteria{R-7} as well as facultative anaerobic organisms{R-53; 60}. However, for clinical purposes, rifampin generally should not be considered broad-spectrum until proven so in each case. Most gram-negative bacteria should be considered resistant or to have unpredictable susceptibilities until susceptibility data are available{R-11}. Because many infections involve more than one species of bacterium and because resistance can develop quickly, rifampin is most often administered in combination with other antimicrobial agents. Rifampin is considered especially active in the treatment of staphylococcal infections and in the eradication of pathogens located in difcult to reach target areas, such as inside phagocytic cells{R-20; 62} . The ability of rifampin to reach intracellular bacteria{R-62} can make it difcult to predict in vivo therapy results based on in vitro sensitivity tests{R-49}. Rifampin has been shown to have in vitro activity against equine Corynebacterium pseudotuberculosis{R-7}, Rhodococcus equi{R-6; 7}, Staphylococcus species{R-7}, Streptococcus equi{R-6; 7}, S. equisimilis{R-7}, and S. zooepidemicus{R-6; 7} isolates. Susceptibility has been variable for the equine gram-negative nonenteric bacteria. It has shown moderate activity against Actinobacillus suis, A. equuli, Bordetella bronchiseptica, and Pasteurella species isolates{R-6; 7}. Equine isolates of Pseudomonas aeruginosa, Escherichia coli, Enterobacter cloacae, Klebsiella pneumoniae, Proteus species, and Salmonella species were found to be resistant{R-7}. Strains of the porcine pathogen Actinobacillus pleuropneumoniae, isolated in Spain, were found to be susceptible to rifampin in vitro at a concentration of 1 mcg/mL or less{R-50}. Rifampin also had activity against Pasteurella multocida species isolated from pigs with pneumonia in Spain{R-55}. Some strains of Mycobacterium paratuberculosis were found to be sensitive to rifampin in in vitro tests{R-43}. Anaerobes found to be susceptible in vitro include 132 strains of Bacteroides species and 25 strains of Fusobacterium species isolated from goats in Spain; with blood concentrations of 2 mcg/mL, only 18% of strains were resistant{R-53}. Although in vitro tests showed rifampin to be active against Clostridium perfringens type A isolates{R-52}, when higher concentrations of pathogens per milliliter were tested, the

ACCEPTED
[Pneumonia, Rhodococcus equi (treatment adjunct)]1 ; or [Extrapulmonary infection, Rhodococcus equi (treatment adjunct)]1 Foals: Rifampin is used in combination with erythromycin in the treatment of pneumonia caused by Rhodococcus (Corynebacterium) equi infection in foals{R-33; 34; 36}. Although the lung appears to be most vulnerable to Rhodococcus equi infection, in some cases susceptible foals have been found to have abdominal or subcutaneous abscesses, bacterial endocarditis, diskospondylitis, gastrointestinal infections, osteomyelitis, or septicemia{R-3742}. In many, but not all, of these cases the foal has a concomitant pneumonia{R-3742}. R. equi are susceptible in vitro to erythromycin alone{R-66; 67}, and erythromycin alone has been effective in the treatment of this infection{R-36; 67; 75}. However, no studies have been performed to compare the efcacy of erythromycin alone with the combination of erythromycin and rifampin in foals. The in vitro evidence of synergistic activity for the combination of erythromycin and rifampin against R. equi{R-10} and the volume of case reports supporting the efcacy of the combination make treatment with a combination of erythromycin and rifampin more commonly recommended for this indication than erythromycin alone{R-32}.

ACCEPTANCE NOT ESTABLISHED

[Infections, bacterial (treatment)]1Although the safety and efcacy have not been established, rifampin is used in combination with other antimicrobials in the treatment of susceptible bacterial infections, and in particular, staphylococcal infections{R-20} in animals. Rifampin is particularly suited for the treatment of organisms that are resistant to other therapies by nature of their intracellular location{R-20; 62}. Because the pharmacokinetics of rifampin have been well-studied in horses{R-6; 7; 13} and minimal side effects have been reported in foals{R33; 34; 36} , the treatment of these infections in horses may be more well-dened than for other species. The use of rifampin in other animals could be based on available pharmacokinetic data for calves{R19} , dogs{R-4; 65}, foals{R-16}, rabbits{R-18}, and sheep{R-22}; knowledge of bacterial susceptibility; case reports describing treatment of infections in a cat{R-58}, a deer{R-60}, and dogs{R-57}; and also efcacy studies that have been performed in rats{R-54; 59}. However, there is

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192 RIFAMPIN VeterinarySystemic limited knowledge about the safety of rifampin use in species other than horses. [Brucellosis (treatment)]1Dogs: Although the safety and efcacy have not been established, rifampin in combination with doxycycline has been recommended in the treatment of brucellosis in dogs. This recommendation is based on demonstrated efcacy in the treatment of human brucellosis{R-6872} and evidence of possible canine pathogen susceptibility to rifampin{R-73}. There are no controlled studies in dogs. [Paratuberculosis (treatment)]1Cattle, goats, and sheep: For use in animals not to be used in food productionAlthough the safety and efcacy have not been established, rifampin has been administered in conjunction with isoniazid in the alleviation of signs associated with paratuberculosis (Mycobacterium paratuberculosis infection or Johnes disease){R-23; 43}. The addition of an aminoglycoside to the regimen has also been used in the initial weeks of severe infection{R-23; 44}. The use of rifampin is based on in vitro culture and sensitivity results{R-43} and on case reports of clinical improvement for extended periods of time{R-23; 44}; however, internal lesions and fecal shedding of the organism are rarely controlled. It should be noted that semen from bulls with paratuberculosis have been found to contain M. paratuberculosis even after freezing and processing. Placental infection of a fetus also can occur in infected cows.{R-23} It is not known if rifampin and isoniazid therapy can prevent transmission in semen or transplacentally. The cost of rifampin therapy, as well as the inability to completely clear infection and prevent spread of disease, limits treatment only to valuable quarantined animals{R-23; 44}. [Potomac horse fever (treatment)]1Horses: Although the efcacy is not established, rifampin is used in combination with erythromycin in the treatment of Potomac horse fever (equine ehrlichial colitis){R-56}. It is as effective as oxytetracycline in the resolution of clinical signs, with the exception that rifampin and erythromycin will not reduce fever as quickly as oxytetracycline, taking up to 12 hours longer to return the body temperature to normal{R-56}. Rifampin and erythromycin have the advantage of being available in oral dosage forms.

CHEMISTRY
Source: Semisynthetic derivative of rifamycin B{R-2}, a natural fermentation product of Nocardia (Streptomyces) mediterranei{R-4; 6}. Chemical group: Macrocyclic antibiotic{R-13}. Chemical name: Rifamycin,3-[[(4-methyl-1-piperazinyl)imino]methyl]{R-1} . Molecular formula: C43H58N4O12{R-1}. Molecular weight: 822.94{R-1}. Description: Rifampin USPRed-brown, crystalline powder{R-3}. pKa: 7.9{R-22}. Solubility: Rifampin USPVery slightly soluble in water; freely soluble in chloroform; soluble in ethyl acetate and in methanol{R-3}.

PHARMACOLOGY/PHARMACOKINETICS
Mechanism of action/effect: Rifampin inhibits DNA-dependent RNA polymerase; however, at therapeutic doses, it inhibits the enzyme in bacteria, while not affecting mammalian polymerase{R-2; 4}. Rifampin is bactericidal and is active against extracellular organisms as well as against susceptible intracellular organisms{R-2; 49}, including intraleukocytic organisms{R-20}. Rifampin can enter neutrophils and macrophages to kill intracellular bacteria{R-4; 20}, while not interfering with phagocytosis{R-20}. Rifampin appears to penetrate the outer membrane of gram-positive bacteria more easily than that of gram-negative bacteria{R-4}. This is reected in the signicantly lower minimum inhibitory concentrations (MIC) required for gram-positive bacteria (0.01 mcg per mL of serum) compared with gram-negative bacteria (8 to 32 mcg per mL){R-4}. Absorption: Rifampin is rapidly absorbed after oral administration to people, calves, dogs, and horses{R-4; 19}, although bioavailability is not high in horses and sheep. Administration with food can prolong the time to peak serum concentration in adult horses and people{R-4; 14}. Adult sheep appear to have prolonged absorption, possibly because of prolonged movement through the rumen{R-4; 20}. Bioavailability Oral: Horses 48.8%, with a single dose of 10 mg per kg of body weight (mg/kg){R-6}. 39.5%, with a single dose of 10 mg/kg, administered in the feed{R-13}. Note: An unpublished study of horses receiving a dose of 5 mg/kg found a bioavailability of 68% when rifampin was administered 1 hour before feeding and 26% when it was administered 1 hour after feeding{R-15}. Because rifampin is most often administered with feed, recommended dosages compensate for the decreased absorption. Sheep 36.6 3.2%, with a dose of 10 mg/kg, as an oral drench{R-19}. 3 to 32%, with a dose of 20 mg/kg, in a gel capsule{R-21}. 14 to 122%, with a dose of 50 mg/kg, in a gel capsule{R-21}. Note: The study performed using gel capsules of rifampin in sheep found that absorption was incomplete and still continuing by the end of the study, producing extremely variable results{R-21}. Absorption was also relatively low and variable with the oral

UNACCEPTED
[Mycobacterial infections (treatment)]1Current therapeutic regimens for mycobacterial infections cannot guarantee that an animal is no longer contagious during treatment. Treatment of Mycobacterium tuberculosis, Mycobacterium bovis, and other mycobacterial species transmissible to human beings is nearly always considered inappropriate{R-45; 47}. The treatment of tuberculosis in cattle is not permitted in Canada or the U.S.{R-64}. The treatment of mycobacterial infections that do not cause human tuberculosis, such as atypical mycobacterial infections in cats, may be acceptable{R-4548} although there is insufcient evidence of efcacy at this time.

REGULATORY CONSIDERATIONS
U.S. and Canada Rifampin is not labeled in the United States or Canada for use in animals, including food-producing animals. There are no established withdrawal times. The treatment of tuberculosis in cattle is not permitted in Canada or the U.S.{R-64}

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RIFAMPIN VeterinarySystemic 193 drench but not to the same extent as with gel capsules; the medication may have been administered directly into the abomasum and would therefore have been rapidly and consistently absorbed{R-21}. IntramuscularHorses: 59.8 3.2%, with a dose of 10 mg/kg{R-13}. Distribution: Rifampin is highly lipid-soluble and is widely distributed in tissues{R-4; 6}. Antimicrobial concentrations are approached in all tissue compartments throughout the body, including milk{R-22}, bone{R-54}, cerebrospinal uid{R-18}, exudates, ascitic uid, and soft tissues{R-4}. Rifampin crosses the blood-brain barrier{R-6; 18} and, in rabbits, the cerebrospinal uid to plasma concentration ratio ranged from 0.52 to 1.17, from 30 minutes to 12 hours after an oral dose of 10 mg/kg{R-18}. Rifampin can penetrate phagocytic cells to kill susceptible intracellular bacteria{R-6; 7; 20}. In many species, as has been documented in dogs and human beings, feces, saliva, sweat, tears, and urine may be discolored red-orange by rifampin and its metabolites{R-4}. Volume of distribution Horses: Area0.93 0.29 liter per kg (L/kg){R-7}; 0.63 0.06 L/kg{R-13}. Steady state0.76 L/kg{R-6}. Sheep: Steady state0.45 0.06 L/kg{R-21}. Protein binding: HorsesHigh (78%), with serum concentrations of 2 to 20 micrograms per milliliter (mcg/mL){R-6}. Human beingsHigh (80%){R-4}. SheepHigh (84%){R-22}. Biotransformation: The biotransformation and elimination of rifampin in animals is not well dened. Induction of hepatic enzymes occurs in response to administration of rifampin in many species{R-17; 25; 26}, but major metabolites of the parent drug in most animals have not yet been traced{R-6; 21} . In human studies, it was found that the primary metabolite of rifampin is 25-desacetylrifampin, which is bioactive{R-4}. Human desacetylrifampin is more profusely secreted in the bile compared with rifampin, but is less concentrated in the serum than the parent drug{R-4}. And while rifampin undergoes extensive human enterohepatic recycling, desacetylrifampin is poorly absorbed and therefore is not recycled{R-6}. HorsesDesacetylrifampin was not detected in serum samples after an intravenous dose of 10 mg/kg or oral doses of 10 mg/kg every 12 hours for seven doses{R-6}. The metabolite was measured in urine, but the parent compound was much more predominant{R-6}; however, only 6.82% of the total dose was recovered in the urine as either rifampin or desacetylrifampin{R-6}. RatsDesacetylrifampin is formed in extremely low quantities in rats{R-25}. SheepDesacetylrifampin was not found in serum samples from sheep administered either intravenous or oral rifampin{R-21}. Rifampin and metabolites have not been measured in sheep urine. Rifampin can induce hepatic enzymes, including increasing its own hepatic biotransformation with multiple doses{R-17; 25}. Induction has been shown to occur in many species, including dogs{R-27}, horses{R17} , pigs{R-30}, and rabbits{R-28; 29}. The dose needed to induce an increase in hepatic enzymes varies among species. Rats administered 2003 Thomson MICROMEDEX 50 mg/kg intraperitoneally every 12 hours for 6 days did not show induction of liver microsomal enzyme activity against substances tested{R-26}, but mice administered the same dose showed signicant induction of the hepatic mixed-function oxidase system and enzymatic activity{R-26}. In horses, enzyme induction has generally not been seen with less than 5 days of therapy, but once there is an increase in hepatic enzyme activity, the increase may last for more than 2 weeks after discontinuation of treatment{R-17}. However; several factors may modify the therapeutic levels of rifampin, such as the variability in its absorption in horses when given alone, and the possible change in pharmacokinetics due to interactions with other medications that often are administered with rifampin; data are insufcient for determining whether the increased elimination of rifampin due to hepatic enzyme induction during prolonged dosing may be corrected for by a dose modication.

Half-life: Absorption Intramuscular administration: Horses6.7 1.5 hours, with a dose of 10 mg/kg{R-13}. Oral, with food: Horses 4.2 1.2 hours, with a dose of 10 mg/kg{R-13}. 2.6 1.3 hours, with a dose of 25 mg/kg{R-13}. DistributionIntravenous: Horses13.8 5.2 minutes, with a dose of 10 mg/kg{R-13}. Elimination Intravenous: Horses8.1 hours{R-6}; 7.3 hours{R-7}; 6 hours{R-13}. Sheep Nonlactating: 2.9 hours{R-19}; 4.56 hours{R-21}. Lactating: 3.3 hours{R-22}. Intramuscular (terminal elimination) Horses: 7.3 hours, with a dose of 10 mg/kg{R-13}. Sheep: 11 hours, with a dose of 20 mg/kg{R-22}. Oral (terminal elimination) Single dose: Dogs8 hours, with a dose of 10 mg/kg{R-4; 65}. Foals 1 week of age: 25.4 1.2 hours, with a dose of 10 mg/ kg{R-14}. 10 weeks of age: 7.9 1.5 hours, with a dose of 10 mg/ kg{R-14}. Horses13.3 hours, with a dose of 10 mg/kg{R-6}. Sheep6.42 hours, with a dose of 20 mg/kg{R-21}. Multiple doses: Horses7.99 hours, after the seventh dose of 10 mg/ kg, administered every 12 hours{R-6}. Note: Multiple doses result in lower peak serum concentrations and a decreased half-life, because of autoinduction of hepatic enzymes{R-4}. Concentrations: Time to peak concentration Intramuscular administration: Horses4.2 0.2 hours, with a dose of 10 mg/kg{R-13}. Sheep3 hours, with a dose of 20 mg/kg{R-22}. Oral: Calves, 2 to 3 weeks of age4 to 8 hours, with a dose of 10 mg/kg{R19} . All rights reserved

194 RIFAMPIN VeterinarySystemic Dogs2 to 4 hours, with a dose of 10 mg/kg{R-4; 65}. Foals, 6 to 8 weeks of age4 hours, with a dose of 10 mg/kg{R-16}. Horses 3 hours{R-6}; 1.6 0.5 hours{R-14}, with a single dose of 10 mg/kg. 3.7 1.2 hours{R-13}; 3.5 1.7 hours{R-14}, with a single dose of 10 mg/kg, administered with food{R-13}. 2.5 hours, with an intragastric dose of 20 mg/kg of oral suspension{R-7}. 3.5 hours, with a dose of 25 mg/kg, administered with food{R-13}. Sheep4 to 8 hours{R-19}; 8 to 24 hours{R-21}. Peak serum concentrationAutoinduction of hepatic enzymes can cause multiple doses of rifampin to result in lower peak serum concentrations than expected, if based on single dose measurements{R-4; 19}. Intramuscular: Horses4 0.3 mcg/mL, with a dose of 10 mg/kg{R-13}. SheepApproximately 8 mcg/mL (from graph), with a dose of 20 mg/kg{R-22}. Oral: Calves, 2 to 3 weeks of age11.7 to 24.6 mcg/mL, with a dose of 10 mg/kg{R-19}. Dogs40 mcg/mL, with a dose of 10 mg/kg{R-4; 65}. Foals, 6 to 8 weeks of age6.7 mcg/mL, with a dose of 10 mg/ kg{R-16}. Horses 3.9 mcg/mL{R-6}; 4.5 1.1 mcg/mL{R-14}, with a dose of 10 mg/kg. 2.9 0.4 mcg/mL{R-13}; 3.3 2.9 mcg/mL{R-14}, with a dose of 10 mg/kg, administered with food. 13.3 2.7 mcg/mL, with intragastric administration of 20 mg/kg of oral suspension{R-7}. 9.8 1.9 mcg/mL, with a dose of 25 mg/kg, administered with food{R-13}. Sheep 0.6 to 2.4 mcg/mL, with a dose of 10 mg/kg{R-19}. 3.27 1.43, with a dose of 20 mg/kg{R-21}. Other concentrations Cerebrospinal uid: Rabbits1.3 to 1.6 mcg/mL from 30 minutes to 12 hours after an oral dose of 10 mg/kg{R-18}. Serum: Dogs9 to 10 mcg/mL, 24 hours after an oral dose of 10 mg/ kg{R-65}. Horses 6.86 1.69 mcg/mL, 12 hours after an intragastric dose of 20 mg/ kg of oral suspension{R-7}. 3.83 0.87 mcg/mL, 24 hours after an intragastric dose of 20 mg/ kg of oral suspension{R-7}. RabbitsRanged from 1.8 to 2.5 mcg/mL from 30 minutes to 12 hours after an oral dose of 10 mg/kg{R-18}. Sheep0.97 0.61 mcg/mL, 24 hours after an oral dose of 20 mg/ kg in a gelatin capsule{R-21}. Duration of action: The National Committee for Clinical Laboratory Standards (NCCLS) in the United States lists minimum inhibitory concentration (MIC) breakpoints for animal isolates and rifampin as 1 mcg/mL for susceptible organisms and 4 mcg/mL for resistant organisms{R-8}. Dogs: Serum concentration was 9 to 10 mcg/mL 24 hours after a single oral dose of 10 mg/kg{R-65}. Horses: Serum concentrations greater than 2 mcg/mL were reached 45 minutes after intragastric rifampin administration of 20 mg/kg and concentrations were maintained at greater than 3 mcg/mL for at least 24 hours. Elimination: Horses: Only 6.82% of the intravenous dose of 10 mg/kg was recovered in the urine as rifampin or desacetylrifampin, an active metabolite{R-6}. It is not known if the rifampin not recovered is predominately sequestered in the tissue or perhaps excreted in bile primarily as desacetylrifampin, a more polar and more easily bile-excreted compound{R-6}. Total clearance Horses: 1.14 mL/min/kg{R-6}; 1.34 mL/min/kg{R-13}. Sheep: 1.16 0.21 mL/min/kg{R-21}; 5.17 mL/min/kg{R-19}.

PRECAUTIONS TO CONSIDER SPECIES SENSITIVITY

Dogs: There is very little information about the effects of rifampin in small animals; however, there is anecdotal information warning that up to 20% or more of dogs receiving 5 to 10 mg per kg of body weight (mg/kg) a day will develop increases in hepatic enzymes that may lead to clinical hepatitis{R-4}. Because one study found peak serum concentrations in dogs that were four times that of horses after a standard dose of 10 mg/kg, it has been suggested that the incidence of side effects in dogs may be due to overdosage{R-4; 65}. Some clinicians have noted lethargy, bilirubinemia, and bilirubinuria in dogs administered rifampin, but there is no information on incidence of adverse effects, dosage administered, pretreatment liver evaluation, or other factors{R-57}.

TUMORGENICITY
Studies in female mice of a strain known to be particularly susceptible to the spontaneous development of hepatomas have shown that rifampin, given in doses of 2 to 10 times the maximum human dose (20 mg per kg of body weight, up to 600 mg every 12 hours) for 1 year, causes a signicant increase in the development of hepatomas. However, studies in male mice of the same strain, in other strains of male or female mice, and in rats have not shown that rifampin is tumorigenic{R-2}.

PREGNANCY/REPRODUCTION
Mice and rats: Oral doses of 150 to 250 mg/kg during pregnancy produced dose-dependent teratogenic effects in offspring, including cleft palate in the mouse and spina bida in the rat{R-2}. Human information: Rifampin has caused postnatal hemorrhage in the mother and infant when administered during the last weeks of pregnancy{R-2}. Treatment with vitamin K may be indicated{R-2}.

LACTATION
Sheep: Rifampin is well-distributed into milk, with a milk to serum concentration ratio of 0.9 to 1.28 in sheep given an intramuscular dose of 10 mg/kg{R-22}.

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RIFAMPIN VeterinarySystemic 195

DRUG INTERACTIONS AND/OR RELATED PROBLEMS

The following drug interactions and/or related problems have been selected on the basis of their potential clinical signicance (possible mechanism in parentheses where appropriate)not necessarily inclusive ( = major clinical signicance): Note: Combinations containing any of the following medications, depending on the amount present, may also interact with this medication. Drugs metabolized by hepatic microsomal enzymes, including: Ciprooxacin{R-29} or Corticosteroids{R-4} or Digitalis glycosides{R-4} or Itraconazole{R-30} or Ketoconazole{R-4} or Phenobarbital{R-5} or Phenylbutazone{R-17} or Warfarin{R-4; 31} (rifampin causes induction of hepatic enzymes in dogs{R-27}, mice{R-26}, horses{R-5; 17}, pigs{R-30}, and rabbits{R-28; 29}, potentially increasing metabolism{R-5} and thereby decreasing serum concentrations{R-4} of the above medications; there is some selectivity in enzyme induction so that not every drug that is oxidized by the system is affected{R-29}; in guinea pigs and rats, hepatic metabolism does not appear to be signicantly induced by commonly administered dosages of rifampin{R-26; 27} but can be by extremely high doses{R-25}; phenobarbital will also increase the metabolism of rifampin by enzyme induction{R-17})

HUMAN DRUG INTERACTIONS AND/OR RELATED PROBLEMS{R-79}

In addition to the above drug interactions reported in animals, the following drug interactions have been reported in humans, and are included in the human monograph Rifampin (Systemic) in USP DI Volume I; these drug interactions are intended for informational purposes only and may or may not be applicable to the use of rifampin in the treatment of animals: Aminophylline or Oxtriphylline or Theophylline (rifampin may increase metabolism of theophylline, oxtriphylline, and aminophylline by induction of hepatic microsomal enzymes, resulting in increased theophylline clearance) Anesthetics, hydrocarbon inhalation, except isourane (chronic use of hepatic enzymeinducing agents prior to anesthesia, except isourane, may increase anesthetic metabolism, leading to increased risk of hepatotoxicity) Anticoagulants, coumarin- or indandione-derivative (concurrent use with rifampin may enhance the metabolism of these anticoagulants by induction of hepatic microsomal enzymes, resulting in a considerable decrease in the activity and effectiveness of the anticoagulants; prothrombin time determinations may be required as frequently as once a day; dosage adjustments of anticoagulants may be required before and after rifampin therapy) Azole antifungals (concurrent use may increase the metabolism of the azole antifungals, lowering their plasma concentrations; depending on the clinical situation, the dose of an azole antifungal may need to be increased during concurrent use with rifampin) 2003 Thomson MICROMEDEX

Barbiturates (concurrent use with rifampin may enhance the metabolism of hexobarbital by induction of hepatic microsomal enzymes, resulting in lower serum concentrations; there are conicting data on rifampins effect on phenobarbital; dosage adjustment may be required) Beta-adrenergic blocking agents, systemic (concurrent use of metoprolol or propranolol with rifampin has resulted in reduced plasma concentrations of these two betaadrenergic blocking agents due to enhanced metabolism of hepatic microsomal enzymes by rifampin; although not documented, other beta-adrenergic blocking agents may also interact with rifampin) Bone marrow depressants (concurrent use of bone marrow depressants with rifampin may increase the leukopenic and/or thrombocytopenic effects; if concurrent use is required, close observation for myelotoxic effects should be considered) Chloramphenicol (concurrent use with rifampin may enhance the metabolism of chloramphenicol by induction of hepatic microsomal enzymes, resulting in signicantly lower serum chloramphenicol concentrations; dosage adjustment may be necessary) Clofazimine (concurrent use with rifampin has resulted in reduced absorption of rifampin, delaying its time to peak concentration, and increasing its half-life) Corticosteroids, glucocorticoid and mineralocorticoid (concurrent use with rifampin may enhance the metabolism of corticosteroids by induction of hepatic microsomal enzymes, resulting in a considerable decrease in corticosteroid plasma concentrations; dosage adjustment may be required; rifampin has also counteracted endogenous cortisol and produced acute adrenal insufciency in patients with Addisons disease) Cyclosporine (rifampin may enhance metabolism of cyclosporine by induction of hepatic microsomal enzymes and intestinal cytochrome P450 enzymes; dosage adjustment may be required) Dapsone (concurrent use with rifampin may decrease the effect of dapsone because of increased metabolism resulting from stimulation of hepatic microsomal enzyme activity; dapsone concentrations may be decreased by half; dapsone dosage adjustments are not required during concurrent therapy with rifampin for leprosy) Diazepam (concurrent use with rifampin may enhance the elimination of diazepam, resulting in decreased plasma concentrations; whether this effect applies to other benzodiazepines has not been determined; dosage adjustment may be necessary) Disopyramide or Mexiletine or Propafenone or Quinidine or Tocainide (concurrent use with rifampin may enhance the metabolism of these antiarrhythmics by induction of hepatic microsomal enzymes, resulting in signicantly lower serum antiarrhythmic concentrations; serum antiarrhythmic concentrations should be monitored and dosage adjustment may be necessary)

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196 RIFAMPIN VeterinarySystemic Estramustine or Estrogens (concurrent use of estramustine or estrogens with rifampin may result in signicantly reduced estrogenic effect because of stimulation of estrogen metabolism or reduction in enterohepatic circulation of estrogens) Hepatotoxic medications, other (concurrent use of rifampin and other hepatotoxic medications may increase the potential for hepatotoxicity; patients should be monitored closely for signs of hepatotoxicity) Human immunodeciency virus (HIV) protease inhibitors, such as Amprenavir or Indinavir or Nelnavir or Ritonavir or Saquinavir (rifampin accelerates the metabolism of protease inhibitors through induction of hepatic P450 cytochrome oxidases, resulting in subtherapeutic levels of the protease inhibitors; in addition, protease inhibitors retard the metabolism of rifampin, resulting in increased serum levels of rifampin and the likelihood of increased drug toxicity; concurrent use of HIV protease inhibitors with rifampin is only recommended under specic circumstances as outlined by the Centers for Disease Control and Prevention [CDC]) Isoniazid (concurrent use of isoniazid with rifampin may increase the risk of hepatotoxicity, especially in patients with preexisting hepatic function impairment and/or in fast acetylators of isoniazid; patients should be monitored closely for signs of hepatotoxicity during the rst 3 months of therapy) Phenytoin (concurrent use with rifampin may stimulate the hepatic metabolism of phenytoin, increasing its elimination and thus counteracting its anticonvulsant effects; careful monitoring of serum hydantoin concentrations and dosage adjustments may be necessary before and after rifampin therapy) Probenecid (may compete with rifampin for hepatic uptake when used concurrently, resulting in increased and more prolonged rifampin serum concentrations and/or toxicity; however, the effect on rifampin serum concentrations is inconsistent, and concurrent use of probenecid to increase rifampin serum concentrations is not recommended) Trimethoprim (concurrent use with rifampin may signicantly increase the elimination and shorten the elimination half-life of trimethoprim) Verapamil, oral (rifampin has been found to accelerate the metabolism of oral doses of verapamil, resulting in a signicant decrease in serum verapamil concentration, and thereby reversing its cardiovascular effects; concurrent use of intravenous verapamil with rifampin was found to have only minor effects on verapamils clearance and no signicant effect on cardiovascular effects) With diagnostic test results Indocyanine green and Sulfobromophthalein sodium excretion test (BSP) (in rats, plasma clearances of indocyanine green and sulfobromophthalein sodium were increasingly and signicantly delayed after 200 mg per kg of body weight a day was administered for 1 to 7 days{R-25}; the impact of recommended doses, such as 20 mg/kg a day, on these excretion tests has not been measured) With physiology/laboratory test values Alkaline phosphatase{R-57} (in the dog, mild increases in serum alkaline phosphatase levels are common and are not considered signicant unless accompanied by elevations in other hepatic enzymes{R-4; 54})

HUMAN LABORATORY VALUE ALTERATIONS{R-79}

The following laboratory value alterations have been reported in humans, and are included in the human monograph Rifampin (Systemic) in the USP DI Volume I; these laboratory value alterations are intended for informational purposes only and may or may not be applicable to the use of rifampin in the treatment of animals: With diagnostic test results Coombs (antiglobulin) tests, direct (may become positive rarely during rifampin therapy) Dexamethasone suppression test (rifampin may prevent the inhibitory action of a standard dexamethasone dose administered for the overnight suppression test, rendering the test abnormal; it is recommended that rifampin therapy be discontinued 15 days before administering the dexamethasone suppression test) Folate determinations, serum and Vitamin B12 determinations, serum (therapeutic concentrations of rifampin may interfere with standard microbiological assays for serum folate and vitamin B12; alternate methods must be considered when determining serum folate and vitamin B12 concentrations in patients taking rifampin) Sulfobromophthalein (BSP) uptake and excretion (hepatic uptake and excretion of BSP in liver function tests may be delayed by rifampin, resulting in BSP retention; the BSP test should be performed prior to the daily dose of rifampin to avoid false-positive test results) Urinalyses based on spectrometry or color reaction (rifampin may interfere with urinalyses that are based on spectrometry or color reaction due to rifampins reddish-orange to reddish-brown discoloration of urine) With physiology/laboratory test values Alanine aminotransferase (ALT [SGPT]) and Alkaline phosphatase and Aspartate aminotransferase (AST [SGOT]) (values may be increased) Bilirubin, serum and Blood urea nitrogen (BUN) and Uric acid, serum (concentrations may be increased)

LABORATORY VALUE ALTERATIONS

The following have been selected on the basis of their potential clinical signicance (possible effect in parentheses where appropriate)not necessarily inclusive ( = major clinical signicance): 2003 Thomson MICROMEDEX

MEDICAL CONSIDERATIONS/CONTRAINDICATIONS
The medical considerations/contraindications included have been selected on the basis of their potential clinical signicance (reasons All rights reserved

RIFAMPIN VeterinarySystemic 197 given in parentheses where appropriate)not necessarily inclusive ( = major clinical signicance). Risk-benet should be considered when the following medical problem exists: Hepatic function impairment, severe (in dogs, hepatic function impairment may predispose to major side effects, and the risk should be carefully considered{R-4}; in any species, dosage adjustments may be necessary with hepatic dysfunction and avoiding use of rifampin should be considered{R-4; 6}) Volume I; these side/adverse effects are intended for informational purposes only and may or may not be applicable to the use of rifampin in the treatment of animals: Incidence more frequent Gastrointestinal disturbances; reddish-orange to reddishbrown discoloration of urine, feces, saliva, sputum, sweat, and tears Incidence less frequent Flu-like syndrome (chills; difcult breathing; dizziness; fever; headache; muscle and bone pain; shivering); fungal overgrowth; hypersensitivity Incidence rare Blood dyscrasias; hepatitis; hepatitis prodromal symptoms; interstitial nephritis Note: Intermittent use of rifampin may increase the chance of a patient developing the u-like syndrome, as well as acute hemolysis or renal failure. These reactions are thought to be immunologically mediated, and intermittent use of the medication should be limited to those conditions in which its safety and efcacy have been established.

PATIENT MONITORING
The following may be especially important in patient monitoring (other tests may be warranted in some patients, depending on condition; = major clinical signicance): Hepatic enzyme tests (particularly in dogs, hepatic enzymes should be monitored during rifampin therapy)

SIDE/ADVERSE EFFECTS
The following side/adverse effects have been selected on the basis of their potential clinical signicance (possible signs and, for humans, symptoms in parentheses where appropriate)not necessarily inclusive:

OVERDOSE
For more information in the case of overdose or unintentional ingestion, contact the American Society for the Prevention of Cruelty to Animals (ASPCA) National Animal Poison Control Center (888426-4435 or 900-443-0000; a fee may be required for consultation) and/or the manufacturer. The lethal dose for 50% of test animals (LD50) is approximately 885 mg per kg of body weight (mg/kg) in the mouse, 1720 mg/kg in the rat, and 2120 mg/kg in the rabbit{R-2}.

THOSE INDICATING NEED FOR MEDICAL ATTENTION

Incidence more frequent Foals Diarrhea, self-limiting{R-34}often occurs in the rst week of therapy and resolves without treatment{R-34} Incidence unknown Dogs Hepatotoxicity{R-4} Horses With intravenous administration (dimethylsulfoxide vehicle) Allergic reactions, specically anaphylactoid reactions{R-17}; central nervous system depression, generalized{R-13}; decreased appetite{R-13}; signs of distress (apprehension, pawing with forefeet, shifting of weight-bearing from one side to another){R-14}; sudden defecation{R-14}; weakness or unsteadiness{R-14} Note: Hemolysis was seen grossly in blood samples of some horses administered intravenous rifampin at a dose of 10 mg/kg{R-13}. The signs listed above have been reported with administration of rifampin in a dimethylsulfoxide vehicle; therefore, it is unclear whether some effects, such as allergic-like reactions or hemolysis, were caused by the vehicle or by rifampin{R-78}.

CLINICAL EFFECTS OF OVERDOSE

In human beings, overdose can cause mental changes, nausea and vomiting, angioedema, generalized pruritus, and red-orange discoloration of the mucous membranes, sclera, and skin{R-63}. Signs of overdose specic to animals are not known.

TREATMENT OF OVERDOSE
From the human therapeutic literature{R-2; 63}: To decrease absorption Evacuating stomach contents using ipecac syrup or gastric lavage. Administering an activated charcoal slurry to help adsorb residual rifampin in the gastrointestinal tract. Supportive therapy.

THOSE INDICATING NEED FOR MEDICAL ATTENTION ONLY IF THEY CONTINUE OR ARE BOTHERSOME
Incidence more frequent Horses Sweating, mild to moderatemay occur with parenteral administration, more prominent with intravenous administration{R-13; 14}.

CLIENT CONSULTATION
Notify your veterinarian of any medications your animal is already receiving before treatment or any medications that may be initiated during treatment with rifampin because drug interactions can occur{R-4}. It is important to be sure that the animal receives the full course of treatment prescribed. However, if new signs occur, such as decreased appetite, depression, diarrhea, or jaundice{R-13; 14; 34}, contact your veterinarian. Reddish-orange to reddish-brown discoloration of urine, stools, saliva, sputum, sweat, and tears may occur as a typical effect of the medication, but is not harmful{R-63; 64}.

HUMAN SIDE/ADVERSE EFFECTS{R-79}

In addition to the above side/adverse effects reported in animals, the following side/adverse effects have been reported in humans, and are included in the human monograph Rifampin (Systemic) in USP DI

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198 RIFAMPIN VeterinarySystemic

VETERINARY DOSING INFORMATION

The National Committee for Clinical Laboratory Standards (NCCLS) in the United States lists minimum inhibitory concentration (MIC) breakpoints of animal isolates for rifampin as 1 mcg/mL for susceptible organisms and 4 mcg/mL for resistant organisms{R-8}. Organisms testing between these values are considered intermediate and may or may not be inhibited{R-8}. Specically for Rhodococcus equi, one study of nine strains found minimum inhibitory concentrations (MICs) for rifampin to be 0.0078 to 0.0625 mcg/mL{R-10}. In another study, a MIC of less than or equal to 0.25 mcg/ mL was found for 18 Rhodococcus equi isolates{R-7}; 83% of these isolates had an MIC of 0.0625 or less{R-7}. Other equine organisms have also been found to have MICs of less than 0.25 mcg/mL, including coagulase-positive Staphylococcus species (MIC of 0.0625 or less), Streptococcus zooepidemicus (MIC of 0.0625 or less), S. equi (MIC of 0.0625 or less), S. equisimilis (MIC of 0.125 or less), and Corynebacterium pseudotuberculosis (MIC of 0.0156 or less){R-7}. Gramnegative organisms have been found to be variably susceptible or resistant{R-7}. The MICs of 19 Actinobacillus isolates from horses ranged from 1 to 4 mcg/mL{R-7}. The possibility of mixed infections involving both gram-positive and gram-negative organisms should be considered in some situations, such as young horses with respiratory tract infections{R-7; 36}. Because nonenteric gram-negative organisms can have variable susceptibility, susceptibility data should be used to determine the appropriate therapy{R-7}. The possibility of mixed infections and the rapid rise of resistance to rifampin make combination therapy the most logical recourse in many cases{R-7}. Rifampin has been shown in in vitro tests to have synergistic activity with erythromycin or trimethoprim and to have an additive effect with ampicillin or penicillin G{R-7; 9; 10}. However, rifampins activity in in vitro tests can be antagonistic to those of other antimicrobials, such as gentamicin{R-10}; it is not certain how this interaction might affect in vivo activity.

[Potomac horse fever]1Horses: Oral, 10 mg per kg of body weight every twelve hours in combination with 25 mg of erythromycin estolate or erythromycin ethylsuccinate per kg of body weight every twelve hours{R-56}. Note: [Horses]1Although the safety and efcacy of rifampin have not been established, an oral dose of 10 mg rifampin per kg of body weight every twelve hours{R-6; 7} has been used in the treatment of susceptible bacterial infections, such as staphylococcal infections in horses, based on pharmacokinetic data. It is usually administered in combination with another antimicrobial, such as erythromycin or penicillin{R-6; 7}. [Cattle]1, [goats]1, and [sheep]1For use in animals not to be used in food production: Although the safety and efcacy of rifampin have not been established, an oral dose of 20 mg per kg of body weight every twenty-four hours has been used in the treatment of susceptible bacterial infections in cattle{R-23} and sheep{R-19; 20}, based on pharmacokinetic data. For the treatment of paratuberculosis in cattle, goats, and sheep, an oral dose of 20 mg per kg of body weight every twenty-four hours, administered in conjunction with 20 mg of oral isoniazid per kg of body weight every twenty-four hours, has been used to control signs, based on case reports{R-23} and the pharmacokinetics known{R-19; 21}; however, clinical improvement only occurs for a short period of time and does not prevent spread of the infection to other animals{R-23; 44}. [Dogs]1If rifampin is administered to dogs, dosing of rifampin should generally be kept below 10 mg per kg of body weight a day, based on limited pharmacokinetic data and reports of hepatic toxicity in dogs{R-4}. A single oral dose of 10 mg per kg appears to produce much higher serum concentrations than the same dose administered to other species{R-4; 65}, with a possibly increased risk of toxicity. The best dose for maximum safety and efcacy has not been established. Strength(s) usually available: U.S. Veterinary-labeled product(s): Not commercially available. Human-labeled product(s): 150 mg (Rx) [Rifadin{R-2}]. 300 mg (Rx) [Rifadin{R-2}; Rimactane{R-24}; generic]. Canada Veterinary-labeled product(s): Not commercially available. Human-labeled product(s): 150 mg (Rx) [Rifadin; Rimactane; Rofact]. 300 mg (Rx) [Rifadin; Rimactane; Rofact]. Withdrawal times: U.S. and CanadaThe use of rifampin in food-producing animals has not been approved by the Food and Drug Administration or the Canadian Health Protection Branch; therefore, there are no established withdrawal times. The issue of whether rifampin should be used in food animals is complicated by its link to hepatic tumors in one strain of female mice (see Tumorgenicity under Precautions in this monograph). The signicance of this link is not known, but any residue of a known carcinogen in animal products for human consumption is considered a violation of the Food, Drug, and Cosmetic Act. As such, the USP Veterinary Medicine Advisory Panel has concluded that rifampin should not be administered to animals intended for production of products for human consumption.

FOR ORAL DOSAGE FORMS ONLY

Administration with food reduces the rate of absorption and prolongs the time to peak concentration in adult horses{R-4}.

ORAL DOSAGE FORMS

Note: In other USP DI monographs, bracketed uses in the Dosage Forms section refer to categories of use and/or indications that are not included in U.S. product labeling, and superscript 1 refers to categories of use and/or indications that are not included in Canadian product labeling. However, since rifampin is not specically approved for veterinary use, there is no product labeling identifying approved indications.

RIFAMPIN CAPSULES USP

Usual dose: [Pneumonia, Rhodococcus equi]1 ; or [Extrapulmonary infection, Rhodococcus equi]1Foals: Oral, 5 mg per kg of body weight every twelve hours in combination with 25 mg of erythromycin estolate or erythromycin ethylsuccinate per kg of body weight every six to eight hours{R-34; 36}. Therapy may be continued for four to nine weeks or until radiographs and complete blood counts are normal{R-66}. 2003 Thomson MICROMEDEX

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RIFAMPIN VeterinarySystemic 199 Packaging and storage: Store below 40 C (104 F), in a tight container, unless otherwise specied by the manufacturer{R-2; 3}. Protect from light{R-3}. Prior to intravenous infusion, the amount calculated for administration is added to 500 mL or, in some cases, 100 mL of infusion medium and mixed well before administration{R-3}. Dextrose 5% for Injection is recommended for infusion medium, but sterile saline may also be used with a slight reduction in stability{R-2}. Stability: The reconstituted 60 mg/mL solution is stable for 24 hours at room temperature{R-2}. Once mixed with infusion medium to produce a 100 mL or 500 mL solution, the product should be administered within 4 hours; precipitation of rifampin may occur after this time{R-2}.

Preparation of dosage form: Human product labeling suggests the preparation of an extemporaneous oral 1% w/v suspension with preprepared syrups when necessary{R-2}. USP requirements: Preserve in tight, light-resistant containers, protected from excessive heat. Contain the labeled amount, within 10%. Meet the requirements for Identication, Dissolution (75% in 45 minutes in 0.1 N hydrochloric acid in Apparatus 1 at 100 rpm), Uniformity of dosage units, and Loss on drying (not more than 3.0%){R-3}.

PARENTERAL DOSAGE FORMS

Note: In other USP DI monographs, bracketed uses in the Dosage Forms section refer to categories of use and/or indications that are not included in U.S. product labeling, and superscript 1 refers to categories of use and/or indications that are not included in Canadian product labeling. However, since rifampin is not specically approved for veterinary use, there is no product labeling identifying approved indications.

USP requirements: Preserve in Containers for Sterile Solids. Contains the labeled amount, within 10% to +15%. Meets the requirements for Identication, Bacterial endotoxins, Sterility, pH (7.88.8, in a solution containing 60 mg of rifampin per mL), Water (not more than 1.0%), and Particulate matter{R-3}. Developed: 11/05/99 Interim revision: 09/30/02; 03/28/03

REFERENCES
1. USP dictionary of USAN and international drug names, 2002 ed. Rockville, MD: The United States Pharmacopeial Convention, Inc.; 2002. 2. Rifadin and Rifadin I.V. package insert (Hoechst Marion Roussel, IncUS), Rev 2/96, Rec 2/4/97. 3. The United States pharmacopeia. The national formulary. USP 26th revision (January 1, 2003). NF 21st ed (January 1, 2003). Rockville, Maryland: The United States Pharmacopeial Convention, Inc.; 2002. p. 16402, 2579. 4. Frank LA. Clinical pharmacology of rifampin. J Am Vet Med Assoc 1990 Jul 1; 197(1): 1147. 5. Burrows GE, MacAllister CG, Tripp P, et al. Interactions between chloramphenicol, acepromazine, phenylbutazone, rifampin, and thiamylal in the horse. Equine Vet J 1989; 21(1): 348. 6. Kohn CW, Sams R, Kowalske JJ, et al. Pharmacokinetics of single intravenous and single and multiple dose oral administration of rifampin in mares. J Vet Pharmacol Ther 1993; 16: 11931. 7. Wilson WD, Spensley MS, Baggot JD, et al. Pharmacokinetics, bioavailability, and in vitro antibacterial activity of rifampin in the horse. Am J Vet Res 1988 Dec; 49(12): 20416. 8. The National Committee for Clinical Laboratory Standards (NCCLS). Performance standards for antimicrobial disk and dilution susceptibility tests for bacteria isolated from animals; proposed standards. NCCLS document M31-P (ISBN 1-56238-258-6). Villanova, PA: National Committee for Clinical Laboratory Standards; 1994. p. 56, 347. 9. Kerry DW, Hamilton-Miller JMT, Brumtt W. Trimethoprim and rifampicin: in vitro activities separately and in combination. J Antimicrob Chemother 1975; 1: 41727. 10. Prescott JF, Nicholson VM. The effects of combinations of selected antibiotics on the growth of Corynebacterium equi. J Vet Pharmacol Ther 1984; 7: 614. 11. Thornsberry C, Hill BC, Swenson JM, et al. Rifampin: spectrum of antibacterial activity. Rev Infect Dis 1983 Jul/Aug; 5(Suppl. 3): S412S417. 12. Wehrli W. Rifampin: mechanisms of action and resistance. Rev Infect Dis 1983 Jul/Aug; 5(Suppl 3): S407S411. 13. Burrows GE, MacAllister CG, Beckstrom DA, et al. Rifampin in the horse: comparison of intravenous, intramuscular, and oral administrations. Am J Vet Res 1985 Feb; 46(2): 4426. 14. Burrows GE, MacAllister CG, Ewing P, et al. Rifampin disposition in the horse: effects of age and method of oral administration. J Vet Pharmacol Ther 1992; 15: 12432. 15. Baggot JD. Bioavailability and bioequivalence of veterinary drug dosage forms, with particular reference to horses: an overview. J Vet Pharmacol Ther 1992 Jun; 15(2): 16073. 16. Castro LA, Brown MP, Gronwall R, et al. Pharmacokinetics of rifampin given as a single oral dose in foals. Am J Vet Res 1986 Dec; 47(12): 25846. 17. Burrows GE, MacAllister CG, Ewing P, et al. Rifampin disposition in the horse: effects of repeated dosage of rifampin or phenylbutazone. J Vet Pharmacol Ther 1992; 15: 3058.

RIFAMPIN FOR INJECTION USP

Note: Although parenteral pharmacokinetic studies have been performed in horses{R-6; 7; 13} and sheep{R-19; 21; 22}, rifampin is generally administered by the oral route in animals. See Rifampin Capsules USP; however, also note that oral dosing for horses is adjusted for poor bioavailability. Use of oral dosing for parenteral administration of rifampin could result in overdosage. Parenteral rifampin should be administered only by the intravenous route, not intramuscularly or subcutaneously. Strength(s) usually available: U.S. Veterinary-labeled product(s): Not commercially available. Human-labeled product(s): 600 mg (Rx) [Rifadin IV]{R-2}. Canada Veterinary-labeled product(s): Not commercially available. Human-labeled product(s): Not commercially available. Withdrawal times: U.S. and CanadaThe use of rifampin in food-producing animals has not been approved by the Food and Drug Administration or the Canadian Health Protection Branch; therefore, there are no established withdrawal times. Packaging and storage: Store below 40 C (104 F), preferably between 15 and 30 C (59 and 86 F), in a tight container, unless otherwise specied by the manufacturer. Protect from light{R-2}. Preparation of dosage form: Human product labeling recommends that 600 mg of rifampin powder be reconstituted with 10 mL of sterile water for injection to produce a 60 mg per mL (mg/mL) solution{R-2}.

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200 RIFAMPIN VeterinarySystemic

18. Chan K. Rifampicin concentrations in cerebrospinal uid and plasma of the rabbit by high performance liquid chromatography. Methods Find Exp Clin Pharmacol 1986 Dec; 8(12): 7216. 19. Sweeney RW, Divers TJ, Benson C, et al. Pharmacokinetics of rifampin in calves and adult sheep. J Vet Pharmacol Ther 1988 Dec; 11(4): 4136. 20. Lobo MC, Mandell GL. Treatment of experimental staphylococcal infection with rifampin. Antimicrob Agents Chemother 1972 Sep; 2(3): 195200. 21. Jernigan AD, St-Jean GD, Rings DM, et al. Pharmacokinetics of rifampin in adult sheep. Am J Vet Res 1991 Oct; 52(10): 16269. 22. Ziv G, Sulman FG. Evaluation of rifamycin SV and rifampin kinetics in lactating ewes. Antimicrob Agents Chemother 1974 Feb; 5(2): 13942. 23. St-Jean G, Jernigan AD. Treatment of Mycobacterium paratuberculosis infection in ruminants. Vet Clin North Am Food Anim Pract 1991 Nov; 7(3): 793804. 24. Physicians desk reference, 51st ed. Montvale, NJ: Medical Economics Data Production; 1995. p. 896. 25. Adachi Y, Nanno T, Yamashita M, et al. Induction of rat liver bilirubinconjugating enzymes and glutathione S-transferase by rifampicin. Gastroenterol Jpn 1985 Apr; 20(2): 10410. 26. Benedetti MS, Dostert P. Induction and autoinduction properties of rifamycin derivatives: a review of animal and human studies. Environ Health Perspect 1994 Nov; 102(Suppl 9): 1015. 27. Abramson FP, Lutz MP. The kinetics of induction by rifampin of alpha1-acid glycoprotein and antipyrine clearance in the dog. Drug Metab Dispos 1986; 14(1): 4651. 28. Whitehouse LW, Iverson F, Wong LT. Effects of rifampin pretreatment on hepatic parameters in the rabbit. Toxicol Lett 1985 Feb-Mar; 24(2-3): 1316. 29. Barriere SL, Kaatz GW, Seo SM. Enhanced elimination of ciprooxacin after multiple-dose administration of rifampin to rabbits. Antimicrob Agents Chemother 1989 Apr; 33(4): 58990. 30. Kaltenback G, Leveque D, Peter J, et al. Pharmacokinetic interaction between itraconazole and rifampin in Yucutan miniature pigs. Antimicrob Agents Chemother 1996 Sep; 40(9): 20436. 31. Wells PS, Holbrook AM, Crowther NR, et al. Interactions of warfarin with drugs and food. Ann Intern Med 1994 Nov 1; 121(9): 67683. 32. Prescott JF, Sweeney CR. Treatment of Corynebacterium equi pneumonia of foals: a review. J Am Vet Med Assoc 1985 Oct; 187(7): 7258. 33. Knottenbelt DC. Rhodococcus equi infection in foals: a report of an outbreak on a thoroughbred stud in Zimbabwe. Vet Rec 1993 Jan 23; 132(4): 7985. 34. Hillidge CJ. Use of erythromycin-rifampin combination in treatment of Rhodococcus equi pneumonia. Vet Microbiol 1987 Aug; 14(3): 33742. 35. Hillidge CJ. Review of Corynebacterium (Rhodococcus) equi lung abscesses in foals; pathogenesis, diagnosis, and treatment. Vet Rec 1986 Sep 13; 119: 2614. 36. Sweeney CR, Sweeney RW, Divers TJ. Rhodococcus equi pneumonia in 48 foals: response to antimicrobial therapy. Vet Microbiol 1987 Aug; 14(3): 32936. 37. Nay TS. Extrapulmonary Rhodococcus equi in a thoroughbred foal. Can Vet J 1996 Oct; 37(10): 6234. 38. Chafn MK, Honnas CM, Crabill MR, et al. Cauda equina syndrome, diskospondylitis, and a paravertebral abscess caused by rhodococcus equi in a foal. J Am Vet Med Assoc 1995 Jan 15; 206(2): 21520. 39. Kenney DG, Robbins SC, Prescott JF, et al. Development of reactive arthritis and resistance to erythromycin and rifampin in a foal during treatment for Rhodococcus equi pneumonia. Equine Vet J 1994; 25(3): 2468. 40. Collatos C, Clark ES, Reef VB, et al. Septicemia, atrial brillation, cardiomegaly, left atrial mass, and Rhodococcus equi septic osteoarthritis in a foal. J Am Vet Med Assoc 1990 Oct 15; 197(8): 103942. 41. Desjardins MR, Vachon AM. Surgical management of Rhodococcus equi metaphysitis in a foal. J Am Vet Med Assoc 1990 Sep 1; 197(5): 60812. 42. Perdrizet JA, Scott DW. Cellulitis and subcutaneous abscesses caused by Rhodococcus equi infection in a foal. J Am Vet Med Assoc 1987 Jun 15; 190(12): 155961. 43. Chiodini RJ. Biochemical characteristics of various strains of Mycobacterium paratuberculosis. Am J Vet Res 1986 Jul; 47(7): 14425. 44. Slocombe RF. Combined streptomycin-isoniazid-rifampin therapy in the treatment of Johnes disease in a goat. Can Vet J 1982 May; 23(5): 1603. 45. Gunn-Moore DA, Jenkins PA, Lucke VM. Feline tuberculosis: a literature review and discussion of 19 cases caused by an unusual mycobacterial variant. Vet Rec 1996 Jan 20; 138(3): 538. 46. de Bolla GJ. Tuberculosis in a cat [letter]. Vet Rec 1994 Mar 26; 134(13): 336. 47. Wilesmith JW, Clifton-Hadley RS. Tuberculosis in cats [comment]. Vet Rec 1994 Apr 2; 134(14): 359. 48. Greth A, Flamand JR, Delhomme A. An outbreak of tuberculosis in a captive herd of Arabian oryx (Orys leucorys): management. Vet Rec 1994 Feb 12; 134(7): 1657. 49. Zak O, Tosch W, Sande MA. Correlation of antibacterial activities of antibiotics in vitro and in animal models of infection. J Antimicrob Chemother 1985 Jan; 25(Suppl A): 27382. 50. Guitierrez CB, Piriz S, Vadillo S, et al. In vitro susceptibility of Actinobacillus pleuropneumoniae strains to 42 antimicrobial agents. Am J Vet Res 1993 Apr; 54(4): 54650. 51. Stevens DL, Laine BM, Mitten JE. Comparison of single and combination antimicrobial agents for prevention of experimental gas gangrene caused by Clostridium perfringens. Antimicrob Agents Chemother 1987 Feb; 31(2): 3126. 52. Traub WH. Chemotherapy of experimental (murine) Clostridium perfringens type A gas gangrene. Chemotherapy 1988; 34(6): 4727. 53. Duran SP, Manzano JV, Valera RC, et al. In-vitro antimicrobial susceptibility of Bacteroides and Fusobacterium isolated from footrot in goats. Br Vet J 1990; 146(5): 43742. 54. OReilly T, Kunz S, Sande E, et al. Relationship between antibiotic concentration in bone and efcacy of treatment of staphylococcal osteomyelitis in rats: azithromycin compared with clindamycin and rifampin. Antimicrob Agents Chemother 1992 Dec; 36(12): 26937. 55. Gutierrez Martin CB, Rodriguez Ferri EF. In vitro susceptibility of Pasteurella multocida subspecies multocida strains isolated from swine to 42 antimicrobial agents. Zentralbl Bakteriol 1993 Aug; 279(3): 38793. 56. Palmer JE, Benson CE. Effect of treatment with erythromycin and rifampin during the acute stages of experimentally induced equine ehrlichial colitis. Am J Vet Res 1992 Nov; 53(11): 20716. 57. Ackerman L. Cutaneous bacterial granuloma (botryomycosis) in ve dogs: treatment with rifampin. Mod Vet Pract 1987 Jul/Aug; 68(7/8): 4049. 58. Beck DM. Can rifampin help manage CNS infections and internal abscesses in cats? Vet Med 1987 Dec; 123940. 59. Renneberg J, Karlsson E, Nilsson B, et al. Interactions of drugs acting against Staphylococcus aureus in vitro and in a mouse model. J Infect 1993 May; 26(3): 26577. 60. St-Jean G, Smeak DD, Hubbell JAE, et al. Resolution of pyothorax in a whitetailed deer by thoracotomy, tube drainage and lavage. Can Vet J 1990 Feb; 31: 1102. 61. Gezon HM, Bither HD, Gibbs HC, et al. Identication and control of paratuberculosis in a large herd. Am J Vet Res 1988 Nov; 49(11): 181723. 62. Sanchez MS, Ford CW, Yancey RJ. Evaluation of antibiotic effectiveness against Staphylococcus aureus surviving within the bovine mammary gland macrophage. J Antimicrob Chemother 1988 Jun; 21(6): 77386. 63. Wong P. Acute rifampin overdose: a pharmacokinetic study and review of the literature. J Pediatr 1984; 104(5): 7813. 64. Essey MA, Koller MA. Status of bovine tuberculosis in North America. Vet Microbiol 1994; 40: 1522. 65. Finel JM, Pittillo RF, Mellett LB. Flourometric and microbiological assays for rifampicin and the determination of serum levels in the dog. Chemotherapy 1971; 16: 3808. 66. Prescott JF. Rhodococcus equi: an animal and human pathogen. Clin Microbiol Rev 1991 Jan; 4(1): 2034. 67. Giguere S, Prescott JF. Clinical manifestations, diagnosis, treatment, and prevention of Rhodococcus equi infections in foals. Vet Microbiol 1997 June 16; 56(3-4): 31334. 68. Molik GM. Early clinical response to different therapeutic regimens for human brucellosis. Am J Trop Med Hyg 1998; 58(2): 1901. 69. Solera J, Rodriquez-Zopoto M, Geijo P, et al. Doxycycline-rifampin versus doxycycline-streptomycin in treatment of human brucellosis due to Brucella melitensis. Antimicrob Agents Chemother 1995 Sep; 39(9): 20617. 70. Colmenero Costillo JD, Alonso A, Ruis Diaz F, et al. Comparative trial of doxycycline plus steptomycin versus doxycycline plus rifampin for the therapy of human brucellosis. Chemotherapy 1989; 35(2): 14652. 71. Acocello G, Bertrand A, Beytout J, et al. Comparison of three different regimens in the treatment of acute brucellosis; a multicenter multinational study. J Antimicrob Chemother 1989; 23(3): 4339. 72. Ariza J, Fernandez-Viladrich P, Ru G, et al. Comparative trial of rifampindoxycycline versus tetracycline-streptomycin in the therapy of human brucellosis. Antimicrob Agents Chemother 1985 Oct; 28(4): 54851. 73. Mateu-de-Antonio EM, Martin M. In vitro efcacy of several antimicrobial combinations against Brucella canis and Brucella melitensis strains isolated from dogs. Vet Microbiol 1995 Jun; 45(1): 110. 74. Decre D, Bergogne-Berezin E, Phillippon A, et al. In vitro susceptibility of Rhodococcus equi to 27 antibiotics [letter]. J Antimicrob Chemother 1991 Aug; 28(2): 3113. 75. Verville TD, Slater LN, Kuhls TL, et al. Rhodococcus equi infections of humans: 12 cases and a review of the literature. Medicine (Baltimore) 1994 May; 73(3): 11932.

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RIFAMPIN VeterinarySystemic 201

76. Nordmann P, Kerestedjion J, Ronco E. Therapy of Rhodococcus equi disseminated infections in nude mice. Antimicrob Agents Chemother 1992 Jan; 36(6): 12448. 77. Arlotti M, Zoboli G, Moscatelli GL, et al. Rhodococcus equi infection in HIVpositive subjects: a retrospective analysis of 24 cases. Scand J Infect Dis 1996; 28: 4637. 78. Panel comment, Rec 6/24/99. 79. Klasco RK, editor. USP DI Drug information for the healthcare professional. Volume I. Greenwood Village, CO: MICROMEDEX, Inc.; 2003.

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202 SPECTINOMYCIN VeterinarySystemic

SPECTINOMYCIN VeterinarySystemic
Some commonly used brand names for veterinary-labeled products are: Adspec Sterile Solution; AmTech Spectam Scour-Halt; Bovispec Sterile Solution; Spectam; Spectam Injectable; Spectam Oral Solution; Spectam Scour-Halt; Spectam Soluble Powder; and Spectam Water Soluble. Note: For a listing of dosage forms and brand names by country availability, see the Dosage Forms section(s). Paratyphoid (treatment)1Chicks, newly hatched: Spectinomycin hydrochloride injection is indicated in the control of mortality and to lessen severity of infections caused by Salmonella typhimurium{R-17}. Pneumonia, bacterial (treatment)Cattle: Spectinomycin sulfate injection is indicated in the treatment of pneumonia (bovine respiratory disease) associated with M. haemolytica, P. multocida, and H. somnus in cattle{R-21; 25}. Salmonella infantis infection (treatment)1Chicks, newly hatched: Spectinomycin hydrochloride injection is indicated in the control of mortality and to lessen severity of infections caused by S. infantis{R-17}; however, S. infantis is not considered to be a major pathogen in the poultry industry. Synovitis (prophylaxis)Chickens, broiler: Spectinomycin powder for oral solution is indicated to aid in the prevention of mortality associated with infectious synovitis due to susceptible Mycoplasma synoviae{R-2; 18} . Synovitis (treatment) Chickens, broiler1: Spectinomycin powder for oral solution is indicated to aid in the control of mortality associated with infectious synovitis due to susceptible M. synoviae{R-18}. Chicks, newly hatched1: Spectinomycin hydrochloride injection is indicated in the control of mortality and to lessen severity of infections caused by susceptible M. synoviae{R-17}. [Fowl cholera (treatment)]Turkeys: Spectinomycin hydrochloride injection is indicated to reduce mortality due to fowl cholera caused by sensitive strains of Pasteurella multocida{R-1}.

CATEGORY:
Antimicrobial (systemic).

INDICATIONS:
Note: Bracketed information in the Indications section refers to uses that either are not included in U.S. product labeling or are for products not commercially available in the U.S.

GENERAL CONSIDERATIONS
Spectinomycin is an antibiotic that is active against a variety of aerobic gram-negative and gram-positive organisms{R-3; 4} as well as Mycoplasma species{R-7}. Spectinomycin is used clinically, primarily for its activity against gram-negative organisms; some gram-positive organisms may also be susceptible to this agent. It has in vitro and in vivo activity against Mannheimia (Pasteurella) haemolytica, Pasteurella multocida, and Haemophilus somnus{R-25}. Anaerobic organisms are generally resistant{R-7}. Spectinomycin is usually bacteriostatic at therapeutic doses{R-5}. As an aminocyclitol antibiotic, spectinomycin is structurally and functionally similar to the aminoglycoside antibiotics, which are also aminocyclitols. Spectinomycin lacks the toxic effects of the aminoglycoside antibiotics; however, its use is limited by the ready development of bacterial resistance{R-5}.

ACCEPTANCE NOT ESTABLISHED

Colibacillosis (treatment)1[Ducklings]: There are insufcient data to establish the safety and efcacy of spectinomycin in the treatment of colibacillosis in ducklings; however, in one study, subcutaneous administration of spectinomycin reduced the mortality and improved weight gain in 1-day-old ducklings experimentally infected with E. coli{R-10}. Infections, bacterial (treatment), including Respiratory tract infections (treatment)[Pigs]1: There are insufcient data to establish the safety and efcacy of spectinomycin injection in the treatment of respiratory infections and systemic infections due to susceptible organisms in pigs; however, the parenteral administration of spectinomycin to pigs has been used in clinical practice to treat these infections{R-5}.
1

ACCEPTED
Air sacculitis (treatment)1Turkey poults, 1- to 3-day-old: Spectinomycin hydrochloride injection is indicated to aid in the control of air sacculitis associated with Mycoplasma meleagridis sensitive to spectinomycin {R-17} . Chronic respiratory disease (CRD) (prophylaxis)Chickens, broiler: Spectinomycin powder for oral solution is indicated to aid in the prevention of mortality due to CRD associated with susceptible Mycoplasma gallisepticum{R-2; 18}. Chronic respiratory disease (CRD) (treatment) Turkey poults, 1- to 3-day-old1: Spectinomycin hydrochloride injection is indicated to aid in the control of CRD associated with Escherichia coli{R-17}. Chickens, broiler: Spectinomycin powder for oral solution is indicated to aid in the control of mortality due to CRD associated with susceptible Mycoplasma gallisepticum{R-2; 18}. Colibacillosis (treatment)1Chicks, newly hatched: Spectinomycin hydrochloride injection is indicated in the control of mortality and to lessen severity of infections caused by E. coli{R-17}. Enteritis, bacterial (treatment)Piglets: Spectinomycin oral solution is indicated in the treatment of bacterial enteritis (white scours) associated with E. coli in piglets younger than 4 weeks of age{R-3; 4}.

Not included in Canadian product labeling or product not commercially available in Canada.

REGULATORY CONSIDERATIONS
U.S. Spectinomycin oral solution is labeled for use in piglets younger than 4 weeks of age or weighing < 6.8 kg{R-3; 4}. Spectinomycin injection is labeled for use only in newly hatched chicks and in 1- to 3-day-old turkey poults{R-17}. Spectinomycin is not labeled for use in birds producing eggs for human consumption{R-18}. Withdrawal times have been established for the use of spectinomycin in newly hatched chicks{R-17}, broiler chickens{R-18}, 1- to

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SPECTINOMYCIN VeterinarySystemic 203 3-day-old turkey poults{R-17}, and piglets{R-4}(see the Dosage Forms section). Canada Spectinomycin is not labeled for use in birds producing eggs for human consumption{R-1}. Spectinomycin injection is not labeled for use in turkeys weighing < 0.5 kg{R-1}. Withdrawal times have been established for the use of spectinomycin in broiler chickens{R-2}, piglets{R-3}, and turkeys{R-1}(see the Dosage Forms section). administration of spectinomycin{R-7}. Tissue/serum ratios of spectinomycin usually do not exceed 0.25 to 0.5 and are much lower in brain, aqueous humor, and bone{R-22}. Volume of distribution (VolD): Cows0.295 Liter per kg (L/kg){R-13}. Ewes0.307 L/kg{R-13}. Protein binding: CowsLow (approximately 10%){R-13}. Biotransformation: Spectinomycin does not appear to undergo any signicant metabolism. In swine, it is excreted unchanged in the urine following intramuscular administration{R-7}. Half-life: Elimination Cows: 1.01{R-13} to 1.2 hours{R-7}. Ewes: 1.01 hours{R-13}. Pigs: 0.98 hour{R-7}. Peak serum concentration/Time to peak serum concentration: Calves, preruminating20 mcg/mL between 0.33 and 0.67 hours following an intramuscular dose of 10 mg/mL{R-7}. CowsApproximately 55 micrograms per mL (mcg/mL) at 1 hour following an intramuscular dose of 20 mg per kg of body weight (mg/kg){R-13}. Dogs Intramuscular: 78 mcg/mL 40 minutes following an intramuscular dose of 40 mg/kg. Oral{R-7}: 22 mcg/mL approximately 4 hours following a dose of 100 mg/kg. 80 mcg/mL approximately 4 hours following a dose of 500 mg/kg. EwesApproximately 53 mcg/mL at 1 hour following an intramuscular dose of 20 mg/kg{R-13}. Elimination: Following intramuscular administrationSpectinomycin is rapidly absorbed, then quickly eliminated from plasma and tissues through renal excretion{R-7}. Because of this rapid excretion, drug accumulation is not observed following repeated administration{R-7}. Renal impairment may cause accumulation of the active drug{R-22}. Following oral administrationBecause spectinomycin is poorly absorbed from the gastrointestinal tract, it is excreted mostly in the feces{R-7}.

CHEMISTRY
Source: Spectinomycin is a product of Streptomyces spectabilis{R-5; 25}. Chemical group: Aminocyclitol{R-5}. Chemical name: Spectinomycin hydrochloride4H-Pyrano[2,3-b][1,4]benzodioxin-4-one, decahydro-4a,7,9-trihydroxy-2-methyl-6,8-bis(methylamino)-, dihydrochloride, pentahydrate{R-6}. Spectinomycin sulfate tetrahydrateDecahydro-4a,7,9-trihydroxy2-methyl-6,8-bis(methylamino)-4H-pyrano[2,3-b][1,4]benzodioxin4-one sulfate, tetrahydrate{R-25}. Molecular formula: Spectinomycin hydrochlorideC14H24N2O7 2HCl 5H2O{R-6}. Molecular weight: Spectinomycin hydrochloride495.35{R-6}. Description: Spectinomycin Hydrochloride USPWhite to pale-buff crystalline powder{R-16}. pKa: 6.95 and 8.70{R-23}. Solubility: Spectinomycin Hydrochloride USPFreely soluble in water; practically insoluble in alcohol, in chloroform, and in ether{R-16}.

PHARMACOLOGY/PHARMACOKINETICS
Note: Unless otherwise noted, pharmacokinetic data in this section are based on a single intravenous injection of spectinomycin. The pharmacokinetics and detection of spectinomycin do not appear to be inuenced by administration in combination with lincomycin{R-7}; some of the pharmacokinetic data in this section are derived from studies in which lincomycin and spectinomycin were administered concomitantly{R-7}. Mechanism of action/effect: Spectinomycin binds to the 30S ribosomal subunit of the microorganism and inhibits protein synthesis by preventing elongation of the polypeptide chain at the translocation step{R-5}. Absorption: Spectinomycin is only slightly absorbed from the gastrointestinal tract{R-7}; however, it is rapidly absorbed following intramuscular administration{R-7}. In cattle, spectinomycin is completely bioavailable following intramuscular administration{R-7}. Repeated administration in cattle does not appear to result in tissue concentrations higher than those achieved with a single dose{R-7}. Distribution: Twelve hours following intramuscular administration and 24 hours following oral administration, concentrations of spectinomycin are found in the following swine tissues in decreasing concentrations: kidney, liver, lung, muscle, and fat{R-7}. An identical prole is seen in cattle 24 and 72 hours following intramuscular

PRECAUTIONS TO CONSIDER LACTATION

Cows: In one experimental study, the milk-to-serum ratio of spectinomycin concentrations ranged from 0.44 to 1.12 in mastitic cows receiving one intramuscular dose of 20 mg per kg of body weight (mg/ kg), followed by three intramuscular doses of 10 mg/kg at hourly intervals{R-13}. Spectinomycin levels in milk from dairy cows receiving an intramuscular dose of 20 mg/kg two times a day for 3 consecutive days were below 0.2 mcg/mL at the fth milking after the last injection{R-7}. No residues of spectinomycin were detectable at the seventh milking{R-7}.

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204 SPECTINOMYCIN VeterinarySystemic

SIDE/ADVERSE EFFECTS
The following side/adverse effects have been selected on the basis of their potential clinical signicance (possible signs and, for humans, symptoms in parentheses where appropriate)not necessarily inclusive:

VETERINARY DOSING INFORMATION SAFETY CONSIDERATIONS

Some individuals who handle spectinomycin develop serious reactions involving skin, nails, and eyes{R-1; 9}. Individuals who have experienced a rash or other evidence of allergic reaction should avoid further contact with spectinomycin{R-2}.

THOSE INDICATING NEED FOR MEDICAL ATTENTION

Incidence unknown All species Anaphylactic reactions{R-25}; neuromuscular blockade{R-5}

ORAL DOSAGE FORMS

Note: The dosing and strengths of the dosage forms available are expressed in terms of spectinomycin base (not the hydrochloride salt).

SPECTINOMYCIN HYDROCHLORIDE ORAL SOLUTION THOSE INDICATING NEED FOR MEDICAL ATTENTION ONLY IF THEY CONTINUE OR ARE BOTHERSOME
Incidence unknown Cattle Discoloration of tissue at the injection site;{R-25} swelling at the injection site, mild{R-25} Usual dose: Enteritis, bacterialPiglets, younger than 4 weeks of age: For piglets weighing < 4.5 kgOral, 50 mg (base) as a total dose per animal two times a day for three to ve days{R-3; 4}. For piglets weighing 4.5 kg to 6.8 kgOral, 100 mg (base) as a total dose per animal two times a day for three to ve days{R-3; 4}. Note: If improvement is not seen within forty-eight hours of initiating treatment, the diagnosis or choice of therapy should be reconsidered{R3; 4} . Strength(s) usually available: U.S. For veterinary-labeled product(s): 50 mg (base) per mL (OTC) [AmTech Spectam Scour-Halt; Spectam Scour-Halt]. Canada For veterinary-labeled product(s): 50 mg (base) per mL (OTC) [Spectam Oral Solution; Spectam Scour-Halt]. Withdrawal times: U.S. and Canada{R-3;

HUMAN SIDE/ADVERSE EFFECTS{R-15}

In addition to the above side/adverse effects reported in animals, the following side/adverse effects have been reported in humans, and are included in the human monograph Spectinomycin (Systemic) in USP DI Volume I; these side/adverse effects are intended for informational purposes only and may or may not be applicable to the use of spectinomycin in the treatment of animals: Incidence rare Dizziness; gastrointestinal disturbance; hypersensitivity; pain at site of injection

4; 19}

Withdrawal time

OVERDOSE
For more information in cases of overdose or unintentional ingestion, contact the American Society for the Prevention of Cruelty to Animals (ASPCA) National Animal Poison Control Center (888426-4435 or 900-443-0000; a fee may be required for consultation) and/or the drug manufacturer. Cattle: When cattle were administered 150 mg per kg a day (10 times the labeled dose) for 5 days, the effects seen at the end of the treatment period included increased relative kidney weights{R-25}. Urinalysis was performed only on steers. Urinary pH was decreased and squamous and transitional cells were found in the urine{R-25}
Species Pigs

Meat (days) 21

Note: The above withdrawal time applies when medication is administered at a total dose of 50 mg (base) two times a day for piglets weighing less than 4.5 kg or 100 mg (base) two times a day for piglets weighing 4.5 kg to 6.8 kg, for a maximum duration of ve days{R-3; 4}. Packaging and storage: Store below 23 C (73 F). Do not freeze {R-3; 4} . Auxiliary labeling: When not in use, the plastic doser should be removed and the original cap replaced on bottle{R-3; 4}. The plastic doser should be rinsed with water after each use. USP requirements: Not in USP{R-16}.

CLINICAL EFFECTS OF OVERDOSE

Note: The following effects have been selected on the basis of their potential clinical signicance (possible signs in parentheses where appropriate)not necessarily inclusive ( = major clinical signicance): Acute effects Turkey poults{R-1} Ataxia{R-1}; coma{R-1} Note: Clinical signs of ataxia and coma following a single, subcutaneous dose of 90 mg per poult were transient, resolving after 4 hours{R-1}; a single, subcutaneous injection of up to 50 mg per poult caused no detectable ill effects{R-1}. 2003 Thomson MICROMEDEX

SPECTINOMYCIN HYDROCHLORIDE POWDER FOR ORAL SOLUTION

Usual dose: Chronic respiratory disease (prophylaxis and treatment)Chickens, broiler: Oral, administered as the sole source of drinking water at a All rights reserved

SPECTINOMYCIN VeterinarySystemic 205 concentration of 0.5 mg (base) per mL (2 grams [base] per gallon) of water for the rst three days of life and for one day following each vaccination{R-2; 18; 24}. Synovitis (prophylaxis and treatment1)Chickens, broiler: Oral, administered as the sole source of drinking water at a concentration of 0.26 mg (base) per mL (1 gram [base] per gallon) of water for the rst three to ve days of life{R-18; 24}. Note: Canadian labeling lists a dose of 0.5 mg (base) per mL (2 grams [base] per gallon) of water for this indication{R-2}. Strength(s) usually available: U.S. Veterinary-labeled product(s): 500 mg (base) per gram of water-soluble powder (OTC) [Spectam Water Soluble]. Canada Veterinary-labeled product(s): 500 mg (base) per gram of water-soluble powder (OTC) [Spectam Soluble Powder]. Withdrawal times: U.S. and Canada{R-2; Chronic respiratory disease (treatment)1Turkey poults, 1- to 3-dayold: Subcutaneous in cervical area, 5 mg (base) as a single, total dose per poult{R-17}. Dilution with sterile physiologic saline is recommended to facilitate accurate dosing{R-17}. Colibacillosis (treatment)1; Paratyphoid (treatment)1; Salmonella infantis infection (treatment)1; or Synovitis (treatment)1Chicks, newly hatched: Subcutaneous in cervical area, 2.5 to 5 mg (base) as a single, total dose per chick{R-17}. Dilution with sterile physiologic saline is recommended so that the total volume administered is 0.2 mL{R-17}. [Fowl cholera (treatment)]Turkeys: Subcutaneous in dorsal cervical area, 11 to 22 mg (base) per kg of body weight as a single injection. The entire ock should be treated as soon as symptoms of fowl cholera are observed{R-1}. Treatment must not be repeated within ve days of the initial treatment{R-1}. Note: [Ducklings]1For use in animals not to be used in food production: Although there are insufcient data to establish safety and efcacy, a single, subcutaneous, total dose of 5 mg (base) per duckling has been shown to reduce mortality and improve weight gain in one-day-old ducklings experimentally infected with E. coli{R-10}. [Pigs]1Although there are insufcient data to establish safety and efcacy, the intramuscular administration of spectinomycin to pigs, at doses ranging from 6.6 to 22 mg (base) per kg of body weight every twelve to twenty-four hours{R-11}, has been used in clinical practice to treat respiratory infections and systemic infections caused by organisms sensitive to spectinomycin{R-5}. Strength(s) usually available{R-22}: U.S. Veterinary-labeled product(s): 100 mg (base) per mL (OTC) [GENERIC]{R-17}. Canada Veterinary-labeled product(s): 100 mg (base) per mL (OTC) [Spectam; Spectam Injectable]{R-1}. Withdrawal times: Note: PigsBecause injectable spectinomycin is not labeled for use in pigs, there are no established withdrawal times in the U.S. or Canada. If spectinomycin is administered intramuscularly at a dose of 20 mg per kg of body weight, evidence has been compiled by the Food Animal Residue Avoidance Databank (FARAD) that suggests a meat withdrawal time of thirty days would be sufcient to avoid violative residues{R-7; 14}. U.S.{R-17}
Withdrawal time Species Meat (days) 0 0

18; 24}

Withdrawal time

Species Chickens

Meat (days) 5

Note: The above withdrawal time applies when medication is administered in the drinking water up to a maximum concentration of 0.5 mg (base) per mL for up to a maximum duration of 5 days{R-2; 18}. Products are not labeled for use in poultry laying eggs for human consumption{R-24}. Packaging and storage: Store below 40 C (104 F), preferably between 15 and 30 C (59 and 86 F), unless otherwise specied by manufacturer. Preparation of dosage form: Water-soluble powder should be mixed with drinking water according to the manufacturers directions. USP requirements: Not in USP{R-16}.
1

Not included in Canadian product labeling or product not commercially available in Canada.

PARENTERAL DOSAGE FORMS

Note: Bracketed information in the Dosage Forms section refers to uses that either are not included in U.S. product labeling or are for products not commercially available in the U.S. The dosing and strengths of the dosage forms available are expressed in terms of spectinomycin base (not the hydrochloride or sulfate salt).

Chicks, newly hatched Turkey poults, 1- to 3-day-old

Note: The above withdrawal time applies when medication is administered up to a maximum dose of 5 mg per animal in chicks and 10 mg per animal in turkey poults as a single injection{R-17}. Canada{R-1}
Withdrawal time Species Turkeys Meat (days) 5

SPECTINOMYCIN HYDROCHLORIDE INJECTION

Usual dose: Air sacculitis (treatment)1Turkey poults, 1- to 3-day-old: Subcutaneous in cervical area, 10 mg (base) as a single, total dose per poult{R-17}. 2003 Thomson MICROMEDEX

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206 SPECTINOMYCIN VeterinarySystemic Note: The above withdrawal time applies when medication is administered up to a maximum dose of 22 mg per kg of body weight as a single injection.{R-1} Preparation of dosage form: Dilution with sterile physiologic saline according to product labeling is recommended when administering total doses <5 mg and is appropriate when large ocks are being treated{R-17}. Aseptic technique must be employed and unused diluted solution should be discarded{R-17}. Packaging and storage: Store below 40 C (104 F), preferably between 15 and 30 C (59 and 86 F), unless otherwise specied by manufacturer. Protect from freezing{R-17}. Auxiliary labeling: Injection site should be disinfected prior to injection and precautions should be taken to prevent contamination of the contents of the bottle{R-1; 17}. USP requirements: Not in USP{R-16}. Package and storage: Store at 20 to 25 C (68 to 77 F), unless otherwise specied by the manufacturer{R-25}. Protect from freezing. USP requirements: Not in USP{R-16}.
1

Not included in Canadian product labeling or product not commercially available in Canada.

Developed: 07/08/98 Interim revision: 10/15/99; 09/30/02; 04/05/03

REFERENCES
1. Spectam Injectable package insert (VetoquinolCanada). In: Arrioja-Dechert A, editor. Compendium of veterinary products, CD ed. Port Huron, MI: North American Compendiums, Inc. 2002. 2. Spectam Soluble Powder package insert (VetoquinolCanada). In: ArriojaDechert A, editor. Compendium of veterinary products, CD ed. Port Huron, MI: North American Compendiums, Inc. 2002. 3. Spectam Scour-Halt package insert (VetoquinolCanada). In: Arrioja-Dechert A, editor. Compendium of veterinary products, CD ed. Port Huron, MI: North American Compendiums, Inc. 2002. 4. Spectam Scour Halt package labeling (Agrilabs/DurvetUS). In: ArriojaDechert A, editor. Compendium of veterinary products, CD ed. Port Huron, MI: North American Compendiums, Inc. 2002. 5. Prescott JF, Baggot JD, editors. Antimicrobial therapy in veterinary medicine. Ames, IA: Iowa State University Press; 1993. p. 1748. 6. USP Dictionary of USAN and international drug names, 2002 ed. Rockville, MD: The United States Pharmacopeial Convention, Inc; 2002. 7. Cuerpo L, Livingston RC. Spectinomycin. In: Residues of some veterinary drugs in animals and foods. Monographs prepared by the forty-second meeting of the joint FAO/WHO expert committee on food additives. FAO Food Nutr Pap 1994; 41(6): 186. 8. Genetzky R, Zeman D, Miskimins D, et al. Intravenous spectinomycinassociated deaths in feedlot cattle. J Vet Diagn Invest 1994; 5: 2669. 9. Monte AD, Laf G, Mancini G. Occupational contact dermatitis due to spectinomycin. Contact Dermatitis 1994; 31: 2045. 10. Freed M, Clarke JP, Bowersock TL, et al. Effect of spectinomycin on Escherichia coli infection in 1-day-old ducklings. Avian Dis 1993; 37: 7636. 11. Panel comment, Rec 2/97. 12. Hjerpe CA. The bovine respiratory disease complex. In: Howard JL, editor. Current veterinary therapy 3: food animal practice. Philadelphia: WB Saunders; 1993. p. 65364. 13. Ziv G, Sulman FG. Serum and milk concentrations of spectinomycin and tylosin in cows and ewes. Am J Vet Res 1973; 34: 32933. 14. Food Animal Residue Avoidance Databank recommendations. Personal communications, J. E. Riviere, Prof Vet Pharmacol, N.C. State Univ. School of Vet. Med., 6/12/96. 15. Klasco RK, editor. USP DI Drug information for the healthcare professional. Volume I. Greenwood Village, CO: MICROMEDEX, Inc.; 2003. 16. The United States pharmacopeia. The national formulary. USP 26th revision (January 1, 2003). NF 21st ed (January 1, 2003). Rockville, MD: The United States Pharmacopeial Convention, Inc; 2002. 17. Spectinomycin Injectable package labeling (DurvetUS). In: Arrioja-Dechert A, editor. Compendium of veterinary products, CD ed. Port Huron, MI: North American Compendiums, Inc. 2002. 18. Spectam Water Soluble Concentrate package labeling (Rhone MerieuxUS), Rec 6/20/96. 19. Spectam Scour-Halt package labeling (Rhone MerieuxUS), Rec 6/20/96. 20. Jenkins WL. Clinical pharmacology of antibacterials used in bacterial bronchopneumonia in cattle. Mod Vet Pract 1985; 66: 2648. 21. Adspec Sterile Solution product information (Pharmacia Animal Health Canada). Downloaded from www.pharmaciaah.ca on 2/19/03. 22. Arrioja-Dechert A, editor. Compendium of veterinary products, CD ed. Port Huron, MI: North American Compendiums, Inc. 2002. 23. ONeil MJ, editor. The Merck index. An encyclopedia of chemicals, drugs, and biologicals. 13th ed. Whitehouse Station, NJ: Merck & Co., Inc; 2001. p. 1558. 24. Spectinomycin Water Soluble (BimedaUS). In: Arrioja-Dechert A, editor. Compendium of veterinary products, CD ed. Port Huron, MI: North American Compendiums, Inc. 2002. 25. Adspec Sterile Solution package insert (Pharmacia Animal HealthUS), Rev 8/00. Downloaded from www.pharmaciaah.com on 8/13/02.

SPECTINOMYCIN SULFATE INJECTION

Usual dose: PneumoniaCattle: Subcutaneous, 10 to 15 mg (base) per kg of body weight every twenty-four hours for three to ve days{R-25}. Note: It is recommended that this medication be administered subcutaneously in the neck and that not more than 50 mL be given per site{R-25}. Strength(s) usually available{R-21; 22; 25}: U.S. Veterinary-labeled product(s): 100 mg (base) per mL (Rx) [Adspec Sterile Solution; Bovispec Sterile Solution]. Canada Veterinary-labeled product(s): 100 mg (base) per mL (Rx) [Adspec Sterile Solution]. Withdrawal times: U.S.
Withdrawal time Species Cattle Meat (days) 11

Note: Product labeling listing the above withdrawal time states that withdrawal times have not been established for preruminating calves or for lactating dairy cattle and that it should not be used in female dairy cattle 20 months of age or older or in calves to be procesed for veal{R-25}. Discoloration of tissue at the injection site may last more than 11 days, making it necessary to trim the site and surrounding tissue at slaughter{R-25}. Canada{R-21}
Withdrawal time Species Cattle Meat(days) 11

Note: Product labeling listing the above withdrawal time states that it applies to a dosage of 10 mg per kg of body weight every twenty-four hours for three to ve days. 2003 Thomson MICROMEDEX

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SULFONAMIDES VeterinarySystemic 207

SULFONAMIDES VeterinarySystemic
This monograph includes information on the following: Sulfachlorpyridazine, Sulfadimethoxine, Sulfamethazine, Sulfanilamide*, Sulfaquinoxaline, Sulfathiazole*. Some commonly used brand names are: For veterinary-labeled products
Albon Boluses [Sulfadimethoxine] Sulfa-Max III Calf Bolus [Sulfamethazine] Albon 12.5% Concentrated Solution Sulfa-Max III Cattle Bolus [Sulfadimethoxine] [Sulfamethazine] Albon Injection 40% [Sulfadimethoxine] 2 Sulfamed [Sulfamethazine and Sulfathiazole] Albon Oral Suspension 5% Sulfa-MT [Sulfamethazine and [Sulfadimethoxine] Sulfathiazole] Albon SR [Sulfadimethoxine] Sulfa-Q 20% [Sulfaquinoxaline] Albon Tablets [Sulfadimethoxine] Sulfasol [Sulfadimethoxine] AmTech Sulfadimethoxine Injection-40% Sulfa 2 Soluble Powder [Sulfadimethoxine] [Sulfamethazine and Sulfathiazole] AmTech Sulfadimethoxine 12.5% Sulfasure SR Calf Bolus Oral Solution [Sulfadimethoxine] [Sulfamethazine] AmTech Sulfadimethoxine Soluble Sulfasure SR Calf Tablets Powder [Sulfadimethoxine] [Sulfamethazine] Calfspan [Sulfamethazine] Sulfasure SR Cattle Bolus [Sulfamethazine] Di-Methox Injection-40% Sulforal [Sulfadimethoxine] [Sulfadimethoxine] Di-Methox 12.5% Oral Solution Sulmet Drinking Water Solution 12.5% [Sulfadimethoxine] [Sulfamethazine] Di-Methox Soluble Powder Sulmet Oblets [Sulfamethazine] [Sulfadimethoxine] Optimed [Sulfaquinoxaline] Sulmet Soluble Powder [Sulfamethazine] 31.92% Sul-Q-Nox [Sulfaquinoxaline] Powder 21 [Sulfamethazine and Sulfathiazole] S-125 [Sulfadimethoxine] Suprasulfa III Calf Bolus [Sulfamethazine] S-250 [Sulfadimethoxine] Suprasulfa III Cattle Bolus [Sulfamethazine] SDM Injection [Sulfadimethoxine] Sustain III [Sulfamethazine] SDM Powder [Sulfadimethoxine] Sustain III Calf Bolus [Sulfamethazine] SDM Solution [Sulfadimethoxine] Sustain III Cattle Bolus [Sulfamethazine] S-M-T [Sulfamethazine Triple Sulfa Bolus [Sulfamethazine, and Sulfathiazole] Sulfanilamide, and Sulfathiazole] Sulfa 25 [Sulfamethazine] Vetisulid Boluses [Sulfachlorpyridazine] Sulfa 25% [Sulfamethazine] Vetisulid Injection [Sulfachlorpyridazine] Sulfalean Powder [Sulfamethazine Vetisulid Powder [Sulfachlorpyridazine] and Sulfathiazole]

as coccidia.{R-17; 18} They are considered ineffective against most obligate anaerobes{R-86; 90; 93} and should not be used to treat serious anaerobic infections. However, they may affect aerobic organisms that contribute to the lowered oxygen tension in the microenvironment and, as such, they may be useful in certain diseases involving Fusobacteria, although the organism itself is often resistant. The activity of sulfonamides is very sensitive to environment, and this limitation affects the activity of sulfonamides in particular uids and tissues, such as purulent material, as well as the ability of laboratories to standardize minimum inhibitory concentrations (MIC) of sulfonamides necessary in vivo to inhibit specic cultured bacteria.{R-17} Resistance of animal pathogens to sulfonamides is widespread as a result of more than 50 years of therapeutic use{R-17; 19} and this limits their effectiveness; however, sulfonamides are still widely used in combination with other medications, as in the case of the potentiated sulfonamides. They are also utilized in herd management of disease and some individual animal applications. Cross-resistance between sulfonamides is considered complete.{R-17}

ACCEPTED
Coccidiosis (treatment)Resistance to sulfonamides by coccidia has been reported in several species, including cattle, chickens{R-22}, and sheep{R-106}. It also should be noted that sulfonamides aid in reducing the number of oocysts shed, but they may not alter the clinical course of a susceptible coccidial infection{R-106}. Calves and cattle: Sulfamethazine extended-release tablets{R-11} are indicated in the treatment of Eimeria bovis and Eimeria zuernii. Sulfaquinoxaline1{R-14} is indicated in the control and treatment of susceptible E. bovis and E. zuernii. Chickens: Sulfadimethoxine oral solution1{R-2} and powder for oral solution1{R-4} are indicated in the treatment of outbreaks of coccidiosis caused by susceptible coccidia. Sulfamethazine oral solution{R-12} and powder for oral solution1{R-9} are indicated in the control of susceptible Eimeria necatrix and Eimeria tenella. Sulfaquinoxaline{R-14} is indicated in the control of outbreaks of coccidiosis caused by susceptible Eimeria acervulina, Eimeria brunetti, Eimeria maxima, E. necatrix, and E. tenella. Dogs: Sulfadimethoxine injection{R-3}, oral suspension, and tablets{R-6} are indicated in the treatment of enteritis associated with coccidiosis caused by susceptible organisms. Turkeys: Sulfadimethoxine oral solution1{R-2} and powder for oral solution1{R-4} are indicated in the treatment of outbreaks of coccidiosis caused by susceptible coccidia. Sulfamethazine oral solution{R-12} and powder for oral solution1{R-9} are indicated in the control of susceptible Eimeria adenoeides and Eimeria meleagrimitis. Sulfaquinoxaline{R-14} is indicated in the control of outbreaks of susceptible E. adenoeides and E. meleagrimitis.{R-14} Coryza, infectious (treatment)Chickens: Sulfadimethoxine oral solution1{R-2} and powder for oral solution1{R-4} are indicated in the treatment of outbreaks of infectious coryza caused by susceptible Haemophilus gallinarum. Sulfamethazine oral solution{R-12} and powder for oral solution1{R-9} are indicated in the control of infectious coryza caused by susceptible H. gallinarum.

*Not commercially available in the U.S. Not commercially available in Canada.

CATEGORY:
Antibacterial (systemic); antiprotozoal.

INDICATIONS
Note: Bracketed information in the Indications section refers to uses that either are not included in U.S. product labeling or are for products not commercially available in the U.S.

GENERAL CONSIDERATIONS
Sulfonamides are broad-spectrum antimicrobials inhibiting both grampositive and gram-negative bacteria, as well as some protozoa, such

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208 SULFONAMIDES VeterinarySystemic Cystitis, bacterial (treatment)Cats and dogs: Sulfadimethoxine injection1, oral suspension1, and tablets{R-3; 6} are indicated in the treatment of cystitis caused by susceptible organisms; however, the potentiated sulfonamides and other antimicrobials have generally replaced sulfonamides administered alone. Diphtheria (treatment)Cattle: Sulfonamides are not directly effective against most obligate anaerobes{R-86; 90; 93}, but may affect aerobic organisms that create the microenvironment in which Fusobacteria thrive; therefore, sulfonamides may be useful in the treatment of diphtheria but are not recommended in advanced or serious infections. Sulfadimethoxine tablets1{R-1}, oral solution1{R-2}, injection1{R-3}, powder for oral solution1{R-4}, and extended-release tablets1{R-5}; and sulfamethazine tablets, oral solution, powder for oral solution1, and extended-release tablets{R-7; 9; 10; 12; 13} are indicated in the treatment of calf diphtheria caused by susceptible Fusobacterium necrophorum. [Sulfamethazine, sulfanilamide, and sulfathiazole combination is indicated as an aid in the treatment of diphtheria in calves{R-97}.] Enteritis, bacterial (treatment)The primary treatment for enteritis in many cases, including those involving colibacillosis in calves, is aggressive uid replacement. Treatment of enteritis with antimicrobials should rely on a specic diagnosis and knowledge of pathogen susceptibility. Calves, less than 1 month of age1: Sulfachlorpyridazine injection and tablets are indicated in the treatment of diarrhea caused or complicated by Escherichia coli{R-89}. Calves and cattle: Sulfamethazine tablets, oral solution, powder for oral solution1, and extended-release tablets;{R-7; 9; 10; 12; 13} and [sulfamethazine and sulfathiazole combination{R-15}] are indicated in the treatment of enteritis (colibacillosis, scours) caused by susceptible E. coli. [Sulfamethazine, sulfanilamide, and sulfathiazole combination{R-97} is indicated as an aid in the treatment of enteritis caused by susceptible organisms.] Dogs: Sulfadimethoxine injection1{R-3}, oral suspension1, and tablets{R-6} are indicated in the treatment of enteritis caused by susceptible Salmonella species. Foals: Sulfamethazine tablets are indicated in the treatment of enteritis caused by susceptible E. coli.{R-13} Pigs: Sulfachlorpyridazine powder for oral solution1{R-89}, and sulfamethazine oral solution{R-12} and powder for oral solution1{R-9} are indicated in the treatment of enteritis caused by susceptible E. coli. [Sulfamethazine and sulfathiazole combination is indicated to aid in the treatment of enteritis.{R-15}] [Sheep]: Sulfamethazine oral solution{R-16} is indicated in the treatment of enteritis caused by susceptible organisms. Fowl cholera (treatment) Chickens: Sulfadimethoxine oral solution1{R-2} and powder for oral solution1{R-4} are indicated in the treatment of acute fowl cholera caused by susceptible Pasteurella multocida. Sulfamethazine oral solution{R-12} and powder for oral solution1{R-9}, and sulfaquinoxaline{R-14} are indicated in the control of acute fowl cholera caused by susceptible P. multocida. Turkeys: Sulfadimethoxine oral solution1{R-2} and powder for oral solution1{R-4} are indicated in the treatment of acute fowl cholera caused by susceptible P. multocida. Sulfaquinoxaline{R-14} is indicated in the control of acute fowl cholera caused by susceptible P. multocida. Fowl typhoid (treatment)Chickens and turkeys: Sulfaquinoxaline is indicated in the control of acute fowl typhoid caused by susceptible Salmonella gallinarum.{R-14} Pneumonia, bacterial (treatment) Calves: Sulfamethazine tablets{R-13} and extended-release tablets{R-7; 10; 11} are indicated in the treatment of pneumonia and bovine respiratory disease complex caused by susceptible Pasteurella species. However, in vitro studies have shown high levels of resistance to sulfamethazine by Mannheimia (Pasteurella) haemolytica and P. multocida{R-23}; therefore, sulfamethazine generally has been replaced by antimicrobials known to be effective against the specic pathogens involved. Cats and dogs: Sulfadimethoxine injection1{R-3}, oral suspension1, and tablets{R-6} are indicated in the treatment of bacterial pneumonia caused by susceptible organisms; however, sulfadimethoxine generally has been replaced by antimicrobials known to be effective against the specic pathogens involved. Cattle: Sulfamethazine oral solution{R-12}, powder for oral solution1{R-9}, and extended-release tablets{R-10}; and sulfadimethoxine tablets1{R-1}, oral solution1{R-2}, injection1{R-3}, powder for oral solution1{R-4}, and extended-release tablets1{R-5}; and [sulfamethazine and sulfathiazole combination{R-15; 96}] are indicated in the treatment of bacterial pneumonia and bovine respiratory disease complex caused by susceptible organisms. [Sulfamethazine, sulfanilamide, and sulfathiazole combination is indicated as an aid in the treatment of pneumonia{R-97}.] However, in vitro studies have shown high levels of resistance to sulfamethazine by M. haemolytica and P. multocida{R-23}, and the sulfonamides generally have been replaced by antimicrobials known to be effective against the specic pathogens involved. Foals: Sulfamethazine tablets{R-13} are indicated in the treatment of pneumonia caused by susceptible Pasteurella species; however, sulfamethazine generally has been replaced by antimicrobials known to be effective against the specic pathogens involved. Pigs: Sulfamethazine oral solution{R-12} and powder for oral solution1{R-9} are indicated in the treatment of pneumonia caused by susceptible organisms; however, sulfamethazine generally has been replaced by antimicrobials known to be effective against the specic pathogens involved. Pododermatitis, necrotic (treatment)Cattle: Sulfonamides are not directly effective against most obligate anaerobes{R-86; 90; 93}, but may affect aerobic organisms that create the microenvironment in which Fusobacteria thrive; therefore, they may be useful in the treatment of pododermatitis but are not recommended in advanced or serious infections. Sulfadimethoxine tablets1{R-1}, oral solution1{R-2}, injection1{R-3}, powder for oral solution1{R-4}, and extended-release tablets1{R-5}; and sulfamethazine oral solution{R-12}, powder for oral solution1{R-9}, and extended-release tablets{R-10} are indicated in the treatment of pododermatitis caused by susceptible Fusobacterium necrophorum. [Sulfamethazine and sulfathiazole combination{R-15; 96} and sulfamethazine, sulfanilamide, and sulfathiazole combination{R-97} are indicated as aids in the treatment of necrotic pododermatitis caused by susceptible F. necrophorum.] Pullorum disease (treatment)Chickens: Sulfamethazine oral solution{R12} and powder for oral solution1{R-9} are indicated in the control of susceptible Salmonella pullorum.

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SULFONAMIDES VeterinarySystemic 209 Respiratory infections, bacterial (treatment) Cats and dogs: Sulfadimethoxine injection{R-3}, oral suspension, and tablets{R-6} are indicated in the treatment of respiratory infections, such as bronchitis, caused by susceptible organisms. [Pigs]: Sulfamethazine and sulfathiazole combination is indicated as an aid in the treatment of respiratory infections caused by susceptible organisms.{R-15} [Sheep]: Sulfamethazine oral solution is indicated in the treatment of acute respiratory infections caused by susceptible organisms{R-16}. Skin and soft tissue infections (treatment)Cats and dogs: Sulfadimethoxine injection1, oral suspension1, and tablets{R-3; 6} are indicated in the treatment of skin and soft tissue infections; however, sulfonamides are not effective in infections associated with purulent debris, such as abscesses. Withdrawal times have been established for sulfachlorpyridazine, sulfadimethoxine, sulfamethazine, and sulfaquinoxaline. See the Dosage Forms section. Federal law restricts the use of some forms of sulfadimethoxine and sulfamethazine to use by or on the order of a licensed veterinarian. See the Dosage Forms section. Canada Withdrawal times have been established for sulfamethazine; sulfamethazine and sulfathiazole combination; and sulfamethazine, sulfanilamide, and sulfathiazole combination. See the Dosage Forms section.

CHEMISTRY
Chemical name: SulfachlorpyridazineN1-(6-Chloro-3-pyridazinyl)sulfanilamide{R-36}. SulfadimethoxineBenzenesulfonamide, 4-amino-N-(2,6-dimethoxy-4pyrimidinyl)-{R-36}. SulfamethazineBenzenesulfonamide, 4-amino-N-(4,6-dimethyl-2-pyrimidinyl)-{R-36}. Sulfanilamidep-Aminobenzenesulfonamide{R-36}. SulfaquinoxalineN1-2-Quinoxalinylsulfanilamide{R-36}. SulfathiazoleBenzenesulfonamide, 4-amino-N-2-thiazolyl-{R-36}. Molecular formula: SulfachlorpyridazineC10H9ClNO2S{R-36}. SulfadimethoxineC12H14N4O4S{R-36}. SulfamethazineC12H14N4O2S{R-36}. SulfanilamideC6H8N2O2S{R-36}. SulfaquinoxalineC14H12N4O2S{R-36}. SulfathiazoleC9H9N3O2S2{R-36}. Molecular weight: Sulfachlorpyridazine284.72{R-36}. Sulfadimethoxine310.34{R-36}. Sulfamethazine278.33{R-36}. Sulfanilamide172.21{R-36}. Sulfaquinoxaline300.34{R-36}. Sulfathiazole255.32{R-36}. Description: Sulfadimethoxine USPPractically white, crystalline powder{R-56}. Sulfamethazine USPWhite to yellowish white powder, which may darken on exposure to light. Practically odorless.{R-56} SulfanilamideWhite, odorless, crystalline powder{R-98}. SulfaquinoxalineYellow, odorless powder{R-94}. Sulfathiazole USPFine, white or faintly yellowish white, practically odorless powder{R-56}. pKa: Sulfadimethoxine6.15{R-33; 35}. Sulfamethazine2.65, 7.4{R-19}. Sulfanilamide10.5{R-19; 35}. Sulfaquinoxaline5.5{R-19; 46}. Sulfathiazole7.1{R-19}. Solubility: Sulfadimethoxine USPSoluble in 2 N sodium hydroxide; sparingly soluble in 2 N hydrochloric acid; slightly soluble in alcohol, in ether, in chloroform, and in hexane; practically insoluble in water{R-56}. Sulfamethazine USPVery slightly soluble in water and in ether; soluble in acetone; slightly soluble in alcohol{R-56}. SulfanilamideSlightly soluble in water, in alcohol, in acetone, in glycerin, in propylene glycol, in hydrochloric acid, and in solutions of All rights reserved

ACCEPTANCE NOT ESTABLISHED

Cats, cattle, dogs, and sheep: Although product labeling in the U.S. and Canada includes the use of sulfonamides in the treatment of metritis in cats, dogs, and cattle, and pyometra{R-3; 6; 9; 10; 15; 16} in cats and dogs, and Canadian labeling also includes the treatment of metritis in sheep, the efcacy of these uses is not established based on current knowledge. Sulfonamides are poorly distributed into the uterus and their activity may be decreased in the presence of purulent debris; sulfonamides therefore rarely are recommended in the treatment of metritis{R-103}. Cattle and sheep: Although product labeling in the U.S. and Canada for cattle and in Canada for sheep includes use of sulfonamides in the treatment of mastitis{R-3; 6; 9; 10; 12; 13; 15; 16; 97}, the efcacy of this use is not established based on current knowledge. Many sulfonamides, including most of those labeled for treatment of mastitis, are poorly distributed into milk. Considering also the high incidence of pathogen resistance reported, sulfonamides rarely are recommended in the treatment of mastitis{R-103}. Horses: Although product labeling in the U.S. and Canada includes the use of sulfonamides in the treatment of equine strangles (Streptococcus equi infection), the efcacy of this use is not established based on current knowledge. The activity of sulfonamides may be decreased in the presence of purulent debris; therefore, they rarely are recommended in the treatment of strangles{R-103; 107}.
1

Not included in Canadian product labeling or product not commercially available in Canada.

REGULATORY CONSIDERATIONS
U.S. The presence of sulfonamide residues in food for human consumption has been a concern in recent years. After a variety of efforts to control residues, the incidence of violative sulfonamide residues recently was reported to be as low as 1% in the U.S.{R-24}; however, because of a study linking moderate to high doses of sulfamethazine, directly or by a secondary mechanism, to the production of thyroid tumors in mice, concern about residues continues.{R-24; 51} The use of sulfonamides in lactating dairy cattle, other than those medications specically approved for use, has been specied by the Food and Drug Administration as a high priority for regulatory attention{R-104}. 2003 Thomson MICROMEDEX

210 SULFONAMIDES VeterinarySystemic potassium and sodium hydroxide; practically insoluble in chloroform, in ether, and in petroleum ether{R-98}. SulfaquinoxalinePractically insoluble in water; very slightly soluble in alcohol; practically insoluble in ether; freely soluble in aqueous solutions of alkalis{R-94}. Sulfathiazole USPVery slightly soluble in water; soluble in acetone, in dilute mineral acids, in solutions of alkali hydroxides, and in 6 N ammonium hydroxide; slightly soluble in alcohol{R-56}. PigsArea: 0.5{R-66; 67}; 0.77 0.06 L/kg{R-70}. Administered in conjunction with sulfathiazole: Area1.01 0.12 L/kg{R-70}. SheepArea: 0.4 L/kg{R-62; 63}; 0.6 L/kg{R-58}. Sulfanilamide: GoatsArea: 1.3 0.13 L/kg{R-35}. Sulfathiazole: PigsArea: 1.16 0.16 L/kg{R-70}. Protein binding: Binding can vary depending on serum concentration{R-43} and other factors. SulfachlorpyridazineCows: High (80 to 85%){R-34}. Sulfadimethoxine Cats: High (87.5%){R-42}. Chickens: Moderate (40%){R-43}. Dogs: High (>75%){R-39}. Goats: High (94%){R-35}. Sulfamethazine Cows: When plasma concentration is less than 50 mcg per mL (mcg/mL)High (79%){R-79}. When plasma concentration is more than 50 mcg/mL Moderate (51%){R-79}. Goats: High (86%){R-35}. Horses: High (70%){R-37}. Sheep: High (77%){R-58}. SulfanilamideCows: Low (<20%){R-34}. SulfathiazoleCows: High (65 to 76%){R-34}. Biotransformation: Sulfonamides are primarily metabolized in the liver but metabolism also occurs in other tissues. Biotransformation occurs mainly by acetylation, glucuronide conjugation, and aromatic hydroxylation in many species{R-17}. The types of metabolites formed and the amount of each varies depending on the specic sulfonamide administered; the species, age, diet, and environment of the animal; the presence of disease; and, with the exception of pigs and ruminants, even the sex of the animal{R-53; 54; 71; 79}. Dogs are considered to be unable to acetylate sulfonamides to any signicant degree{R-108}. N4-acetyl metabolites have no antimicrobial activity and hydroxymetabolites have 2.5 to 39.5% of the activity of the parent compound{R-37}. Metabolites may compete with the parent drug for involvement in folic acid synthesis but have little detrimental effect on the bacterial cell, and so could lower the activity of the remaining parent drug.{R-37} In pigs, sulfamethazine is metabolized into N4-acetylsulfamethazine, desaminosulfamethazine and the N4-glucose conjugate of sulfamethazine{R-72}. In general, metabolites of sulfonamides are cleared more quickly than the parent drug{R-78}; however, the desaminosulfamethazine half-life of elimination can vary from 1 to 9 days, while sulfamethazine and other metabolites have a shorter half-life of 10 to 20 hours{R-73}. It has been theorized that diets containing nitrate, which is then reduced by bacteria to nitrite, will greatly increase the amount of sulfamethazine biotransformed to the desaminosulfamethazine metabolite and prolong tissue residues of metabolite{R-71}, but there is no conclusive evidence. Half-life: AbsorptionSulfadimethoxine: DogsOral dose of 55 mg/kg: 1.9 hours{R-39}. Elimination Sulfachlorpyridazine: Cows1.2 hours{R-34}. All rights reserved

PHARMACOLOGY/PHARMACOKINETICS
Note: Unless otherwise noted, pharmacokinetic values are based on a single intravenous administration of medication.

Mechanism of action: Bacteriostatic. Sulfonamides interfere with the biosynthesis of folic acid in bacterial cells; they compete with paraaminobenzoic acid (PABA) for incorporation in the folic acid molecule. By replacing the PABA molecule and preventing the folic acid formation required for DNA synthesis, the sulfonamides prevent multiplication of the bacterial cell. Susceptible organisms must synthesize their own folic acid; mammalian cells use preformed folic acid and, therefore, are not susceptible. Cells that produce excess PABA or environments with PABA, such as necrotic tissues, allow for resistance by competition with the sulfonamide{R-17; 18}.

Absorption: Most sulfonamides are well absorbed orally with the exception of the enteric sulfonamides, such as sulfaquinoxaline, which are minimally absorbed{R-19}. Delays in absorption may occur in adult ruminants or when sulfonamides are administered with food to monogastric animals{R-17; 20}.

Bioavailability: Oral Sulfadimethoxine: Cattle59% (107 mg per kg of body weight [mg/kg] dose){R-44}. Dogs48.8% (55 mg/kg dose){R-41}. Sulfamethazine: Pigs86% (50 mg/kg dose){R-66}. Ponies84% (160 mg/kg dose){R-57}.

Distribution: Sulfonamides are widely distributed throughout the body. They cross the placenta, and a few penetrate into the cerebrospinal uid{R-20}. Sulfonamides may be distributed into milk; however, they vary greatly in their ability to do so. The process depends on several factors, including protein binding and pKa values{R-102}. Volume of distribution Sulfadimethoxine: GoatsArea: 0.49 0.095 L/kg{R-35}. PigsArea: Suckling (1 to 2 weeks)0.483 0.078 L/kg{R-45}. Growing (11 to 12 weeks)0.345 0.016 L/kg{R-45}. RabbitsSteady state: 0.213 0.007 L/kg{R-40}. Sulfamethazine: BuffaloArea: 0.44 0.17 L/kg{R-55}. CattleExtrapolated: 0.35 L/kg{R-82}. GoatsArea: 0.28 to 0.39 L/kg; 0.44 L/kg{R-35}. HorsesSteady state: 0.63 0.074 L/kg{R-57}. LambsArea: 0.334 0.031 L/kg{R-61}. 2003 Thomson MICROMEDEX

SULFONAMIDES VeterinarySystemic 211 Sulfadimethoxine: Cats10.2 hours{R-42}. Cattle12.5 hours{R-38}. Dogs13.1 hours{R-39}. Goats8.6 hours{R-34}. Pigs Single dose: Suckling pig (1 to 2 weeks of age)16.2 hours{R-45}. Growing pig (11 to 12 weeks of age)9.4 hours{R-45}. After 5 days of once-daily intravenous dosing: 9.2 hours{R-40}. RabbitsAfter 6 days of once-daily intravenous dosing: 5.2 hours{R-40}. Sulfamethazine: Buffalo5.5 hours{R-55}. Calves, 2 to 3 months of age5.2 to 5.7 hours{R-78; 79}. Cattle5 to 11.3 hours{R-34; 78; 79; 82}. Goats2.4 to 4.1 hours{R-35}; 8.5 to 9.6 hours{R-35; 82}. Horses5.4 hours{R-37}; 11.4 hours{R-57}. Lambs7.2 hours{R-61}. Pigs9.8 hours{R-70}; 16.9 hours{R-66; 67}. Sheep4.5 hours{R-58}; 9.5 to 10.8 hours{R-62; 63}. Sulfanilamide: Cows6.2 hours{R-34}. Goats7.7 hours{R-34}. Sulfathiazole: Cows1.5 hours{R-34}. Pigs9 hours{R-70}. Sheep1.3 hours{R-84}. Peak serum concentration: SulfadimethoxineOral: Chickens106.3 mcg/mL at 12 hours (100 mg/kg dose).{R-43} Cattle114 10 mcg/mL at 10 hours (107 mg/kg dose).{R-44} Dogs67 16 mcg/mL of serum at 3.75 hours (55 mg/kg dose).{R-39} SulfamethazineOral: Ponies301.4 mcg/mL of serum at 0.83 hour (160 mg/kg dose).{R-57} Duration of action: The sulfonamides have been loosely categorized according to their duration of action:{R-19} Short-actingSulfathiazole. Intermediate-actingSulfachlorpyridazine, sulfamethazine. Intermediate- to long-actingSulfadimethoxine. Note: Duration of action may be estimated by the length of time target serum concentrations are maintained. Target concentrations are generally based on minimum inhibitory concentrations for each organism. Many sources use 50 mcg sulfonamide per mL (5 mg per decaliter) of blood as the minimum effective concentration for sulfonamides in animals.{R-64; 76; 80} SulfadimethoxineOral: ChickensA single dose of 100 mg per kg of body weight (mg/kg) maintained plasma concentration of greater than or equal to 50 mcg/mL for 36 hours.{R-43} Sulfamethazine Intravenous: LambsAn intravenous dose of 107.3 mg/kg maintained a plasma concentration of greater than 50 mcg/mL for 18 to 24 hours.{R-64} Oral (powder for oral solution): Calves, 8 months of age{R-76} Oral dose of 214.3 mg/kg a day (1848 mg/L of water) administered in the only source of drinking water maintained a serum concentration of at least 50 mcg/mL from 18 hours to at least 120 hours after start of treatment.{R-76} Oral dose of 142.9 mg/kg a day (1028 mg/L of water) administered in the only source of drinking water maintained a serum concentration of at least 50 mcg/mL from 24 to 180 hours after the start of treatment.{R-76} Oral dose of 71.4 mg/kg a day (572 mg/L of water) administered in the only source of drinking water maintained a serum concentration of at least 50 mcg/mL from only 72 to 96 hours after the start of treatment.{R-76} Oral (extended-release tablets): Calves, 3 to 5 days of age: An oral dose of 396 mg/kg, administered as a single extended-release tablet, maintained a serum concentration of at least 50 mcg/mL from 4 to 96 hours postadministration.{R-80} Calves and cattle: An oral dose of 264 mg/kg maintained a serum concentration greater than 50 mcg/mL from 12 to 48 or 72 hours post-administration.{R-81} Elimination: Renal excretion is the primary route of elimination for most nonenteric sulfonamides and it occurs by glomerular ltration of parent drug, tubular excretion of unchanged drug and metabolites, and passive reabsorption of nonionized drug.{R-17; 20} Alkalization of the urine increases the fraction of the dose that is eliminated in the urine.{R-20} In general, the metabolites of the parent drug are more quickly eliminated by the kidney than the original sulfonamide is{R-78}, but the proportions of metabolites formed can vary, depending on many factors. Sulfonamides are also distributed in relatively small amounts into milk, saliva, and into the gastrointestinal tract.{R-77; 79} SulfadimethoxineCattle: 17.9% of an intravenous dose of 107 mg per kg of sulfadimethoxine is excreted into the urine unchanged and at least 58.4% is excreted as metabolites into urine.{R-44} Only 6.3% of an oral dose of 107 mg of sulfadimethoxine per kg is excreted unchanged in the urine and 37.7% as metabolites in the urine.{R-44} Total clearance: Cats0.31 mL per minute per kg (mL/min/kg).{R-42} Dogs0.36 mL/min/kg.{R-39} Goats0.65 mL/min/kg.{R-35} Pigs Suckling pig (1 to 2 weeks): 0.35 mL/min/kg.{R-45} Growing pig (11 to 12 weeks): 0.44 mL/min/kg.{R-45} Sulfamethazine Cattle: 11 to 37% of a dose of sulfamethazine is excreted into the urine as parent drug.{R-78; 82} Horses: Only 43% of the administered dose is eliminated in the urine and only 7.8% of it is in the form of parent drug.{R-37} Pigs: 24.5% of a sulfamethazine dose is excreted in the urine as unchanged drug and 52.1% as measured metabolites.{R-67} Sheep: 18% of a sulfamethazine dose is excreted into the urine as parent compound and 53% as metabolites.{R-64} Total clearance: Buffalo0.93 mL/min/kg{R-55}. Calves, 5 days of age0.33 mL/min/kg{R-79}. Calves, 2 to 3 months of age0.57 mL/min/kg{R-79}. Cows0.73 mL/min/kg{R-79}. Goats0.55 to 0.65 mL/min/kg; 1.13 to 1.4 mL/min/kg{R-35}.

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212 SULFONAMIDES VeterinarySystemic Horses0.92 mL/min/kg{R-37}. Pigs0.35 mL/min/kg{R-66}. Ponies0.7 mL/min/kg{R-57}. Sheep1.6 mL/min/kg{R-58}. SulfathiazoleTotal clearance: Pigs1.5 mL/min/kg{R-70}.

DRUG INTERACTIONS AND/OR RELATED PROBLEMS

The following drug interactions and/or related problems have been selected on the basis of their potential clinical signicance (possible mechanism in parentheses where appropriate)not necessarily inclusive ( = major clinical signicance): Note: Drug interactions relating specically to the use of sulfonamides in animals are rarely reported in veterinary literature. Human drug interactions have been reported and are included in the following section.

PRECAUTIONS TO CONSIDER SPECIES SENSITIVITY

Dogs: An idiosyncratic sulfonamide toxicosis can occur in any breed of dog, but has been reported more frequently in the Doberman Pinscher than in other breeds. This specic type of drug reaction includes blood dyscrasias, nonseptic polyarthritis, and skin rash.{R26; 27} Dogs given sulfonamides may also develop cutaneous eruptions, hepatitis, or keratitis sicca.{R-17; 27} Dogs are reported to develop a hemorrhagic syndrome when doses of sulfaquinoxaline that are tolerated by many chickens are administered in their drinking water.{R-4750}

HUMAN DRUG INTERACTIONS{R-69}

The following drug interactions have been reported in humans, and are included in the human monograph Sulfonamides (Systemic) in USP DI Volume I; these drug interactions are intended for informational purposes only and may or may not be applicable to the use of sulfonamides in the treatment of animals: Note: Combinations containing any of the following medications, depending on the amount present, may also interact with this medication. Anticoagulants, coumarin- or indandione-derivative, or Anticonvulsants, hydantoin, or Antidiabetic agents, oral (these medications may be displaced from protein binding sites and/ or their metabolism may be inhibited by some sulfonamides, resulting in increased or prolonged effects and/or toxicity; dosage adjustments may be necessary during and after sulfonamide therapy) Bone marrow depressants (concurrent use of bone marrow depressants with sulfonamides may increase the leukopenic and/or thrombocytopenic effects; if concurrent use is required, close observation for myelotoxic effects should be considered) Cyclosporine (concurrent use with sulfonamides may increase the metabolism of cyclosporine, resulting in decreased plasma concentrations and potential transplant rejection, and additive nephrotoxicity; plasma cyclosporine concentrations and renal function should be monitored) Hemolytics, other (concurrent use with sulfonamides may increase the potential for toxic side effects) Hepatotoxic medications, other (concurrent use with sulfonamides may result in an increased incidence of hepatotoxicity; patients, especially those on prolonged administration or those with a history of liver disease, should be carefully monitored) Methenamine (in acid urine, methenamine breaks down into formaldehyde, which may form an insoluble precipitate with certain sulfonamides, especially those that are less soluble in urine, and may also increase the danger of crystalluria; concurrent use is not recommended) Methotrexate or Phenylbutazone (the effects of methotrexate may be potentiated during concurrent use with sulfonamides because of displacement from plasma protein binding sites; phenylbutazone may displace sulfonamides from plasma protein binding sites, increasing sulfonamide concentrations)

CROSS-SENSITIVITY AND/OR RELATED PROBLEMS

Patients allergic to one sulfonamide may be allergic to other sulfonamides also.

CARCINOGENICITY
For sulfamethazineHigh doses have been shown to induce follicular cell hyperplasia of the thyroid gland and splenic changes in specic pathogen-free mice. When the highest doses (4800 parts per million in the diet) were fed for 24 months, 26 to 33% of the mice developed thyroid gland adenomas.{R-51} The applicability of these results to other species with recommended doses is unclear at this time.

PREGNANCY/REPRODUCTION
Sulfonamides cross the placenta in pregnant animals.{R-20; 60} Some teratogenic effects have been seen when very high doses were given to pregnant mice and rats.{R-20}

LACTATION
Sulfonamides are distributed into milk; however, the sulfonamides that are clinically relevant to food-producing animals are distributed into milk in concentrations too low to be therapeutic but high enough to produce residues{R-103; 105}. Sulfadiazine and sulfanilamide are more efciently distributed into milk than most sulfonamides, but are not used in dairy cattle{R-103}. For many sulfonamides, 0.5 to 2% of the total dose is found in the milk.{R-31; 32} Distribution into milk varies depending on the amount of nonprotein-bound sulfonamide present in the blood and the amount of the nonionized and therefore liposoluble form of the medication present. Sulfonamides with higher pKa values produce a higher proportion of drug in the blood that is non-ionized{R-31}, and if other factors, such as the rate of biotransformation, also support it, may be distributed more easily into milk. For lactating dairy cattle, concentration of the active parent compound of sulfamethazine, measured at a specic time in milk, is about 20% of the concentration in the blood.{R-77}

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SULFONAMIDES VeterinarySystemic 213 Penicillins (since bacteriostatic drugs may interfere with the bactericidal effect of penicillins in the treatment of meningitis or in other situations where a rapid bactericidal effect is necessary, it is best to avoid concurrent therapy) Hepatic function impairment (systemically absorbed sulfonamides are metabolized by the liver; delayed biotransformation may increase the risk of adverse effects) Renal function impairment (systemically absorbed sulfonamides are renally excreted; delayed elimination could cause accumulation of sulfonamide and metabolites, increasing the risk of adverse effects)

LABORATORY VALUE ALTERATIONS

The following have been selected on the basis of their potential clinical signicance (possible effect in parentheses where appropriate)not necessarily inclusive ( = major clinical signicance): Note: Laboratory value alterations relating specically to the use of sulfonamides in animals are rarely reported in veterinary literature. Human laboratory value alterations have been reported and are included in the following section.

PATIENT MONITORING
The following may be especially important in patient monitoring (other tests may be warranted in some patients, depending on condition; = major clinical signicance): Culture and susceptibility, in vitro, and Minimum inhibitory concentration (MIC) (in vitro cultures and MIC test should be done on samples collected prior to sulfonamide administration to determine pathogen susceptibility)

HUMAN LABORATORY VALUE ALTERATIONS{R-69}

The following laboratory value alterations have been reported in humans, and are included in the human monograph Sulfonamides (Systemic) in USP DI Volume I; these laboratory value alterations are intended for informational purposes only and may or may not be applicable to the use of sulfonamides in the treatment of animals: With diagnostic test results Benedicts test (sulfonamides may produce a false-positive Benedicts test for urine glucose) Jaffe alkaline picrate reaction assay (sulfamethoxazole may interfere with the Jaffe alkaline picrate reaction assay for creatinine, resulting in overestimations of approximately 10% in the normal values for creatinine) Sulfosalicylic acid test (sulfonamides may produce a false-positive sulfosalicylic acid test for urine protein) Urine urobilinogen test strip (e.g., Urobilistix) (sulfonamides may interfere with the urine urobilinogen [Urobilistix] test for urinary urobilinogen) With physiology/laboratory test values Alanine aminotransferase (ALT [SGPT]), serum, and Aspartate aminotransferase (AST [SGOT]), serum, and Bilirubin, serum (values may be increased) Blood urea nitrogen (BUN) and Creatinine, serum (concentrations may be increased)

SIDE/ADVERSE EFFECTS
The following side/adverse effects have been selected on the basis of their potential clinical signicance (possible signs and, for humans, symptoms in parentheses where appropriate)not necessarily inclusive:

THOSE INDICATING NEED FOR MEDICAL ATTENTION

Incidence unknown All species Crystallization in the urinary tract Note: Crystallization of sulfonamides can occur in the kidneys or urine with high doses of sulfonamide or when an animal is dehydrated. Solubility in the urine is dependent on the concentration of drug in the urine, urinary pH (less soluble in an acidic pH), the patients hydration, and the amount of drug in the acetylated form. Because dogs do not produce acetylated metabolites, they may be less susceptible to this adverse effect{R-85}. It can be minimized in susceptible animals by maintaining a high urine ow and, if necessary, alkalinizing the urine. Dogs Cutaneous drug eruption{R-27}; hepatitis; hypothyroidism{R-100; 101} ; idiosyncratic toxicosis{R-26; 27} (blood dyscrasias, including anemia, leukopenia or thrombocytopenia; fever; focal retinitis; lymphadenopathy; nonseptic polyarthritis; polymyositis; skin rash); keratoconjunctivitis sicca{R-2830} Note: Iatrogenic hypothyroidism may occur and thyroid function test values may be lowered in dogs administered sulfonamides{R-100; 101} . Although studies have looked at this reaction with potentiated sulfonamides{R-100; 101}, sulfonamides administered alone have been reported to impair thyroid function{R-100}. With administration of sulfamethoxazole and trimethoprim combination at high doses or of ormetoprim and sulfadimethoxine, thyrotropin stimulation test values and serum thyroxine values have been signicantly reduced{R-100}. Sulfadiazine and trimethoprim combination, administered at labeled doses (25 mg of sulfadiazine and 5 mg of trimethoprim per kg every 24 hours), has not affected thyroid test values in studies performed. Idiosyncratic toxicosis can occur 8 to 20 days after initiation of treatment and is believed to be caused either by an immunemediated syndrome or by an idiosyncratic reaction in dogs, perhaps due to toxic metabolites of the sulfonamide. Of 22 reported cases

MEDICAL CONSIDERATIONS/CONTRAINDICATIONS
The medical considerations/contraindications included have been selected on the basis of their potential clinical signicance (reasons given in parentheses where appropriate)not necessarily inclusive ( = major clinical signicance). Except under special circumstances, this medication should not be used when the following medical problem exists: Hypersensitivity to sulfonamides (animals that have had a previous reaction to sulfonamides may be much more likely to react on subsequent administration) Risk-benet should be considered when the following medical problems exist:

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214 SULFONAMIDES VeterinarySystemic compiled in one study, 7 involved Doberman Pinschers, and it has been theorized that they are more susceptible to this toxicosis{R-26}. A large majority of the animals in which idiosyncratic toxicosis occurs have had a previous exposure to a sulfonamide. Most cases involve a trimethoprim and sulfonamide combination{R-27}. When sulfonamide therapy is discontinued, recovery generally occurs within 2 to 5 days.{R-27} Keratoconjunctivitis sicca is considered a possible side/adverse effect in any dog on sulfonamide therapy for more than a month; however, it can occur at any time after therapy is initiated. Reports conict over whether this is a dose-related or idiosyncratic reaction{R-108}. The most frequent reports have been with sulfasalazine or trimethoprim and sulfonamide combination{R-2830}, perhaps because these medications are most commonly used for long-term therapy in dogs. Lacrimation may not return to normal after discontinuation of sulfonamide treatment. For sulfaquinoxaline Chickens and dogs Hemorrhagic syndrome (anorexia, epistaxis, hemoptysis, lethargy, pale mucous membranes, possibly death){R-4650} Note: Hemorrhagic syndrome has been reported in chickens and dogs but may occur in other species. It is most often reported with the addition of sulfaquinoxaline to feed for chickens, but in dogs has been reported to follow administration in the water supply of products labeled for poultry.{R-4750} Sulfaquinoxaline is a vitamin K antagonist that inhibits vitamin K eposide and vitamin K quinone reductase and causes an effect similar to that of coumarin anticoagulants.{R-46} Rapid hypoprothrombinemia occurs in dogs, and sulfaquinoxaline may have an additional adverse effect on specic cell types; this may explain why supplementation of chicken feeds with vitamin K has not always prevented the syndrome in chickens.{R-4647} Rapid discontinuation of medication and initiation of therapy with vitamin K1 may reverse the effects. and other blood dyscrasias. Therapy should be discontinued at the rst appearance of skin rash or any serious side/adverse effects. The multiorgan toxicity of sulfonamides is thought to be the result of the way sulfonamides are metabolized in certain patients. It is probably due to the inability of the body to detoxify reactive metabolites. Sulfonamides are metabolized primarily by acetylation. Patients can be divided into slow and fast acetylators. Slow acetylation of sulfonamides makes more of the medication available for metabolism by the oxidative pathways of the cytochrome P450 system. These pathways produce reactive toxic metabolites, such as hydroxylamine and nitroso compounds. The metabolites are normally detoxied by scavengers, such as glutathione. However, some populations, such as human immunodeciency virus (HIV)infected patients, have low concentrations of glutathione and these metabolites accumulate, producing toxicity. Patients who are slow acetylators have a higher incidence of sulfonamide hypersensitivity reactions, although severe toxicity has also been seen in fast acetylators. Acetylation status alone cannot fully explain sulfonamide toxicity since approximately 50% of North American blacks and whites are slow acetylators and severe reactions occur in less than 1% of patients treated with sulfonamides. However, decreased acetylation may increase the amount of sulfonamide metabolized to toxic metabolites.

OVERDOSE
For more information in cases of overdose or unintentional ingestion, contact the American Society for the Prevention of Cruelty to Animals (ASPCA) National Animal Poison Control Center (888426-4435 or 900-443-0000; a fee may be required for consultation) and/or the drug manufacturer. Toxicities secondary to acute overdose of sulfonamides are not typically reported. Side effects may be more likely to occur with high doses and long-term administration, but are seen at recommended doses as well.

HUMAN SIDE/ADVERSE EFFECTS{R-69}

In addition to the above side/adverse effects reported in animals, the following side/adverse effects have been reported in humans, and are included in the human monograph Sulfonamides (Systemic) in USP DI Volume I; these side/adverse effects are intended for informational purposes only and may or may not be applicable to the use of sulfonamides in the treatment of animals: Incidence more frequent Central nervous system effects; gastrointestinal disturbances; hypersensitivity; photosensitivity Incidence less frequent Blood dyscrasias; hepatitis; Lyells syndrome (difculty in swallowing; redness, blistering, peeling, or loosening of skin); StevensJohnson syndrome (aching joints and muscles; redness, blistering, peeling, or loosening of skin; unusual tiredness or weakness) Incidence rare Central nervous system toxicity; Clostridium difcile colitis; crystalluria or hematuria; goiter or thyroid function disturbance; interstitial nephritis or tubular necrosis Note: C. difcile colitis may occur up to several weeks after discontinuation of these medications. Fatalities have occurred, although rarely, due to severe reactions such as Stevens-Johnson syndrome, toxic epidermal necrolysis, fulminant hepatic necrosis, agranulocytosis, aplastic anemia,

CLIENT CONSULTATION
Dosage and length of treatment recommendations should be followed; high doses or long-term use can increase the risk of side effects. Animals should have a good water supply and should be monitored to ensure adequate water consumption during treatment.

VETERINARY DOSING INFORMATION

Residue avoidance: Management practices can affect depletion of residues in pigs. When pigs have environmental access to urine and manure from pigs treated with sulfamethazine, the residues are easily recycled and can cause these animals to have positive urine tests for sulfonamide and violative tissue residues. Hot or cold environmental temperatures do not appear to inactivate sulfamethazine in the environment.{R-70; 74}

FOR ORAL DOSAGE FORMS ONLY

Intestinal parasites, among other factors, can affect the pharmacokinetics of sulfamethazine in lambs and probably in other species also. In parasitized lambs given a single dose of 99 mg per kg of body weight (mg/kg), sulfamethazines half-life of elimination and time to peak concentration were doubled.{R-65}

2003 Thomson MICROMEDEX

All rights reserved

SULFONAMIDES VeterinarySystemic 215

FOR TREATMENT OF ADVERSE EFFECTS

Recommended treatment consists of the following: For anaphylaxis Parenteral epinephrine. Oxygen administration and respiratory support.

Canada Veterinary-labeled product(s): Not commercially available. Withdrawal times:{R-88} U.S.

Withdrawal time Species Meat (days) 7

SULFACHLORPYRIDAZINE SUMMARY OF DIFFERENCES

Pharmacology/pharmacokinetics: Intermediate duration of action.{R-19}

Calves, ruminating

ORAL DOSAGE FORMS SULFACHLORPYRIDAZINE POWDER FOR ORAL SOLUTION

Usual dose: Enteritis (diarrhea associated with E. coli)1 Calves, less than 1 month of age: Oral, 33 to 49.5 mg per kg of body weight every twelve hours.{R-89} Pigs: Oral, 22 to 38.5 mg per kg of body weight, administered as a drench every twelve hours or 44 to 77 mg per kg of body weight a day administered in the only source of drinking water.{R-89} Strength(s) usually available{R-92}: U.S. Veterinary-labeled product(s): 50 grams per bottle (OTC) [Vetisulid Powder].{R-89} Canada Veterinary-labeled product(s): Not commercially available. Withdrawal times:{R-89} U.S.
Withdrawal time Species Calves Pigs Meat (days) 7 4

Note: Product labeling listing the above withdrawal time states that it applies when medication is administered for a maximum of ve days. No withdrawal times have been established for use in preruminating calves.{R-88} Packaging and storage: Store below 40 C (104 F), preferably between 15 and 30 C (59 and 86 F), unless otherwise specied by manufacturer. Avoid excessive heat.{R-88} Additional information: Animals should maintain an adequate water intake during the treatment period. USP requirements: Not in USP.
1

Not included in Canadian product labeling or product not commercially available in Canada.

PARENTERAL DOSAGE FORMS SULFACHLORPYRIDAZINE INJECTION

Usual dose: Enteritis (diarrhea associated with E. coli)1Calves, less than 1 month of age: Intravenous, 33 to 49.5 mg per kg of body weight every twelve hours.{R-87} Strength(s) usually available: U.S. Veterinary-labeled product(s): 200 mg per mL (OTC) [Vetisulid Injection]. Canada Veterinary-labeled product(s): Not commercially available. Withdrawal times: U.S.
Withdrawal time Species Meat (days) 5

Packaging and storage: Store below 40 C (104 F), preferably between 15 and 30 C (59 and 86 F), unless otherwise specied by manufacturer. Additional information: Animals should maintain an adequate water intake during the treatment period. USP requirements: Not in USP.

Calves, ruminating

Note: Product labeling listing the above withdrawal time states that it applies when medication is administered for a maximum of ve days. No withdrawal times have been established for use in preruminating calves. Packaging and storage: Store below 40 C (104 F), preferably between 15 and 30 C (59 and 86F), unless otherwise specied by manufacturer. Protect from light. Protect from freezing{R-87}. Additional information: Animals should maintain an adequate water intake during the treatment period. USP requirements: Not in USP.
1

SULFACHLORPYRIDAZINE TABLETS
Usual dose: Enteritis (diarrhea associated with Escherichia coli)1Calves, less than 1 month of age: Oral, 33 to 49.5 mg per kg of body weight every twelve hours.{R-88} Strength(s) usually available{R-92}: U.S. Veterinary-labeled product(s): 2 grams (OTC) [Vetisulid Boluses]. 2003 Thomson MICROMEDEX

Not included in Canadian product labeling or product not commercially available in Canada. All rights reserved

216 SULFONAMIDES VeterinarySystemic

SULFADIMETHOXINE SUMMARY OF DIFFERENCES

Pharmacology/pharmacokinetics: Intermediate to long duration of action{R-19}.

Stability: Freezing or discoloration does not affect stability. Medication should be thawed before using.{R-2} Preparation of dosage form: Prepare fresh drinking water daily. Additional information: Animals should maintain an adequate water intake during the treatment period. USP requirements: Not in USP.

ORAL DOSAGE FORMS SULFADIMETHOXINE ORAL SOLUTION

Usual dose: Calf diphtheria1; Pneumonia, bacterial1; or Necrotic pododermatitis1Calves and cattle: Oral, 55 mg per kg of body weight (2.4 to 3.75 grams per gallon of water) as an initial dose, followed by 27.5 mg per kg of body weight (1.2 to 1.8 grams per gallon of water) a day for four days.{R-2} Coccidiosis1; or Fowl cholera1 Chickens, broiler and replacement: Oral, 1875 mg per gallon of water (0.05% solution), administered as the only source of drinking water for six days{R-2}. Turkeys: Oral, 938 mg per gallon of water (0.025% solution), administered as the only source of drinking water for six days{R-2}. Infectious coryza outbreaks1Chickens, broiler and replacement: Oral, 1875 mg per gallon of water (0.05% solution), administered as the only source of drinking water for six days{R-2}. Note: Administration of sulfadimethoxine for longer than the recommended time can result in slowed growth rates and other adverse effects.{R-83} Strength(s) usually available : U.S. Veterinary-labeled product(s): 125 mg per mL (OTC) [Albon 12.5% Concentrated Solution; AmTech Sulfadimethoxine 12.5% Oral Solution; Di-Methox 12.5% Oral Solution; SDM Solution; Sulforal; generic]. Canada Veterinary-labeled product(s): Not commercially available. Withdrawal times: U.S.
Withdrawal time Species Cattle Chickens, turkeys Meat (days) 7 5
{R-92}

SULFADIMETHOXINE ORAL SUSPENSION USP

Usual dose: Bacterial pneumonia and other respiratory infections1; Cystitis1; or Skin and soft tissue infections1Cats and dogs: Oral, 55 mg per kg of body weight as an initial dose, followed by 27.5 mg per kg of body weight every twenty-four hours.{R-6} Enteritis associated with coccidiosis or Salmonella1Dogs: Oral, 55 mg per kg of body weight as an initial dose, followed by 27.5 mg per kg of body weight every twenty-four hours.{R-6} Strength(s) usually available{R-92}: U.S. Veterinary-labeled product(s): 50 mg per mL (Rx) [Albon Oral Suspension 5%]. Canada Veterinary-labeled product(s): Not commercially available. Packaging and storage: Store below 40 C (104 F), preferably between 15 and 30 C (59 and 86 F), unless otherwise specied by manufacturer. Additional information: Animals should maintain an adequate water intake during the treatment period. USP requirements: Preserve in tight, light-resistant containers, and store at controlled room temperature. Label it to indicate that it is for veterinary use only. Contains the labeled amount, within 10%. Meets the requirements for Identication and pH (5.07.0){R-56}.

SULFADIMETHOXINE SOLUBLE POWDER USP

Usual dose: Bacterial pneumonia1; Calf diphtheria1; or Necrotic pododermatitis1Calves and cattle: Oral, 55 mg per kg of body weight (2.4 to 3.3 grams per gallon) as an initial dose, followed by 27.5 mg per kg of body weight (1.2 grams per gallon) every twenty-four hours for four days.{R-4} Coccidiosis1; or Fowl cholera1 Chickens, broiler and replacement: Oral, 1892 mg per gallon of water (0.05% solution), administered as the only source of drinking water for six days{R-4}. Turkeys: Oral, 946 mg per gallon of water (0.025% solution), administered as the only source of drinking water for six days{R-4}.

Note: Product labeling listing the above withdrawal times states that they are not labeled for use in chickens older than 16 weeks of age, turkeys older than 24 weeks of age, preruminating calves, or lactating dairy cattle.{R-2} Packaging and storage: Store below 40 C (104 F), preferably between 15 and 30 C (59 and 86 F), unless otherwise specied by manufacturer. Protect from light.{R-2}

2003 Thomson MICROMEDEX

All rights reserved

SULFONAMIDES VeterinarySystemic 217 Infectious coryza outbreaks1Chickens, broiler and replacement: Oral, 1892 mg per gallon of water (0.05% solution), administered as the only source of drinking water for six days{R-4}. Strength(s) usually available{R-92}: U.S. Veterinary-labeled product(s): 28.3 grams per ounce of powder (OTC) [AmTech Sulfadimethoxine Soluble Powder; Di-Methox Soluble Powder; SDM Powder; Sulfasol; generic]. Canada Veterinary-labeled product(s): Not commercially available. Withdrawal times: U.S.
Withdrawal time Species Cattle Chickens, turkeys Meat (days) 7 5

5000 mg (5 grams) (OTC) [Albon Boluses]. 15,000 mg (15 grams) (OTC) [Albon Boluses]. Note: The 125-mg, 250-mg, and 500-mg tablets listed above are labeled for use only in cats and dogs, while the 5-gram and 15-gram tablets are labeled for use only in cattle. Canada{R-19} Veterinary-labeled product(s): 125 mg (OTC) [S-125]. 250 mg (OTC) [S-250]. Withdrawal times:{R-1} U.S.
Withdrawal time Species Cattle Meat (days) 7 Milk (hours) 60

Note: Product labeling listing the above withdrawal times states that they are not labeled for use in preruminating calves. Additional information: Animals should maintain an adequate water intake during the treatment period{R-1}. Packaging and storage: Store below 40 C (104 F), preferably between 15 and 30 C (59 and 86 F), unless otherwise specied by manufacturer. USP requirements: Preserve in tight, light-resistant containers, and store at controlled room temperature. Label the Tablets to indicate that they are for veterinary use only. Contains the labeled amount, within 10%. Meets the requirements for Identication, Disintegration (30 minutes), and Uniformity of dosage units{R-56}.

Note: Product labeling listing the above withdrawal times states that they are not labeled for use in preruminating calves, lactating dairy cattle, chickens older than 16 weeks of age, or turkeys older than 24 weeks of age. Packaging and storage: Store below 40 C (104 F), preferably between 15 and 30 C (59 and 86 F), unless otherwise specied by manufacturer. Additional information: Animals should maintain an adequate water intake during the treatment period. USP requirements: Preserve in tight, light-resistant containers, and store at controlled room temperature. Label it to indicate that it is for veterinary use only. Contains the labeled amount, within 10%. Meets the requirements for Identication, Minimum ll, and pH (7.08.0, in a solution [1 in 20]){R-56}.

SULFADIMETHOXINE EXTENDED-RELEASE TABLETS

Usual dose: Bacterial pneumonia1; Calf diphtheria1; or Pododermatitis1Cattle: Oral, 137.5 mg per kg of body weight as a single dose.{R-5} Note: To maintain sustained release of medication, tablets should not be divided; it is recommended that animals should receive a tablet for the nearest 91 kg (200 pounds) of body weight.{R-5} Strength(s) usually available{R-92}: U.S. Veterinary-labeled product(s): 12.5 grams (Rx) [Albon SR]. Canada Veterinary-labeled product(s): Not commercially available. Withdrawal times: U.S.
Withdrawal time Species Cattle Meat (days) 21

SULFADIMETHOXINE TABLETS USP

Usual dose: Bacterial pneumonia and other respiratory infections; Cystitis; or Skin and soft tissue infectionsCats and dogs: Oral, 55 mg per kg of body weight as an initial dose, followed by 27.5 mg per kg of body weight every twenty-four hours{R-6}. Calf diphtheria1; Pneumonia, bacterial1; or Pododermatitis1Cattle: Oral, 55 mg per kg of body weight as the initial dose, followed by 27.5 mg per kg of body weight every twentyfour hours for ve days{R-1}. Enteritis associated with coccidiosis or SalmonellaDogs: Oral, 55 mg per kg of body weight as an initial dose, followed by 27.5 mg per kg of body weight every twenty-four hours.{R-6} Strength(s) usually available{R-92}: U.S. Veterinary-labeled product(s): 125 mg (Rx) [Albon Tablets]. 250 mg (Rx) [Albon Tablets]. 500 mg (Rx) [Albon Tablets]. 2003 Thomson MICROMEDEX

Note: Product labeling listing the above withdrawal time states that they are not labeled for use in lactating dairy cattle or preruminating calves.{R-5} All rights reserved

218 SULFONAMIDES VeterinarySystemic Packaging and storage: Store below 40 C (104 F), preferably between 15 and 30 C (59 and 86 F), unless otherwise specied by manufacturer. Additional information: Animals should maintain an adequate water intake during the treatment period. USP requirements: Not in USP.
1

Packaging and storage: Store below 40 C (104 F), preferably between 15 and 30 C (59 and 86 F), unless otherwise specied by manufacturer. Protect from light. USP requirements: Not in USP.
1

Not included in Canadian product labeling or product not commercially available in Canada.

Not included in Canadian product labeling or product not commercially available in Canada.

SULFAMETHAZINE SUMMARY OF DIFFERENCES

Pharmacology/pharmacokinetics: Intermediate duration of action{R-19}.

PARENTERAL DOSAGE FORMS SULFADIMETHOXINE INJECTION

Usual dose: Bacterial respiratory infections1; Cystitis1; or Skin and soft tissue infections1Cats and dogs: Intravenous or subcutaneous, 55 mg per kg of body weight as an initial dose, followed by 27.5 mg per kg of body weight every twenty-four hours.{R-3} Calf diphtheria1; Pneumonia, bacterial1; or Necrotic pododermatitis1Cattle: Intravenous, 55 mg per kg of body weight as an initial dose, followed by 27.5 mg per kg of body weight every twenty-four hours.{R-3} Enteritis associated with coccidiosis or Salmonella1Dogs: Intravenous or subcutaneous, 55 mg per kg of body weight as an initial dose, followed by 27.5 mg per kg of body weight every twenty-four hours.{R-3} Note: Intramuscular injection can cause local pain and inammation and result in lower serum concentrations of sulfadimethoxine.{R-3} Strength(s) usually available{R-92}: U.S. Veterinary-labeled product(s): 400 mg per mL (Rx) [Albon Injection 40%; AmTech Sulfadimethoxine Injection-40%; Di-Methox Injection-40%; SDM Injection; generic]. Canada Veterinary-labeled product(s): Not commercially available. Withdrawal times: U.S.{R-3}
Withdrawal time Species Cattle Meat (days) 5 Milk (hours) 60

ORAL DOSAGE FORMS

Note: Bracketed information in the Dosage Forms section refers to uses that either are not included in U.S. product labeling or are for products not commercially available in the U.S.

SULFAMETHAZINE ORAL SOLUTION

Usual dose: Calf diphtheria; or Necrotic pododermatitisCalves and cattle: Oral, 247.5 mg per kg of body weight as an initial dose, followed by 123.8 mg per kg of body weight every twenty-four hours for three days, administered in the only source of drinking water{R-12}. Coccidiosis Chickens: Oral, 134 to 196 mg per kg of body weight a day for two days, followed by 67 to 98 mg per kg of body weight for four days, administered in the only source of drinking water{R-12}. Turkeys: Oral, 117 to 286 mg per kg of body weight a day for two days, followed by 58.5 to 143 mg per kg of body weight for four days, administered in the only source of drinking water{R-12}. Enteritis, bacterial Calves, cattle, and pigs: Oral, 247.5 mg per kg of body weight as an initial dose, followed by 123.8 mg per kg of body weight every twenty-four hours for three days, administered in the only source of drinking water{R-12}. [Sheep]: Oral, 225 mg per kg of body weight the rst day, followed by 112.5 mg per kg of body weight for three days, administered in the only source of drinking water{R-16}. Fowl cholera, acute; or Pullorum diseaseChickens: Oral, 134 to 196 mg per kg of body weight a day for six days, administered in the only source of drinking water{R-12}. Infectious coryzaChickens: Oral, 134 to 196 mg per kg of body weight a day for two days, administered in the only source of drinking water{R-12}. Pneumonia, bacterialCalves, cattle, and pigs: Oral, 247.5 mg per kg of body weight as an initial dose, followed by 123.8 mg per kg of body weight every twenty-four hours for three days, administered in the only source of drinking water{R-12}. Respiratory infections, bacterial[Sheep]: Oral, 225 mg per kg of body weight the rst day, followed by 112.5 mg per kg of body weight for three days, administered in the only source of drinking water{R-16}. Strength(s) usually available{R-92}: U.S. Veterinary-labeled product(s): 125 mg per mL (OTC) [Sulmet Drinking Water Solution 12.5%]. All rights reserved

Note: Product labeling listing the above withdrawal times states that withdrawal times have not been established for use in preruminating calves. Additional information: Animals should maintain an adequate water intake during the treatment period. Stability: Crystallization does not change the potency of sulfadimethoxine injection.{R-3} 2003 Thomson MICROMEDEX

SULFONAMIDES VeterinarySystemic 219 Canada Veterinary-labeled product(s): 125 mg per mL (OTC) [generic]. 250 mg per mL (OTC) [Sulfa 25; Sulfa 25%; generic]. Withdrawal times: U.S.
Withdrawal time Species Cattle, chickens, turkeys Pigs Meat (days) 10 15

Fowl cholera, acute1; or Pullorum disease1Chickens: Oral, 128 to 187 mg per kg of body weight a day for six days, administered in the only source of drinking water{R-9}. Infectious coryza1Chickens: Oral, 128 to 187 mg per kg of body weight a day for two days, administered in the only source of drinking water{R-9}. Strength(s) usually available{R-92}: U.S. Veterinary-labeled product(s): 453.5 grams of sulfamethazine powder per packet (OTC) [Sulmet Soluble Powder]. Canada Veterinary-labeled product(s): Not commercially available. Withdrawal times: U.S.{R-9}
Withdrawal time Milk (hours) 96 Species Calves, cattle, chickens, turkeys Pigs Meat (days) 10 15

Note: Product labeling listing the above withdrawal times states that they apply when administered for a maximum of ve days in cattle or pigs. Products are not labeled for use in chickens and turkeys producing eggs for human consumption, calves less than 1 month of age or fed an all-milk diet, or dairy cows 20 months of age or older. Canada
Withdrawal time Species Cattle Calves, pigs, sheep Chickens, turkeys Meat (days) 10 or 12, depending on product 10 or 12, depending on product 12

Note: Product labeling listing the above withdrawal times states that they are not labeled for use in laying birds or for use in swine feeds. Packaging and storage: Store below 40 C (104 F), preferably between 15 and 30 C (59 and 86 F), unless otherwise specied by manufacturer. Protect from freezing. Additional information: Animals should maintain an adequate water intake during the treatment period. USP requirements: Not in USP.

Note: Product labeling listing the above withdrawal times states that they apply when administered for a maximum of ve days in cattle or pigs. Products are not labeled for use in chickens and turkeys producing eggs for human consumption, calves less than 1 month of age or fed all-milk diets, or dairy cows 20 months of age or older. Packaging and storage: Store below 40 C (104 F), preferably between 15 and 30 C (59 and 86 F), unless otherwise specied by manufacturer. Preparation of dosage form: Fresh solutions should be prepared daily.{R-12}

SULFAMETHAZINE POWDER FOR ORAL SOLUTION

Usual dose: Calf diphtheria1; or Necrotic pododermatitis1Cattle: Oral, 237.6 mg per kg of body weight as an initial dose, followed by 118.8 mg per kg of body weight every twenty-four hours for three days, administered as an individual animal drench or in the only source of drinking water{R-9}. Coccidiosis1 Chickens: Oral, 128 to 187 mg per kg of body weight a day for two days, followed by 64 to 93.5 mg per kg of body weight for four days, administered in the only source of drinking water{R-9}. Turkeys: Oral, 110 to 273 mg per kg of body weight a day for two days, followed by 55 to 136.5 mg per kg of body weight for four days, administered in the only source of drinking water{R-9}. Enteritis, bacterial1; or Pneumonia, bacterial1Cattle and pigs: Oral, 237.6 mg per kg of body weight as an initial dose, followed by 118.8 mg per kg of body weight every twenty-four hours for three days, administered as an individual animal drench or in the only source of drinking water{R-9}. 2003 Thomson MICROMEDEX Additional information: Animals should maintain an adequate water intake during the treatment period. USP requirements: Not in USP.

SULFAMETHAZINE TABLETS
Usual dose: Calf diphtheriaCalves: Oral, 220 mg per kg of body weight as an initial dose, followed by 110 mg per kg of body weight every twentyfour hours{R-13}. Enteritis associated with Escherichia coliCalves and foals: Oral, 220 mg per kg of body weight as an initial dose, followed by 110 mg per kg of body weight every twenty-four hours{R-13}. Pneumonia, bacterialCalves and foals: Oral, 220 mg per kg of body weight as an initial dose, followed by 110 mg per kg of body weight every twenty-four hours{R-13}. All rights reserved

220 SULFONAMIDES VeterinarySystemic Strength(s) usually available{R-92}: U.S. Veterinary-labeled product(s): 2.5 grams (OTC) [Sulmet Oblets]. 5 grams (OTC) [Sulmet Oblets]. Canada Veterinary-labeled product(s): 15 grams (OTC) [generic]. 15.6 grams (OTC) [generic]. Withdrawal times: U.S.
Withdrawal time Species Calves, cattle Meat (days) 10 Species Calves, ruminating and cattle

Strength(s) usually available{R-92}: U.S.{R-7; 10; 11} Veterinary-labeled product(s): 8 grams (OTC) [Sulfa-Max III Calf Bolus; Sustain III Calf Bolus]. 8.25 grams (OTC) [Sulfasure SR Calf Bolus; Suprasulfa III Calf Bolus]. 30 grams (OTC) [Sulfasure SR Cattle Bolus; Suprasulfa III Cattle Bolus]. 32.1 grams (OTC) [Sulfa-Max III Cattle Bolus; Sustain III Cattle Bolus] Canada Veterinary-labeled product(s): 8 grams (OTC) [Calfspan]. 8.25 grams (OTC) [Sulfasure SR Calf Tablets]. 32.1 grams (OTC [Sustain III]. Withdrawal times: U.S.{R-7; 10}
Withdrawal time Meat (days) 8 or 12, depending on product

Note: Product labeling listing the above withdrawal time states that it applies to a maximum of ve days treatment. Products are not labeled for use in calves less than 1 month of age or those fed an all-milk diet, female dairy cattle 20 months of age or older, or horses intended for food. Canada
Withdrawal time Species Calves, cattle
{R-8}

Meat (days) 10

Milk (hours) 96

Note: Product labeling listing the above withdrawal times states that they apply to animals given a maximum of two doses. Products are not labeled for use in calves less than 1 month of age, calves fed an all-milk diet, or dairy cattle 20 months of age or older. Canada
Withdrawal time

Note: Product labeling listing the above withdrawal times states that they apply to a maximum of ve days treatment. Products are not labeled for use in calves less than 1 month of age or those fed an all-milk diet, or horses intended for food. Packaging and storage: Store below 40 C (104 F), preferably between 15 and 30 C (59 and 86 F), unless otherwise specied by manufacturer. Additional information: Animals should maintain an adequate water intake during the treatment period. USP requirements: Not in USP.

Species Cattle

Meat (days) 8, 12, or 28, depending on product

Note: Product labeling listing the above withdrawal times states that they are not labeled for use in lactating dairy cattle. Packaging and storage: Store below 40 C (104 F), preferably between 15 and 30 C (59 and 86 F), unless otherwise specied by manufacturer. Additional information: Animals should maintain an adequate water intake during the treatment period. USP requirements: Not in USP.

SULFAMETHAZINE EXTENDED-RELEASE TABLETS

Usual dose: Calf diphtheria; Coccidiosis; Enteritis, bacterial; or Pneumonia, bacterial Calves, 1 month of age or older: Oral, 350 to 400 mg per kg of body weight, administered as a single dose{R-7; 11}. The dose may be repeated in three days, if necessary{R-7; 11}. Cattle: Oral, 330 to 350 mg per kg of body weight as a single dose{R-10}. The dose may be repeated in three days, if necessary{R-11}. Necrotic pododermatitisCattle: Oral, 330 to 350 mg per kg of body weight as a single dose{R-10}. The dose may be repeated in three days, if necessary{R-11}. Note: Tablets can be broken at the score line, but should not be crushed. 2003 Thomson MICROMEDEX

Not included in Canadian product labeling or product not commercially available in Canada.

SULFAMETHAZINE, SULFANILAMIDE, AND SULFATHIAZOLE ORAL DOSAGE FORMS

Note: Bracketed information in the Dosage Forms section refers to uses that either are not included in U.S. product labeling or are for products not commercially available in the U.S.

SULFAMETHAZINE, SULFANILAMIDE, AND SULFATHIAZOLE TABLETS

Usual dose: [Bacterial enteritis]; [Bacterial pneumonia]; [Calf diphtheria]; or All rights reserved

SULFONAMIDES VeterinarySystemic 221 [Necrotic pododermatitis]Cattle: Oral, 48.8 mg sulfamethazine, 73 mg sulfanilamide, and 73 mg sulfathiazole per kg of body weight as an initial dose, followed by 24.4 mg sulfamethazine, 36.5 mg sulfanilamide, and 36.5 mg sulfathiazole per kg of body weight, administered twelve hours later.{R-97} Strength(s) usually available{R-92}: U.S. Veterinary-labeled product(s): Not commercially available. Canada{R-97} Veterinary-labeled product(s): 3.9 grams sulfamethazine, 5.85 grams sulfanilamide, and 5.85 grams sulfathiazole (OTC) [Triple Sulfa Bolus]. Withdrawal times: Canada
Withdrawal time Species Cattle Meat (days) 10 Milk (hours) 96

Strength(s) usually available{R-92}: U.S. Veterinary-labeled product(s): Not commercially available. Canada Veterinary-labeled product(s): 630 mg sulfamethazine and 315 mg of sulfathiazole per gram of powder (OTC) [2 Sulfamed; S-M-T; Sulfa-MT]. 641 mg sulfamethazine and 320 mg of sulfathiazole per gram of powder (OTC) [Sulfalean Powder]. 667 mg of sulfamethazine and 333 mg of sulfathiazole per gram of powder (OTC) [Powder 21; Sulfa 2 Soluble Powder]. Withdrawal times: Canada
Withdrawal time Species Cattle Pigs Meat (days) 10 10 Milk (hours) 96

Note: Some products are not labeled for use in lactating dairy cattle. Packaging and storage: Store below 40 C (104 F), preferably between 15 and 30 C (59 and 86 F), unless otherwise specied by manufacturer. Protect from moisture. Additional information: Animals should maintain an adequate water intake during the treatment period. USP requirements: Not in USP. Packaging and storage: Store below 40 C (104 F), preferably between 15 and 30 C (59 and 86 F), unless otherwise specied by manufacturer. Protect from moisture.{R-15} Additional information: Animals should maintain an adequate water intake during the treatment period. These products should not be administered in animal feeds. USP requirements: Not in USP.

SULFAMETHAZINE AND SULFATHIAZOLE ORAL DOSAGE FORMS

Note: Bracketed information in the Dosage Forms section refers to uses that either are not included in U.S. product labeling or are for products not commercially available in the U.S.

SULFAQUINOXALINE SUMMARY OF DIFFERENCES

Pharmacology/pharmacokinetics: Sulfaquinoxaline is minimally absorbed systemically and is referred to as an enteric sulfonamide.{R-19} Side/adverse effects: Clotting disorders similar to those resulting from coumarin anticoagulants have been reported in chickens and dogs.{R-4650}

SULFAMETHAZINE AND SULFATHIAZOLE POWDER FOR ORAL SOLUTION

Usual dose: [Enteritis]Cattle and pigs: Oral, 144 mg of sulfamethazine and 72 mg of sulfathiazole per kg of body weight as an initial dose, followed by 72 mg of sulfamethazine and 36 mg of sulfathiazole per kg of body weight a day for three days, administered as an individual animal drench or in the only source of drinking water{R-15}. [Pneumonia, bacterial]; or [Pododermatitis]Cattle: Oral, 144 mg of sulfamethazine and 72 mg of sulfathiazole per kg of body weight as an initial dose, followed by 72 mg of sulfamethazine and 36 mg of sulfathiazole per kg of body weight a day for three days, administered as an individual animal drench or in the only source of drinking water{R-15}. [Respiratory infections, bacterial]Pigs: Oral, 144 mg of sulfamethazine and 72 mg of sulfathiazole per kg of body weight as an initial dose, followed by 72 mg of sulfamethazine and 36 mg of sulfathiazole per kg of body weight a day for three days, administered as an individual animal drench or in the only source of drinking water{R-15}. 2003 Thomson MICROMEDEX

ORAL DOSAGE FORMS SULFAQUINOXALINE ORAL SOLUTION USP

Usual dose: Acute fowl cholera; or Acute fowl typhoidChickens and turkeys: Oral, a 0.04% solution, administered in the only source of drinking water for two to three days{R-14}. Coccidiosis Calves1 and cattle1: Oral, 13.2 mg per kg of body weight a day, administered in the only source of drinking water as a 0.015% solution for three to ve days{R-14}. Chickens: Oral, a 0.04% solution, administered in the only source of drinking water for two to three days{R-14}. Treatment should be stopped for three days, then the medication readministered as a All rights reserved

222 SULFONAMIDES VeterinarySystemic 0.025% solution for two to four more days. The schedule may be repeated, if necessary{R-14}. Turkeys: Oral, a 0.025% solution of sulfaquinoxaline, administered as the only source of drinking water for two days. Treatment should be stopped for three days, then the medication readministered as a 0.025% solution for two days; treatment is then stopped for three days, then medication is readministered as the 0.025% solution for two nal days. The complete schedule may be repeated, if necessary{R-14}. Note: For treatment of coccidiosis in chickens and turkeys, it is recommended that litter not be changed until absolutely necessary. Strength(s) usually available{R-92}: U.S. Veterinary-labeled product(s): 200 mg per mL (OTC) [Sulfa-Q 20%; generic]. 319.2 mg per mL (OTC) [Optimed; 31.92% Sul-Q-Nox]. Canada Veterinary-labeled product(s): 192 mg per mL (OTC) [generic]. Withdrawal times: U.S.
Withdrawal time Species Calves, cattle, chickens, turkeys Meat (days) 10

drinking water for more than twenty-four to thirty-six hours may result in reduced growth rate from decreased feed or water consumption.{R-14; 95} USP requirements: Preserve in tight, light-resistant containers. Label it to indicate that it is for veterinary use only. Contains the equivalent of the labeled concentration of sulfaquinoxaline, within 10%. Meets the requirements for Identication, Deliverable volume and pH (not less than 12){R-56}.
1

Not included in Canadian product labeling or product not commercially available in Canada.

Developed: 07/01/97 Interim revision: 07/10/98; 11/10/99; 06/30/02; 04/05/03

REFERENCES
1. Sulfadimethoxine package insert (Albon bolus, RocheUS), Rec 1/16/96. 2. Sulfadimethoxine product information (Albon 12.5% Drinking Water Solution, SmithKline BeechamUS), Rev 9/93, Rec 11/27/95. 3. Sulfadimethoxine product information (Albon Injection 40%, SmithKline BeechamUS), Rev 9/93, Rec 11/27/95. 4. Sulfadimethoxine product information (Albon Soluble Powder, SmithKline BeechamUS), Rev 9/93, Rec 11/27/95. 5. Sulfadimethoxine package label (Albon SR, RocheUS), Rec 1/16/96. 6. Sulfadimethoxine product information (Albon Tablets and Oral Suspension, SmithKline BeechamUS), Rev 9/93, Rec 11/27/95. 7. Sulfamethazine package insert (Calfspan, SolvayUS), Rec 10/19/95. 8. Sulfamethazine product information (Sulfamethazine bolus, PVLCanada), Rec 12/1/95. 9. Sulfamethazine package insert (Sodium Sulfamethazine Soluble Powder, DurvetUS), Rec 10/19/95. 10. Sulfamethazine package insert (Sustain III, DurvetUS), Rec 10/19/95. 11. Sulfamethazine package insert (Sulfasure SR, FermentaUS), Rec 10/27/95. 12. Sulfamethazine package insert (Sulmet Drinking Water Solution, CyanamidUS), Rec 11/13/95. 13. Sulfamethazine package insert (Sulmet Oblets, Fort DodgeUS), Rec 11/13/ 95. 14. Sulfaquinoxaline product information (31.95% Sul-Q-Nox, AlpharmaUS). In: Arrioja-Dechert A, editor. Compendium of veterinary products, CD ed. Port Huron, MI: North American Compendiums, Inc., 2002. 15. Sulfamethazine and sulfathiazole package insert (S-M-T, SanoCanada), Rec 10/27/95. 16. Sulfamethazine product information (Sodium sulfamethazine solution, PVLCanada), Rev 10/92, Rec 12/1/95. 17. Prescott JF, Baggott, JD, editors. Antimicrobial therapy in veterinary medicine, 2nd ed. Ames, IA: Iowa State University Press, 1993. p. 11926. 18. Appelgate J. Clinical pharmacology of sulfonamides. Mod Vet Pract 1983: 6679. 19. Riviere J, Craigmill AL, Sundlof SF. Handbook of comparative pharmacokinetics and residues of veterinary antimicrobials. Boca Raton, FL: CRC Press, Inc., 1991. p. 339407. 20. Plumb DC. Veterinary drug handbook. White Bear Lake, MN: PharmaVet Publishing, 1991. p. 5209. 21. Vree TB, Reekers-Ketting JJ, Hekster CA, et al. Acetylation and deacetylation of sulphonamides in dogs. J Vet Pharmacol Ther 1983; 6: 1536. 22. Mathis GF, McDougald LR. Drug responsiveness of eld isolates of chicken coccidia. Poultry Sci 1982; 61: 3845. 23. Watts JL, Yancey RJ, Salmon SA, et al. A 4-year survey of antimicrobial susceptibility trends for isolates from cattle with bovine respiratory disease in North America. J Clin Microbiol 1994 Mar; 32(3): 72531. 24. Barragry TB. Veterinary drug therapy. Baltimore, MD: Lea & Febiger, 1994. p. 295313. 25. Charm SE, Zoner E, Salter R. Conrmation of widespread sulfonamide contamination in Northeast United States market milk. J Food Prod 1988 Dec; 51(12): 9204. 26. Cribb AE, Spielberg SP. An in vitro investigation of predisposition to sulphonamide idiosyncratic toxicity in dogs. Vet Res Comm 1990; 14: 24152.

Note: Products are not labeled for use in chickens and turkeys laying eggs for human consumption, preruminant calves, or lactating dairy cattle. Canada
Withdrawal time Species Chickens, turkeys Meat (days) 12

Note: Products are not labeled for use in chickens and turkeys laying eggs for human consumption. Preparation of dosage form: Fresh solutions should be prepared daily. To help avoid toxic reactions, the medication should be evenly mixed in drinking water. Caution: People who handle this medication should avoid contact with eyes, skin, or clothing to prevent eye and skin burns. In case of contact, the areas affected should be ushed for at least fteen minutes; medical attention should be sought for eye exposure.{R-14} Keep out of the reach of children.{R-14} Packaging and storage: Store below 40 C (104 F), preferably between 15 and 30 C (59 and 86 F), unless otherwise specied by manufacturer. Protect from moisture.{R-15} Additional information: Animals should maintain an adequate water intake during the treatment period. Chickens: Prolonged administration of sulfaquinoxaline may result in deposition of crystals in the kidney or interference with normal blood clotting.{R-14; 95} Sulfaquinoxaline levels of greater than 0.012% in 2003 Thomson MICROMEDEX

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SULFONAMIDES VeterinarySystemic 223

27. Cribb AE. Idiosyncratic reactions to sulfonamides in dogs. J Am Vet Med Assoc 1989 Dec; 195(11): 1615. 28. Collins BK, Moore CP, Hagee JH. Sulfonamide-associated keratoconjunctivitis sicca and corneal ulceration in a dysuric dog. J Am Vet Med Assoc 1986 Oct; 189(8): 9246. 29. Sansom J, Barnett KC, Long RD. Keratoconjunctivitis sicca in the dog associated with the administration of salicylazosulphapyridine (sulphasalazine). Vet Rec 1985; 116: 3913. 30. Morgan RV, Bachrach A. Keratoconjunctivitis sicca associated with sulfonamide therapy in dogs. J Am Vet Med Assoc 1982; 180: 4324. 31. Roudaut B, Moretain JP. Sulphonamide residues in milk of dairy cows following intravenous injection. Food Addit Contam 1990; 7(4): 52733. 32. Paulson GD, Feil VJ, Giddings JM, et al. Lactose conjugation of sulphonamide drugs in the lactating dairy cow. Xenobiotica 1992; 22(8): 92539. 33. Van Gogh H, Van Deurzen JM, Van Duin CTM, et al. Inuence of gestation on the pharmacokinetics of four sulphonamides in goats. Res Vet Sci 1990; 48: 1527. 34. Nielsen P, Rasmussen F. Half-life, apparent volume of distribution, and proteinbinding for some sulphonamides in cows. Res Vet Sci 1977; 22: 2058. 35. Van Gogh H. Pharmacokinetics of nine sulphonamides in goats. J Vet Pharmacol Ther 1980; 3: 6981. 36. USP dictionary of USAN and international drug names, 2002 ed. Rockville, MD: The United States Pharmacopeial Convention, Inc., 2002. 37. Nouws JFM, Firth EC, Vree TB, et al. Pharmacokinetics and renal clearance of sulfamethazine, sulfamerazine, and sulfadiazine and their N4-acetyl and hydroxy metabolites in horses. Am J Vet Res 1987 Mar; 48(3): 392402. 38. Boxenbaum HG, Fellig J, Hansen LJ, et al. Pharmacokinetics of sulphadimethoxine in cattle. Res Vet Sci 1977; 23: 248. 39. Baggot JD, Ludden TM, Powers TE. The bioavailability, disposition kinetics and dosage of sulphadimethoxine in dogs. Can J Comp Med 1976 Jul; 40: 3107. 40. Ladefoged O, Christiansen SE. A computer method for the calculation of pharmacokinetic parameters after repetitive drug administration, and its use in calculations of kinetic parameters of sulphadimethoxine in pigs and rabbits. J Vet Pharmacol Ther 1979; 2: 959 41. Sams RA, Baggot JD. Bioavailability, disposition kinetics, and dosage of sulfadimethoxine in dogsa correction. Can J Comp Med 1977 Oct; 41(4): 47980. 42. Baggot JD. Pharmacokinetics of sulfadimethoxine in cats. Aust J Exp Biol Med Sci 1977; 55(6): 66370. 43. Bajwa RS, Singh J. Studies on the levels of sulphadimethoxine and sulphamethoxypyridazine in blood of poultry. Indian J Anim Sci 1977 Sep; 47(9): 54953. 44. Bourne DWA, Bialer M, Dittert LW, et al. Disposition of sulfadimethoxine in cattle: inclusion of protein binding factors in a pharmacokinetic model. J Pharm Sci 1981 Sep; 79(9): 106872. 45. Righter JF, Showalter DH, Teske RH. Pharmacokinetic study of sulfadimethoxine depletion in suckling and growing pigs. Am J Vet Res 1979; 40(5): 7135. 46. Preusch PC, Hazelett SE, Lemasters KK. Sulfaquinoxaline inhibition of vitamin K epoxide and quinone reductase. Arch Biochem Biophys 1989 Feb 15; 269(1): 1824. 47. Daft BM, Bickford AA, Hammarlund MA. Experimental and eld sulfaquinoxaline toxicosis in leghorn chickens. Avian Dis 1989; 33: 304. 48. Brown MJ. Adverse reactions to sulfaquinoxaline in coyote pups. J Am Vet Med Assoc 1982; 181(11): 141920. 49. Osweiler GD, Green RA. Canine hypoprothrombinemia resulting from sulfaquinoxaline administration. Vet Hum Tox 1978 Jun; 20(3): 1902. 50. Neer TM, Savant RL. Hypoprothrombinemia secondary to administration of sulfaquinoxaline to dogs in a kennel setting. J Am Vet Med Assoc 1992 May; 200(9): 13445. 51. Littleeld NA, Gaylor DW, Blackwell BN, et al. Chronic toxicity/carcinogenicity studies of sulphamethazine in B6C3F1 mice. Food Chem Toxicol 1989; 27(7): 45563. 52. Paulson G, Struble C, Mitchell A. Comparative metabolism of sulfamethazine [4-Amino-N-(4,6 dimethyl-2-pyrimidinyl)benzenesulfonamide] in the rat, chicken, pig, and sheep. 5th International Congress of Pesticide Chemistry 1983: 37580. 53. Witkamp RF, Yun HI, vant Klooster GA, et al. Comparative aspects and sex differentiation of plasma sulfamethazine elimination and metabolite formation in rats, rabbits, dwarf goats, and cattle. Am J Vet Res 1992 Oct; 53(10): 18305. 54. Paulson GD. The effect of dietary nitrite and nitrate on the metabolism of sulphamethazine in the rat. Xenobiotica 1986; 16(1): 5361. 55. Khan FH, Nawaz M, Anwar-Ul-Hasson S. Pharmacokinetics of sulfamethazine in buffaloes. Ann Rech Vet 1980; 11(1): 912. 56. The United States pharmacopeia. The national formulary. USP 26th revision (January 1, 2003). NF 21st ed (January 1, 2003). Rockville, MD: The United States Pharmacopeial Convention, Inc., 2002. p. 1732, 1733, 1742, 2582, 2583. 57. Wilson RC, Hammond LS, Clark CH, et al. Bioavailability and pharmacokinetics of sulfamethazine in the pony. J Vet Pharmacol Ther 1989; 12: 99102. 58. Srivastava AK, Rampal S. Disposition kinetics and dosage regimen of sulphamethazine in sheep (ovis aries). Br Vet J 1990; 146: 23942. 59. Siddique AB, Simunek J. Blood-brain barrier to sulfamethazine in rat and sheep fetus. Acta Vet Brno 1977; 46: 1019. 60. Siddique AB, Simunek J. Placental transfer of sulfamethazine in sheep at different stages of gestation. Acta Vet Brno 1977; 46: 95100. 61. Bourne DWA, Bevill RG, Sharma RM, et al. Disposition of sulfonamides in food-producing animals: pharmacokinetics of sulfamethazine in lambs. Am J Vet Res 1977; 38(7): 96772. 62. Bulgin MS, Lane VM, Archer TE, et al. Pharmacokinetics, safety, and tissue residues of sustained-release sulfamethazine in sheep. J Vet Pharmacol Ther 1991; 14: 3645. 63. Abdel Hamid Youssef S, El-Gendi AYI, El-Sayed MGA, et al. Some pharmacokinetic and biochemical aspects of sulphadiazine and sulphadimidine in ewes. J Vet Pharmacol Ther 1981; 4: 17382. 64. Bevill RF, Rajinder MS, Meachum SH, et al. Disposition of sulfonamides in food-producing animals: concentrations of sulfamethazine and its metabolites in plasma, urine, and tissues of lambs following intravenous administration. Am J Vet Res 1977 Jul; 30(7): 8737. 65. Righter HF, Showalter DH, Teske RH. Comparative plasma kinetics of orally administered sulfamethazine in clinically parasitized and parasitism-treated lambs. J Vet Pharmacol Ther 1979; 2: 2038. 66. Sweeney RW, Bordalaye PC, Smith CM, et al. Pharmacokinetic model for predicting sulfamethazine disposition in pigs. Am J Vet Res 1993 May; 54(5): 7504. 67. Duffee NE, Bevill RF, Thurman JC, et al. Pharmacokinetics of sulfamethazine in male, female, and castrated male swine. J Vet Pharmacol Ther 1984; 7: 20311. 68. Ashworth RB, Epstein RL, Thomas MH, et al. Sulfamethazine blood/tissue correlation study in swine. Am J Vet Res 1986 Dec; 47(12): 2596603. 69. Klasco RK, editor. USP DI Drug information for the healthcare professional. Volume I. Greenwood Village, CO: MICROMEDEX, Inc.; 2003. 70. Van Poucke LSG, Van Peteghem CH. Pharmacokinetic and tissue residues of sulfathiazole and sulfamethazine in pigs. L Food Protect 1994 Sep; 57(9): 796801. 71. Struble LB, Paulson GD. The metabolism and deamination of [14C]-sulphamethazine in a germ-free pig: the inuence of nitrate and nitrite. Food Chem Toxicol 1988 May; 260: 797801. 72. Mitchell AD, Paulson GD, Saylskie RG. Steady state kinetics of 14Csulfamethazine {4-amino-N-(4,6-dimethyl-2-pyrimidinyl)benzene[U-14C]sulfonamide} metabolism in swine. Drug Metab Dispos 1986; 14(2): 15560. 73. Mitchell AD, Paulson GD. Depletion kinetics of 14C-sulfamethazine in swine. Drug Metab Dispos 1986; 14(2): 1617. 74. Whipple DM, Samuelson G, Heath GE, et al. Tissue residue depletion and recycling of sulfamethazine in swine. J Am Vet Med Assoc 1980; 176(12): 134852. 75. Kuiper HA, Aerts RMC, Haagsma N, et al. Case study of the depletion of sulfamethazine from plasma and tissues upon oral administration to piglets affected with atrophic rhinitis. J Agric Food Chem 1988; 36: 8225. 76. Church TL, Janzen ED, Sisodia CS, et al. Blood levels of sulfamethazine achieved in beef calves on medicated drinking water. Can Vet J 1979; 20: 41 4. 77. Paulson GD, Feil VJ, Zaylskie RG, et al. Depletion of residues from milk and blood of cows dosed orally and intravenously with sulfamethazine. J Assoc Off Anal Chem 1994; 77(4): 895900. 78. Nouws JFM, Mevius D, Vree TB, et al. Pharmacokinetics, metabolism, and renal clearance of sulfadiazine, sulfamerazine, and sulfamethazine and of their N4-acetyl and hydroxy metabolites in calves and cows. Am J Vet Res 1988 Jul; 49(7): 105965. 79. Nouws JFM, Vree TB, Baakman M, et al. Age and dosage dependency in the plasma disposition and the renal clearance of sulfamethazine and its N4-acetyl and hydroxy metabolites in calves and cows. Am J Vet Res 1986 Mar; 47(3): 6429. 80. Murphy J, Wong M, Ray WH. The advantages of a timed-release sulfamethazine bolette for calves. Vet Med 1986 Sep; 8(9): 8825.

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81. Miller GE, Stowe CM, Jegers A, et al. Blood concentration studies of a sustained release form of sulfamethazine in cattle. J Am Vet Med Assoc 1969; 154: 7738. 82. Bevill RF, Dittert LW, Bourne DWA. Disposition of sulfonamides in foodproducing animals IV: pharmacokinetics of sulfamethazine in cattle following administration of an intravenous dose and 3 oral dosage forms. J Pharm Sci 1977 May; 66(5): 61923. 83. Bajwa RS, Singh J. Studies on the effect of prolonged administration of sulphadimethoxine and sulphamethoxypyridazine on the growth rate and hematology of chicks. Indian J Anim Sci 1977 Oct; 47(10): 6923. 84. Koritz D, Bourne DWA, Dittert LW, et al. Disposition of sulfonamides in foodproducing animals: pharmacokinetics of sulfathiazole in sheep. Am J Vet Res 1977; 38(7): 97982. 85. Panel comment, Rec 6/20/96. 86. National Committee for Clinical Laboratory Standards publication. Villanova, PA: NCCLS, 1983; 3(14): M2T3. 87. Sulfachlorpyridazine package label (Vetisulid injection, SolvayUS), Rec 11/ 3/95. 88. Sulfachlorpyridazine package label (Vetisulid boluses, SolvayUS), Rec 11/3/ 95. 89. Sulfachlorpyridazine package label (Vetisulid powder, SolvayUS), Rec 11/ 3/95. 90. Duran SP, Valera RC, Manzano JV, et al. Comparative in-vitro susceptibility of Bacteroides and Fusobacterium isolated from footrot in sheep to 28 antimicrobial agents. J Vet Pharmacol Ther 1991; 14: 18592. 91. Sulfadimethoxine package insert (S-125, SanoCanada), Rec 10/27/95. 92. Arrioja-Dechert A, editor. Compendium of veterinary products, CD ed. Port Huron, MI: North American Compendiums, Inc., 2002. 93. Stowe CM, Sisodia CS. The pharmacologic properties of sulfadimethoxine in dairy cattle. Am J Vet Res 1963; 24: 52535. 94. Reynolds JEF, editor. Martindale, the extra pharmacopeia. 29th ed. London: The Pharmaceutical Press, 1989. p. 301. 95. Sulfaquinoxaline package label (34% Sul-Q-Nox, RussellUS), Rec 10/23/95. 96. Sulfamethazine and sulfathiazole combination product information (Powder 21, PVLCanada), Rev 9/94, Rec 12/1/95. 97. Sulfamethazine, sulfanilamide, and sulfathiazole product information (Triple sulfa bolus, PVLCanada), Rev 8/92, Rec 12/1/95. 98. AVC (Marion Merrell Dow), Rev 4/91. In: PDR Physicians desk reference. 49th ed. 1995. Montvale, NJ: Medical Economics Data Production Company, 1995. p. 13945. 99. Reece RL, Barr DA, Gould JA. Poisoning in a chicken ock caused by sulphachloropyrazine. Vet Rec 1986; 119: 3245. 100. Hall IA, Campbell KL, Chambers MD, et al. Effect of trimethoprim/ sulfamethoxazole on thyroid function in dogs with pyoderma. J Am Vet Med Assoc 1993 Jun 15; 202(12): 195962. 101. Panciera DL, Post K. Effect of oral administration of sulfadiazine and trimethoprim in combination on thyroid function in dogs. Can J Vet Res 1992; 56: 34952. 102. Rasmussen F. Mammary excretion of sulphonamides. Acta Pharmacol Toxicol 1958; 15: 13948. 103. Panel comment, 5/8/96. 104. Extra-label use of drugs in food-producing animals (Compliance Policy Guide 7125.06). Rev 7/20/92. Food and Drug Administration Center for Veterinary Medicine. 105. Langston VC, Davis LE. Factors to consider in the selection of antimicrobial drugs for therapy. Compend Contin Educ Pract Vet 1989 Mar; 11(3): 355 63. 106. Panel comment, 5/21/96. 107. Panel comment, 5/23/96. 108. Panel comment, 5/21/96.

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TETRACYCLINES VeterinarySystemic 225

TETRACYCLINES VeterinarySystemic
This monograph includes information on the following: Chlortetracycline; Doxycycline; Oxytetracycline; Tetracycline. Some commonly used brand names are: For veterinary-labeled products
Agrimycin 100 [Oxytetracycline] Agrimycin 200 [Oxytetracycline] Agrimycin-343 [Oxytetracycline] Alamycin LA [Oxytetracycline] AmTech Chlortetracycline HCL Soluble Powder [Chlortetracycline] AmTech Maxim-100 [Oxytetracycline] AmTech Maxim-200 [Oxytetracycline] AmTech Oxytetracycline HCL Soluble Powder [Oxytetracycline] AmTech Oxytetracycline HCL Soluble Powder-343 [Oxytetracycline] AmTech Tetracycline Hydrochloride Soluble Powder-324 [Tetracycline] Aureomycin 110G [Chlortetracycline] Aureomycin 220G [Chlortetracycline] Aureomycin 50 Granular [Chlortetracycline] Aureomycin 90 Granular [Chlortetracycline] Aureomycin 100 Granular [Chlortetracycline] Aureomycin Soluble Powder [Chlortetracycline] Aureomycin Soluble Powder Concentrate [Chlortetracycline] Aureomycin Uterine Oblets [Chlortetracycline] Biomycin 200 [Oxytetracycline] Calf Scour Bolus Antibiotic [Tetracycline] Chlor 50 [Chlortetracycline] Chlor 100 [Chlortetracycline] ChlorMax 50 [Chlortetracycline] Chlorosol-50 [Chlortetracycline] CLTC 100 MR [Chlortetracycline] CTC 50 [Chlortetracycline] CTC Soluble Powder Concentrate [Chlortetracycline] Duramycin 10 [Tetracycline] Duramycin 72-200 [Oxytetracycline] Duramycin 100 [Oxytetracycline] Duramycin-324 [Tetracycline] Foul Brood Mix [Oxytetracycline] Geomycin 200 [Oxytetracycline] Kelamycin [Oxytetracycline] Liquamycin LA-200 [Oxytetracycline] Maxim-200 [Oxytetracycline] Onycin 62.5 [Tetracycline] Onycin 250 [Tetracycline] Onycin 1000 [Tetracycline] OT 200 [Oxytetracycline] OTC 50 [Oxytetracycline] OXTC 50 [Oxytetracycline] OXTC 100 [Oxytetracycline] OXTC 200 [Oxytetracycline] Oxytet-250 Concentrate [Oxytetracycline] Oxytetra-A [Oxytetracycline] Oxytetracycline 50 [Oxytetracycline] Oxytetracycline 100 [Oxytetracycline] Oxytetracycline 200 [Oxytetracycline] Oxytetracycline 100LP [Oxytetracycline] Oxy Tetra Forte [Oxytetracycline] Oxytetramycin 100 [Oxytetracycline] Oxytet-25-S [Oxytetracycline] Oxytet Soluble [Oxytetracycline] Oxytet-SP [Oxytetracycline] Oxytet-343 Water Soluble Powder [Oxytetracycline] Oxyvet 200 LA [Oxytetracycline] Oxyvet 100 LP [Oxytetracycline] Panmycin Aquadrops [Tetracycline] Oxysol-1000 [Oxytetracycline] Pennchlor 50G [Chlortetracycline] Pennchlor 90G [Chlortetracycline] Pennchlor 100 Hi-Flo Meal [Chlortetracycline] Pennchlor 50 Meal [Chlortetracycline] Pennchlor 70 Meal [Chlortetracycline] Pennchlor 100 MR [Chlortetracycline] Pennchlor 64 Soluble Powder [Chlortetracycline] Pennox 100 Hi-Flo Meal [Oxytetracycline] Pennox 200 Hi-Flo Meal [Oxytetracycline] Pennox 200 Injectable [Oxytetracycline] Pennox 50 Meal [Oxytetracycline] Pennox 100-MR [Oxytetracycline] Pennox 343 Soluble Powder [Oxytetracycline] PolyOtic Soluble Powder [Tetracycline] Promycin 100 [Oxytetracycline] Solu-Tet [Tetracycline] Solu-Tet 324 [Tetracycline] Terramycin 50 [Oxytetracycline] Terramycin 100 [Oxytetracycline] Terramycin 200 [Oxytetracycline] Terramycin-50 [Oxytetracycline] Terramycin-100 [Oxytetracycline] Terramycin-200 [Oxytetracycline] Terramycin-Aqua [Oxytetracycline] Terramycin 100 For Fish [Oxytetracycline] Terramycin Scours Tablets [Oxytetracycline] Terramycin Soluble Powder [Oxytetracycline] Terramycin-343 Soluble Powder [Oxytetracycline] Terra-Vet 100 [Oxytetracycline] Terra-Vet Soluble Powder [Oxytetracycline] Oxy-110 [Oxytetracycline] Oxy-220 [Oxytetracycline] Oxy 250 [Oxytetracycline] Oxy-440 [Oxytetracycline] Oxy 1000 [Oxytetracycline] Oxybiotic-100 [Oxytetracycline] Oxybiotic-200 [Oxytetracycline] Oxy 500 Calf Bolus [Oxytetracycline] Oxy 1000 Calf Bolus [Oxytetracycline] Oxycure 100 [Oxytetracycline] Oxycure 200 [Oxytetracycline] Oxy LA [Oxytetracycline] Oxy LP [Oxytetracycline] Oxy-Mycin 100 [Oxytetracycline] Oxy-Mycin 200 [Oxytetracycline] Oxymycine LA [Oxytetracycline] Oxymycine LP [Oxytetracycline] Oxyshot LA [Oxytetracycline] Oxysol-62.5 [Oxytetracycline] Oxysol-110 [Oxytetracycline] Oxysol-220 [Oxytetracycline] Oxysol-250 [Oxytetracycline] Oxysol-440 [Oxytetracycline] Terra-Vet Soluble Powder 343 [Oxytetracycline] Tet-324 [Tetracycline] Tetra 55 [Tetracycline] Tetra 250 [Tetracycline] Tetra 1000 [Tetracycline] Tetra 4000 [Tetracycline] Tetra Bac 324 [Tetracycline] Tetrabol [Tetracycline] Tetracycline 250 [Tetracycline] Tetracycline 1000 [Tetracycline] Tetracycline 250 Concentrate Soluble Powder [Tetracycline] Tetracycline 62.5 Soluble Powder [Tetracycline] Tetradure LA 300 [Oxytetracycline] Tetraject LA [Oxytetracycline] Tetraject LP [Oxytetracycline] Tetramed 250 [Tetracycline] Tetramed 1000 [Tetracycline] Tetrasol Soluble Powder [Tetracycline] Tetravet-CA [Oxytetracycline] Tet-Sol 10 [Tetracycline] Tet-Sol 324 [Tetracycline] Tetroxy-100 [Oxytetracycline] Tetroxy HCA Soluble Powder [Oxytetracycline] 5-Way Calf Scour Bolus [Tetracycline]

For human-labeled products

Achromycin V [Tetracycline] Alti-Doxycycline [Doxycycline] Apo-Doxy [Doxycycline] Apo-Doxy-Tabs [Doxycycline] Apo-Tetra [Tetracycline] Doryx [Doxycycline] Doxycin [Doxycycline] Doxytec [Doxycycline] Novo-Doxylin [Doxycycline] Novo-Tetra [Tetracycline] Nu-Doxycycline [Doxycycline] Nu-Tetra [Tetracycline] Vibramycin [Doxycycline] Vibra-Tabs [Doxycycline] Vibra-Tabs C-Pak [Doxycycline]

Note: For a listing of dosage forms and brand names by country availability, see the Dosage Forms section(s).

CATEGORY:
Antibacterial (systemic); antiprotozoal; antirickettsial.

INDICATIONS
Note: Bracketed information in the Indications section refers to uses that either are not included in U.S. product labeling or are for products not commercially available in the U.S.

GENERAL CONSIDERATIONS
The tetracyclines are broad-spectrum antibiotics with activity against gram-positive and gram-negative bacteria, including some anaerobes. They are also active against chlamydia, mycoplasmas, some protozoa{R-28; 133}, and several rickettsiae, including Anaplasma, Ehrlichia, and Haemobartonella. The activity range of the tetracyclines also includes Escherichia coli, Klebsiella species, Pasteurella species, Salmonella species, Staphylococcus species, and Streptococcus species{R-4}. Susceptibility testing has demonstrated that some coliforms, mycoplasma, streptococci, and staphylococci have developed resistance to tetracyclines{R-21; 150}. However, the breakpoints used to classify these organisms as susceptible or resistant are not validated for animal indications. Susceptibility testing should not be the sole basis for selecting tetracyclines for therapy{R-65}. All rights reserved

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226 TETRACYCLINES VeterinarySystemic

ACCEPTED
Abortion, vibrionic (prophylaxis) Sheep: Chlortetracycline for medicated feed{R-16; 152} is indicated to aid in reduction of the incidence of vibrionic abortion caused by susceptible Campylobacter fetus. Abscesses, cervical (prophylaxis)1Pigs: Chlortetracycline for medicated feed{R-152} is indicated for reduction of the incidence of cervical abscesses caused by susceptible organisms. Abscesses, hepatic (prophylaxis)1Cattle: Chlortetracycline for medicated feed{R-16; 152} is indicated as an aid in the prevention of hepatic abscesses in cattle. Actinobacillosis (treatment)1Cattle: Oxytetracycline injection{R-45} is indicated in the treatment of actinobacillosis (wooden tongue) caused by susceptible Actinobacillus lignieresii. Anaplasmosis (treatment)1Cattle: Chlortetracycline for medicated feed{R-16; 152} is indicated in the control of active infection caused by susceptible Anaplasma marginale. Diphtheria (treatment)1Cattle: Oxytetracycline injection{R-24; 45} is indicated in the treatment of diphtheria (necrotic laryngitis, necrotic necrophorus stomatitis) caused by susceptible Fusobacterium necrophorum. Enteritis, bacterial (treatment)The treatment of enteritis should be dependent on a specic diagnosis and knowledge of pathogen susceptibility to tetracyclines. Some pathogens associated with enteritis, such as Escherichia coli, are found to be resistant to the tetracyclines. Calves: Chlortetracycline soluble powder1, oxytetracycline tablets{R60} , and tetracycline boluses and soluble powder{R-1} are indicated in the control of bacterial enteritis (scours) caused by susceptible E. coli. Chlortetracycline for medicated feed{R-16; 152} and soluble powder; oxytetracycline for medicated feed{R-117}, injection, soluble powder, and tablets1{R-23; 24; 60; 61}; and tetracycline bolus and soluble powder{R-1; 18} are indicated in the treatment of bacterial enteritis caused by susceptible E. coli and Salmonella species. Cattle: Chlortetracycline for medicated feed1{R-16; 152} and oxytetracycline for medicated feed1{R-117}, injection1{R-45}, and soluble powder{R-61} are indicated in the treatment of bacterial enteritis caused by susceptible E. coli and Salmonella{R-11}. Pigs: Chlortetracycline soluble powder1{R-17}, oxytetracycline soluble powder{R-11; 54}, and tetracycline powder for oral solution{R-18} are indicated in the control and treatment of bacterial enteritis caused by susceptible E. coli. Chlortetracycline for medicated feed{R-16; 152} and oxytetracycline injection{R-24; 45} and for medicated feed{R-117} are indicated in the treatment of bacterial enteritis (scours) caused by susceptible E. coli and Salmonella. Sheep: Oxytetracycline for medicated feed1{R-117} and soluble powder{R-54; 61} and [tetracycline soluble powder]{R-18} are indicated in the treatment of enteritis caused by susceptible organisms. Turkeys, growing: Chlortetracycline soluble powder1{R-17} and oxytetracycline soluble powder{R-11; 54} are indicated in the control of susceptible organisms involved in the development of enteritis (bluecomb). Turkeys: Chlortetracycline for medicated feed{R-16; 152} and [powder for oral solution]{R-17} and tetracycline soluble powder{R-18; 19} are indicated in the control and treatment of enteritis caused by susceptible organisms. Oxytetracycline for medicated feed{R-117} is indicated in the treatment of susceptible E. coli involved in the development of enteritis (bluecomb).
1

[Chickens]: Oxytetracycline soluble powder{R-54} and chlortetracycline for medicated feed are indicated in the treatment of susceptible E. coli involved in the development of enteritis. [Lambs]: Oxytetracycline for medicated feed{R-26} is indicated in the reduction of bacterial enteritis in creep-fed suckling lambs. Escherichia coli infections (treatment)1Chickens: Chlortetracycline for medicated feed{R-16; 115; 152} is indicated as an aid in reducing mortality due to E. coli infections. Feed efciency, improved; or Weight gain, increased rateCalves1, cattle1, chickens, pigs, sheep1, and turkeys: Chlortetracycline for medicated feed{R-16; 152} and oxytetracyline for medicated feed1{R-117} are indicated for growth promotion and feed efciency. Foul brood (treatment)Bees: Oxytetracycline for medicated feed{R-117} and soluble powder{R-61; 117} are indicated in the treatment of American and European foul brood caused by susceptible organisms. Fowl cholera (prophylaxis)Chickens: Oxytetracycline for medicated feed{R-122} and soluble powder1{R-61; 122} are indicated in the prevention of fowl cholera caused by susceptible organisms. Fowl cholera (treatment) Chickens: Chlortetracycline soluble powder1 and oxytetracycline for medicated feed1{R-117} and soluble powder{R-11} are indicated in the control of mortality from fowl cholera caused by susceptible Pasteurella multocida{R-80}. [Tetracycline soluble powder{R-18} is indicated in the treatment of fowl cholera caused by susceptible organisms.] Ducks1: Chlortetracycline for medicated feed{R-152} is indicated as an aid in the control and treatment of fowl cholera caused by susceptible Pasteurella multocida. Furunculosis (treatment)Salmonids (salmon and trout): Oxytetracycline for medicated feed{R-62; 124} is indicated in the control of furunculosis caused by susceptible Aeromonas salmonicida. Gaffkemia (treatment)Lobsters: Oxytetracycline for medicated feed{R-27; 124} is indicated in the treatment of gaffkemia caused by susceptible Aerococcus viridans. Gastroenteritis (treatment)1Cats and dogs: Tetracycline oral suspension{R-4} is indicated in the treatment of bacterial gastroenteritis, but use should be reserved for treatment of organisms known to be susceptible. Hemorrhagic septicemia, bacterial (treatment)1Catsh and salmonids: Oxytetracycline for medicated feed{R-62; 124} is indicated in the control of hemorrhagic septicemia caused by susceptible Aeromonas hydrophila, A. sobia, and Pseudomonas species{R-173}. Hexamitiasis (treatment)Turkeys: Chlortetracycline for medicated feed1{R-16; 152} and oxytetracycline for medicated feed1{R-117} are indicated in the control of hexamitiasis, and oxytetracycline soluble powder1{R-11; 61} and [tetracycline soluble powder]{R-18} are indicated in the treatment of hexamitiasis caused by susceptible Hexamita meleagridis. Keratoconjuntivitis, infectious (treatment)Cattle: Long-acting oxytetracycline injection{R-45} is indicated in the treatment of keratoconjunctivitis caused by susceptible Moraxella bovis. Leptospirosis (treatment) Pigs: Chlortetracycline for medicated feed1{R-16; 152} and oxytetracycline for medicated feed{R-122} are indicated to aid in reducing the shedding of leptospirosis and the incidence of abortion. Oxytetracycline for medicated feed is indicated as an aid in the reduction of abortion and urinary shedding of leptospirosis, production of

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TETRACYCLINES VeterinarySystemic 227 healthier newborn pigs, and maintenance of weight gains in the presense of leptospirosis{R-122}. Oxytetracycline injection{R-24; 45} and soluble powder{R-11} are indicated in the treatment of leptospirosis caused by susceptible Leptospira pomona. Oxytetracycline can reduce the incidence of abortions and shedding of leptospira;{R-11} however, it can be ineffective in eliminating the organism{R-113}. Cattle: Oxytetracycline injection{R-24; 45} is indicated in the treatment of leptospirosis caused by susceptible Leptospira pomona. Paratyphoid (treatment)1Turkeys, less than 4 weeks of age: Chlortetracycline for medicated feed{R-16; 152} is indicated as an aid in reducing mortality from paratyphoid infection caused by susceptible Salmonella typhimurium. Pneumonia, bacterial (prophylaxis)Cattle: Oxytetracycline for medicated feed1{R-117; 122} is indicated in the prevention of pneumonia and as an aid in the reduction of losses due to bovine respiratory disease complex. Pneumonia, bacterial (treatment) Calves: Chlortetracycline soluble powder1, oxytetracycline tablets1{R-60}, and tetracycline boluses{R-1} are indicated in the control of pneumonia and bovine respiratory disease complex caused by susceptible organisms, including Pasteurella species. Chlortetracycline soluble powder; oxytetracycline injection, soluble powder, and tablets1{R-60; 61}; and tetracycline boluses and soluble powder{R-1; 18} are indicated in the treatment of pneumonia caused by susceptible organisms, including Pasteurella species. However, due to resistance{R-51; 171; 180} by pathogens, the tetracyclines may no longer be effective in the treatment of some types of bacterial pneumonia. Cattle: Chlortetracycline for medicated feed{R-152} is indicated in the control1 and treatment of pneumonia caused by susceptible organisms. Oxytetracycline{R-24; 45; 61} is indicated in the treatment of pneumonia and shipping fever complex caused by susceptible Pasteurella and Haemophilus species. Increasing resistance to tetracyclines by strains of organisms involved in bovine pneumonia is reported{R-51; 171; 180}. Pigs: Chlortetracycline soluble powder1{R-17} is indicated in the control of pneumonia caused by susceptible Actinobacillus pleuropneumoniae (Haemophilus species), Pasteurella species, and Klebsiella species. Chlortetracycline for medicated feed1{R-152} and oxytetracycline soluble powder are indicated in the treatment of pneumonia caused by susceptible Pasteurella multocida. Chlortetracycline soluble powder{R-17}, oxytetracycline injection{R-24; 45}, and tetracycline soluble powder{R-1; 18} are indicated in the treatment of pneumonia caused by susceptible Actinobacillus pleuropneumonia (Haemophilus species), Klebsiella, and Pasteurella species. Increasing resistance to tetracycline by strains of organisms involved in porcine pneumonia is reported{R-50}. Sheep: Oxytetracycline for medicated feed1{R-117}, [injection]{R-24; 121}, and soluble powder{R-6; 13}, and [tetracycline soluble powder]{R-18} are indicated in the treatment of pneumonia caused by susceptible organisms. Pododermatitis (treatment)Cattle: Long-acting oxytetracycline injection{R-24; 45} is indicated in the treatment of pododermatitis (foot rot) caused by susceptible Fusobacterium necrophorum. Signs may not be completely resolved by oxytetracycline alone and other treatment or surgery may be required. Pseudomonas disease (treatment)1Catsh and salmonids: Oxytetracycline for medicated feed{R-62} is indicated in the control of pseudomonas disease caused by susceptible organisms. Psittacosis (treatment)1Cockatoos, macaws, and parrots: Chlortetracycline for medicated feed{R-152} is indicated in the treatment of psittacosis caused by susceptible Chlamydia psittaci. Respiratory disease, bacterial, chronic (prophylaxis)Chickens: Oxytetracycline for medicated feed{R-122} is indicated in the prevention of chronic respiratory disease caused by susceptible organisms. Respiratory disease, bacterial, chronic (treatment)Chickens: Chlortetracycline for medicated feed and soluble powder1{R-16; 17; 152}, oxytetracycline for medicated feed1 and soluble powder{R-11; 22}, and tetracycline soluble powder{R-18; 127} are indicated in the control of respiratory disease, including air sac disease, caused by susceptible Mycoplasma gallisepticum and E. coli. Chlortetracycline for medicated feed{R-16; 115} and powder for oral solution{R-17} are indicated in the treatment of chronic respiratory disease caused by susceptible organisms. Skeletal tissue marking1Salmon, Pacic: Oxytetracycline for medicated feed{R-117} is indicated to mark skeletal tissue in Pacic salmon. Skin and soft tissue infections (treatment)1Cattle:{R-45} Oxytetracycline injection is indicated in the treatment of wounds infected by susceptible Staphylococcus species or Streptococcus species. Synovitis, infectious (treatment)Chickens and turkeys: Chlortetracycline for medicated feed1{R-16; 152} and soluble powder1{R-17}, oxytetracycline for medicated feed{R-117} and soluble powder{R-11}, and tetracycline soluble powder{R-3} are indicated in the control of infectious synovitis caused by susceptible Mycoplasma synoviae. Chlortetracycline powder for oral solution{R-17} is indicated in the treatment of infectious synovitis caused by susceptible M. synoviae. Ulcer disease (treatment)Salmonids (salmon, trout): Oxytetracycline for medicated feed{R-62; 124} is indicated in the control of ulcer disease caused by susceptible Haemophilus piscium. Urinary tract infections (treatment)1Cats and dogs: Tetracycline oral suspension{R-4} is indicated in the treatment of urinary tract infections caused by susceptible Staphylococcus species and E. coli. Also, concentrations of tetracycline in urine are high enough to be effective against Pseudomonas species{R-150}. Uterine infections, acute (treatment) Cattle: Oxytetracycline injection{R-24; 45} is indicated in the treatment of acute metritis caused by susceptible strains of Staphylococcus and Streptococcus species. [Pigs]: Oxytetracycline injection{R-24} is indicated in the treatment of acute metritis caused by susceptible organisms. [Sheep]: Oxytetracycline injection{R-24; 121} is indicated in the treatment of uterine infections. [Arthritis, bacterial (treatment)]Cattle and sheep: Oxytetracycline injection{R-24; 25} is indicated in the treatment of septic arthritis (joint ill) caused by susceptible organisms. [Atrophic rhinitis (treatment)]Pigs: Oxytetracycline for medicated feed{R-122} is indicated for use as an aid in maintaining weight gain in pigs infected with atrophic rhinitis. [Blackleg (treatment)]; or [Malignant edema (treatment)]Cattle: Oxytetracycline injection{R-24; 25; 121} is indicated in the treatment of infections caused by susceptible Clostridia species.

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228 TETRACYCLINES VeterinarySystemic [Bloat]Cattle: Oxytetracycline for medicated feed{R-26} is indicated as an aid in reducing the incidence of bloat in young cattle on pasture and in feedlots. [Cold water disease (treatment)]Salmonids:{R-124} Oxytetracycline for medicated feed is indicated in the treatment of cold water disease caused by susceptible Cytophaga psychrophilia. [Columnaris disease (treatment)]Salmonids: Oxytetracycline for medicated feed{R-124} is indicated in the treatment of columnaris disease caused by susceptible Chondrococcus (Flexibacter) columnaris. [Egg production, increased]; or [Egg hatchability, increased]Chickens and turkeys: Chlortetracycline for medicated feed is indicated for use in increasing egg production or egg hatchability. [Ehrlichiosis, equine (treatment)]1Horses: Oxytetracycline is used in the treatment of ehrlichiosis caused by susceptible Ehrlichia equi{R-46; 138}. [Enteric redmouth disease (treatment)]Salmonids: Oxytetracycline for medicated feed{R-124} is indicated in the treatment of enteric redmouth disease caused by susceptible Yersinis ruckeri. [Enterotoxemia (treatment)]Lambs: Chlortetracycline for medicated feed and oxytetracycline for medicated feed{R-26} are indicated in the reduction of losses due to enterotoxemia in feedlot lambs. [Erysipelas (treatment)]Pigs: Oxytetracycline injection{R-24; 25; 121} is indicated in the treatment of erysipelas caused by susceptible organisms. [Mastitis (treatment)]Cattle, pigs, and sheep: Oxytetracycline injection{R-24; 25} is indicated in the treatment of mastitis caused by susceptible organisms. Oxytetracycline, administered at the dosage recommended in product labeling, does not appear to be effective for the cure of Staphylococcus aureus infections in the dry cow{R-103}. [Omphalophlebitis (treatment)]Cattle: Oxytetracycline injection{R-24; 25} is indicated in the treatment of omphalophlebitis (navel ill) caused by susceptible organisms. [Peritonitis (treatment)]Cattle: Oxytetracycline injection{R-25; 121} is indicated in the treatment of peritonitis caused by susceptible organisms. [Pododermatitis (prophylaxis)]Cattle: Chlortetracycline for medicated feed is indicated as an aid in the prevention of pododermatitis{R-116}. [Potomac horse fever (treatment)]1Horses: Oxytetracycline is used in the treatment of Potomac horse fever (equine ehrlichial colitis) caused by susceptible Ehrlichia risticii{R-47; 48}. Treatment of exposed animals to prevent development of disease is not recommended; the incubation period will be increased but the disease is not prevented{R-48}. [Rocky Mountain spotted fever (treatment)]1Dogs: Tetracycline or doxycycline{R-151} is used in the treatment of Rocky Mountain spotted fever caused by susceptible Rickettsia rickettsii{R-140; 141}. [Sinusitis, infectious (prophylaxis)]Turkeys: Chlortetracycline for medicated feed is indicated in the prevention of sinusitis caused by susceptible organisms. [Sinusitis, infectious (treatment)]Turkeys: Oxytetracycline for medicated feed{R-26; 122} and tetracycline soluble powder are indicated in the control of sinusitis caused by susceptible organisms, such as susceptible Mycoplasma gallisepticum. that specic dosage regimens may be successful in treating the infection{R-160}. No controlled studies are available. [Chlamydial infection (treatment)]1; or [Respiratory tract infections, bacterial (treatment)]1Cats: There are insufcient data to establish the safety and efcacy of doxycycline in the treatment of chlamydial infections or bacterial respiratory infections in cats; however, it is used in the treatment of infections caused by susceptible organisms{R-151; 177}. [Ehrlichiosis (treatment)]1Dogs: There are insufcient data to establish the efcacy of doxycycline in the treatment of ehrlichiosis in dogs. Clinical signs are often resolved by administration of doxycycline or tetracycline{R-40; 41; 43; 139}, but it is uncertain whether the organism is cleared from dogs treated{R-40; 139}. Serum Ehrlichia canis antibody titers can remain increased in some dogs for over 2 years after the resolution of clinical signs during treatment with tetracycline{R-139}; also, in some dogs, blood and tissue cultures have tested positive for Ehrlichia canis 2 months after treatment with doxycycline{R-40}. [Flexural limb deformities (treatment)]1Foals: There are insufcient data to establish the efcacy of oxytetracycline in the treatment of exural limb deformities in foals; however, studies show that oxytetracycline can cause a short-term moderate improvement in metacarpophalangeal joint angle and an increase in range of joint motion in newborn foals as compared to untreated foals{R-157; 158}. The available studies were performed in healthy foals rather than foals with deformities and both the ideal dose and actual short- and long-term benets and risks of this treatment are unknown. [Haemobartonella felis infection (treatment)]1Cats: There are insufcient data to establish the safety and efcacy of doxycycline in the treatment of feline infectious anemia, caused by susceptible Haemobartonella felis; however, it is used in the treatment of acute infections{R-147}. If considered clinically necessary, corticosteroids{R-149} and blood transfusions are used concurrently with doxycycline in the treatment of this infection{R-147}. Acutely infected cats may clinically recover without treatment{R-147; 159}, although it is believed that the organism is not cleared from these animals; there is also some question about the efcacy of doxycycline or other tetracyclines in completely clearing the organism from infected cats{R-148}. Controlled clinical efcacy trials have not been conducted for any medication; however, a tetracycline is usually administered when a cat is diagnosed and doxycycline is considered the tetracycline of choice{R-147} because of an expectation of fewer side effects. Cats with serious underlying viral infections, such as feline leukemia virus, are not expected to respond well to therapy. [Leptospirosis (treatment)]1Dogs: Although doxycyline is proposed in some veterinary references for use in the clearance of the leptospirosis carrier state in dogs, there are insufcient data showing clearance or prevention of a potential carrier state to support this use as an established indication. [Lyme disease (treatment)]1Dogs: There are insufcient data to establish the efcacy of tetracyclines in the treatment of Lyme borreliosis. Doxycycline has been effective in the resolution of early Borrelia burgdorferi infection in people{R-163}; therefore, doxycycline and tetracycline are used to treat the infection in dogs{R-164; 165}; however, it is uncertain whether this is the best medication to produce long-term resolution of the infection{R-163}. [Thromboembolic meningoencephalitis (treatment)]1Cattle: There are insufcient data to establish the efcacy of oxytetracycline in the treatment of thromboembolic meningoencephalitis; however, if cattle are diagnosed in the early stages of the disease, before recumbency,

ACCEPTANCE NOT ESTABLISHED

[Brucellosis (treatment)]1Dogs: There are insufcient data to establish the efcacy of tetracycline administered concurrently with streptomycin in the treatment of brucellosis in dogs; however, studies suggest

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TETRACYCLINES VeterinarySystemic 229 treatment can be effective against susceptible Haemophilus somnus{R-161; 166}. [Uterine infections, bacterial (treatment)]Cattle, horses, pigs, and sheep: Although Canadian product labeling includes the use of intrauterine chlortetracycline, oxytetracycline, and tetracycline in the treatment of uterine infections, there are insufcient available data concerning the efcacy and safety of this use. Intrauterine tetracycline treatment can reduce the incidence of putrefaction of retained fetal membranes and fever associated with infection in cattle, but because it is believed to penetrate only into the endometrium from infusion into the uterus{R-104; 130}, parenteral antibiotics are recommended for those animals that have evidence of infection or develop signs of septicemia{R-144}. The intrauterine administration of tetracyclines for the treatment of uterine infections such as endometritis or treatment of infection associated with retained placentas in cattle is not effective in shortening the interval from parturition to conception, increasing pregnancy rates, or reducing culling rates{R-144146}. Considering costs, risks of residues{R-129}, and a lack of signicant change in longterm fertility in cattle, there is no evidence to support the routine use of intrauterine tetracyclines in cattle, horses, pigs, and sheep. 1,11-dioxo-, monohydrochloride, compd. with ethanol (2:1), monohydrate, [4S-(4 alpha, 4a alpha, 5 alpha, 5a alpha, 6 alpha, 12a alpha)]-{R-114}. Oxytetracycline2-Naphthacenecarboxamide, 4-(dimethylamino)-1,4,4a,5,5a,6,11,12a-octahydro-3,5,6,10,12,12a-hexahydroxy-6-methyl1,11-dioxo-, [4S-(4 alpha,4a alpha,5 alpha,5a alpha,6 beta,12a alpha)]-, dihydrate{R-114}. Oxytetracycline hydrochloride2-Naphthacenecarboxamide, 4-(dimethylamino)-1,4,4a,5,5a,6,11,12a-octahydro-3,5,6,10,12,12a-hexahydroxy-6-methyl-1,11-dioxo-, monohydrochloride, [4S-(4 alpha,4a alpha,5 alpha,5a alpha,6 beta,12a alpha)]-{R-114}. Tetracycline2-Naphthacenecarboxamide, 4-(dimethylamino)-1,4,4a, 5,5a,6,11,12a-octahydro-3,6,10,12,12a-pentahydroxy-6-methyl-1,11dioxo-, [4S-(4 alpha,4a alpha,5a alpha,6 beta,12a alpha)]-{R-114}. Tetracycline hydrochloride2-Naphthacenecarboxamide, 4-(dimethylamino)-1,4,4a,5,5a,6,11,12a-octahydro-3,6,10,12,12a-pentahydroxy6-methyl-1,11-dioxo-, monohydrochloride, [4S-(4 alpha,4a alpha,5a alpha,6 beta,12a alpha)]-{R-114}. Molecular formula: Chlortetracycline hydrochlorideC22H23ClN2O83 HCl{R-114}. DoxycyclineC22H24N2O8 H2O{R-114}. Doxycycline hyclate(C22H24N2O8HCl)2 C2H6O H2O{R-114}. OxytetracyclineC22H24N2O9 2H2O{R-114}. Oxytetracycline hydrochlorideC22H24N2O9 HCl{R-114}. TetracyclineC22H24N2O8{R-114}. Tetracycline hydrochlorideC22H24N2O8 HCl{R-114}. Molecular weight: Chlortetracycline hydrochloride515.34{R-114}. Doxycycline462.45{R-114}. Doxycycline hyclate1025.87{R-114}. Oxytetracycline496.46{R-114}. Oxytetracycline hydrochloride496.89{R-114}. Tetracycline444.43{R-114}. Tetracycline hydrochloride480.90{R-114}. Description: Chlortetracycline Hydrochloride USPYellow, crystalline powder. Is odorless. Is stable in air, but is slowly affected by light{R-128}. Doxycycline USPYellow, crystalline powder{R-128}. Doxycycline Hyclate USPYellow, crystalline powder{R-128}. Oxytetracycline USPPale yellow to tan, odorless, crystalline powder. Is stable in air, but exposure to strong sunlight causes it to darken. It loses potency in solutions of pH below 2, and is rapidly destroyed by alkali hydroxide solutions{R-128}. Oxytetracycline Hydrochloride USPYellow, odorless, crystalline powder. Is hygroscopic. Decomposes at a temperature exceeding 180 C, and exposure to strong sunlight or to temperatures exceeding 90 C in moist air causes it to darken. Its potency is diminished in solutions having a pH below 2, and is rapidly destroyed by alkali hydroxide solutions{R-128}. Tetracycline USPYellow, odorless, crystalline powder. Is stable in air, but exposure to strong sunlight causes it to darken. It loses potency in solutions of pH below 2, and is rapidly destroyed by alkali hydroxide solutions{R-128}. Tetracycline Hydrochloride USPYellow, odorless, crystalline powder. Is moderately hygroscopic. Is stable in air, but exposure to strong sunlight in moist air causes it to darken. It loses potency in solution at a pH below 2, and is rapidly destroyed by alkali hydroxide solutions{R-128}.

Not included in Canadian product labeling or product not commercially available in Canada.

REGULATORY CONSIDERATIONS
U.S. Withdrawal times have been established for chlortetracycline for medicated feed and soluble powder; oxytetracycline soluble powder, for medicated feed, tablets, and injection; and tetracycline soluble powder and boluses. See the Dosage Forms section. Canada Withdrawal times have been established for chlortetracycline for medicated feed, and uterine tablets; oxytetracycline soluble powder, for medicated feed, uterine infusion, and injection; and tetracycline soluble powder, boluses, and uterine tablets. See the Dosage Forms section.

CHEMISTRY
Source: ChlortetracyclineIsolated from the fungus Streptomyces aureofaciens{R-22}. DoxycyclineProduced semisynthetically.{R-22} OxytetracyclineIsolated from the fungus Streptomyces rimosus{R-22}. TetracyclineProduced by some streptomyces strains; however, it is manufactured by hydrogenolysis of chlortetracycline{R-113}. Chemical name: Chlortetracycline hydrochloride2-Naphthacenecarboxamide, 7-chloro4-(dimethylamino)-1,4,4a,5,5a,6,11,12a-octahydro-3,6,10,12,12apentahydroxy-6-methyl-1,11-dioxo-, monohydrochloride [4S-(4 alpha, 4a alpha,5a alpha,6 beta,12a alpha)]-{R-114}. Doxycycline2-Naphthacenecarboxamide, 4-(dimethylamino) - 1,4,4a, 5,5a,6,11,12a-octahydro-3,5,10,12,12a-pentahydroxy-6-methyl1,11-dioxo-, [4S-(4 alpha,4a alpha,5 alpha,5a alpha,6 alpha,12a alpha)]-, monohydrate{R-114}. Doxycycline hyclate2-Naphthacenecarboxamide, 4-(dimethylamino)1,4,4a,5,5a,6,11,12a-octahydro-3,5,10,12,12a-pentahydroxy-6-methyl-

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230 TETRACYCLINES VeterinarySystemic pKa: Chlortetracycline: 3.3, 7.4, 9.3{R-133}. Oxytetracycline: 3.3, 3.7, 9.1{R-156}. Tetracycline: 8.3, 10.2{R-133}. Solubility: Chlortetracycline Hydrochloride USPSparingly soluble in water; soluble in solutions of alkali hydroxides and carbonates; slightly soluble in alcohol; practically insoluble in acetone, in chloroform, in dioxane, and in ether{R-128}. Doxycycline USPVery slightly soluble in water; freely soluble in dilute acid and in alkali hydroxide solutions; sparingly soluble in alcohol; practically insoluble in chloroform and in ether{R-128}. Doxycycline Hyclate USPSoluble in water and in solutions of alkali hydroxides and carbonates; slightly soluble in alcohol; practically insoluble in chloroform and in ether{R-128}. Oxytetracycline USPVery slightly soluble in water; freely soluble in 3 N hydrochloric acid and in alkaline solutions; sparingly soluble in alcohol{R-128}. Oxytetracycline Hydrochloride USPFreely soluble in water, but crystals of oxytetracycline base separate as a result of partial hydrolysis of the hydrochloride. Sparingly soluble in alcohol and in methanol, and even less soluble in dehydrated alcohol; insoluble in chloroform and in ether{R-128}. Tetracycline USPVery slightly soluble in water; freely soluble in dilute acid and in alkali hydroxide solutions; sparingly soluble in alcohol; practically insoluble in chloroform and in ether{R-128}. Tetracycline Hydrochloride USPSoluble in water and in solutions of alkali hydroxides and carbonates; slightly soluble in alcohol; practically insoluble in chloroform and in ether{R-128}. interference with oral absorption by calcium or other substances{R. See the Drug interactions section. ParenteralOxytetracycline: As with other parenteral medications, the absorption and bioavailability of intramuscularly administered oxytetracycline can vary depending on the site of administration. Oxytetracycline is more bioavailable when administered intramuscularly into the shoulder of calves than when administered intramuscularly into the neck or particularly into the buttock.{R-94} The absorption of the long-acting formulations of oxytetracycline (with 2-pyrrolidone excipient) administered intramuscularly has been described as having a rapid phase of 48 minutes for 14% of the dose and a slow phase of 18 hours for 38% of the dose in cattle administered a 20 mg/kg dose{R-99}. With a 10 mg/kg dose, the rapid phase is 16 minutes and the slow phase is 11 hours.{R-100}
133}

PHARMACOLOGY/PHARMACOKINETICS
Note: Unless otherwise noted, pharmacokinetic values are based on a single intravenous dose of medication. Mechanism of action/effect: Tetracyclines are broad-spectrum bacteriostatic agents that inhibit protein synthesis by binding reversibly to receptors of the 30 S ribosomal subunit of susceptible microorganisms. The binding of a tetracycline to the subunit blocks the binding of the aminoacyl-tRNA to the acceptor site on the mRNA-ribosomal complex and prevents the addition of new amino acids to the peptide chain, inhibiting protein synthesis.{R-22} Tetracyclines must enter the target cell to be effective. Uptake appears to depend on passive diffusion and active transport, with the exception of doxycycline, which enters the cell by passive diffusion{R-28}. Susceptible cells concentrate the antibiotic; resistant strains appear to carry an R-factor that inhibits uptake of drug.{R-22} Absorption: OralDoxycycline: Generally is more completely absorbed from the gastrointestinal tract than are the tetracyclines developed less recently{R-40; 64; 74}, which can be poorly and variably absorbed. Human studies have shown that the absorption of oxytetracycline or tetracycline is decreased when either is administered with food; the effect of food on doxycycline absorption is insignicant. Doxycycline is also less likely than the older tetracyclines to form chelation complexes with divalent and trivalent metals and, therefore, there is less

Bioavailability: Oral Chlortetracycline: Chickens1% (25 mg per kg of body weight [mg/kg] dose).{R-78; 79} PigsFasted or fed: 18 to 19%{R-77}. Turkeys6% (15 mg/kg dose).{R-78; 80} Doxycycline: Chickens41.3% (20 mg/kg dose).{R-64} Human value90 to 95%{R-169}. Oxytetracycline: Pigs4.8% (50 mg/kg dose).{R-109} Piglets, weaned, 10 weeks of age By drench: 9% (20 mg/kg dose).{R-82} In medicated feed for 3 days: 3.7% (400 parts per million [ppm] of feed).{R-82} Trout, rainbow (Oncorhynchus mykiss)5.6% (75 mg/kg dose).{R-89} Turkeys Fasted: 47.6% (10 mg/kg dose).{R-85} Fed: 9.4% (10 mg/kg dose).{R-85} Tetracycline: Pigs, fasted23% (22 mg/kg dose).{R-74} Intramuscular Oxytetracycline, conventional formulation: Buffalo63.2% (22 mg/kg dose).{R-87} Calves, 17 days of age61% (20 mg/kg dose){R-99}. Calves, 3 months of age76 hours postinjection of 18 mg/kg dose: Buttock administration83.1%.{R-94} Neck administration93.3%.{R-94} Shoulder administration99.4%.{R-94} Catsh, African, and trout, rainbow85% (60 mg/kg dose).{R-90} Cows80.8% (8 mg/kg dose){R-95}; 95% (20 mg/kg dose){R-174}. Goats65.5% (20 mg/kg dose).{R-81} Oxytetracycline, long-acting formulation: Camels93.7% (10 mg/kg dose).{R-88} Cattle51%; 78.5%; 95% (20 mg/kg dose).{R-98; 99; 174} Goats79.4% (20 mg/kg dose).{R-81} Distribution: Tetracyclines are lipid soluble and are well distributed to most tissues. Doxycycline is the most lipid soluble and shows the greatest degree of tissue penetration.{R-28; 71} Volume of distribution Chlortetracycline: Calves, ruminatingArea volume of distribution: 1.93 0.15 liters per kg (L/kg).{R-76}

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TETRACYCLINES VeterinarySystemic 231 PigsSteady state volume of distribution: Fasted0.97 0.21 L/kg.{R-77} Fed1.39 0.31 L/kg.{R-77} TurkeysArea: 0.23 0.05 L/kg.{R-78} Doxycycline: CalvesSteady state: Preruminating1.81 0.24 L/kg.{R-68} Ruminating1.31 0.11 L/kg.{R-68} CatsSteady state: 0.34 0.03 L/kg.{R-70} DogsSteady state: 0.93 0.14 L/kg.{R-70} PigsSteady state: 0.53 0.04 L/kg.{R-69} Oxytetracycline: BuffaloArea: 0.28 to 0.45 L/kg.{R-87} Calves, newborn to 8 monthsArea: 1.67 L/kg.{R-93; CamelsSteady state: 0.71 L/kg.{R-88} CowsArea: 0.80 0.03 L/kg.{R-95} DogsArea: 2.10 0.42 L/kg.{R-84} Donkeys Area: 0.78 L/kg{R-92}. Steady state: 0.65 L/kg{R-92}. Foals Area: 2.19 L/kg.{R-154} Steady state: 2.17 L/kg.{R-154} GoatsArea: 1.44 L/kg.{R-81} Horses Apparent: 1.35 L/kg.{R-96} Area: 0.67 L/kg.{R-92} Steady state: 0.34 L/kg.{R-92} PigsArea: Adult1.8 L/kg.{R-83} Adult with pneumonia1.53 L/kg.{R-83} Ponies Area: 1.05 L/kg.{R-92} Steady state: 0.47 L/kg.{R-92} Rabbits0.86 L/kg.{R-86} RatsArea: 0.79 L/kg.{R-91} Tetracycline: ChickensSteady state: 0.17 L/kg.{R-73} PigsArea: 4.5 1.1 L/kg.{R-74} RabbitsArea: 1.05 .88 L/kg.{R-72} Tetracycline Cows: Low to moderate (31 to 41%).{R-67} Sheep: Low (28 to 32%).{R-67}

Biotransformation: All speciesThe tetracyclines are not known to be biotransformed to any signicant extent before elimination.{R-28; 6870}

100}

Protein binding: Chlortetracycline Cows: Moderate (47 to 51%).{R-67} Sheep: Moderate (46 to 50%).{R-67} Doxycycline Calves: Very high (92%).{R-68} Cats: Very high (98%);{R-70} albumin binding76%.{R-70} Dogs: Very high (91%);{R-70} albumin binding54%.{R-70} Pigs: Very high (93%).{R-69} Sheep: High (84 to 90%).{R-67} Oxytetracycline Buffalo: Moderate (42%).{R-87} Cows: Low (18 to 22%){R-67}. Horses and cows: Combined resultsModerate (50%).{R-96} Pigs, weaned, 10 weeks of age: High (75.5%).{R-82} Sheep: Low (21 to 25%).{R-67} Trout, rainbow: Moderate (55%).{R-89}

Half-life: Elimination Chlorotetracycline: Calves, ruminant8.3 hours.{R-76} Turkeys0.88 hour.{R-78} Doxycycline: Calves Preruminant: 9.8 hours.{R-68} Ruminant: 14.2 hours.{R-68} Cats4.6 hours.{R-70} Chickens4.8 hours.{R-64} Dogs7 to 10.4 hours.{R-63; 70} HorsesOral administration (apparent half-life): 8.7 1.6 hours{R-131}. Pigs3.9 hours.{R-69} Oxytetracycline: Buffalo2.8 to 3.6 hours.{R-87} Calves Newborn: 11.2 hours.{R-93} 6 weeks of age: 3.5 to 7.2 hours.{R-93; 100; 106} 6 weeks of age with induced Mannheimia (Pasteurella) haemolytica pneumonia: 2.5 hours.{R-106} 8 months of age: 6.3 hours.{R-93} Camels7.7 hours.{R-88} Catsh, African80.3 hours.{R-90} Cows10 hours.{R-95} Dogs6 hours.{R-84} Donkeys6.5 hours.{R-92} Foals6.7 to 7.3 hours.{R-154} Goats6.5 hours.{R-81} Horses13 hours{R-92}; 15.7 hours{R-175}. Pigs 10 weeks of age, weaned: 11.6 to 17.2 hours.{R-82} Adult: 3.8 to 6.7 hours.{R-77; 83} Adult, with pneumonia: 5.1 to 5.2 hours.{R-83} Ponies15 hours.{R-92} Rabbits1.3 hours.{R-86} Trout, rainbow Oncorhynchus mykiss: 60.3 hours.{R-89} Salmo gairdneri: 89.5 hours.{R-90} Turkeys0.73 hour.{R-85} Tetracycline: Cats2.5 hours.{R-75} Chickens2.8 hours.{R-73} Dogs1.6 to 2 hours.{R-75} Pigs16 hours.{R-74} Rabbits2 hours.{R-72} Time to peak concentation/Peak serum concentration: ChlortetracyclineOral: Calves (22 mg/kg dose)

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232 TETRACYCLINES VeterinarySystemic Milk fed: 15.7 0.33 hours to a peak serum concentration of 1.86 0.54 mcg per mL (mcg/mL).{R-76} Ruminant: 13.3 2.67 hours to a peak serum concentration of 0.67 0.24 mcg/mL.{R-76} Turkeys2.5 hours to a peak serum concentration of 0.6 mcg/mL (15 mg/kg dose).{R-80} DoxycyclineOral: Single dose Chickens0.35 0.02 hour to a peak serum concentration of 54.6 2.4 mcg/mL (20 mg/kg dose).{R-64} Horses 1 hour to a peak serum concentration of 0.22 mcg/mL (3 mg/kg dose){R-131}. 1 hour to a peak serum concentration of 0.32 mcg/mL (dose of 10 mg/kg){R-131}. Multiple dosing: Horses2 hours postadministration to a serum concentration of 0.42 mcg/mL at 2 hours after the fth dose (ve intragastric doses of 10 mg/kg administered at twelve hour intervals){R-131}. Note: The MIC90 of doxycycline has been reported as 1 mcg/mL for Streptococcus zooepidemicus and 0.25 mcg/mL for Staphylococcus aureus in horses{R-131}. Oxytetracycline Oral: Pigs, weaned, 10 weeks of age 30 hours after start of administration to a peak serum concentration of 0.2 0.06 mcg/mL (dose of 400 parts per million in feed for 3 days).{R-82} 1 to 5 hours to a peak serum concentration of 1.18 to 1.41 mcg/mL (20 mg per kg single dose). Intramuscular: Conventional formulation Calves, 14 weeks of age: 6 hours to a peak serum concentration of 5.5 1.25 mcg/mL (dose of 18 mg/kg in the neck).{R-95} Catsh, African: 7 hours to a peak serum concentration of 43.4 mcg/mL (60 mg/kg dose).{R-90} Cows: 6.7 hours to a peak serum concentration of 5.7 2.39 mcg/ mL (dose of 8 mg/kg in the neck).{R-95} Pigs: 1.5 hours to a peak serum concentration of 6.7 3.4 (dose of 20 mg/kg in the hindquarter).{R-107} Trout, rainbow: 4 hours to a peak serum concentration of 56.9 mcg/ mL (60 mg/kg dose).{R-90} Long-acting formulation Calves, nonruminating, 5 weeks of age: 1 to 1.5 hours to a peak serum concentration of 4 mcg/mL (dose of 20 mg/kg in the gluteal muscles).{R-99} Calves, nonruminating, 6 weeks of age: 4.01 2.84 hours to a peak serum concentration of 3.01 0.72 mcg/mL (dose of 10 mg/kg in the hindquarter).{R-100} Calves, ruminating: 7.6 4 hours to a peak serum concentration of 9.6 2.6 mcg/mL (dose of 40 mg/kg in the hindquarter).{R-101} Camels: 7.3 3.5 hours to a peak serum concentration of 3.49 0.44 mcg/mL (10 mg/kg dose).{R-88} Cows: 5 to 10 hours to a peak serum concentration of 4.5 to 6.8 mcg/mL (dose of 10 mg/kg in the neck).{R-97} Pigs: 0.5 hour to a peak serum concentration of 6 2.2 mcg/mL (dose of 20 mg/kg in the hindquarters).{R-107} Steers: 8 hours to a peak serum concentration of 3.13 mcg/mL (dose of 20 mg/kg in the hindquarters).{R-98} TetracyclineOral: Pigs72 hours to a peak serum concentration of 0.6 mcg/mL (dose of 0.55 gram per kg of feed).{R-74}

Duration of action: Note: Duration of action may be estimated by the time target serum concentrations are maintained. Target concentrations are generally based on minimum inhibitory concentrations (MIC) for each organism. While 0.5 mcg/mL has been considered the MIC of oxytetracycline for many pathogens in the past and research studies were based on that target, there are now many pathogens with MICs of 4 to 16 mcg/mL. Duration of action may be minimal or nonexistent for these isolates. Chlortetracycline Pigs: When administered 110 mg chlortetracycline per kg of feed, fed as the only ration, therapeutic plasma or tissue concentrations were not produced{R-155}. Turkeys: A single oral dose of 15 mg/kg produces serum concentrations above 0.4 mcg/mL for 8 to 10 hours.{R-80} DoxycyclineDogs: An intravenous dose of 5 mg/kg produces serum concentrations above 2 mcg/mL for 8 hours.{R-63} Oxytetracycline Oral: PigsA single oral 50 mg/kg dose produces >0.5 mcg/mL serum concentrations for at least 8 hours.{R-109} Pigs, after challenge with Actinobacillus pleuropneumoniaA single oral 50 mg/kg dose produces >0.5 mcg/mL serum concentrations for at least 24 hours.{R-109} PigsWhen administered 550 mg of oxytetracycline per kg of feed, fed as the only diet, plasma concentrations peaked at 0.4 mcg/ mL{R-107}. Note: These results may vary by size of pig and amount of feed intake. Intramuscular: Conventional formulation Calves: A single dose of 18 mg/kg maintains serum concentrations > 1 mcg/mL for at least 32 hours.{R-94} Cows: A single dose of 20 mg/kg in the hindquarters maintains serum concentrations of > 0.5 mcg/mL for 52 hours{R-98}. Pigs: A single dose of 20 mg/kg maintains serum concentrations > 0.5 mcg/mL for 28 to 36 hours.{R-107; 174} Long-acting formulation Calves, milk fed: A single dose of 10 mg/kg maintains serum concentrations > 0.5 mcg/mL for 12 to 24 hours.{R-100} Calves, ruminating: A single dose of 40 mg/kg maintains serum concentrations > 2 mcg/mL for 48 hours;{R-101} also lung concentrations produced are 2 mcg/mL at 48 hours.{R-101} Camels: A single dose of 10 mg/kg maintains serum concentrations > 0.5 mcg/mL for 72 hours.{R-88} Cows: A single dose of 10 mg/kg in the neck maintains > 0.5 mcg/mL serum concentrations for 48 to 70 hours and milk concentrations for 33 to 49 hours.{R-97} A single dose of 20 mg/kg in the hindquarters maintains serum concentrations of > 0.5 mcg/mL for 86 hours.{R-98} A single dose of 20 mg/kg in the gluteal muscles maintains serum concentrations > 4 mcg/mL for 12 hours; also lung concentrations are > 0.5 mcg/mL for 65 hours.{R-99}

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TETRACYCLINES VeterinarySystemic 233 Pigs: A single dose of 20 mg/kg produces serum concentrations > 0.5 mcg/mL for 35 to 48 hours{R-107; 174}; however, the use of the long-acting formulation does not produce signicantly different plasma oxytetracycline concentrations from those produced by the conventional formulation{R-107}. TetracyclinePigs: A ration containing 0.55 gram of tetracycline hydrochloride per kg of feed, fed as the only ration, produces 0.3 to 0.4 mcg/mL serum concentrations for the 96 hours that it is fed.{R-74} Note: These results may vary by size of pig and amount of feed intake. Elimination: ChlortetracyclineTotal clearance: Calves, ruminating2.70 0.17 mL per minute per kg (mL/min/ kg).{R-76} Pigs, fasted2.75 0.92 mL/min/kg.{R-77} Pigs, fed5.12 0.88 mL/min/kg.{R-77} Turkeys3.77 0.77 mL/min/kg.{R-78} DoxycyclineDoxycycline differs from the other tetracyclines in that a large percentage is excreted into the intestines and is inactive there.{R-133} Dogs: 90% of a single intravenous dose is eliminated within 48 hours in nonmetabolized form. Of the 90%, 16% is eliminated in urine, <5% in the bile, and the remainder in the intestines.{R-63} Total clearance: Calves Preruminant: 2.20 mL/min/kg.{R-68} Ruminant: 1.07 mL/min/kg.{R-68} Cats1.09 0.21 mL/min/kg.{R-70} Dogs1.7 mL/min/kg{R-63; 70}. Pigs1.67 0.18 mL/min/kg.{R-69} OxytetracyclineCalves, cows, dogs, pigs, and turkeys: The conventional formulation of oxytetracycline is eliminated primarily by glomerular ltration; only a small amount (1 to 2% in pigs and turkeys) is eliminated in the bile.{R-63; 82; 85; 93; 97} Total clearance: Oxytetracycline Buffalo: 1.02 to 1.45 mL/min/kg.{R-87} Calves, 6 to 8 weeks of age: 1.66 to 1.88{R-93}; 2.67 to 4.67 mL/ min/kg.{R-100} Camels: 1.26 mL/min/kg{R-88}. Dogs: 4.23 1.29 mL/min/kg.{R-84} Donkeys: 1.52 mL/min/kg.{R-92} Foals, 4 to 5 days of age: 3.17 mL/min/kg{R-154}. Goats: 2.67 mL/min/kg.{R-81} Horses: 0.66 mL/min/kg.{R-92} Pigs, 10 weeks of age: 4.17 mL/min/kg.{R-82} Pigs, adult: 3.5 mL/min/kg.{R-83} Ponies: 1.01 mL/min/kg.{R-92} Rabbits: 7.23 mL/min/kg.{R-86} Rats: 2.79 mL/min/kg.{R-91} TetracyclineTotal clearance: Chickens1.63 0.18 mL/min/kg.{R-73} Pigs3.08 0.4 mL/min/kg.{R-74} Rabbits6.1 0.6 mL/min/kg.{R-72} Some studies have linked the cardiovascular effects of intravenous administration in calves to the propylene glycol vehicle in some preparations{R-33; 170}; however, adverse cardiovascular effects and collapse have been shown to occur after intravenous administration of tetracycline without propylene glycol vehicle{R-34}; the electrocardiographic abnormalities may be due to chelation of free calcium ions{R-34}. Tetracyclines ideally should be diluted in uids and administered slowly if given by the intravenous route{R-176}. If this is not possible, intravenous injections should be made as a slow push, with the dose administered over 1 to 2 minutes. Horses: While rapid intravenous administration of tetracyclines causes reactions in many species, doxycycline in particular can lead to severe cardiovascular dysfunction and death when administered intravenously at any rate to horses.{R-35} Administration of tetracyclines can also lead to severe diarrhea in some horses. However, oral, multiple-dose administration of doxycycline to horses without observed side effects has been reported{R-131}.

PREGNANCY/REPRODUCTION
Tetracyclines have been shown to cross the placenta{R-22} and may affect fetal bone formation.{R-135}

LACTATION
Tetracyclines are distributed into milk.

PEDIATRICS
Use of tetracyclines during tooth development (the last 2 to 3 weeks of pregnancy to 1 month of age){R-22} may cause discoloration of the bones and teeth.{R-4} In neonates that have not yet developed full renal function, excretion of chlortetracycline, oxytetracycline, and tetracycline may occur more slowly than in a mature animal. One exception is that 4-day-old foals have a faster elimination half-life and more rapid clearance of oxytetracycline compared to adults{R-154}.

DRUG INTERACTIONS AND/OR RELATED PROBLEMS

The following drug interactions and/or related problems have been selected on the basis of their potential clinical signicance (possible mechanism in parentheses where appropriate)not necessarily inclusive ( = major clinical signicance): Note: Although methoxyurane has been suspected of increasing the potential for tetracycline-induced nephrotoxicity in people, this has not been shown to be true in dogs.{R-137} Combinations containing any of the following medications, depending on the amount present, may also interact with this medication. Antacids or Calcium supplements, such as calcium carbonate, or Iron supplements or Magnesium-containing laxatives or Sodium bicarbonate (concurrent use with tetracyclines may result in formation of nonabsorbable complexes; also, concurrent use within 1 to 3 hours of antacid or sodium bicarbonate administration may result in decreased absorption of oral tetracyclines because of increased intragastric pH) Phenobarbital or Microsomal enzyme inducers, other All rights reserved

PRECAUTIONS TO CONSIDER SPECIES SENSITIVITY

All species: Rapid intravenous administration of tetracyclines can result in cardiovascular dysfunction and collapse in any species{R-3335; 169}. 2003 Thomson MICROMEDEX

234 TETRACYCLINES VeterinarySystemic (concurrent use with doxycycline may result in decreased doxycycline serum concentrations due to induction of microsomal enzyme activity; adjustment of doxycycline dosage or substitution of another tetracycline may be necessary) Tereftalic acid (blood concentrations of chlortetracycline are increased when it is administered concurrently with tereftalic acid{R-156})

MEDICAL CONSIDERATIONS/CONTRAINDICATIONS
The medical considerations/contraindications included have been selected on the basis of their potential clinical signicance (reasons given in parentheses where appropriate)not necessarily inclusive ( = major clinical signicance). Risk-benet should be considered when the following medical problem exists: Renal function impairment, severe (chlortetracycline, oxytetracycline, and tetracycline are eliminated primarily by the kidney and can accumulate in animals with severe renal dysfunction; doxycycline is only partially eliminated renally and is much less likely to accumulate{R-71})

HUMAN DRUG INTERACTIONS AND/OR RELATED PROBLEMS{R-132}

In addition to the above drug interactions reported in animals, the following drug interactions have been reported in humans, and are included in the human monograph Tetracyclines (Systemic) in USP DI Volume I; these drug interactions are intended for informational purposes only and may or may not be applicable to the use of tetracyclines in the treatment of animals: Cholestyramine (concurrent use with cholestyramine may result in binding of oral tetracyclines, thus impairing their absorption; an interval of several hours between administration of cholestyramine and oral tetracyclines is recommended) Vitamin A (concurrent use with tetracycline has been reported to cause benign intracranial hypertension)

PATIENT MONITORING
The following may be especially important in patient monitoring (other tests may be warranted in some patients, depending on condition; = major clinical signicance): Culture and susceptibility, in vitro, and Minimum inhibitory concentration (MIC) (in vitro cultures and MIC test should be done on samples collected prior to administration of tetracyclines to determine pathogen susceptibility)

SIDE/ADVERSE EFFECTS
The following side/adverse effects have been selected on the basis of their potential clinical signicance (possible signs and, for humans, symptoms in parentheses where appropriate)not necessarily inclusive:

LABORATORY VALUE ALTERATIONS

The following have been selected on the basis of their potential clinical signicance (possible effect in parentheses where appropriate)not necessarily inclusive ( = major clinical signicance): With physiology/laboratory test values Urinalysis (transient hemoglobinuria has been reported in cattle given parenteral oxytetracycline){R-38; 45; 56}

THOSE INDICATING NEED FOR MEDICAL ATTENTION

Incidence rare All species Hypersensitivity reactions, specically anaphylaxis{R-32; 45} (defecation; eruption of skin plaques; frothing from the mouth; glassy-eyed appearance; labored breathing; muscle trembling; piloerection; prostration; restlessness; swelling of eyelids, ears, muzzle, anus, vulva or scrotum and sheath){R-45}; photosensitization{R-39} Cattle, dogs, and horses Nephrotoxicosis{R-2931; 112; 168}with high doses, concurrent debilitating conditions, or use of outdated tetracyclines Incidence unknown All species Overgrowth of nonsusceptible organisms Cats, cattle, dogs, horses, monkeys, rabbits, rats, and sheep{R-3335} Cardiovascular dysfunction, including atrioventricular block, atrial tachycardia, ventricular bradycardia, hypotension (in order of appearanceagitation or nervousness, dyspnea, muscle fasciculations, urination, defecation, collapse, death)a dose-dependent effect{R-34} with rapid intravenous administration; cardiovascular dysfunction, including hypertension, arterial{R-35}in horses given doxycycline Note: Although the propylene glycol vehicle of some oxytetracycline preparations has been shown to have some cardiovascular effects when administered intravenously{R-33}, the calcium-binding nature of the tetracyclines has been implicated in cardiovascular dysfunction and sudden collapse in cattle and sheep after intravenous administration of tetracyclines.{R-34; 35} Although pretreatment with calcium borogluconate has been considered before intravenous All rights reserved

HUMAN LABORATORY VALUE ALTERATIONS{R-132}

The following laboratory value alterations have been reported in humans, and are included in the human monograph Tetracyclines (Systemic) in USP DI Volume I; these laboratory value alterations are intended for informational purposes only and may or may not be applicable to the use of tetracyclines in the treatment of animals: With diagnostic test results Catecholamine determinations, urine (may produce false elevations of urinary catecholamines because of interfering uorescence) With physiology/laboratory test values Alanine aminotransferase (ALT [SGPT]) and Alkaline phosphatase and Amylase and Aspartate aminotransferase (AST [SGOT]) and Bilirubin (serum concentrations may be increased) Blood urea nitrogen (BUN) (antianabolic effect of tetracyclines [except doxycycline] may increase BUN concentrations; in patients with signicantly impaired renal function, increased serum concentrations of tetracyclines may lead to azotemia, hyperphosphatemia, and acidosis) 2003 Thomson MICROMEDEX

TETRACYCLINES VeterinarySystemic 235 administration{R-34}, specic postreaction therapy for possible hypocalcemia has not been recommended. In horses, doses of doxycycline as low as 0.2 to 0.4 mg per kg of body weight administered intravenously have caused cardiovascular dysfunction, collapse, and death. Instead of hypotension, hypertension is reported in horses given intravenous doxycycline and is associated with the other signs of cardiovascular dysfunction seen with rapid intravenous tetracycline administration in other species. Cats Fever (anorexia, sometimes diarrhea)usually resolves within 48 hours of discontinuing oxytetracycline or tetracycline{R-39} Cattle Hemoglobinuria, transient{R-38; 45; 56} (brownish-red urine)with parenteral administration of oxytetracycline; hepatitis with fatty degeneration and/or bile stasis{R-168}with repeated high doses or concurrent debilitating conditions Horses Colitis; diarrhea, severe Psittacine birds (cockatoos, macaws, and parrots) Aspergillosis, increased risk ofmay occur with prolonged chlortetracycline treatment{R-152} Rabbits Anorexia; diarrheawith doses administered that are two times the recommended dose{R-86} women, in patients receiving high-dose intravenous therapy, and in patients with renal function impairment. However, hepatotoxicity has also occurred in patients without these predisposing conditions. Tetracycline-induced pancreatitis has also been described in association with hepatotoxicity, and without associated liver disease.

OVERDOSE
For more information in cases of overdose or unintentional ingestion, contact the American Society for the Prevention of Cruelty to Animals (ASPCA) National Animal Poison Control Center (888426-4435 or 900-443-0000; a fee may be required for consultation) and/or the drug manufacturer. Overdose of tetracyclines in animals is unusual because very high doses are often tolerated; however, effects that have been associated with overdose in animals include nephrotoxicosis and possible hepatotoxicity. Acute toxicity of intravenously-administered tetracyclines{R-33; 34} in many species is most often seen with rapid administration; however, intravenous doxycycline administration in horses has caused collapse even when administered over a 3- to 7-minute period. This reaction to intravenous tetracyclines is dose-dependent, but is not only associated with high doses. Administration of repeated high doses of intravenous or intramuscular oxytetracycline to calves or cattle can result in renal cortical tubular nephrosis. While a single intramuscular dose of 40 mg of an oxytetracycline per kg (in a 2-pyrrolidine formulation) administered to healthy calves produced no signicant toxicity{R-101}, studies have shown that 33 to 44 mg of oxytetracycline per kg of body weight a day administered intravenously or intramuscularly for 2 or more days can produce renal protein casts, tubular necrosis, and death in calves with respiratory disease{R-30; 168}. A similar dose of 33 mg oxytetracycline per kg of body weight administered intravenously for 3 days produces a rise in blood urea nitrogen and the appearance of renal casts in the urine of normal heifers{R-167}. The vehicles used in formulations, such as propylene glycol, have been linked to reduced renal blood ow and have been suspected of exacerbating adverse effects{R-29; 33}. Tetracycline and its degradation products have been reported to also cause nephrotoxicity in cattle and foals{R-29; 112}. Serious toxicity can be expected to be more likely in animals that are already compromised by disease or dehydration. Hepatotoxicity has been reported as a human side effect of tetracyclines and may be more common in pregnant women{R-167}. Hepatic fatty degeneration has been observed in people and has been induced in mice and rats given extremely high doses (100 to 300 mg of tetracycline per kg of body weight); however, fatty inltration of the liver was also observed in calves that had respiratory disease and that developed renal tubular necrosis after administration of two doses of 33 mg of oxytetracycline per kg of body weight 24 hours apart{R-168}.

THOSE INDICATING NEED FOR MEDICAL ATTENTION ONLY IF THEY CONTINUE OR ARE BOTHERSOME
Incidence more frequent All species Discoloration of teeth in young animals (yellow, brown, or grey discoloration)when administered during late pregnancy or during period of tooth development{R-39}; local tissue irritation at site of injectionwith intramuscular administration{R-37; 101} Cats and dogs Nausea or vomitingwith oral administration{R-39}, in particular, with doxycycline on an empty stomach{R-156}

HUMAN SIDE/ADVERSE EFFECTS{R-132}

In addition to the above side/adverse effects reported in animals, the following side/adverse effects have been reported in humans, and are included in the human monograph Tetracyclines (Systemic) in USP DI Volume I; these side/adverse effects are intended for informational purposes only and may or may not be applicable to the use of tetracyclines in the treatment of animals: Incidence more frequent Central nervous system toxicity; staining of infants or childrens teeth; gastrointestinal disturbances; photosensitivity Incidence less frequent Fungal overgrowth; hypertrophy of the papillae; nephrogenic diabetes insipidus; pigmentation of skin and mucous membranes Incidence rare Benign intracranial hypertension; hepatotoxicity; pancreatitis Note: Tetracycline-induced hepatotoxicity is usually seen as a fatty degeneration of the liver. It is more likely to occur in pregnant 2003 Thomson MICROMEDEX

VETERINARY DOSING INFORMATION FOR ORAL DOSAGE FORMS ONLY

For some tetracyclines, serum concentrations from animal to animal vary more widely when administered in drinking water than when administered in feed.{R-59} Unlike other tetracyclines, doxycycline can be used without dosage adjustment in animals with renal function impairment.

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236 TETRACYCLINES VeterinarySystemic

FOR PARENTERAL DOSAGE FORMS ONLY

Care should be taken to administer intravenous tetracyclines slowly and/ or dilute them in uids to avoid cardiovascular side effects.{R-3335} Intramuscular injection of oxytetracycline will affect the quality of meat for a prolonged period. Whenever possible, subcutaneous administration should be chosen{R-65}.

Canada Veterinary-labeled products: 500 mg (OTC) [Aureomycin Uterine Oblets]. Withdrawal times: Canada
Withdrawal time

DIET/NUTRITION
Oral tetracyclines are absorbed more efciently when administered without food, particularly without foods containing divalent or trivalent metals, such as milk or milk replacer. Doxycycline absorption appears to be less affected than other tetracyclines.

Species Cattle, pigs, sheep

Meat (days) 0

Packaging and storage: Store below 40 C (104 F), preferably between 15 and 30 C (59 and 86 F), unless otherwise specied by manufacturer. USP requirements: Not in USP.

FOR TREATMENT OF ADVERSE EFFECTS

Recommended treatment consists of the following: For anaphylaxis Parenteral epinephrine. Oxygen administration and respiratory support.

ORAL DOSAGE FORMS

Note: Bracketed information in the Dosage Forms section refers to uses that either are not included in U.S. product labeling or are for products not commercially available in the U.S.

FOR TREATMENT OF ACUTE REACTIONS TO INTRAVENOUS ADMINISTRATION

Recommended treatment consists of the following: Intravenous uids. Oxygen administration and respiratory support. Note: Because the specic causes of acute reactions may be difcult to immediately determine, an electrocardiogram should be monitored when possible to identify cardiac arrythmias and direct the course of therapy.

CHLORTETRACYCLINE HYDROCHLORIDE SOLUBLE POWDER USP

Usual dose: Calves1 and pigs1 Bacterial enteritis; or Bacterial pneumonia: Oral, 22 mg per kg of body weight a day, administered in the only source of drinking water.{R-17} Chickens1 Chronic respiratory disease: Oral, 400 to 800 mg per gallon of water{R-17} (approximately 22 to 59 mg per kg of body weight a day{R-143}), administered in the only source of drinking water.{R-17} Fowl cholera: Oral, 1000 mg (1 gram) per gallon of water, administered in the only source of drinking water. Synovitis: Oral, 200 to 400 mg per gallon of water (approximately 11 to 29.5 mg per kg of body weight a day), administered in the only source of drinking water.{R-17; 143} Turkeys, growing1 Enteritis: Oral, 55 mg per kg of body weight a day, administered in the only source of drinking water.{R-17} Infectious synovitis: Oral, 400 mg per gallon of water (approximately 7 to 37 mg per kg of body weight a day), administered in the only source of drinking water.{R-143} Note: Environmental and health conditions may affect the intake of water and the amount of medication consumed.{R-17} Administration of medication in food or water to animals with pneumonia or other infections can be affected by reduced feed and water intake{R-109}. Strength(s) usually available{R-58}: U.S.{R-17} Veterinary-labeled products: 25 grams per pound of powder (OTC) [Aureomycin Soluble Powder]. 64 grams per pound of powder (OTC) [AmTech Chlortetracycline HCL Soluble Powder; Aureomycin Soluble Powder Concentrate; CTC Soluble Powder Concentrate; Pennchlor 64 Soluble Powder]. All rights reserved

CHLORTETRACYCLINE ADDITIONAL DOSING INFORMATION

When possible, oral chlortetracycline should be administered 1 hour before or 2 hours after milk replacer.{R-1}

MUCOSAL DOSAGE FORMS

Note: Bracketed information in the Dosage Forms section refers to uses that either are not included in U.S. product labeling or are for products not commercially available in the U.S.

CHLORTETRACYCLINE UTERINE TABLETS

Usual dose: Note: [Cattle]Although the efcacy and safety are not currently established, an intrauterine dose of 500 to 1000 mg administered as a single dose after parturition{R-118} for the treatment of acute uterine infections is included in Canadian product labeling. [Ewes] and [sows]Although the efcacy and safety are not currently established, an intrauterine dose of 250 to 500 mg administered as a single dose after parturition{R-118} for the treatment of acute uterine infections is included in Canadian product labeling. Strength(s) usually available{R-58}: U.S. Veterinary-labeled products: Not commercially available. 2003 Thomson MICROMEDEX

TETRACYCLINES VeterinarySystemic 237 Canada Veterinary-labeled products: Not commercially available. Withdrawal times: Note: With chlortetracycline soluble powder, withdrawal times vary greatly from product to product and may differ from those listed below. See also individual manufacturers labeling. U.S.{R-17; 58}
Withdrawal time Species Calves, chickens, and turkeys Pigs Meat (days) 1 1 or 5, depending on product

Note: Product labeling with the above withdrawal time listed for poultry states that it applies when the medication is mixed at 1000 mg of chlortetracycline per gallon of drinking water. Product labeling with the above withdrawal times states that they apply when cattle and pigs are treated for a maximum of ve days and chickens and turkeys are treated for a maximum of fourteen days. Not labeled for use in laying hens, preruminating calves, or lactating dairy cattle. Packaging and storage: Store below 40 C (104 F), preferably between 15 and 30 C (59 and 86 F), in a tight container, unless otherwise specied by manufacturer. Protect from light. Preparation of dosage form: Fresh solutions should be prepared every 24 hours. When administered in a galvanized waterer, fresh solutions should be prepared every 12 hours. Incompatibilities: Administration 1 hour before or 2 hours after giving milk or milk replacers is recommended. Chlortetracycline hydrochloride soluble powder should not be mixed with milk replacers. USP requirements: Preserve in tight containers, protected from light. Label it to indicate that it is intended for oral veterinary use only. Contains the labeled amount, within 10% to +25%. Meets the requirement for Loss on drying (not more than 2.0%).{R-128}

CHLORTETRACYCLINE FOR MEDICATED FEED

Usual dose: Calves Improved feed efciency and increased weight gain for calves weighing up to 250 pounds1: Oral, 0.22 mg per kg of body weight a day administered in the feed, fed as the only ration.{R-16;
152}

Improved feed efciency and increased weight gain for calves weighing 250 to 400 pounds1: Oral, 25 to 70 mg per animal a day administered in the feed, fed as the only ration.{R-16; 152} Enteritis: Oral, 22 mg per kg of body weight a day, administered in the feed and fed as the only ration{R-152}. Note: Products made to add to calf milk replacer are indicated for treatment of bacterial enteritis and for improved feed efciency and increased weight gain only. 2003 Thomson MICROMEDEX

Cattle Anaplasmosis (treatment)1: Cattle weighing < 700 poundsOral, 350 mg per animal a day, administered in the feed and fed as the only ration{R-16; 152}. Cattle weighing 700 poundsOral 1.1 mg per kg of body weight a day, administered in the feed and fed as the only ration{R-152}. Bacterial enteritis1; or bacterial pneumonia (treatment)1: Oral, 22 mg per kg of body weight a day, administered in the feed and fed as the only ration{R-152}. Bacterial pneumonia (control)1: Oral, 350 mg per animal a day administered in the feed, fed as the only ration.{R-16; 152} Improved feed efciency and increased rate of weight gain1; or hepatic abscesses (prophylaxis)1: Oral, 70 mg a day per animal administered in the feed, fed as the only ration.{R-16; 152} [Pododermatitis (prophylaxis)]: Oral, 0.22 mg per kg of body weight a day or 70 mg per animal a day, administered in the feed and fed as the only ration{R-116}. Chickens Chronic respiratory disease: Oral, 200 to 400 grams per ton of feed, fed as the only ration.{R-16; 152} Escherichia coli infections1: Oral, 500 grams per ton of feed, fed as the only ration.{R-16; 115} Improved feed efciency and increased rate of weight gain: Oral, 10 to 50 grams per ton of feed, fed as the only ration.{R-152} Synovitis1: Oral, 100 to 200 grams per ton of feed, fed as the only ration{R-152}. [Enteritis; or increased egg production or hatchability]: Oral, 100 to 200 grams per ton of feed (110 to 220 grams per metric ton [1000 kg] of feed), fed as the only ration. Note: Canadian product labeling also lists the above dose for feed efciency. Cockatoos, macaws, and parrotsPsittacosis1: Oral, 10 mg per gram of mash or feed, administered continuously for 45 days as the only ration{R-152}. Ducks1Fowl cholera: Oral, 200 to 400 grams per ton of feed (approximately 17.6 to 61.6 mg per kg of body weight a day) administered in the feed, fed as the only ration.{R-16; 152} Pigs Cervical abscesses (prophylaxis)1: Oral, 50 to 100 grams per ton of feed, fed as the only ration.{R-115} Bacterial enteritis; or bacterial pneumonia1: Oral, 22 mg per kg of body weight a day, administered in the only ration{R-152}. Improved feed efciency and increased rate of weight gain: Oral, 10 to 50 grams per ton of feed, fed as the only ration.{R-152} For reducing the shedding of leptospirosis and the incidence of associated abortion1: Oral, 400 grams per ton of feed, fed as the only ration for fourteen days.{R-152} Note: Canadian product labeling lists a dose in the treatment of enteritis and for increasing feed efciency and improving weight gain of 50 to 100 grams per ton of feed (55 to 110 grams per metric ton [1000 kg] of feed), fed as the only ration{R-116}. SheepVibrionic abortion (prophylaxis)1: Oral, 80 mg per animal a day administered in the feed, fed as the only ration continuously during pregnancy.{R-16; 152} Sheep, growing1Improved feed efciency and increased rate of weight gain1: Oral, 20 to 50 grams per ton of feed, fed as the only ration.{R-16}

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238 TETRACYCLINES VeterinarySystemic Turkeys Bacterial enteritis: Oral, 55 mg per kg of body weight a day, administered in the only ration{R-16; 152}. Note: Canadian product labeling lists a dose in the treatment of enteritis of 100 to 200 grams per ton of feed (110 to 220 grams per metric ton [1000 kg] of feed), fed as the only ration{R-116}. Hexamitiasis1: Oral, 400 grams per ton of feed, fed as the only ration{R-16; 152}. Synovitis1: Oral, 200 grams per ton of feed, fed as the only ration{R-16; 152}. [Increased egg production; or sinusitis (prophylaxis)]: Oral, 100 to 200 grams per ton of feed (110 to 220 grams per metric ton [1000 kg] of feed), fed as the only ration. Turkeys, growing, less than 4 weeks of ageParatyphoid1: Oral, 400 grams per ton of feed, fed as the only ration.{R-115} Turkeys, growingImproved efciency or; increased rate of weight gain: Oral 10 to 50 grams per ton of feed, fed as the only ration{R-16; 152} . [Lambs]Enterotoxemia: Oral, 20 grams per ton of feed (22 grams per metric ton [1000 kg] of feed), fed as the only ration. Note: Environmental and health conditions may affect the intake of water and the amount of medication consumed.{R-17} Administration of medication in food or water to animals with pneumonia or other infections can be affected by reduced feed and water intake{R-109}.
{R-58}

a day, and to cattle at a dose of 350 mg per animal a day or 1.1 mg per kg of body weight a day in feed, to chickens at 500 grams or more per ton of feed for a maximum of ve days, to pigs at 400 grams or less per ton of feed or 22 mg per kg of body weight a day for up to fourteen days, and to sheep when fed 80 mg per animal a day or 20 to 50 grams per ton of feed. Not labeled for use in preruminating calves, lactating dairy cows, or horses to be used for food.{R-16} Some products are not labeled for use in chickens, ducks, or turkeys producing eggs for human consumption.{R-152} When fed at 22 mg per kg of body weight a day:
Withdrawal time Species Calves, cattle Meat (days) 0 or 10, depending on product

Note: Not labeled for use in lactating dairy cows.{R-16} Canada

Withdrawal time Species Calves, cattle Chickens, pigs, turkeys Lambs Meat (days) 5 7 4

: Strength(s) usually available U.S. Veterinary-labeled products: 110 grams per kg of premix (OTC) [Aureomycin 50 Granular; ChlorMax 50; CTC 50; Pennchlor 50G; Pennchlor 50 Meal]. 154 grams per kg of premix (OTC) [Pennchlor 70 Meal]. 198 grams per kg of premix (OTC) [Aureomycin 90 Granular; Pennchlor 90G]. 220 grams per kg of premix (OTC) [Aureomycin 100 Granular; CLTC 100 MR; Pennchlor 100 Hi-Flo Meal; Pennchlor 100MR]. Canada Veterinary-labeled products: 110 grams per kg of premix (OTC) [Aureomycin 110G; Chlor 50; Chlorosol-50]. 220 grams per kg of premix (OTC) [Aureomycin 220G; Chlor 100]. Withdrawal times{R-58}: Note: With chlortetracycline oral premix, withdrawal times vary greatly from product to product and may differ from those listed below. See also individual manufacturers labeling. U.S.{R-123}
Withdrawal time Species Calves, cattle Chickens Pigs, sheep, turkeys Meat (days) 0, 1, or 2, depending on product and dose 0 or 1, depending on product and dose 0 Eggs (hours)

Note: Product labeling listing the above withdrawal times states that they apply when the product is fed to chickens and turkeys at 55 to 220 mg per kg of feed, to pigs at 55 to 110 mg per kg of feed, to calves at 55 mg per kg of feed, to lambs at 22 mg per kg of feed, and to cattle at 0.22 mg per kg of body weight or 70 mg per animal. Not labeled for use in lactating diary cows.

Packaging and storage: Store below 40 C (104 F), preferably between 15 and 30 C (59 and 86 F), unless otherwise specied by manufacturer. USP requirements: Not in USP.

Not included in Canadian product labeling or product not commercially available in Canada.

DOXYCYCLINE SUMMARY OF DIFFERENCES

Pharmacology/pharmacokinetics: More completely absorbed from the gastrointestinal tract than the tetracyclines developed earlier and absorption is less likely to be affected by food or calcium or other divalent or trivalent metals. Doxycycline is also more lipid-soluble than other tetracyclines. In dogs, doxycycline is eliminated primarily through intestinal excretion.{R-63} Precautions: Medical considerationsDoxycycline is only partially eliminated renally and is less likely to accumulate in animals with renal function impairment; it can be used without dosage adjustment. Side/adverse effects: HorsesIntravenous administration can lead to cardiovascular dysfunction and death.{R-34}

0 for some products

Note: Product labeling listing the above withdrawal times states that they apply when product is fed to calves at a dose of up to 70 mg per animal

2003 Thomson MICROMEDEX

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TETRACYCLINES VeterinarySystemic 239

ORAL DOSAGE FORMS

Note: Bracketed information in the Dosage Forms section refers to uses that either are not included in U.S. product labeling or are for products not commercially available in the U.S. The dosing and strengths of the dosage forms available are expressed in terms of doxycycline base.

volume, pH (5.06.5, in the suspension constituted as directed in the labeling), and Water (not more than 3.0%).{R-128}

DOXYCYCLINE CALCIUM ORAL SUSPENSION USP

Usual dose: See Doxycycline for Oral Suspension USP. Strength(s) usually available: U.S. Veterinary-labeled products: Not commercially available. Human-labeled products: 10 mg (base) per mL (Rx) [Vibramycin]. Canada Veterinary-labeled products: Not commercially available. Human-labeled products: Not commercially available. Packaging and storage: Store below 40 C (104 F), preferably between 15 and 30 C (59 and 86 F), unless otherwise specied by manufacturer. Store in a tight, light-resistant container. Protect from freezing. Auxiliary labeling: Shake well. USP requirements: Preserve in tight, light-resistant containers. Prepared from Doxycycline Hyclate, and contains one or more suitable buffers, colors, diluents, avors, and preservatives. Contains an amount of doxycycline calcium equivalent to the labeled amount of doxycycline, within 10% to +25%. Meets the requirements for Identication, Uniformity of dosage units (single-unit containers), Deliverable volume, and pH (6.58.0).{R-128}

DOXYCYCLINE FOR ORAL SUSPENSION USP

Usual dose: [Rocky Mountain spotted fever]1Dogs: Oral, 5 mg per kg of body weight every twelve hours{R-151} for fourteen days. Note: [Cats]1Although the efcacy has not been established, an oral dose of 5 mg per kg of body weight every twelve hours for twenty-one days has been used in the treatment of feline infectious anemia{R-147; 151} . For chlamydial infections or respiratory infections in cats, a dose of 5 mg per kg of body weight every twelve hours or 10 mg per kg of body weight every twenty-four hours has been used{R-151}. [Dogs]1Although the efcacy has not been established, an oral dose of 10 mg per kg of body weight every twelve hours for two to three weeks has been used for the treatment of ehrlichiosis; this regimen is based on a clinical trial that found, however, that only two out of ve dogs treated with the above dose and a twenty-four-hour dosing interval for one week were cleared of Ehrlichia canis, as shown by negative blood and tissue cultures{R-40}. A dose of 5 mg per kg of body weight every twelve hours for six to eight weeks has been used in the treatment of ehrlichiosis to decrease the risk of side effects{R-176}; however, the efcacy of this regimen has not been conrmed. Retesting serum immunoourescent antibody for E. canis two months posttreatment is recommended, and retreatment should be started if values have not dropped signicantly.{R-40} Strength(s) usually available: U.S. Veterinary-labeled products: Not commercially available. Human-labeled products: 5 mg (base) per mL, when reconstituted according to manufacturers instructions (Rx) [Vibramycin]. Canada Veterinary-labeled products: Not commercially available. Human-labeled products: Not commercially available. Packaging and storage: Prior to reconstitution, store below 40 C (104 F), preferably between 15 and 30 C (59 and 86 F), unless otherwise specied by manufacturer. Store in a tight, light-resistant container. Stability: After reconstitution, suspensions retain their potency for 14 days at room temperature. Auxiliary labeling: Shake well. USP requirements: Preserve in tight, light-resistant containers. Contains one or more suitable buffers, colors, diluents, avors, and preservatives. Contains the labeled amount, within 10% to +25% when constituted as directed. Meets the requirements for Identication, Uniformity of dosage units (single-unit containers), Deliverable 2003 Thomson MICROMEDEX

DOXYCYCLINE HYCLATE CAPSULES USP

Usual dose: See Doxycycline for Oral Suspension USP. Strength(s) usually available: U.S.{R-135} Veterinary-labeled products: Not commercially available. Human-labeled products: 50 mg (base) (Rx) [Vibramycin; generic]. 100 mg (base) (Rx) [Vibramycin; generic]. Canada Veterinary-labeled products: Not commercially available. Human-labeled products: 100 mg (base) (Rx) [Alti-Doxycycline; Apo-Doxy; Doxycin; Doxytec (lactose); Novo-Doxylin; Nu-Doxycycline; Vibramycin]. Packaging and storage: Store below 40 C (104 F), preferably between 15 and 30 C (59 and 86 F), unless otherwise specied by manufacturer. Store in a tight, light-resistant container. USP requirements: Preserve in tight, light-resistant containers. Contain an amount of doxycycline hyclate equivalent to the labeled amount of doxycycline, within 10% to +20%. Meet the requirements for Identication, Dissolution (80% in 30 minutes in water in

All rights reserved

240 TETRACYCLINES VeterinarySystemic Apparatus 2 at 75 rpm), Uniformity of dosage units, and Water (not more than 8.5%).{R-128} amount of doxycycline, within 10% to +20%. Meet the requirements for Identication, Dissolution (85% in 90 minutes in water in Apparatus 2 at 75 rpm), Uniformity of dosage units, and Water (not more than 5.0%).{R-128}

DOXYCYCLINE HYCLATE DELAYED-RELEASE CAPSULES USP

Note: Delayed-release capsules must be swallowed whole and, in general, absorption of delayed-release dosage forms is unpredictable in animals. Doxycycline Hyclate Delayed-release Capsules USP are not recommended for use in animals. Strength(s) usually available: U.S. Veterinary-labeled products: Not commercially available. Human-labeled products: 100 mg (base) (Rx) [Doryx (lactose)]. Canada Veterinary-labeled products: Not commercially available. Human-labeled products: Not commercially available. Packaging and storage: Store below 40 C (104 F), preferably between 15 and 30 C (59 and 86 F), unless otherwise specied by manufacturer. Store in a tight, light-resistant container. USP requirements: Preserve in tight, light-resistant containers. The label indicates that the contents of the Capsules are enteric-coated. Contain an amount of doxycycline hyclate equivalent to the labeled amount of doxycycline, within 10% to +20%. Meet the requirements for Identication, Drug release (Acid stage: 50% [Level 1 and Level 2] in 20 minutes in 0.06 N hydrochloric acid in Apparatus 1 at 50 rpm; Buffer stage: 85% in 30 minutes in neutralized phthalate buffer [pH 5.5] in Apparatus 1 at 50 rpm), Uniformity of dosage units, and Water (not more than 5.0%).{R-128}
1

Not included in Canadian product labeling or product not commercially available in Canada.

PARENTERAL DOSAGE FORMS

Note: Bracketed information in the Dosage Forms section refers to uses that either are not included in U.S. product labeling or are for products not commercially available in the U.S. The dosing and strengths of the dosage forms available are expressed in terms of doxycycline base (not the hyclate salt).

DOXYCYCLINE FOR INJECTION USP

Usual dose: Note: [Dogs]1Although the efcacy has not been established, an intravenous dose of 3 to 5 mg (base) per kg of body weight every twelve hours has been used in the treatment of susceptible bacterial infections.{R-70} This dose is based on pharmacokinetic studies. Size(s) usually available: U.S. Veterinary-labeled products: Not commercially available. Human-labeled products: 100 mg (base) (Rx) [Vibramycin]. 200 mg (base) (Rx) [Vibramycin]. Canada Veterinary-labeled products: Not commercially available. Human-labeled products: Not commercially available. Packaging and storage: Prior to reconstitution, store below 40 C (104 F), preferably between 15 and 30 C (59 and 86 F), unless otherwise specied by manufacturer. Protect from light.

DOXYCYCLINE HYCLATE TABLETS USP

Usual dose: See Doxycycline for Oral Suspension USP. Strength(s) usually available: U.S.{R-135} Veterinary-labeled products: Not commercially available. Human-labeled products: 100 mg (base) (Rx) [Vibra-Tabs; generic]. Canada Veterinary-labeled products: Not commercially available. Human-labeled products: 100 mg (base) (Rx) [Alti-Doxycycline; Apo-Doxy-Tabs; Doxycin; NovoDoxylin; Nu-Doxycycline; Vibra-Tabs; Vibra-Tabs C-Pak]. Packaging and storage: Store below 40 C (104 F), preferably between 15 and 30 C (59 and 86 F), unless otherwise specied by manufacturer. Store in a tight, light-resistant container. USP requirements: Preserve in tight, light-resistant containers. Contain an amount of doxycycline hyclate equivalent to the labeled 2003 Thomson MICROMEDEX

Preparation of dosage form: To prepare initial dilution for intravenous use, 10 mL of sterile water for injection or other suitable diluent (see manufacturers package insert) should be added to each 100-mg vial or 20 mL of diluent should be added to each 200-mg vial. The resulting solution containing the equivalent of 100 to 200 mg of doxycycline may be further diluted in 100 to 1000 mL or in 200 to 2000 mL of suitable diluent, respectively.

Stability: After reconstitution, intravenous infusions of doxycycline hyclate retain their potency for twelve hours at room temperature or for seventy-two hours if refrigerated at concentrations of 100 mcg (0.1 mg) to 1 mg per mL in suitable uids (see manufacturers package insert). Intravenous infusions of doxycycline hyclate retain their potency for six All rights reserved

TETRACYCLINES VeterinarySystemic 241 hours at room temperature at concentrations of 100 mcg (0.1 mg) to 1 mg per mL in lactated Ringers injection or 5% dextrose and lactated Ringers injection. Infusions must be protected from direct sunlight during administration. If frozen immediately after reconstitution with sterile water for injection, solutions at concentrations of 10 mg per mL retain their potency for up to eight weeks at 20 C (4 F). Once thawed, solutions should not be refrozen. Additional information: Concentrations of less than 100 mcg (0.1 mg) per mL or greater than 1 mg per mL are not recommended. Infusions may be administered over a one- to four-hour period. Rapid administration should be avoided. Intramuscular or subcutaneous administration is not recommended. USP requirements: Preserve in Containers for Sterile Solids, protected from light. Contains an amount of doxycycline hyclate equivalent to the labeled amount of doxycycline, within 10% to +20%. Meets the requirements for Constituted solution, Identication, Bacterial endotoxins, Sterility, pH (1.83.3, in the solution constituted as directed in the labeling), Loss on drying (not more than 4.0%), and Particulate matter.{R-128} Withdrawal times: Canada
Withdrawal time Species Cows Meat (days) 18 Milk (hours) 24

Packaging and storage: Store below 40 C (104 F), preferably between 15 and 30 C (59 and 86 F), unless otherwise specied by manufacturer. Preparation of dosage form: Warm to body temperature to ease administration.{R-12} Stability: Preparation may darken on standing, but the potency remains unaffected.{R-12} USP requirements: Not in USP.

ORAL DOSAGE FORMS

Note: Bracketed information in the Dosage Forms section refers to uses that either are not included in U.S. product labeling or are for products not commercially available in the U.S.

Not included in Canadian product labeling or product not commercially available in Canada.

OXYTETRACYCLINE HYDROCHLORIDE SOLUBLE POWDER USP OXYTETRACYCLINE ADDITIONAL DOSING INFORMATION

When possible, oral oxytetracycline should be administered 1 hour before or 2 hours after milk replacer.{R-1} Usual dose: BeesAmerican and European foul brood: Oral, 200 mg per colony once every four to ve days for three treatments in the spring and/or fall. Powder is dusted on the outer parts of the frames or mixed as a syrup and fed in feeder pails or in the combs.{R-6; 61;
134}

MUCOSAL DOSAGE FORMS

Note: Bracketed information in the Dosage Forms section refers to uses that either are not included in U.S. product labeling or are for products not commercially available in the U.S.

OXYTETRACYCLINE HYDROCHLORIDE UTERINE SUSPENSION

Usual dose: Note: [Cows]Although the efcacy and safety are not currently established, an intrauterine dose of 3.9 to 4.4 mg per kg of body weight, administered as a single dose{R-12}, is included in Canadian product labeling for the treatment of uterine infections. Strength(s) usually available{R-58}: U.S. Veterinary-labeled products: Not commercially available. Canada{R-12} Veterinary-labeled products: 50 mg per mL (Rx) [Kelamycin].

Note: Honey from infected colonies should not be used for the preparation of medicated syrup. Calves and cattle Bacterial enteritis: Oral, 22 mg per kg of body weight every twentyfour hours, administered in the only source of drinking water or as a drench.{R-61} Bacterial pneumonia1: Oral, 22 mg per kg of body weight every twenty-four hours, administered in the only source of drinking water or as a drench.{R-61} Chickens Chronic respiratory disease; or fowl cholera: Oral, 400 to 800 mg per gallon of water (approximately 22 to 59 mg per kg of body weight a day), administered as the only source of drinking water.{R-11} Synovitis1: Oral, 200 to 400 mg per gallon of water, administered as the only source of drinking water.{R-11; 13; 61} [Bacterial enteritis]: Oral, 200 to 400 mg per gallon of water, administered as the only source of drinking water. Pigs Bacterial enteritis: Oral, 22 mg per kg of body weight, administered in the only source of drinking water.{R-11; 13; 61} Bacterial pneumonia: Oral, 22 mg per kg of body weight, administered in the only source of drinking water{R-6; 13}.

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242 TETRACYCLINES VeterinarySystemic Leptospirosis1: Oral, 22 mg per kg of body weight, administered in the only source of drinking water{R-6; 13}. Sheep Bacterial enteritis: Oral, 22 mg per kg of body weight every twenty-four hours, administered in the only source of drinking water.{R-61} Bacterial pneumonia1: Oral, 22 mg per kg of body weight every twenty-four hours, administered in the only source of drinking water{R-13}. Turkeys, growingBacterial enteritis: Oral, 55 mg per kg of body weight a day for seven to fourteen days.{R-7; 11; 13} Turkeys Hexamitiasis1: Oral, 200 to 400 mg per gallon of water (approximately 3.5 to 37 mg per kg of body weight a day), administered as the only source of drinking water.{R-11} Synovitis1: Oral, 400 mg per gallon of water (7 to 37 mg per kg of body weight a day), administered as the only source of drinking water.{R-7; 11; 13} Note: Environmental and health conditions may affect the intake of water and the amount of medication consumed.{R-17} Administration of medication by food or water to animals with pneumonia or other infections can be affected by reduced feed and water intake{R-109}.
Withdrawal time Species Calves, cattle, sheep Chickens Pigs Turkeys Meat (days) 5 0 0, 5, or 13, depending on product 0 or 5, depending on product

Note: Product labeling listing the above withdrawal times states that treatment of calves, cattle, pigs, and sheep should be for a maximum of ve days and chickens and turkeys for a maximum of fourteen days. Not labeled for use in lactating dairy cattle, preruminating calves, or birds producing eggs for human consumption. Canada{R-54}
Withdrawal time Species Calves, pigs, sheep Chickens, turkeys Meat (days) 10 7

Strength(s) usually available{R-58}: U.S. Veterinary-labeled products: 25 grams per pound of powder (OTC) [AmTech Oxytetracycline HCL Soluble Powder; Terramycin Soluble Powder; Terra-Vet Soluble Powder]. 166 grams per pound of powder (OTC) [Oxytet Soluble; Tetravet-CA; Tetroxy HCA Soluble Powder]. 343 grams per pound of powder (OTC) [Agrimycin-343; AmTech Oxytetracycline HCL Soluble Powder-343; Oxytet-343 Water Soluble Powder; Pennox 343 Soluble Powder; Terramycin-343 Soluble Powder; Terra-Vet Soluble Powder 343; generic]. Canada Veterinary-labeled products: 11 mg per gram of powder (OTC) [Foul Brood Mix]. 55 mg per gram of powder (OTC) [Oxytetra-A; Oxytet-25-S]. 62.5 mg per gram of powder (OTC) [Oxysol-62.5; Oxytet-SP]. 220 mg per gram of powder (OTC) [Oxy Tetra Forte]. 250 mg per gram of powder (OTC) [Oxy 250; Oxysol-250; Oxytet250 Concentrate]. 1 gram per gram of powder (OTC) [Oxy 1000; Oxysol-1000].

Note: Product labeling listing the above withdrawal times states that they apply to doses of 5 to 10 mg per kg of body weight every twelve hours for three to ve days for calves, 10 mg per kg of body weight every twelve hours for three or four days for pigs, 50 mg per L of drinking water for three or four days for chickens and turkeys, and 5 mg per kg of body weight every twelve hours for three or four days for sheep. These products are not labeled for use in lactating dairy cattle or birds producing eggs for human consumption{R-54}.
Withdrawal time Species Cattle Meat (days) 10 Milk (hours) 60 or 96, depending on product 60 or 120, depending on product Eggs (hours)

Chickens, turkeys Pigs, sheep

10

Note: Some products are not labeled for use in lactating cattle and some are not labeled for use in poultry laying eggs for human consumption. Product labeling listing the above withdrawal times states that they apply to doses of 22 mg per kg of body weight a day for ve days for calves and cattle, 33 mg per kg of body weight a day for pigs, and 111 mg per L of water for chickens and turkeys. Packaging and storage: Store below 40 C (104 F), preferably between 15 and 30 C (59 and 86 F), unless otherwise specied by manufacturer. Preparation of dosage form: Oxytetracycline soluble powder can be mixed with water and administered as a drench. Fresh drinking water and drench solutions should be prepared daily as recommended by the manufacturer.{R-11} For bees, medication is mixed with powdered sugar and dusted on the frames or mixed with sugar and water to form a paste or syrup and applied as recommended by manufacturer.{R-54} Stability: Stable for twenty-four hours.{R-11}

Withdrawal times{R-58}: Note: With oxytetracycline soluble powder, withdrawal times vary greatly from product to product and may differ from those listed below. See also individual manufacturer labeling. Bees: To avoid contamination of honey, oxytetracycline hydrochloride soluble powder should be fed early in the spring or fall before the main honey ow begins. Honey stored during treatment should be removed following last medication and cannot be used for human food.{R-61}

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TETRACYCLINES VeterinarySystemic 243 Incompatibilities: Milk replacerOxytetracycline is bound to milk replacer at a rate of 63%; this is a binding that is not readily reversible.{R-111} Administration of oral oxytetracycline in milk replacer will result in lower bioavailability.{R-111} USP requirements: Preserve in well-closed containers. A mixture of Oxytetracycline Hydrochloride and one or more suitable excipients. Label it to indicate that it is for oral veterinary use only. Contains the labeled amount, within 10%. Meets the requirements for Identication, pH (1.53.0, in the solution obtained as directed in the labeling), Loss on drying (not more than 3.0%, and Minimum ll.{R-128} Chronic respiratory disease (control): Oral, 400 grams per ton of feed, fed as the only ration{R-117}. Note: Canadian labeling lists a dose of 100 grams per ton (110 grams per metric ton [1000 kg]) in the treatment of chronic respiratory disease{R-26}. Fowl cholera1; or synovitis: Oral, 100 to 200 grams per ton of feed, fed as the only ration{R-117}. Improved feed efciency1 and increased weight gain1: Oral, 10 to 50 grams per ton of feed, fed as the only ration{R-117}. LobstersGaffkemia: Oral, 2.2 grams per kg of feed, fed as the only ration{R-27; 124}. Pigs Bacterial enteritis: Oral, 22 mg per kg of body weight a day, administered in the feed and fed as the only ration{R-117}. Note: Canadian labeling lists a dose of 100 grams per ton (110 grams per metric ton [1000 kg]) in the treatment of bacterial enteritis{R-26}. For reducing the shedding of leptospirosis and reducing the incidence of associated abortions: Oral, 22 mg per kg of body weight per animal a day, administered in the feed and fed as the only ration{R117} . Note: Canadian labeling lists a dose of 500 grams per ton (550 grams per metric ton [1000 kg]) in the treatment of leptospirosis{R-26}. Improved feed efciency and increased weight gain1: Oral, 10 to 50 grams per ton of feed, fed as the only ration{R-117}. [Atrophic rhinitis]: Oral, 50 grams per ton (55 grams per metric ton [1000 kg]) of feed, fed as the only ration{R-26}. Note: Different feeding regimens will result in differences in actual mg of oxytetracycline per kg of body weight consumed by individual pigs{R-110}. Therapeutic serum concentrations of > 0.5 mcg/mL were not produced when 550 mg of oxytetracycline per kg of feed was administered to 30-kg pigs in one study{R-107}. An oral dose of 54 to 108 mg per kg of body weight a day (concentrations of 1600 and 2400 mg of oxytetracycline per kg of feed) was reported to be required to produce 1 mcg per mL serum concentrations in pigs{R-110}. Salmon, Pacic1Marking of skeletal tissue: Oral, 250 mg per kg of body weight a day{R-27}. Salmonids[Cold water disease]; [columnaris disease]; [enteric redmouth disease]; furunculosis; hemorrhagic septicemia1; pseudomonas disease1; or ulcer disease: Oral, 55 to 82.5 mg per kg of body weight a day, administered in the feed and fed as the only ration{R-27; 124}. Sheep1 Bacterial enteritis; or bacterial pneumonia: Oral 22 mg per kg of body weight per animal a day, administered in the feed and fed as the only ration{R-117}. Improved feed efcacy and increased weight gain: Oral, 10 to 20 grams per ton of feed, fed as the only ration{R-117}. Turkeys Bacterial enteritis (bluecomb): Oral, 55 mg per kg of body weight a day, administered in the feed and fed as the only ration{R-117}. Note: Canadian labeling lists a dose of 100 grams per ton (110 grams per metric ton [1000 kg]) of feed, fed as the only ration{R-26}. Hexamitiasis1: Oral, 100 grams per ton of feed, fed as the only ration{R-117}.

OXYTETRACYCLINE FOR MEDICATED FEED

Usual dose: Bees, honeyFoul brood: Oral, 200 mg per colony of bees every four to ve days in the spring and/or fall{R-117}. Powder is dusted on the outer parts of the frames or mixed as a syrup and fed in feeder pails or in the combs{R-117}. Note: Honey from infected colonies should not be used for the preparation of medicated syrup{R-117}. Calves Bacterial enteritis: Oral, 22 mg per kg of body weight a day{R-117}. Note: Canadian labeling lists a dose of 50 grams per ton (55 grams per metric ton [1000 kg]) in the treatment of bacterial enteritis{R-26}. Improved feed efciency1; or increased weight gain1 in calves weighing less than 113.6 kg (250 pounds): Oral 0.11 to 0.22 mg per kg of body weight a day, administered in the feed and fed as the only ration{R-117}. Improved feed efciency1; or increased weight gain1 in calves weighing 113 to 181 kg (250 to 400 pounds): Oral, 25 mg per animal a day, administered in the feed and fed as the only ration{R-117}. Note: According to product labeling, when administered in milk replacer, the 22 mg per kg of body weight dose is indicated in the treatment of bacterial enteritis only{R-117}. Catsh1Hemorrhagic septicemia; or pseudomonas disease: Oral 55 to 82.5 mg per kg of body weight a day for a maximum of ten days, administered in the feed and fed as the only ration{R-27}. Cattle Bacterial enteritis1: Oral, 22 mg per kg of body weight a day{R-117}. Bacterial pneumonia, acute (prophylaxis and treatment)1: Oral, 500 to 2000 mg (2 grams) per animal a day, administered in the feed and fed as the only ration for three to ve days prior to shipping and three to ve days after shipping{R-122; 117}. Bacterial pneumonia (treatment)1: Oral, 22 mg per kg of body weight a day, administered in feed and fed as the only ration for seven to fourteen days{R-117}. Improved feed efciency1; or increased weight gain1, in growing cattle weighing over 400 pounds: Oral, 75 mg per animal a day, administered in the feed and fed as the only ration{R-117}. [Bloat]Oral, 75 mg per animal a day, administered in the feed and fed as the only ration{R-26}. Chickens Chronic respiratory disease, specically air sacculitis, reduction in associated mortality1: Oral, 500 grams per ton of feed, fed as the only ration{R-117}.

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244 TETRACYCLINES VeterinarySystemic Improved feed efciency1 and increased weight gain1: Oral, 10 to 50 grams per ton of feed, fed as the only ration{R-117}. Synovitis: Oral, 200 grams per ton of feed, fed as the only ration{R-26}. [Sinusitis]: Oral, 100 grams per ton (110 grams per metric ton [1000 kg]) of feed, fed as the only ration{R-26}. [Lambs] Bacterial enteritis: Oral, 100 grams per ton (110 grams per metric ton [1000 kg]) of feed, fed as the only ration{R-26}. Enterotoxemia: Oral, 20 grams per ton (22 grams per metric ton [1000 kg]) of feed, fed as the only ration{R-26}. Note: Environmental and health conditions may affect the intake of water and the amount of medication consumed.{R-17} Administration of medication by food or water to animals with pneumonia or other infections can be affected by reduced feed and water intake{R-109}. Strength(s) usually available{R-58}: U.S.{R-62; 122} Veterinary-labeled products: 110 grams per kg of premix (OTC) [OTC 50; OXTC 50; Pennox 50 Meal; Terramycin 50]. 220 grams per kg of premix (OTC) [OXTC 100; Pennox 100 Hi-Flo Meal; Pennox 100-MR; Terramycin 100; Terramycin 100 For Fish]. 440 grams per kg of premix (OTC) [OXTC 200; Pennox 200 Hi-Flo Meal; Terramycin 200]. Canada{R-26; 55} Veterinary-labeled products: 110 grams per kg of premix (OTC) [Oxy-110; Oxysol-110; Oxytetracycline 50; Terramycin-50]. 220 grams per kg of premix (OTC) [Oxy-220; Oxysol-220; Oxytetracycline 100; Terramycin-100]. 440 grams per kg of premix (OTC) [Oxy-440; Oxysol-440; Oxytetracycline 200; Terramycin-200; Terramycin-Aqua]. Withdrawal times{R-58}: Note: BeesTo avoid contamination of honey, oxytetracycline hydrochloride soluble powder should be fed early in the spring or fall before the main honey ow begins. Honey stored during therapy should be removed following the last medication and should not be used for human food{R-117}. U.S.{R-27; 186} When fed 500 grams per ton of feed:
Withdrawal time Species Chickens If fed low-calcium feed Meat (days) 1 3

When fed up to 200 grams per ton of feed:

Withdrawal time Species Turkeys Meat (days) 0

Note: Not labeled for turkeys producing eggs for human consumption{R-117}. When fed to turkeys at 200 grams or more per ton of feed, and to cattle, pigs, and sheep at 22 mg/kg:
Withdrawal time Species Bees Catsh Calves (some products), cattle, sheep, turkeys Lobsters Pacic salmon Pigs Salmonids Meat (days) 42 (honey) 21 5 30 7 0 or 5, depending on product 21

Note: Not labeled for poultry producing eggs for human consumption{R-117}. A withdrawal time has not been established for preruminating calves for some products{R-117}. Canada{R-26; 55} Note: BeesWithdraw medication 4 weeks prior to honey ow.
Withdrawal time Species Bees Calves, cattle Chickens, pigs, turkeys Lambs Lobsters Salmonids, 10 C or warmer Salmonids, below 10 C Meat (days) 28 (honey) 5 7 4 30 40 80

Note: Not labeled for chickens producing eggs for human consumption{R117} . Withdrawal time has not been established for preruminating calves{R-117}. Packaging and storage: Store below 40 C (104 F), preferably between 15 and 30 C (59 and 86 F), unless otherwise specied by manufacturer. Preparation of dosage form: For use in dry feeds only, as indicated on manufacturers labeling. Should not be used without diluting.{R-122} Incompatibilities: Salmonid and lobster feeds having a high ash content (calcium, copper, iron, or zinc) may bind oxytetracycline and prevent absorption. Oxytetracycline also should not be administered with feeds containing bentonite.{R-124} Additional information: U.S.For sh, this medication should not be used when water temperature is below 16.7 C (62 F) for catsh or below 9 C (48.2 F) for salmonids.{R-62} USP requirements: Not in USP. All rights reserved

Note: Not labeled for chickens producing eggs for human consumption{R117} . When fed up to 400 grams per ton of feed:
Withdrawal time Species Chickens If fed low-calcium feed Meat (days) 0 3

Note: Not labeled for chickens producing eggs for human consumption{R-117}. 2003 Thomson MICROMEDEX

TETRACYCLINES VeterinarySystemic 245

OXYTETRACYCLINE TABLETS USP

Usual dose: Bacterial enteritis1; or Bacterial pneumonia1Calves: ControlOral, 5.5 mg per kg of body weight every twelve hours.{R-2;
60}

TreatmentOral, 11 mg per kg of body weight every twelve hours for up to four days.{R-2; 60} Strength(s) usually available{R-58}: U.S.{R-2; 60} Veterinary-labeled products: 250 mg (OTC) [Terramycin Scours Tablets]. 500 mg (OTC) [Oxy 500 Calf Bolus]. 1000 mg (OTC) [Oxy 1000 Calf Bolus]. Canada Veterinary-labeled products: Not commercially available. Withdrawal times: U.S.{R-60}
Withdrawal time Species Calves Meat (days) 0 or 7, depending on product

Note: Product labeling with the above withdrawal time states that it applies when calves are treated for up to four days. Products are not labeled for use in preruminating calves{R-58}. USP requirements: Preserve in tight, light-resistant containers. Contain the labeled amount, within 10% to +20%. Meet the requirements for Identication, Dissolution (75% in 45 minutes in 0.1 N hydrochloric acid in Apparatus 1 at 100 rpm), Uniformity of dosage units, and Water (not more than 7.5%).{R-128}
1

Not included in Canadian product labeling or product not commercially available in Canada.

PARENTERAL DOSAGE FORMS

Note: Bracketed information in the Dosage Forms section refers to uses that either are not included in U.S. product labeling or are for products not commercially available in the U.S.

OXYTETRACYCLINE INJECTION USP

Usual dose: CattleActinobacillosis1; [bacterial arthritis]; bacterial enteritis; [blackleg/malignant edema]; diphtheria1; [leptospirosis]; [mastitis]; [omphalophlebitis]; [peritonitis]; pneumonia and bovine respiratory disease complex; pododermatitis; skin and soft tissue infections1; or uterine infections: Intramuscular or intravenous, 6.6 to 11 mg per kg of body weight every twenty-four hours.{R-24; 121} Note: For uterine infections in cattle, an [intravenous dose of 11 mg per kg of body weight every eight to twelve hours]1 has been recommended, based on distribution studies{R-104}. The shortened dosing interval will require an extended withdrawal time{R-14}. 2003 Thomson MICROMEDEX

For pneumonia caused by Pasteurella, an [intravenous dose of 11 mg per kg of body weight every twelve hours]1 has been recommended, based on pharmacokinetic changes in calves with induced pneumonia{R-106}; however, this regimen is usually reserved for serious cases. The shortened dosing interval will require an extended withdrawal time{R-14}. For [thromboembolic meningoencephalitis]1, a dose of 11 mg per kg of body weight every twenty-four hours has been recommended; however, there are no specic research data to support the efcacy of this use{R-178; 179}. [Pigs]Bacterial enteritis; bacterial pneumonia; erysipelas; leptospirosis; mastitis; or uterine infections: Intramuscular or intravenous, 6.6 to 11 mg per kg of body weight every twenty-four hours.{R-10} Note: No more than 10 mL should be injected per site in adult cattle and no more than 5 mL per site in pigs. Less mature animals should have decreasing volumes injected per site (but not total mg per kg of body weight) so that small animals receive 0.5 to 2 mL per injection site. Intravenously administered oxytetracycline should be injected slowly.{R-21} Intramuscularly administered oxytetracycline causes a notable tissue reaction (see note on slaughter trim below under Withdrawal times). [Horses]1Ehrlichiosis (Ehrlichiosis equi); or Potomac horse fever (Ehrlichiosis risticii): Intravenous, 10 mg per kg of body weight every twenty-four hours.{R-4648; 92; 138} Note: Gastrointestinal side effects are possible following oxytetracycline administration to horses. The above dose is based on clinical trials and retrospective doseresponse studies. [Foals]1Although the efcacy and safety have not been established, a single intravenous dose of 44 mg of oxytetracycline per kg of body weight has been used in the treatment of exural limb deformities in newborn foals, based on controlled studies in healthy foals{R-157; 158} . The dose is most often administered as a single intravenous dose of 2 to 3 grams per foal{R-158} or as an intravenous dose of 1.5 grams per foal, repeated in twenty-four hours. In some cases, clinicians have repeated an initial 2- to 3-gram dose twenty-four hours following the initial dose{R-20; 157}. Studies have demonstrated the safety, including lack of renal toxicity, of doses of up to 54.5 to 75 mg per kg of body weight, administered two times, twenty-four hours apart, to twenty newborn foals{R-20; 158}; however, because high doses of oxytetracyclines have been associated with renal toxicity in many species{R-15}, some clinicians prefer to test renal function before treatment. It is recommended that this high dose of oxytetracycline not be administered to foals with any systemic illness or disorder predisposing to renal compromise, including dehydration or endotoxemia. [Sheep]Bacterial arthritis; bacterial pneumonia; mastitis; or uterine infections: Intramuscular or intravenous, 6.6 mg per kg of body weight every twenty-four hours{R-24; 121}. Strength(s) usually available{R-58}: U.S. Veterinary-labeled products: 100 mg per mL (OTC) [Agrimycin 100; AmTech Maxim-100; Duramycin 100; Oxybiotic-100; Oxycure 100; Oxy-Mycin 100; Promycin 100; Terra-Vet 100; Tetroxy-100]. All rights reserved

246 TETRACYCLINES VeterinarySystemic Canada Veterinary-labeled products: 100 mg per mL (OTC) [Oxy LP; Oxymycine LP; Oxytetracycline 100LP; Oxytetramycin 100; Oxyvet 100 LP; Tetraject LP]. Withdrawal times{R-58}: U.S.{R-21; 56}
Withdrawal time Species Cattle Meat (days) 18, 19, 20, or 22, depending on product

Note: Product labeling listing the above withdrawal times states that they apply to a dose of 6.6 to 11 mg per kg of body weight a day in cattle for a maximum of four days. Not labeled for use in lactating cattle or preruminating calves. Cattle slaughtered within 20 days of intramuscular administration of oxytetracycline may require trimming of the injection sites and surrounding tissues during dressing procedure. Canada{R-24}
Withdrawal time Species Cattle Pigs, sheep Meat (days) 18 18 Milk (hours) 60 or 72, depending on product

Note: The above withdrawal times are based on Canadian labeling that lists a dose of 6.6 mg per kg of body weight a day for a maximum of two to three days.{R-24} Packaging and storage: Store below 40 C (104 F), preferably between 15 and 30 C (59 and 86 F), unless otherwise specied by manufacturer. Protect from light. Protect from freezing. Preparation of dosage form: For intravenous administration, dilution in water for injection or physiological saline is recommended. Doses of up to 2500 mg (50 mL) can be diluted in 250 mL of diluent, and larger doses in 500 mL of diluent. Stability: Diluted medication should be used or discarded immediately after mixing.{R-21} Solution may darken on standing but this color change does not affect the potency of the medication. USP requirements: Preserve in single-dose or in multiple-dose containers, protected from light. A sterile solution of Oxytetracycline with or without one or more suitable anesthetics, antioxidants, buffers, complexing agents, preservatives, and solvents. Contains the labeled amount, within 10% to +20%. Meets the requirements for Identication, Bacterial endotoxins, Sterility, and pH (8.09.0).{R-128}

intramuscular injection, when they are administered at the same dose.{R-107; 162}. As such, use of the long-acting formulations at standard doses of 6 to 11 mg per kg of body weight may not result in a prolonged duration of action. Also, there is no difference in duration of action between conventional and long-acting formulations when they are administered intravenously{R-99; 151}. Usual dose: CattleActinobacillosis1; bacterial enteritis1; bacterial pneumonia and bovine respiratory disease complex; diphtheria1; keratoconjunctivitis; leptospirosis; metritis, acute1; pododermatitis; or skin and soft tissue infections1: Intramuscular, intravenous, or, when labeled, subcutaneous, 6.6 to 11 mg per kg of body weight every twenty-four hours for four days{R-3; 45}. Note: When it is impractical to give cattle more than a single dose for the treatment of keratoconjunctivitis or pneumonia, an intramuscular or, when labeled, subcutaneous dose of 20 mg per kg of body weight administered as a single dose is recommended.{R-45} In calves, [40 mg per kg of body weight as a single dose]1 has been used in the treatment of bacterial pneumonia that is unresponsive to 20 mg per kg of body weight, based on pharmacokinetic and toxicity data{R-95; 101}; however, the clinical efcacy was not established in this study. This higher dose should not be repeated because of the risk of adverse effects{R-30; 167; 168}. For [thromboembolic meningoencephalitis]1 in cattle, a dose of 11 mg per kg of body weight every twenty-four hours has been recommended; however, there are no specic research data to support the efcacy of this use{R-178; 179}. PigsBacterial enteritis1; bacterial pneumonia; or leptospirosis: Intramuscular, 6.6 to 11 mg per kg of body weight every twenty-four hours for four days.{R-45} Note: When it is impractical to give pigs more than a single dose for the treatment of pneumonia, an intramuscular dose of 20 mg per kg of body weight administered as a single dose is recommended.{R-45} SowsBacterial enteritis in suckling pigs: Intramuscular, 6.6 mg per kg of body weight, administered once eight hours before farrowing or immediately after farrowing.{R-45} Note: No more than 10 mL should be administered intramuscularly at any one site in adult cattle. No more than 5 mL should be injected intramuscularly at any one site in adult pigs.{R-45} Injections should be administered deep into the eshy part of the muscle.{R-25} Less mature animals should have size-dependent decreasing volumes injected per site so that small calves receive only 1 to 2 mL per injection site. Strength(s) usually available{R-58}: U.S.{R-3; 45} Veterinary-labeled products: 200 mg per mL (OTC) [Agrimycin 200; AmTech Maxim-200; Biomycin 200; Duramycin 72-200; Geomycin 200; Liquamycin LA-200; Maxim-200; OT 200; OxyBiotic-200; Oxycure 200; OxyMycin 200; Oxyshot LA; Pennox 200 Injectable]. Note: The above products contain the following viscosity excipients: Biomycin 200 contains polyethylene glycol; Duramycin 72-200, Liquamycin LA-200, Maxim-200; and Pennox 200 contain 2pyrrolidone; and Oxyshot LA contains N-methylpyrrolidone. Canada{R-25; 120} Veterinary-labeled products: 200 mg per mL (OTC) [Alamycin LA; Biomycin 200; Liquamycin LA200; Oxy LA; Oxymycine LA; Oxyvet 200 LA; Tetraject LA]. 300 mg per mL (OTC) [Tetradure LA 300]. All rights reserved

OXYTETRACYCLINE INJECTION USP (LONG-ACTING)

Note: The formulations listed below have a viscosity excipient intended to prolong therapeutic serum antibiotic concentrations. These products are believed to differ from other oxytetracycline injection products only in the rate of absorption from intramuscular injection; moreover, some studies using oxytetracycline products with 2-pyrrolidone viscosity excipient have failed to show that the duration of action is signicantly prolonged over that of the conventional formulation after 2003 Thomson MICROMEDEX

TETRACYCLINES VeterinarySystemic 247 Withdrawal times{R-58}: U.S.{R-3; 5; 45; 153} Note: If oxytetracycline injection is administered to calves as a single intramusuclar dose of 40 mg per kg of body weight, there is some evidence to suggest that a withdrawal time of 49 days would be sufcient to avoid residues, based on tissue depletion studies of the parent drug{R-101}.
Withdrawal time Species Cattle Pigs Meat (days) 28 28 or 42, depending on product

TETRACYCLINE ADDITIONAL DOSING INFORMATION

When possible, oral tetracycline should be administered 1 hour before or 2 hours after milk replacer.{R-1}

MUCOSAL DOSAGE FORMS

Note: Bracketed information in the Dosage Forms section refers to uses that either are not included in U.S. product labeling or are for products not commercially available in the U.S.

TETRACYCLINE UTERINE TABLETS

Usual dose: Note: [Cows] and [mares]Although the efcacy and safety are not currently established, the use of a 4-gram bolus administered as a single intrauterine dose is included in Canadian product labeling{R-9} for the treatment of uterine infections. The dose may be repeated in two days if necessary.{R-9} Strength(s) usually available: U.S. Veterinary-labeled products: Not commercially available. Canada{R-9} Veterinary-labeled products: 4 grams (OTC) [Tetra 4000; Tetrabol]. Withdrawal times: Canada{R-9}
Withdrawal time Species Cows Meat (days) 18 Milk (hours) 72

Note: Some products are not labeled for use in lactating dairy cattle and list the above withdrawal times. Product labeling listing the above withdrawal times states that they apply to a dose of 6.6 to 11 mg per kg of body weight a day for a maximum of four days or 20 mg per kg of body weight administered as a single dose.
Withdrawal time Species Cattle Pigs Meat (days) 28 28 Milk (hours) 96

Note: Product labeling listing the above withdrawal times states that they apply to a dose of 6.6 to 11 mg per kg of body weight a day for a maximum of four days or 20 mg per kg of body weight administered as a single dose. Canada{R-25; 120}
Withdrawal time Species Cattle and pigs Intramuscular injection Cattle Subcutaneous injection Meat (days)

21 or 28, depending on product 48

Packaging and storage: Store below 40 C (104 F), preferably between 15 and 30 C (59 and 86 F), in a tight container, unless otherwise specied by manufacturer. Auxiliary labeling: Protect from excessive moisture.{R-9} USP requirements: Not in USP.

Note: Product labeling listing the above withdrawal times states that they apply to a dose of 20 mg per kg of body weight administered once. Not labeled for use in lactating dairy cattle. One product recommends a 42-day withdrawal to avoid excess trim at the injection site{R-58}. Packaging and storage: Store between 15 and 30 C (59 and 86 F), unless otherwise specied by manufacturer. Protect from light. Protect from freezing.{R-45} Preparation of dosage form: Warm to room temperature before administration. USP requirements: Preserve in single-dose or in multiple-dose containers, protected from light. A sterile solution of Oxytetracycline with or without one or more suitable anesthetics, antioxidants, buffers, complexing agents, preservatives, and solvents. Contains the labeled amount, within 10% to +20%. Meets the requirements for Identication, Bacterial endotoxins, Sterility, and pH (8.09.0).{R-128}
1

ORAL DOSAGE FORMS

Note: Bracketed information in the Dosage Forms section refers to uses that either are not included in U.S. product labeling or are for products not commercially available in the U.S.

TETRACYCLINE BOLUSES USP

Usual dose: Bacterial enteritis; or bacterial pneumoniaCalves: Oral, 11 mg per kg of body weight every twelve hours for ve days.{R-1} Strength(s) usually available{R-58}: U.S.{R-1} Veterinary-labeled products: 500 mg (OTC) [Calf Scour Bolus Antibiotic; 5-Way Calf Scour Bolus]. Canada{R-9} Veterinary-labeled products: 4 grams (OTC) [Tetra 4000; Tetrabol]. All rights reserved

Not included in Canadian product labeling or product not commercially available in Canada.

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248 TETRACYCLINES VeterinarySystemic Withdrawal times{R-58}: U.S.{R-1}

Withdrawal time Species Calves Meat (days) 12, 14 or 24, depending on product

Human-labeled products: 250 mg (Rx) [Achromycin V; generic]. 500 mg (Rx) [Achromycin V; generic]. Canada Veterinary-labeled products: Not commercially available. Human-labeled products: 250 mg (Rx) [Apo-Tetra; Novo-Tetra; Nu-Tetra]. Packaging and storage: Store below 40 C (104 F), preferably between 15 and 30 C (59 and 86 F), unless otherwise specied by manufacturer. Store in a tight, light-resistant container. USP requirements: Preserve in tight, light-resistant containers. Contain the labeled amount, within )10% to +25%. Meet the requirements for Identication, Dissolution (80% in 60 minutes, 90 minutes for 500-mg capsules, in water in Apparatus 2 at 75 rpm), Uniformity of dosage units, Loss on drying (not more than 4.0%), and Limit of 4-epianhydrotetracycline (not more than 3.0%).{R-128}

Canada{R-9}
Withdrawal time Species Calves Cattle Meat (days) 5 18

Note: Product labeling with the above withdrawal times state that they apply to a dose of 20 mg per kg of body weight a day for three to ve days. Packaging and storage: Store below 40 C (104 F), preferably between 15 and 30 C (59 and 86 F), unless otherwise specied by manufacturer. Store in a tight container. Auxiliary labeling: {R-9} Protect from excessive moisture. USP requirements: Preserve in tight containers. Label Boluses to indicate that they are intended for veterinary use only. Contain the equivalent of the labeled amount of tetracycline hydrochloride, within 10% to +20%. Meet the requirements for Identication, Uniformity of dosage units, and Loss on drying (not more than 3.0%; or for Boluses greater than 15 mm in diameter, not more than 6.0%).{R-128}

TETRACYCLINE HYDROCHLORIDE SOLUBLE POWDER USP

Usual dose: Calves and pigsBacterial enteritis; or bacterial pneumonia: Oral, 11 mg per kg of body weight every twelve hours, administered in the only source of drinking water for three to ve days.{R-19} ChickensChronic respiratory disease; or infectious synovitis: Oral, 27.5 mg per kg of body weight every twelve hours, administered in the only source of drinking water for seven to fourteen days.{R-19} TurkeysInfectious synovitis; or bacterial enteritis: Oral, 27.5 mg per kg of body weight every twelve hours, administered in the only source of drinking water for seven to fourteen days.{R-19} [Sheep]Bacterial enteritis; or respiratory tract diseases: Oral, 40 mg per kg of body weight every twelve hours for four to ve days{R-18}. Note: Environmental and health conditions may affect the intake of water and the amount of medication consumed.{R-17} Administration of medication by food or water to animals with pneumonia or other infections can be affected by reduced feed and water intake{R-109}. Strength(s) usually available{R-58}: U.S.{R-8; 19} Veterinary-labeled products: 25 grams per pound of powder (OTC) [Duramycin 10; PolyOtic Soluble Powder; Solu-Tet; Tet-Sol 10]. 324 grams per pound of powder (OTC) [AmTech Tetracycline Hydrochloride Soluble Powder-324; Duramycin-324; Solu-Tet 324; Tet-324; Tetra Bac 324; Tetrasol Soluble Powder; Tet-Sol 324; generic]. Canada{R-18} Veterinary-labeled products: 55 mg per gram of powder (OTC) [Tetra 55; generic]. 62.5 mg per gram of powder (OTC) [Onycin 62.5; Tetracycline 62.5 Soluble Powder]. 250 mg per gram of powder (OTC) [Onycin 250; Tetra 250; Tetracycline 250; Tetracycline 250 Concentrate Soluble Powder; Tetramed 250]. 1000 mg per gram of powder (OTC) [Onycin 1000; Tetra 1000; Tetracycline 1000; Tetramed 1000]. All rights reserved

TETRACYCLINE HYDROCHLORIDE CAPSULES USP

Usual dose: [Rocky Mountain spotted fever]1Dogs: Oral, 22 mg per kg of body weight every eight hours for fourteen days.{R-140; 141} Note: [Dogs]1The above dose is based on clinical trials and retrospective dose-response studies. The same dosage regimen has also been used in the treatment of ehrlichiosis in dogs{R-43; 139}, although the efcacy of this treatment has not been conrmed. A dose of 22 mg per kg of body weight every six to eight hours has also been used in the treatment of other susceptible bacterial infections in dogs. Dosing trials suggest that 30 mg of oral tetracycline per kg of body weight every twelve hours for twenty-eight days, administered in conjunction with 20 mg of intramuscular streptomycin every twenty-four hours for the rst fourteen days, may be successful in resolving brucellosis in dogs. It has been recommended that all dogs be treated in a population in which some have tested positive for brucellosis; good management practices are recommended and repeated follow-up testing is needed for several months to conrm that all dogs remain seronegative{R-160}. See also Tetracycline Oral Suspension USP. Strength(s) usually available: U.S. Veterinary-labeled products: Not commercially available. 2003 Thomson MICROMEDEX

TETRACYCLINES VeterinarySystemic 249 Withdrawal times: U.S.{R-8; 19}

Withdrawal time Species Calves Chickens, pigs, turkeys Meat (days) 4 or 5, depending on product 4 or 7, depending on product

Auxiliary labeling: {R-4} Shake well before each dose . USP requirements: Preserve in tight, light-resistant containers. It is Tetracycline with or without one or more suitable buffers, preservatives, stabilizers, and suspending agents. Contains the equivalent of the labeled amount of tetracycline hydrochloride, within 10% to +25%. Meets the requirements for Identication, Uniformity of dosage units (single-unit containers), Deliverable volume, pH (3.56.0), and Limit of 4-epianhydrotetracycline (not more than 5.0%).{R-128}
1

Note: Products are not labeled for use in preruminating calves or poultry producing eggs for human consumption{R-58}. Canada{R-18}
Withdrawal time Species Calves, chickens, pigs, sheep, turkeys Meat (days) 5

Not included in Canadian product labeling or product not commercially available in Canada.

Developed: 07/17/96 Revised: 7/14/98; 10/12/99; 6/30/02; 04/05/03

Note: Product labeling with the above withdrawal time states that it applies to a dose of 20 to 40 mg per kg of body weight every twelve hours for a maximum of ve days for calves, pigs, and sheep and a dose of 200 mg per liter of water for three to ve days for chickens and turkeys. Although a milk withdrawal time is included on one product label, these products are not specically labeled for use in lactating dairy cows in Canada. Products are not labeled for use in laying hens{R-18; 58}. Packaging and storage: Store below 40 C (104 F), preferably between 15 and 30 C (59 and 86 F), in a tight container, unless otherwise specied by manufacturer. Preparation of dosage form: Fresh solutions should be prepared every 24 hours when administered in plastic or stainless steel waterers and every 12 hours when administered in galvanized waterers. Stability: Solutions are stable for 24 hours.{R-8} USP requirements: Preserve in tight containers. Label it to indicate that it is intended for veterinary use only. Contains the labeled amount, within 10% to +25%. Meets the requirements for Identication and Loss on drying (not more than 2.0%).{R-128}

REFERENCES
1. Tetracycline package insert (5-Way Calf Scour Bolus, AgrilabsUS), Rev 91, Rec 4/4/95. 2. Oxytetracycline package insert (Oxy 500 Calf Bolus, Boehringer IngelheimUS). Downloaded 2/26/03 from www.bi-vetmedica.com. 3. Oxytetracycline package insert (Biomycin 200, Boehringer IngelheimUS). Downloaded 2/26/03 from www.bi-vetmedica.com. 4. Tetracycline package insert (Panmycin Aquadrops, PharmaciaUS), Rev 11/01. 5. Liquamycin LA-200 Freedom of Information Summary. NADA 113-232 (Supplement). Sponsor: Pzer, Inc. July 21, 1998. 6. Terramycin Soluble Powder Freedom of Information Summary. NADA 008622 (Supplement). Sponsor: Pzer Inc. July 7, 1993. 7. Oxytetracycline Freedom of Information Summary. NADA number 200247. Sponsor: Phoenix Scientic Inc. 2/10/99. 8. Tetracycline package label (Solu-Tet 324, AlpharmaUS). 9. Tetracycline package insert (Tetrabol, VetoquinolCanada). 10. Oxytetracycline package label (Oxybiotic-P, VedcoUS), discontinued product. 11. Oxytetracycline package label (Oxytet Soluble, AlpharmaUS). 12. Oxytetracycline package label (Kelamycin, PVLCanada). 13. Oxytetracycline product labeling (Pennox 343, PenneldUS), Rec 5/7/99. 14. Panel consensus, on monograph revision of 3/97. 15. Vivrette S, Cowgill LD, Pascoe J, et al. Hemodialysis for treatment of oxytetracycline-induced acute renal failure in a neonatal foal. J Am Vet Med Assoc 1993 Jul 1: 203(1): 1057. 16. Chlortetracycline package insert (Pennchlor 50, PenneldUS), Rev 4/97, Rec 6/18/98. 17. Chlortetracycline pacakage insert (CTC Soluble Powder, Agri LabsUS). 18. Tetracycline package insert (Onycin 250, VetoquinolCanada). 19. Tetracycline package insert (Duramycin-324, DurvetUS). 20. Wright AK, Petrie L, Papich MG, et al. Effect of high dose oxytetracycline on renal parameters in neonatal foals. In: Caddel LB, editor. Proceedings of the 38th Annual Convention of the American Association of Equine Practitioners. Orlando, FL; 1993. p. 2978. 21. Oxytetracycline package insert (Oxytetracycline hydrochloride injection, VedcoUS), Rec 8/1/95. 22. Barragry TB. Veterinary drug therapy. Baltimore: Lea & Febiger, 1994: 26492. 23. Oxytetracycline package insert (Oxysol-220, A.P.A.Canada). 24. Oxytetracycline package insert (Oxyvet 100 LP, VetoquinolCanada). 25. Oxytetracycline package insert (Oxyvet 200 LA, VetoquinolCanada). 26. Oxytetracycline package insert (Oxysol-110, A.P.ACanada). 27. Oxytetracycline supplemental approval (Terramycin Type A Medicated Article PzerUS). NADA 008-804. Approved Animal Drug Products (Green Book). Virginia Tech: Blacksburg, VA. 1996 Nov 15: 8.43. 28. Aronson AL. Pharmacotherapeutics of the newer tetracyclines. J Am Vet Med Assoc 1980 May 15; 176(10): 10618. 29. Vaala WE, Ehren SJ, Divers TJ. Acute renal failure associated with administration of excessive amounts of tetracycline in a cow. J Am Vet Med Assoc 1987 Dec 15; 191(12): 16013.

TETRACYCLINE ORAL SUSPENSION USP

Usual dose: Bacterial gastroenteritis1 or urinary tract infections1Cats and dogs: Oral, 14 to 22 mg per kg of body weight every six to eight hours.{R-177} See also Tetracycline Hydrochloride Capsules USP. Strength(s) usually available: U.S.{R-4} Veterinary-labeled products: 100 mg per mL (Rx) [Panmycin Aquadrops]. Canada{R-126} Veterinary-labeled products: Not commercially available. Packaging and storage: Store between 15 and 30 C (59 and 86 F), in a tight container, unless otherwise specied by manufacturer. Protect from light.

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250 TETRACYCLINES VeterinarySystemic

30. Lairmore MD, Alexander AF, Powers DE, et al. Oxytetracycline-associated nephrotoxicosis in feedlot calves. J Am Vet Med Assoc 1984; 185(7): 7935. 31. Riond J, Riviere JE. Effects of tetracyclines on the kidney in cattle and dogs. J Am Vet Med Assoc 1989 Oct 1; 195(7): 9957. 32. Ward GS, Guiry CC, Alexander LL. Tetracycline-induced anaphylactic shock in a dog. J Am Vet Med Assoc 1982 Apr 1; 180(7): 7701. 33. Gross DR, Dodd KT, Williams JD, et al. Adverse cardiovascular effects of oxytetracycline preparations and vehicles in intact awake calves. Am J Vet Res 1981 Aug; 42(8): 13717. 34. Gyrd-Hansen N, Rasmussen F, Smith M. Cardiovascular effects of intravenous administration of tetracycline in cattle. J Vet Pharmacol Ther 1981; 4: 15 25. 35. Riond JL, Riviere JE, Duckett WM, et al. Cardiovascular effects and fatalities associated with intravenous administration of doxycycline to horses and ponies. Equine Vet J 1992; 24(1): 415. 36. Kaufman AG, Greene CE. Increased alanine transaminase activity associated with tetracycline administration in a cat. J Am Vet Med Assoc 1993 Feb 15; 202(4): 62830. 37. Immelman A, Botha WS, Grib D. Muscle irritation caused by different products containing oxytetracycline. J S Afr Vet Assoc 1978; 49(2): 1035. 38. Anderson WI, Wilson RC, Goetsch DD. Hemoglobinuria in cattle given longacting oxytetracycline. Mod Vet Pract 1983 Dec; 64(12): 9978. 39. Longhofer SL. Chemotherapy of rickettsial, protozoal, and chlamydial diseases. Vet Clin North Am Small Anim Pract 1988 Nov; 18(6): 118396. 40. Iqbal Z, Rikihisa Y. Reisolation of Ehrlichia canis from blood and tissues of dogs after doxycycline treatment. J Clin Microbiol 1994; 32(7): 16449. 41. Waddle JR, Littman MP. A retrospective study of 27 cases of naturally occurring canine ehrlichiosis. J Am Anim Hosp Assoc 1988 Nov/Dec; 24(6): 61520. 42. Ogunkoya AB, Adeyanju JB, Abduhllahi R. Experimental and clinical trials of long acting oxytetracycline in the treatment of canine erhlichiosis. Vet Q 1985 Apr; 7(2): 15861. 43. Magnorelli LA, Litwin HJ, Holland CJ, et al. Canine ehrlichiosis in Connecticut. J Clin Microbiol 1990 Feb; 28(2): 3667. 44. George LW. Antibiotic treatment of infectious bovine keratoconjunctivitis. Cornell Vet 1990 Jul; 80(3): 22934. 45. Oxytetracycline package insert (Duramycin 72200, DurvetUS), Rev 2/95, Rec 8/11/95. 46. Madigan JE, Gribble D. Equine ehrlichiosis in northern California: 49 cases (196881). J Am Vet Med Assoc 1987 Feb 15; 190(4): 4458. 47. Palmer JE, Benson CE, Whitlock RH. Effect of treatment with oxytetracycline during the acute stages of experimentally induced equine ehrlichial colitis in ponies. Am J Vet Res 1992 Dec; 53(12): 23004. 48. Palmer JE, Whitlock RH, Benson CE. Equine ehrlichial colitis: effect of oxytetracycline treatment during the incubation period of Ehrlichia risticii infection in ponies. J Am Vet Med Assoc 1988; 192: 3435. 49. Eidson M, Thistead JP, Rollag OJ. Clinical, clinicopathologic and pathologic features of plague in cats: 119 cases (19771988). J Am Vet Med Assoc 1991 Nov 1; 199(9): 11917. 50. Gutierrez CB, Piriz S, Vadillo S, et al. In vitro susceptibility of Actinobacillus pleuropneumoniae strains to 42 antimicrobial agents. Am J Vet Res 1993 Apr; 54(4): 54650. 51. Watts JL, Yancey RJ, Salmon SA, et al. A 4-year survey of antimicrobial susceptibility trends for isolates from cattle with bovine respiratory disease in North America. J Clin Microbiol 1994 Mar; 32(3): 72531. 52. Cairoli F, Ferrario L, Carli S, et al. Efciency of oxytetracycline and tetracycline-benzydamine in the prevention of infection after placental retention in cattle. Vet Rec 1993; 133: 3945. 53. Timms LM, Marshall RN, Breslin MF. Evaluation of the efcacy of chlortetracycline for the control of chronic respiratory disease caused by Escherichia coli and Mycoplasma gallisepticum. Res Vet Sci 1989; 47: 37782. 54. Oxytetracycline package insert (Oxysol-62.5, A.P.A.Canada). 55. Oxytetracycline package insert (Oxysol-220, SanoCanada), Rec 8/14/95. 56. Oxytetracycline package insert (Oxy-Tet 100, VedcoUS), discontinued product. 57. Chlortetracycline package insert (Calf Scour Bolus, DurvetUS), Rec 8/4/95. 58. Arrioja-Dechert A, editor. Compendium of veterinary products, CD ed. Port Huron, MI: North American Compendiums, Inc. 2002. 59. Kung K, Wanner M. Pharmacokinetics of doxycycline in turkey and comparison between feed and water medication. Archiv Fur Geugelkunde 1994 Apr; 58(2): 848. 60. Oxytetracycline product information (Terramycin Scours Tablets, PzerUS), Rev 3/98. 61. Oxytetracycline product information (Terramycin Soluble Powder, PzerUS), Rec 12/14/95. 62. Oxytetracycline product information (TM 100F, PzerUS), Rec 12/14/95. 63. Wilson RC, Kemp DT, Kutzman JV, et al. Pharmacokinetics of doxycycline in dogs. Can J Vet Res 1988; 52: 124. 64. Anadon A, Martinez Larranga MR, Diaz MJ, et al. Pharmacokinetics of doxycycline in broiler chickens. Avian Pathol 1994; 23(1): 7990. 65. Committee comment, Rec 2/14/02. 66. Riond JL, Riviere JE. Doxycycline binding to plasma albumin of several species. J Vet Pharmacol Ther 1989; 12: 25360. 67. Ziv G, Sulman G. Binding of antibiotics to bovine and ovine serum. Antimicrobial agents and chemotherapy 1972 Sep; 2(3): 20613. 68. Riond J, Tyczkowska K. Riviere J. Pharmacokinetics and metabolic inertness of doxycycline in calves with mature or immature rumen function. Am J Vet Res 1989 Aug; 50(8); 132933. 69. Riond J. Riviere JE. Pharmacokinetics and metabolic inertness of doxycycline in young pigs. Am J Vet Res 1990 Aug; 51(8): 12715. 70. Riond JL, Vaden SL, Riviere JE. Comparative pharmacokinetics of doxycycline in cats and dogs. J Vet Pharmacol Ther 1990; 13: 41524. 71. Shaw DH, Rubin SI. Pharmacologic activity of doxycline. J Am Vet Med Assoc 1986; 189(7): 80810. 72. Percy DH, Black W. Pharmacokinetics of tetracycline in the domestic rabbit following intravenous or oral administration. Can J Vet Res 1988; 52: 511. 73. Anadon A. Pharmacokinetics of tetracycline in chickens after intravenous administration. Poult Sci 1985; 64: 22739. 74. Kniffen TS, Bane DP, Hall WF, et al. Bioavailability, pharmacokinetics, and plasma concentration of tetracycline fed to swine. Am J Vet Res 1989 Apr; 50(4): 51821. 75. Kietzman M, Nolte I, Mischke R. Pharmacokinetics and bioavailability of orally-administered tetracycline in dogs and cats. Kleintierpraxis 1995 Apr; 40(4): 253. 76. Bradley BD, Allen EH, Showalter DH, et al. Comparative pharmacokinetics of chlortetracycline in milk fed versus conventionally fed calves. J Vet Pharmacol Ther 1982; 5: 26778. 77. Kilroy CR, Hall WF, Bane DP, et al. Chlortetracycline in swine-bioavailability and pharmacokinetics in fasted and fed pigs. J Vet Pharmacol Ther 1990; 13: 4958. 78. Dyer DC. Pharmacokinetics of chlortetracycline in the turkey: evaluation of biliary secretion. Am J Vet Res 1988 Jan; 49(1): 367. 79. Pollet RA, Glatz CE, Dyer DC, et al. Pharmacokinetics of chlortetracycline potentiation with citric acid in the chicken. Am J Vet Res 1983 Sep; 44(9): 171821. 80. Pollet RA, Glatz CE, Dyer DC. The pharmacokinetics of chlortetracycline orally administered to turkeys: inuence of citric acid and Pasteurella multocida infection. J Pharmacokinet Biopharm 198; 13: 24364. 81. Escudero E, Carceles CM, Serrano JM. Pharmacokinetics of oxytetracycline in goats: modications induced by a long-acting formulation. Vet Rec 1994; 135: 54852. 82. Mevius DJ, Vellenga L, Breukink HJ. Pharmacokinetics and renal clearance of oxytetracycline in piglets following intravenous and oral administration. Vet Q 1986 Oct; 8(4): 7485. 83. Pijpers A, Schoevers EJ, Van Gogh J, et al. The pharmacokinetics of oxytetracycline following intravenous administration in healthy and diseased pigs. J Vet Pharmacol Ther 1989; 13: 3206. 84. Baggot JD, Powers TE, Powers JD, et al. Pharmacokinetics and dosage of oxytetracycline in dogs. Res Vet Sci 1977; 24: 7781. 85. Dyer DC. Pharmacokinetics of oxytetracycline in the turkey: evaluation of biliary and urinary excretion. Am J Vet Res 1989 Apr; 50(4): 5224. 86. McElroy DE, Ravis WR, Clark CH. Pharmacokinetics of oxytetracycline hydrochloride in rabbits. Am J Vet Res 1987; 48(8): 12613. 87. Varma KJ, Paul BS. Pharmacokinetics and plasma protein binding (in vitro) of oxytetracycline in buffalo (Bubalus bubalis). Am J Vet Res 1983 Mar; 44(3): 4978. 88. Oukessou M, Uccelli-Thomas V, Toutain P. Pharmacokinetics and local tolerance of a long acting oxytetracycline formulation in camels. Am J Vet Res 1992 Sep; 53(9): 165862. 89. Bjorklund HV, Bylund G. Comparative pharmacokinetics and bioavailability of oxilinic acid and oxytetracycline in rainbow trout (Onchorhynchus mykiss). Xenobiotica 1991; 21(11): 151120. 90. Grondel JL, Nouws JFM, Schutte AR, et al. Comparative pharamockinetics of oxytetracycline in rainbow trout (Salmo Gairdneri) and African catsh (Clarias gariepinus). J Vet Pharmacol Ther 1989; 12: 15762. 91. Curl JL, Curl JS, Harrison JK. Pharmacokinetics of long acting oxytetracycline in the laboratory rat. Lab Anim Sci 1988; 38(4): 4304.

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92. Hospool CJI, McKellar QA. Disposition of oxytetracycline in horses, ponies, and donkeys after intravenous administration. Equine Vet J 1990; 22(4): 2845. 93. Burrows GE, Barto PB, Martin B. Comparative pharmacokinetics of gentamicin, neomycin, and oxytetracycline in newborn calves. J Vet Pharmacol Ther 1987; 10: 5463. 94. Nouws JFM, Vree TB. Effect of injection site on the bioavailability of an oxytetracycline formulation in ruminant calves. Vet Q 1983; 5(4): 16570. 95. Nouws JFM, Van Ginneken CAM, Ziv G. Age-dependent pharmacokinetics of oxytetracycline in ruminants. J Vet Pharmacol Ther 1983; 6: 5966. 96. Pilloud M. Pharmacokinetics, plasma protein binding and dosage of oxytetracycline in cattle and horses. Res Vet Sci 1973; 15: 22430. 97. Mevius DJ, Nouws JFM, Breukink JF, et al. Comparative pharmacokinetics, bioavailability and renal clearance of ve parenteral oxytetracycline-20% formulations in dairy cows. Vet Q 1986; 8(4): 28594. 98. Davey LA, Ferber MT, Kaye B. Comparison of the serum pharmacokinetics of a long acting and a conventional oxytetracycline injection. Vet Rec 1985; 117: 4269. 99. Toutain PL, Raynaud JP. Pharmacokinetics of oxytetracycline in young cattle: comparison of conventional versus long-acting formulations. Am J Vet Res 1983 Jul; 44(7): 12039. 100. Schifferli K, Galeazzi RL, Nicolet J, et al. Pharmacokinetics of oxytetracycline and therapeutic implications in veal calves. J Vet Pharmacol Ther 1982; 5: 24757. 101. Terhune TN, Upson DW. Oxytetracycline pharmacokinetics, tissue depletion, and toxicity after administration of a long acting preparation at double the label dosage. J Am Vet Med Assoc 1989 Apr; 194(7): 9117. 102. Anderson KL, Moats WA, Rushing JE, et al. Potential for oxytetracycline administration by three rates to cause milk residues in lactating cows, as detected by radioimmunoassay (Charm II) and high-performance liquid chromatography test methods. Am J Vet Res 1995 Jan; 56(1): 707. 103. Soback S, Ziv G, Winkler M, et al. Systemic dry cow therapya preliminary report. J Dairy Sci 1990; 73: 6616. 104. Bretzlaff KN, Ott RS, Koritz GD, et al. Distribution of oxytetracycline in genital tract tissues of postpartum cows given the drug by intravenous and intrauterine routes. Am J Vet Res 1983 May; 44(5): 7649. 105. Bretzlaff KN, Ott RS, Koritz GD. Distribution of oxytetracycline in the healthy and diseased postpartum genital tract of cows. Am J Vet Res 1983 May; 44(5): 7603. 106. Burrows GE, Barto PB, Weeks BR. Chloramphenicol, lincomycin, and oxytetracycline disposition in calves with experimental pneumonic pasteurellosis. J Vet Pharmacol Ther 1986; 9: 21322. 107. Hall WF, Kniffen TS, Bane DP, et al. Plasma concentrations of oxytetracycline in swine after administration of the drug intramuscularly and orally in feed. J Am Vet Med Assoc 1989 May; 194(9): 12658. 108. Banting AD, Duval M, Gregoire S. A comparative study of serum kinetics of oxytetracycline in pigs and calves following intramuscular administration. J Vet Pharmacol Ther 1985; 8: 41820. 109. Pijpers A, Schoevers EJ, Van Gogh FH, et al. The inuence of disease on feed and water consumption and on pharmacokinetics of orally administered oxytetracycline in pigs. J Anim Sci 1991; 69: 294754. 110. Pijpers A, Schoevers EJ, Haagsma N, et al. Plasma levels of oxytetracycline, doxycycline, and minocycline in pigs after oral administration in feed. J Anim Sci 1991; 69: 451222. 111. Palmer GH, Bywater RJ, Stanton A. Absorption in calves of amoxicillin, ampicillin, and oxytetracycline given in milk replacer, water, or an oral rehydration formulation. Am J Vet Res 1983 Jan; 44(1): 6871. 112. Vivrette S, Cowgil LD, Pascoe J, et al. Hemodialysis for treatment of oxytetracycline-induced acute renal failure in a neonatal foal. J Am Vet Med Assoc 1993 Jul; 203(1): 1057. 113. Ketterer PJ, Dunster PJ. Failure to eliminate Leptospira pomona from pigs by treatment with long acting oxytetracycline. Aust Vet J 1985 Oct; 62(10): 3489. 114. USP dictionary of USAN and international drug names, 2002 ed. Rockville, MD: The United States Pharmacopeial Convention, Inc., 2002. 115. Chlortetracycline package insert (Aureomycin 50 Granular Type A Medicated Article, Hoffman LaRocheUS), Rec 6/18/98. 116. Chlortetracycline package insert (Chlor 50, Bio-Agri-Mix LtdCanada), Rec 8/29/95. 117. Oxytetracycline product literature (Oxytetracycline 50, PenneldUS), Rev 11/95, Rec 11/30/96. 118. Chlortetracycline (Aureomycin Uterine Oblets, Wyeth). In: Compendium of veterinary products, CD ed. Hensall, Ontario: North American Compendiums Inc., 2003. 119. Hunneman WA, Pijpers A, Lommerse J, et al. Prophylaxis of pleuropneumonia in pigs by in-feed medication with oxytetracycline and the subsequent transmission of infection. Vet Rec 1994 Feb; 134(9): 2158. 120. Oxytetracycline package insert (Biomycin 200, Boehringer Ingelheim Ltd.Canada). 121. Oxytetracycline package insert (Oxytetracycline 100, A.P.A.Canada). 122. Oxytetracycline product information (OXTC 100, PzerUS), Rev 93, Rec 12/15/95. 123. Aureomycin Type A Medicated Article Freedom of Information Summary. NADA 48761. Sponsor: Roche Vitamins Inc. July 31, 1998. 124. Oxytetracycline product label (Terramycin-Aqua, PzerCanada), Rec 12/5/ 95. 125. Oxytetracycline (Oxytetra-A, Dominion). In: Bennett K, editor. Compendium of veterinary products. 4th ed. Hensall, ON: North American Compendiums Inc., 1995: 483. 126. Tetracycline hydrochloride package insert (Panmycin Aquadrops, UpjohnCanada), discontinued product. 127. Tetracycline hydrochloride package insert (Onycin 62.5, SanoCanada), Rec 4/11/95. 128. The United States pharmacopeia. The national formulary. USP 26th revision (January 1, 2003). NF 21st ed (January 1, 2003). Rockville, MD: The United States Pharmacopeial Convention, Inc., 2002. p. 439, 440, 667-71, 1378, 1379, 1382, 1790-2, 1794, 2554, 2559, 2572, 2573, 2583, 2584. 129. Dinsmore RP, Stevens RD, Cattell MB, et al. Oxytetracycline residues in milk after intrauterine treatment of cows with retained fetal membranes. J Am Vet Med Assoc 1996 Nov 15; 209(10): 17535. 130. Masera J, Gustafsson BK, Aefy MM, et al. Disposition of oxytetracycline in the bovine genital tract: systemic vs. intrauterine administration. J Am Vet Med Assoc 1980 May 15; 176(10): 1099102. 131. Bryant JE, Brown MP, Gronwall RR, et al. Study of intragastric administration of doxycycline: pharmacokinetics including body uid, endometrial and minimum inhibitory concentrations, Equine Veterinary Journal 2000; 32: 233238. 132. Klasco RK, editor. USP DI Drug information for the healthcare professional. Volume I. Greenwood Village, CO: MICROMEDEX, Inc.; 2003. 133. Riviere J, Craigmill AL, Sundlof SF. Handbook of comparative pharmacokinetics and residues of veterinary antimicrobials. Boca Raton, FL: CRC Press, Inc, 1991: 175226. 134. Oxytetracycline (Foul Brood Mix, Medivet). In: Bennett K, editor. Compendium of veterinary products. 4th ed. Hensall, ON: North American Compendiums Inc., 1995: 324. 135. Doxycycline hyclate package insert (Novo-Doxylin, NovopharmCanada), Rev 3/2/95, Rec 7/18/95. 136. Doxycycline hyclate package insert (Doxy 100 & 200, LymphomedUS), Rev 5/92, Rec 1/94. 137. Pedersoli WM, Jackson JA. Tetracycline, methoxyurane anesthesia and severe renal failure in dogs. J Am Anim Hosp Assoc 1973; 9(1): 5765. 138. Nyindo MBA, Ristic M, Lewis G, et al. Immune response of ponies to experimental infection with Ehrlichia equi. Am J Vet Res 1978; 39(1): 158. 139. Davidson DE, Dill GS, Tingpalapong M, et al. Prophylactic and therapeutic use of tetracycline during an epizootic among military dogs. J Am Vet Med Assoc 1978 Mar; 172(6): 697700. 140. Breitschwerdt EB, Davidson MG, Aucoin DP, et al. Efcacy of chloramphenicol, enrooxacin, and tetracycline for treatment of experimental Rocky Mountain spotted fever in dogs. Antimicrob Agents Chemother 1991 Nov; 35(11): 237581. 141. Greene CE, Burgdorfer W, Caragnolo R, et al. Rocky Mountain spotted fever in dogs and its differentiation from canine ehrlichiosis. J Am Vet Med Assoc 1985; 186(5): 46572. 142. Oxytetracycline (TM 50, Pzer). In: Bennett K, editor. Compendium of veterinary products. 4th ed. Port Huron, MI: North American Compendiums Inc., 1995: 11001. 143. Chlortetracycline (Fermycin Soluble, Fermenta) In: Bennett K, editor. Compendium of veterinary products. 4th ed. Port Huron, MI: North American Compendiums Inc., 1995: 491. 144. Stevens RD, Dinsmore RP, Cattell MB. Evaluation of the use of intrauterine infusions of oxytetracycline, subcutaneous injections of fenprostalene, or a combination of both, for the treatment of retained fetal membranes in dairy cows. J Am Vet Med Assoc 1995 Dec 15; 207(12): 16125. 145. Thurmond MC, Jameson CM, Picanso JP. Effect of intrauterine antimicrobial treatment in reducing calving-to-conception interval in cows with endometritis. J Am Vet Med Assoc 1993 Dec 1; 203(11): 15768.

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146. Heinonen M, Heinonen K. Retained placenta in cattle: the effect of treatment or nontreatment on puerperal diseases and subsequent fertility. Acta Vet Scand 1989; 30: 4259. 147. Carney HC, England JJ. Feline hemobartonellosis. Vet Clin North Am Small Anim Prac 1993 Jan; 23(1): 7980. 148. Bobade PA, Nash AS, Rogerson P. Feline haemobartonellosis: clinical, haematological and pathological studies in natural infections and the relationship to infection with feline leukemia virus. Vet Rec 1988; 122: 326. 149. Harvey JW, Gaskin JM. Feline haemobartonellosis: attempts to induce relapses of clinical disease in chronically infected cats. J Am Anim Hosp Assoc 1978; 14: 4536. 150. Panel comment, Rec 3/1/96. 151. Panel comment, Rec 2/23/96. 152. Freedom of Information Summary. NADA 48761 Aureomycin Type A Medicated Article. Sponsor: Hoffman-LaRoche. 153. Oxytetracycline package insert (Maxim-200, PhoenixUS), Rev 6/94, Rec 2/ 5/96. 154. Papich MG, Wright AK, Patrie L, et al. Pharmacokinetics of oxytetracycline administered intravenously to 4 to 5-day-old foals. J Vet Pharmacol Ther 1995; 18: 3758. 155. Korsrud GO, Papich MG, Fesser ACE, et al. Residue depletion in tissues and uids from swine fed sulfamethazine, chlortetracycline, and penicillin G in combination. Food Addit Contam 1996 Apr; 13(3): 28792. 156. Panel comment, Rec 3/5/96. 157. Kasper CA, Clayton HM, Wright AK, et al. Effects of high doses of oxytetracycline on metacarpophalangeal joint kinematics in neonatal foals. J Am Vet Med Assoc 1995, Jul 1; 207(1): 713. 158. Madison JB, Garber JL, Rice B, et al. Effect of oxytetracycline on metacarpophalangeal and distal interphalangeal joint angles in newborn foals. J Am Vet Med Assoc 1994 Jan 15; 204(2): 2469. 159. Harvey JW, Gaskin JM. Feline haemobartonellosis. J Am Anim Hosp Assoc 1977; 13: 2838. 160. Nicoletti P. Further studies on the use of antibiotics in canine brucellosis. Compend Contin Educ Pract Vet 1991 Jun; 13(6): 9447. 161. Smith BP, Biberstein EL. Septicemia and meningoencephalitis in pastured cattle caused by a Haemophilus-like organism (Haemophilus somnus). Cornell Vet 1977; 67(3): 32732. 162. Xia W, Nielsen P, Gyrd-Hansen N. Oxytetracyclines in cattle: a comparison between a conventional and a long-acting preparation. Acta Vet Scand 1983; 24: 1208. 163. Dersten A, Poitschek C, Rauch S, et al. Effects of penicillin, cetriaxone, and doxycycline on morphology of Borrelia burgdorferi. Antimicrob Agents Chemother 1995 May; 39(5): 112733. 164. Appel MJG. Lyme disease in dogs and cats. Compend Contin Ed Pract Vet Small Anim 1990 May; 12(5): 61725. 165. Greene RT. Canine Lyme borreliosis. Vet Clin North Am Small Anim Pract 1991 Jan; 21(1): 5164. 166. Garcia-Delgado GA, Little PB, Barnum DA. A comparison of various Haemophilus somnus strains. Can J Comp Med 1977 Oct; 41: 3808. 167. Griffen DD, Morter RL, Amstutz HE, et al. Experimental oxytetracycline toxicity in feedlot heifers. Bovine Practitioner 1979; 14: 3740. 168. Griffen DD, Amstutz HE, Morter RL, et al. Oxytetracycline toxicity associated with bovine respiratory disease therapy. Bovine Practitioner 1979; 14: 29 35. 169. Riond J, Riviere JE. Pharmacology and toxicology of doxycycline. Vet Hum Toxicol 1988 Oct; 30(5): 43143. 170. Gross DR, Kitzman JV, Adams HR. Cardiovascular effects of intravenous administration of propylene glycol and of oxytetracycline in propylene glycol in calves. Am J Vet Res 1979; 40: 78391. 171. Panel comment, Rec 3/14/96. 172. Panel comment, Rec 3/14/96. 173. Panel comment, Rec 2/5/96. 174. Xia W, Gyrd-Hansen N, Nielsen P. Comparison of pharmacokinetic parameters for two oxytetracycline preparations in pigs. J Vet Pharmacol Ther 1983; 6: 11320. 175. Teske RH, Rollins LD, Condon RJ, et al. Serum oxytetracycline concentrations after intravenous and intramuscular administration in horses. J Am Vet Med Assoc 1973; 162: 119. 176. Panel comment, Rec 3/26/96. 177. Panel consensus, 5/16/96. 178. Panel comment, Rec 5/21/ 96. 179. Manufacturer comment, Rec 5/10/96. 180. Panel comment, Rec 5/24/96.

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Indications Index 253

Indications Index
Note: Both labeled and extra-labeled indications are included in this index without differentiation. Please consult the individual monograph Indications section for US and Canadian product labeling status for each species and for more information on when use is appropriate. This reference does not include every antimicrobial product available; therefore, it should not be assumed that all medications appropriate for a given indication are listed or that those not listed are inappropriate. Because clinical variables play an important role in choice of antimicrobial treatment, it cannot be assumed that the agents listed for any indication are interchangeable in a particular situation. Indications may be found under more than one Indications subheading (Accepted, Acceptance not established, Unaccepted) when recommended for more than one species or medication within a monograph. Indications below can be found under the Accepted subheading of the listed monographs Indications section for at least one species unless Not estab is stated. Not estab signies a drug monograph in which the indication is listed under the Acceptance not established subheading. Unaccepted uses have not been indexed. Listing as Accepted, Acceptance not established, or Unaccepted in a monograph is not meant to signify label versus extra-label status. Abortion, vibrionic (prophylaxis) Tetracyclines, 226 Abscesses, cervical (prophylaxis) Tetracyclines, 226 Abscesses, hepatic (prophylaxis) Macrolides, 119 Tetracyclines, 226 Abscesses, laryngeal (treatment) Lincosamides, Not estab, 110 Actinobacillosis (treatment) Tetracyclines, 226 Actinomycosis (treatment) Penicillin G, 151 Air sacculitis (treatment) Spectinomycin, 202 Amebiasis, intestinal (treatment) Metronidazole, Not estab, 144 Anaplasmosis (treatment) Tetracyclines, 226 Arthritis, bacterial (treatment) Lincosamides, Not estab, 110 Macrolides, 119 Penicillin G, 151 Potentiated Sulfonamides, 165 Tetracyclines, 227 Atrophic rhinitis (treatment) Macrolides, 119 Tetracyclines, 227 Bacteremia (treatment) Aminoglycosides, 2 Balantidiasis, intestinal (treatment) Metronidazole, Not estab, 144 Bartonella infections (treatment) Fluoroquinolones, Not estab, 88 Blackleg (treatment) Penicillin G, 151 Tetracyclines, 227 Bloat Tetracyclines, 228 Bone and joint infections (treatment) Aminoglycosides, 2 Bovine respiratory disease (treatment)See Pneumonia and Respiratory tract infections Bowel disease, inammatory (treatment) Metronidazole, Not estab, 144 Brucellosis (treatment) Fluoroquinolones, Not estab, 88 Tetracyclines, Not estab, 228 Chlamydial infections (treatment) Fluoroquinolones, Not estab, 88 Macrolides, Not estab, 121 Rifampin, Not estab, 192 Tetracyclines, Not estab, 228 Chronic respiratory disease (CRD) (prophylaxis) Macrolides, 120 Spectinomycin, 202 Chronic respiratory disease (CRD) (treatment) Macrolides, 120 Spectinomycin, 202 Tetracyclines, 227 Coccidiosis (prophylaxis) Potentiated Sulfonamides, 164 Coccidiosis (treatment) Potentiated Sulfonamides, 164 Potentiated Sulfonamides, Not estab, 166 Sulfonamides, 207 Cold water disease (treatment) Tetracyclines, 228 Colibacillosis (prophylaxis) Potentiated Sulfonamides, 164 Colibacillosis (treatment) Fluoroquinolones, 87 Potentiated Sulfonamides, 164 Spectinomycin, 202 Spectinomycin, Not estab, 202 Colitis, antibiotic-associated (treatment) Metronidazole, Not estab, 144 Colitis, chronic (treatment) Macrolides, Not estab, 121 Colitis, clostridial (treatment) Metronidazole, Not estab, 144 Columnaris disease (treatment) Tetracyclines, 228 Coryza, infectious (prophylaxis) Macrolides, 119 Coryza, infectious (treatment) Macrolides, 119 Sulfonamides, 207 Cryptosporidiosis (treatment) Macrolides, Not estab, 121

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254 Indications Index Cystitis (treatment) Fluoroquinolones, 87 Sulfonamides, 208 Dermatitis, bacterial (treatment) Aminopenicillins, 36 Diphtheria (treatment) Macrolides, 120 Sulfonamides, 208 Tetracyclines, 226 Distemper, canine (treatment) Aminoglycosides, Not estab 3 Potentiated Sulfonamides, Not estab, 165 Dysentery, swine (prophylaxis) Macrolides, 120 Dysentery, swine (treatment) Lincosamides, 109 Macrolides, 120 Egg hatchability, increased Tetracyclines, 228 Egg production, increased Tetracyclines, 228 Ehrlichiosis, canine (treatment) Tetracyclines, Not estab, 228 Ehrlichiosis, equine (treatment) Tetracyclines, 228 Encephalopathy, hepatic (treatment) Metronidazole, Not estab, 144 Endometritis (treatment) Metronidazole, Not estab, 144 Endophthlalmitits, bacterial (treatment) Fluoroquinolones, Not estab, 88 Enteric redmouth disease (treatment) Tetracyclines, 228 Enteric septicemia (treatment) Potentiated Sulfonamides, 165 Enteritis, bacterial (treatment) Aminoglycosides, 2 Macrolides, 120 Potentiated Sulfonamides, 165 Spectinomycin, 202 Sulfonamides, 208 Tetracyclines, 226 Enteritis, Campylobacter (treatment) Macrolides, 121 Enteritis, necrotic (treatment) Lincosamides, 109 Enterotoxemia (prophylaxis) Macrolides, 120 Enterotoxemia (treatment) Tetracyclines, 228 Equine infectious arthritis (treatment) Potentiated Sulfonamides, Not estab, 166 Equine protozoal myeloencephalitis (treatment) Potentiated Sulfonamides, Not estab, 166 Pyrimethamine, 185 Erysipelas (treatment) Macrolides, 120 Penicillin G, 151 Tetracyclines, 228 Escherichia coli infection (treatment) Aminoglycosides, 2 Cephalosporins, 51 Tetracyclines, 226 Feed efciency, improved Macrolides, 120 Tetracyclines, 226 Flexural limb deformities (treatment) Tetracyclines, Not estab, 228 Foul brood (treatment) Tetracyclines, 226 Fowl cholera (prophylaxis) Potentiated Sulfonamides, 165 Tetracyclines, 226 Fowl cholera (treatment) Fluoroquinolones, 87 Potentiated Sulfonamides, 165 Spectinomycin, 202 Sulfonamides, 208 Tetracyclines, 226 Fowl typhoid (treatment) Sulfonamides, 208 Furunculosis (treatment) Florfenicol, 81 Potentiated Sulfonamides, 165 Tetracyclines, 226 Gaffkemia (treatment) Tetracyclines, 226 Gastroenteritis/Gastrointestinal infections, bacterial (treatment) Aminoglycosides, Not estab, 3 Aminopenicillins, 36 Potentiated Sulfonamides, 165 Tetracyclines, 226 Genitourinary tract infections, bacterial (treatment) Aminopenicillins, 36 Giardiasis (treatment) Metronidazole, 144 Growth promotion and feed efciency, increased Lincosamides, 109 Haemobartonella felis infection (treatment) Fluoroquinolones, Not estab, 88 Tetracyclines, Not estab, 228 Helicobacter species infections (treatment) Metronidazole, Not estab, 144 Hemorrhagic septicemia, bacterial (treatment) Tetracyclines, 226 Hexamitiasis (treatment) Tetracyclines, 226 Infections, bacterial (treatment) Aminoglycosides, Not estab, 3 Aminopenicillins, Not estab, 36 Cephalosporins, Not estab, 52 Fluoroquinolones, 87 Metronidazole, Not estab, 144 Potentiated Sulfonamides, Not estab, 165 Rifampin, Not estab, 191 Spectinomycin, Not estab, 202

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Indications Index 255 Infectious coryza (prophylaxis) Potentiated Sulfonamides, 165 Joint infections (treatment) Lincosamides, 109 Keratoconjunctivitis (treatment) Florfenicol, 81 Tetracyclines, 226 Leptospirosis (treatment) Aminoglycosides, Not estab, 3 Aminopenicillins, Not estab, 36 Macrolides, 120 Penicillin G, 151 Tetracyclines, 226 Lyme disease (treatment) Tetracyclines, Not estab, 228 Malignant edema (treatment) Penicillin G, 151 Tetracyclines, 227 Mastitis (treatment) Aminoglycosides, Not estab, 3 Aminopenicillins (Intramammary), 33 Cephapirin (Intramammary), 71 Erythromycin (Intramammary), 79 Lincosamides, Not estab, 110 Macrolides, Not estab, 121 Penicillin G (Intramammary), 149 Pirlimycin (Intramammary), 161 Potentiated Sulfonamides, 165 Tetracyclines, 228 Meningitis, bacterial (treatment) Fluoroquinolones, Not estab, 88 Potentiated Sulfonamides, Not estab, 166 Metritis (treatment) Cephalosporins, 51 Lincosamides, 109 Macrolides, 120 Penicillin G, 151 Potentiated Sulfonamides, 165 Mycobacterial infections (treatment) Fluoroquinolones, Not estab, 88 Mycoplasmal infections (treatment) Fluoroquinolones, Not estab, 88 Neospora caninum infection (treatment) Pyrimethamine, Not estab, 185 New duck disease (treatment) Potentiated Sulfonamides, 165 Nocardiosis (treatment) Potentiated Sulfonamides, Not estab, 166 Omphalophlebitis (treatment) Tetracyclines, 228 Osteomyelitis (treatment) Amoxicillin and Clavulanate, Not estab, 46 Lincosamides, 109 Otitis media (treatment) Aminoglycosides, Not estab, 3 Pancreatitis (treatment) Aminoglycosides, Not estab, 3 Panleukopenia (treatment) Aminoglycosides, Not estab, 3 Paracolon (treatment) Aminoglycosides, 2 Paratuberculosis (treatment) Rifampin, Not estab, 192 Paratyphoid (treatment) Spectinomycin, 202 Tetracyclines, 227 Pasteurellosis (treatment) Fluoroquinolones, Not estab, 88 Periodontal infections (treatment) Amoxicillin and Clavulanate, 46 Lincosamides, 109 Metronidazole, Not estab, 144 Perioperative infections (prophylaxis) Cephalosporins, 52 Potentiated Sulfonamides, 165 Peritonitis (treatment) Tetracyclines, 228 Pharyngitis (treatment) Penicillin G, 151 Pneumonia, bacterial (prophylaxis) Tetracyclines, 227 Pneumonia, bacterial (treatment) Aminopenicillins, 36 Florfenicol, 81 Fluoroquinolones, 87 Lincosamides, 109 Macrolides, 120 Penicillin G, 151 Potentiated Sulfonamides, 165 Potentiated Sulfonamides, Not estab, 166 Spectinomycin, 202 Sulfonamides, 208 Tetracyclines, 227 Pneumonia, Rhodococcus equi (treatment) Macrolides, 120 Macrolides, Not estab, 121 Rifampin, 191 Pneumonitis (treatment) Aminoglycosides, Not estab, 3 Pododermatitis (prophylaxis) Tetracyclines, 228 Pododermatitis (treatment) Aminopenicillins, 36 Cephalosporins, 51 Florfenicol, 81 Macrolides, 120 Potentiated Sulfonamides, 165 Sulfonamides, 208 Tetracyclines, 227 Potomac horse fever (treatment) Rifampin, Not estab, 192 Tetracyclines, 228 Proliferative enteropathy, porcine (prophylaxis and treatment) Lincosamides, 109 Macrolides, 120 Prostate infection (treatment)

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256 Indications Index Potentiated Sulfonamides, Not estab, 166 Protozoal infections (treatment) Potentiated Sulfonamides, Not estab, 166 Pseudomonas aeruginosa infection (treatment) Aminoglycosides, 2 Pseudomonas disease (treatment) Tetracyclines, 227 Psittacosis (treatment) Tetracyclines, 227 Pullorum disease (treatment) Sulfonamides, 208 Pyelonephritis (treatment) Penicillin G, 151 Pyoderma (treatment) Macrolides, 121 Respiratory disease, bacterial, chronic (prophylaxis) Tetracyclines, 227 Respiratory tract infections, bacterial (treatment) Aminoglycosides, 3 Cephalosporins, 51 Fluoroquinolones, 87 Lincosamides, 109 Macrolides, 120 Potentiated Sulfonamides, 165 Sulfonamides, 209 Tetracyclines, Not estab, 228 Rhinitis (treatment) Penicillin G, 151 Rocky Mountain spotted fever Macrolides, Not estab, 121 Tetracyclines, 228 Salmonella infantis infection (treatment) Spectinomycin, 202 Salmonella typhimurium infection (treatment) Aminoglycosides, 2 Septicemia (treatment) Aminoglycosides, 2 Potentiated Sulfonamides, 165 Sinusitis, infectious (prophylaxis) Tetracyclines, 228 Sinusitis, infectious (treatment) Macrolides, 121 Tetracyclines, 228 Skeletal tissue marking Tetracyclines, 227 Skin and soft tissue infections (treatment) Aminoglycosides, 3 Aminopenicillins, 36 Amoxicillin and Clavulanate, 46 Cephalosporins, 52 Fluoroquinolones, 87 Lincosamides, 109 Penicillin G, 151 Potentiated Sulfonamides, 165 Sulfonamides, 209 Tetracyclines, 227 Strangles (treatment) Aminopenicillins, 36 Penicillin G, 151 Potentiated Sulfonamides, 165 Swine dysentery (treatment) Aminoglycosides, 3 Synovitis, infectious (prophylaxis) Macrolides, 121 Spectinomycin, 202 Synovitis, infectious (treatment) Spectinomycin, 202 Tetracyclines, 227 Tetanus (treatment) Penicillin G, 151 Thromboembolic meningoencephalitis (treatment) Tetracyclines, Not estab, 228 Tonsillitis, bacterial (treatment) Aminopenicillins, 36 Toxoplasmosis (treatment) Lincosamides, Not estab, 110 Pyrimethamine, Not estab, 185 Tracheobronchitis, bacterial (treatment) Aminopenicillins, 36 Trichomoniasis, intestinal (treatment) Metronidazole, Not estab, 144 Ulcer disease (treatment) Tetracyclines, 227 Upper respiratory tract infections (treatment) Aminopenicillins, 36 Urinary tract infections, bacterial (treatment) Aminoglycosides, 3 Amoxicillin and Clavulanate, 46 Cephalosporins, 52 Potentiated Sulfonamides, 165 Tetracyclines, 227 Urogenital tract infections (treatment) Potentiated Sulfonamides, 165 Uterine infections, bacterial (treatment) Aminoglycosides, 3 Tetracyclines, 227 Tetracyclines, Not estab, 229 Vibrio anguillarum infection Potentiated Sulfonamides, 165 Weight gain, increased rate Macrolides, 120 Tetracyclines, 226

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Dosing Index 257

Dosing Index
Note: Both labeled and extra-labeled dosage recommendations are included in this index without differentiation. Please consult the individual monograph for US and Canadian product labeling status for each species and for more information on when use is appropriate. AmikacinIncluded in Aminoglycosides (VeterinarySystemic), 1 Cats, dogs, calves, donkeys, foals, goats, guinea pigs, hawks, parrots, ponies, pythons, snakes, tortoises Amikacin Sulfate Injection, 14 Horses Amikacin Sulfate Injection, 14 Amikacin Sulfate Uterine Solution, 13 Amoxicillin Included in Aminopenicillins (VeterinaryIntramammary-Local), 33 Cows Amoxicillin Intramammary Infusion, 34 Included in Aminopenicillins (VeterinarySystemic), 36 Calves Amoxicillin Tablets, 40 Cats, dogs Amoxicillin For Injectable Suspension, 41 Amoxicillin For Oral Suspension, 40 Amoxicillin Tablets, 40 Cattle Amoxicillin For Injectable Suspension, 41 Amoxicillin and ClavulanateIncluded in Amoxicillin and Clavulanate (VeterinarySystemic), 46 Cats, dogs Amoxicillin and Clavulanate Potassium For Oral Suspension, 48 Amoxicillin and Clavulanate Potassium Tablets, 49 AmpicillinIncluded in Aminopenicillins (VeterinarySystemic), 36 Calves, cattle Ampicillin For Injectable Suspension, 42 Cats, dogs Ampicillin Capsules, 42 Ampicillin For Injectable Suspension, 42 Ampicillin For Injection, 43 Horses Ampicillin For Injection, 43 ApramycinIncluded in Aminoglycosides (VeterinarySystemic), 1 Pigs Apramycin Sulfate Powder For Oral Solution, 15 AzithromycinIncluded in Macrolides (VeterinarySystemic), 119 Cats, dogs, foals Azithromycin For Oral Suspension, 128 Azithromycin Tablets, 128 CefaclorIncluded in Cephalosporins (VeterinarySystemic), 51 Dogs Cefaclor Capsules, 56 Cefaclor For Oral Suspension, 57 CefadroxilIncluded in Cephalosporins (VeterinarySystemic), 51 Cats, dogs Cefadroxil For Oral Suspension, 57 Cefadroxil Tablets, 57 CefazolinIncluded in Cephalosporins (VeterinarySystemic), 51 Dogs Cefazolin For Injection, 58 Cefazolin Injection, 58 CeximeIncluded in Cephalosporins (VeterinarySystemic), 51 Dogs Cexime For Oral Suspension, 59 Cexime Tablets, 59 CefotaximeIncluded in Cephalosporins (VeterinarySystemic), 51 Cats, dogs, foals Cefotaxime For Injection, 60 Cefotaxime Injection, 60 CefotetanIncluded in Cephalosporins (VeterinarySystemic), 51 Dogs Cefotetan For Injection, 60 CefoxitinIncluded in Cephalosporins (VeterinarySystemic), 51 Dogs, horses Cefoxitin For Injection, 61 Cefoxitin Injection, 61 CeftiofurIncluded in Cephalosporins (VeterinarySystemic), 51 Cattle, pigs Ceftiofur Hydrochloride Injection, 62 Ceftiofur Sodium For Injection, 62 Chicks, dogs, goats, horses, sheep, turkey poults Ceftiofur Sodium For Injection, 62 CephalexinIncluded in Cephalosporins (VeterinarySystemic), 51 Birds, dogs Cephalexin Capsules, 63 Cephalexin For Oral Suspension, 64 Cephalexin Hydrochloride Tablets, 64 Cephalexin Tablets, 64 CephalothinIncluded in Cephalosporins (VeterinarySystemic), 51 Birds, dogs, horses Cephalothin For Injection, 65 Cephapirin Included in Cephalosporins (VeterinarySystemic), 51 Dogs, horses Cephapirin For Injection, 66 In Cephapirin (VeterinaryIntramammary-Local), 71 Cows Cephapirin Benzathine Intramammary Infusion, 72 Cephapirin Sodium Intramammary Infusion, 72 Cephradine Included in Cephalosporins (VeterinarySystemic), 51 Dogs, foals Cephradine Capsules, 66 Cephradine For Oral Suspension, 66 ChloramphenicolIn Chloramphenicol (VeterinarySystemic), 74

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258 Dosing Index Cats, dogs Chloramphenicol Capsules, 76 Chloramphenicol Palmitate Oral Suspension, 76 Chloramphenicol Sodium Succinate For Injection, 77 Chloramphenicol Tablets, 77 Horses Chloramphenicol Capsules, 76 Chloramphenicol Sodium Succinate For Injection, 77 Chloramphenicol Tablets, 77 ChlortetracyclineIncluded in Tetracyclines (VeterinarySystemic), 225 Calves, chickens, pigs, turkeys Chlortetracycline For Medicated Feed, 237 Chlortetracycline Hydrochloride Soluble Powder, 236 Cattle Chlortetracycline For Medicated Feed, 237 Chlortetracycline Uterine Tablets, 236 Cockatoos, ducks, lambs, macaws, parrots, sheep Chlortetracycline For Medicated Feed, 237 Ewes, sows Chlortetracycline Uterine Tablets, 236 CiprooxacinIncluded in Fluoroquinolones (VeterinarySystemic), 87 Dogs Ciprooxacin For Oral Suspension, 97 Ciprooxacin Injection, 97 Ciprooxacin Tablets, 97 Horses Ciprooxacin For Oral Suspension, 97 Ciprooxacin Tablets, 97 ClarithromycinIncluded in Macrolides (VeterinarySystemic), 119 Dogs Clarithromycin For Oral Suspension, 129 Clarithromycin Tablets, 129 ClindamycinIncluded in Lincosamides (VeterinarySystemic), 109 Cats Clindamycin Hydrochloride Oral Solution, 114 Dogs Clindamycin Hydrochloride Capsules, 114 Clindamycin Hydrochloride Oral Solution, 114 DioxacinIncluded in Fluoroquinolones (VeterinarySystemic), 87 Dogs Dioxacin Hydrochloride Tablets, 98 DihydrostreptomycinIncluded in Aminoglycosides (Veterinary Systemic), 1 Cattle, dogs, pigs Dihydrostreptomycin Injection, 15 DoxycyclineIncluded in Tetracyclines (VeterinarySystemic), 225 Cats, dogs Doxycycline Calcium Oral Suspension, 239 Doxycycline For Oral Suspension, 239 Doxycycline Hyclate Capsules, 239 Doxycycline Hyclate Tablets, 240 Dogs Doxycycline For Injection, 240 EnrooxacinIncluded in Fluoroquinolones (VeterinarySystemic), 87 Bustards, cats, dogs, ducks, horses, pacu, parrots, rabbits Enrooxacin Injection, 100 Enrooxacin Tablets, 99 Camels, cattle, emus, llamas, oryx, potbellied and minature pigs, pythons, sheep Enrooxacin Injection, 100 Chickens, turkeys Enrooxacin Oral Solution, 99 Foals Enrooxacin Tablets, 99 Erythromycin Included in Erythromycin (VeterinaryIntramammary-Local), 79 Cows Erythromycin Intramammary Infusion, 80 Included in Macrolides (VeterinarySystemic), 119 Dogs Erythromycin Tablets, 130 Cattle, lambs, pigs, piglets, sheep Erythromycin Injection, 131 Erythromycin EstolateIncluded in Macrolides (VeterinarySystemic), 119 Foals Erythromycin Estolate Capsules, 132 Erythromycin Estolate Oral Suspension, 132 Erythromycin Estolate Tablets, 132 Erythromycin GluceptateIncluded in Macrolides (Veterinary Systemic), 119 Foals Sterile Erythromycin Gluceptate, 134 Erythromycin PhosphateIncluded in Macrolides (Veterinary Systemic), 119 Chickens, turkeys Erythromycin Phosphate Powder For Oral Solution, 135 Erythromycin StearateIncluded in Macrolides (VeterinarySystemic), 119 Dogs Erythromycin Stearate Oral Suspension, 135 Erythromycin Stearate Tablets, 136 Erythromycin ThiocyanateIncluded in Macrolides (Veterinary Systemic), 119 Chickens, turkeys Erythromycin Thiocyanate For Medicated Feed, 136 FlorfenicolIn Florfenicol (VeterinarySystemic), 81 Cattle Florfenicol Injection, 84 Salmon Florfenicol For Medicated Feed, 84 GentamicinIncluded in Aminoglycosides (VeterinarySystemic), 1 Cats, chicks, dogs, baboons, buffalo calves, budgerigars, calves, cattle, eagles, foals, goats, hawks, llamas, owls, pythons, turkey poults Gentamicin Injection, 17 Horses

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Dosing Index 259 Gentamicin Injection, 17 Gentamicin Uterine Infusion, 16 Pigs Gentamicin Injection, 17 Gentamicin Oral Solution, 16 Gentamicin Powder For Oral Solution, 17 HetacillinIncluded in Aminopenicillins (VeterinaryIntramammary-Local), 33 Cows Hetacillin Potassium Intramammary Infusion, 34 KanamycinIncluded in Aminoglycosides (VeterinarySystemic), 1 Cats, dogs Kanamycin Injection, 19 LincomycinIncluded in Lincosamides (VeterinarySystemic), 109 Cats and dogs Lincomycin Hydrochloride Syrup, 116 Lincomycin Hydrochloride Tablets, 116 Lincomycin Injection, 116 Cattle Lincomycin Injection, 116 Chickens Lincomycin Hydrochloride For Medicated Feed, 115 Lincomycin Hydrochloride Soluble Powder, 115 Pigs Lincomycin Hydrochloride For Medicated Feed, 115 Lincomycin Hydrochloride Soluble Powder, 115 Sheep Lincomycin Injection, 116 MarbooxacinIncluded in Fluoroquinolones (VeterinarySystemic), 87 Cats, dogs Marbooxacin Tablets, 101 MetronidazoleIn Metronidazole (VeterinarySystemic), 144 Cats, dogs, horses Metronidazole Capsules, 146 Metronidazole Injection, 147 Metronidazole Hydrochloride For Injection, 147 Metronidazole Tablets, 146 NeomycinIncluded in Aminoglycosides (VeterinarySystemic), 1 Cattle, goats, pigs, and sheep Neomycin Sulfate For Medicated Feed, 19 Neomycin Sulfate Oral Solution, 19 Neomycin Sulfate Powder For Oral Solution, 20 Horses Neomycin Sulfate Oral Solution, 19 Neomycin Sulfate Powder For Oral Solution, 20 Turkeys Neomycin Sulfate Powder For Oral Solution, 20 OrbioxacinIncluded in Fluoroquinolones (VeterinarySystemic), 87 Cats, dogs, horses Orbioxacin Tablets, 102 Ormetoprim and SulfadimethoxineIncluded in Potentiated Sulfonamides (VeterinarySystemic), 164 Catsh, chickens, ducks, partridges, salmon, trout, turkeys Ormetoprim and Sulfadimethoxine For Medicated Feed, 175 Dogs Ormetoprim and Sulfadimethoxine Tablets, 176 OxytetracyclineIncluded in Tetracyclines (VeterinarySystemic), 225 Bees Oxytetracycline For Medicated Feed, 243 Oxytetracycline Hydrochloride Soluble Powder, 241 Calves Oxytetracycline For Medicated Feed, 243 Oxytetracycline Hydrochloride Soluble Powder, 241 Oxytetracycline Tablets, 245 Catsh, lobsters, salmon, salmonids Oxytetracycline For Medicated Feed, 243 Cattle Oxytetracycline For Medicated Feed, 243 Oxytetracycline Hydrochloride Soluble Powder, 241 Oxytetracycline Hydrochloride Uterine Suspension, 241 Oxytetracycline Injection, 245 Oxytetracycline Injection (Long-Acting), 246 Chickens, turkeys Oxytetracycline For Medicated Feed, 243 Oxytetracycline Hydrochloride Soluble Powder, 241 Horses Oxytetracycline Injection, 245 Lambs Oxytetracycline For Medicated Feed, 243 Pigs Oxytetracycline For Medicated Feed, 243 Oxytetracycline Hydrochloride Soluble Powder, 241 Oxytetracycline Injection, 245 Oxytetracycline Injection (Long-Acting), 246 Sheep Oxytetracycline For Medicated Feed, 243 Oxytetracycline Hydrochloride Soluble Powder, 241 Oxytetracycline Injection, 245 Sows Oxytetracycline Injection, 245 Oxytetracycline Injection (Long-Acting), 246 Penicillin G Included in Penicillin G (VeterinaryIntramammary-Local), 149 Cows Penicillin G Procaine Intramammary Infusion, 150 Included in Penicillin G (VeterinarySystemic), 151 Cats, dogs, horses Penicillin G Potassium For Injection, 156 Penicillin G Procaine Injectable Suspension, 156 Penicillin G Sodium For Injection, 157 Cattle, pigs, sheep Penicillin G Procaine Injectable Suspension, 156 Turkeys Penicillin G Potassium For Oral Solution, 154 PirlimycinIn Pirlimycin (VeterinaryIntramammary-Local), 161 Cows Pirlimycin Intramammary Infusion, 162 PyrimethamineIn Pyrimethamine (VeterinarySystemic), 185 Cats, dogs, horses Pyrimethamine Tablets, 188

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260 Dosing Index Pyrimethamine and SulfaquinoxalineIncluded in Potentiated Sulfonamides (VeterinarySystemic), 164 Chickens, turkeys Pyrimethamine and Sulfaquinoxaline Oral Solution, 177 RifampinIn Rifampin (VeterinarySystemic), 191 Cattle, dogs, foals, goats, horses, sheep Rifampin Capsules, 198 SpectinomycinIn Spectinomycin (VeterinarySystemic), 202 Cattle Spectinomycin Sulfate Injection, 206 Chicks, ducklings, pigs, turkeys, turkey poults Spectinomycin Hydrochloride Injection, 205 Chickens Spectinomycin Hydrochloride Powder For Oral Solution, 204 Piglets Spectinomycin Hydrochloride Oral Solution, 204 StreptomycinIncluded in Aminoglycosides (VeterinarySystemic), 1 Calves, chickens, pigs Streptomycin Sulfate Oral Solution, 21 SulfachlorpyridazineIncluded in Sulfonamides (VeterinarySystemic), 207 Calves Sulfachlorpyridazine Injection, 215 Sulfachlorpyridazine Powder For Oral Solution, 215 Sulfachlorpyridazine Tablets, 215 Pigs Sulfachlorpyridazine Powder For Oral Solution, 215 Sulfadiazine and TrimethoprimIncluded in Potentiated Sulfonamides (VeterinarySystemic), 164 Calves Sulfadiazine and Trimethoprim Tablets, 178 Cats, dogs Sulfadiazine and Trimethoprim Injection, 179 Sulfadiazine and Trimethoprim Tablets, 178 Horses Sulfadiazine and Trimethoprim Injection, 179 Sulfadiazine and Trimethoprim Oral Paste, 177 Sulfadiazine and Trimethoprim Oral Powder, 177 Piglets Sulfadiazine and Trimethoprim Oral Suspension, 178 Salmon Sulfadiazine and Trimethoprim Oral Powder, 177 SulfadimethoxineIncluded in Sulfonamides (VeterinarySystemic), 207 Calves, cattle Sulfadimethoxine Extended-Release Tablets, 217 Sulfadimethoxine Injection, 218 Sulfadimethoxine Oral Solution, 216 Sulfadimethoxine Soluble Powder, 216 Sulfadimethoxine Tablets, 217 Cats, dogs Sulfadimethoxine Injection, 218 Sulfadimethoxine Oral Suspension, 216 Sulfadimethoxine Tablets, 217 Chickens, turkeys Sulfadimethoxine Oral Solution, 216 Sulfadimethoxine Soluble Powder, 216 Sulfadoxine and TrimethoprimIncluded in Potentiated Sulfonamides (VeterinarySystemic), 164 Cattle, pigs Sulfadoxine and Trimethoprim Injection, 180 SulfamethazineIncluded in Sulfonamides (VeterinarySystemic), 207 Calves, cattle Sulfamethazine Extended-Release Tablets, 220 Sulfamethazine Oral Solution, 218 Sulfamethazine Powder For Oral Solution, 219 Sulfamethazine Tablets, 219 Chickens, turkeys Sulfamethazine Oral Solution, 218 Sulfamethazine Powder For Oral Solution, 219 Foals Sulfamethazine Tablets, 219 Pigs Sulfamethazine Oral Solution, 218 Sulfamethazine Powder For Oral Solution, 219 Sheep Sulfamethazine Oral Solution, 218 Sulfamethazine, Sulfanilamide, and SulfathiazoleIncluded in Sulfonamides (VeterinarySystemic), 207 Cattle Sulfamethazine, Sulfanilamide, and Sulfathiazole Tablets, 220 Sulfamethazine and SulfathiazoleIncluded in Sulfonamides (VeterinarySystemic), 207 Cattle, pigs Sulfamethazine and Sulfathiazole Powder For Oral Solution, 221 Sulfamethoxazole and TrimethoprimIncluded in Potentiated Sulfonamides (VeterinarySystemic), 164 Dogs Sulfamethoxazole and Trimethoprim Oral Suspension, 180 Sulfamethoxazole and Trimethoprim Tablets, 180 Foals Sulfamethoxazole and Trimethoprim Injection, 181 Horses Sulfamethoxazole and Trimethoprim Injection, 181 Sulfamethoxazole and Trimethoprim Oral Suspension, 180 Sulfamethoxazole and Trimethoprim Tablets, 180 SulfaquinoxalineIncluded in Sulfonamides (VeterinarySystemic), 207 Calves, cattle, chickens, turkeys Sulfaquinoxaline Oral Solution, 221 TetracyclineIncluded in Tetracyclines (VeterinarySystemic), 225 Calves Tetracycline Boluses, 247 Tetracycline Hydrochloride Soluble Powder, 248 Cats Tetracycline Oral Suspension, 249 Chickens, pigs, sheep, turkeys Tetracycline Hydrochloride Soluble Powder, 248 Cows, mares Tetracycline Uterine Tablets, 247 Dogs Tetracycline Hydrochloride Capsules, 248 Tetracycline Oral Suspension, 249

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Dosing Index 261 TilmicosinIncluded in Macrolides (VeterinarySystemic), 119 Calves, cattle, and lambs Tilmicosin Injection, 137 Pigs Tilmicosin For Medicated Feed, 137 Tylosin BaseIncluded in Macrolides (VeterinarySystemic), 119 Cats, cattle, dogs, pigs Tylosin Injection, 138 Tylosin PhosphateIncluded in Macrolides (VeterinarySystemic), 119 Cattle, chickens, pigs Tylosin Granulated, 138 Tylosin TartrateIncluded in Macrolides (VeterinarySystemic), 119 Chickens, dogs, pigs, turkeys Tylosin Tartrate Powder For Oral Solution, 139 Withdrawal times, extra-label Note: Label and extra-label withdrawal recommendations can be found in the Withdrawal times section for each dosage form. Amoxicillin Tablets, 41 Lincomycin Injection, 116 Oxytetracycline Injection (Long-Acting), 246 Penicillin G Procaine Injectable Suspension, 156 Spectinomycin Hydrochloride Injection, 205 Sulfadiazine and Trimethoprim Tablets, 178

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262 Veterinary Brand and Generic Name Index

Veterinary Brand and Generic Name Index

Note: Includes both United States and Canadian products. Adspec Sterile SolutionSpectinomycin Sulfate Injection, 206 Agri-cillinPenicillin G Procaine Injectable Suspension, 156 Agrimycin 100Oxytetracycline Injection, 245 Agrimycin 200Oxytetracycline Injection (Long-Acting), 246 Agrimycin-343Oxytetracycline Hydrochloride Soluble Powder, 241 Alamycin LAOxytetracycline Injection (Long-Acting), 246 Albon BolusesSulfadimethoxine Tablets, 217 Albon 12.5% Concentrated SolutionSulfadimethoxine Oral Solution, 216 Albon Injection 40%Sulfadimethoxine Injection, 218 Albon Oral Suspension 5%Sulfadimethoxine Oral Suspension, 216 Albon SRSulfadimethoxine Extended-Release Tablets, 217 Albon TabletsSulfadimethoxine Tablets, 217 Ambi-penPenicillin G Benzathine and Penicillin G Procaine Injectable Suspension, 155 Amifuse EAmikacin Sulfate Uterine Solution, 13 Amiglyde-VAmikacin Sulfate Uterine Solution, 13 Amiglyde-V InjectionAmikacin Sulfate Injection, 14 Amiglyde-V Intrauterine SolutionAmikacin Sulfate Uterine Solution, 13 Amiject DAmikacin Sulfate Injection, 14 Amikacin C InjectionAmikacin Sulfate Injection, 14 Amikacin E SolutionAmikacin Sulfate Uterine Solution, 13 Amikacin (Amifuse E; Amiglyde-V; Amiglyde-V Injection; Amiglyde-V Intrauterine Solution; Amiject D; Amikacin C Injection; Amikacin E Solution; AmTech AmiMax C Injection; AmTech AmiMax E Solution; CaniGlide; Equi-Phar EquiGlide) See Aminoglycosides (VeterinarySystemic), 1 Injection, 14 Uterine Solution, 13 Amoxicillin (Amoxi-Drop; Amoxi-Inject; Amoxil Tablets; Amoxi-Tabs; Biomox Oral Suspension; Biomox Tablets; Moxilean-50 Suspension; Robamox-V Oral Suspension; Robamox-V Tablets) See Aminopenicillins (VeterinarySystemic), 36 For Injectable Suspension, 41 For Oral Suspension, 40 Tablets, 40 Amoxicillin, Intramammary (Amoxi-Mast) See Aminopenicillins (VeterinaryIntramammary-Local), 33 Intramammary Infusion, 34 Amoxicillin and Clavulanate (Clavamox) See Amoxicillin and Clavulanate (VeterinarySystemic), 46 For Oral Suspension, 48 Tablets, 49 Amoxi-DropAmoxicillin For Oral Suspension, 40 Amoxi-InjectAmoxicillin For Injectable Suspension, 41 Amoxi-MastAmoxicillin Intramammary Infusion, 34 Amoxil TabletsAmoxicillin Tablets, 40 Amoxi-TabsAmoxicillin Tablets, 40 Amphicol Film-coated TabletsChloramphenicol Tablets, 77 Ampicillin (Polyex) See Aminopenicillins (VeterinarySystemic), 36 For Injectable Suspension, 42 AmTech Amikacin Sulfate Injection, 14 Amikacin Sulfate Uterine Solution, 13 2003 Thomson MICROMEDEX Chlortetracycline Hydrochloride Soluble Powder, 236 Clindamycin Hydrochloride Oral Solution, 114 Gentamicin Injection, 17 Gentamicin Oral Solution, 16 Gentamicin Uterine Infusion, 16 Neomycin Sulfate Oral Solution, 19 Oxytetracycline Hydrochloride Soluble Powder, 241 Oxytetracycline Injection, 245 Oxytetracycline Injection (Long-Acting), 246 Spectinomycin Hydrochloride Oral Solution, 204 Sulfadimethoxine Injection, 218 Sulfadimethoxine Oral Solution, 216 Sulfadimethoxine Soluble Powder, 216 Tetracycline Hydrochloride Soluble Powder, 248 AntirobeClindamycin Hydrochloride Capsules, 114 Antirobe AquadropsClindamycin Hydrochloride Oral Solution, 114 ApralanApramycin Sulfate Powder For Oral Solution, 15 Apralan SolubleApramycin Sulfate Powder For Oral Solution, 15 Apramycin (Apralan; Apralan Soluble) See Aminoglycosides (VeterinarySystemic), 1 Powder For Oral Solution, 15 AquacillinPenicillin G Procaine Injectable Suspension, 156 AquaorFlorfenicol For Medicated Feed, 84 Aureomycin 110G, Aureomycin 220GChlortetracycline For Medicated Feed, 237 Aureomycin 50 Granular, Aureomycin 90 Granular, Aureomycin 100 GranularChlortetracycline For Medicated Feed, 237 Aureomycin Soluble PowderChlortetracycline Hydrochloride Soluble Powder, 236 Aureomycin Soluble Powder ConcentrateChlortetracycline Hydrochloride Soluble Powder, 236 Aureomycin Uterine ObletsChlortetracycline Uterine Tablets, 236 Azramycine S125, Azramycine S250Chloramphenicol Palmitate Oral Suspension, 76 Baytril 3.23% Concentrate SolutionEnrooxacin Oral Solution, 99 Baytril Injectable SolutionEnrooxacin Injection, 100 Baytril Injectable Solution 2.27%Enrooxacin Injection, 100 Baytril 100 Injectable SolutionEnrooxacin Injection, 100 Baytril TabletsEnrooxacin Tablets, 99 Baytril Taste TabsEnrooxacin Tablets, 99 BenzaproPenicillin G Benzathine and Penicillin G Procaine Injectable Suspension, 155 BimotrimSulfadoxine and Trimethoprim Injection, 180 Biomox Oral SuspensionAmoxicillin For Oral Suspension, 40 Biomox TabletsAmoxicillin Tablets, 40 Biomycin 200Oxytetracycline Injection (Long-Acting), 246 Biosol LiquidNeomycin Sulfate Oral Solution, 19 BorgalSulfadoxine and Trimethoprim Injection, 180 Bovispec Sterile SolutionSpectinomycin Sulfate Injection, 206 Calf Scour Bolus AntibioticTetracycline Boluses, 247 CalfspanSulfamethazine Extended-Release Tablets, 220 CaniGlideAmikacin Sulfate Injection, 14 Cefa-DriCephapirin Benzathine Intramammary Infusion, 72 Cefa-DropsCefadroxil For Oral Suspension, 57 Cefadroxil (Cefa-Drops; Cefa-Tabs)

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Veterinary Brand and Generic Name Index 263 See Cephalosporins (VeterinarySystemic), 51 For Oral Suspension, 57 Tablets, 57 Cefa-LakCephapirin Sodium Intramammary Infusion, 72 Cefa-TabsCefadroxil Tablets, 57 Ceftiofur (Excenel; Excenel RTU; Naxcel) See Cephalosporins (VeterinarySystemic), 51 Ceftiofur Hydrochloride Injection, 62 Ceftiofur Sodium For Injection, 62 Cephapirin (Cefa-Dri; Cefa-Lak; ToDay; ToMorrow) See Cephapirin (VeterinaryIntramammary-Local), 71 Cephapirin Benzathine Intramammary Infusion, 72 Cephapirin Sodium Intramammary Infusion, 72 Chlor 50, Chlor 100Chlortetracycline For Medicated Feed, 237 Chlor 100, Chlor 250, Chlor 500, Chlor 1000Chloramphenicol Tablets, 77 Chloramphenicol (Amphicol Film-Coated Tablets; Azramycine S125; Azramycine S250; Chlor 100; Chlor 250; Chlor 500; Chlor 1000; Chlor Palm 125; Chlor Palm 250; Duricol; Karomycin Palmitate 125; Karomycin Palmitate 250; Viceton) See Chloramphenicol (VeterinarySystemic), 74 Capsules, 76 Oral Suspension, 76 Tablets, 76 ChlorMax 50Chlortetracycline For Medicated Feed, 237 Chlorosol-50Chlortetracycline For Medicated Feed, 237 Chlor Palm 125, Chlor Palm 250Chloramphenicol Palmitate Oral Suspension, 76 Chlortetracycline (AmTech Chlortetracycline HCL Soluble Powder; Aureomycin 110G; Aureomycin 220G; Aureomycin 50 Granular; Aureomycin 90 Granular; Aureomycin 100 Granular; Aureomycin Soluble Powder; Aureomycin Soluble Powder Concentrate; Aureomycin Uterine Oblets; Chlor 50; Chlor 100; ChlorMax 50; Chlorosol-50; CLTC 100 MR; CTC 50; CTC Soluble Powder Concentrate; Pennchlor 50G; Pennchlor 90G; Pennchlor 100 Hi-Flo Meal; Pennchlor 50 Meal; Pennchlor 70 Meal; Pennchlor 100 MR; Pennchlor 64 Soluble Powder) See Tetracyclines (VeterinarySystemic), 225 For Medicated Feed, 237 Soluble Powder, 236 Uterine Tablets, 236 Clavamox Amoxicillin and Clavulanate Potassium For Oral Suspension, 48 Amoxicillin and Clavulanate Potassium Tablets, 49 ClincapsClindamycin Hydrochloride Capsules, 114 ClindaCureClindamycin Hydrochloride Oral Solution, 114 Clinda-GuardClindamycin Hydrochloride Oral Solution, 114 Clindamycin (AmTech; Antirobe; Antirobe Aquadrops; Clincaps; ClindaCure; Clinda-Guard; Clindrops; nvClindamycin Capsules) See Lincosamides (VeterinarySystemic), 109 Capsules, 114 Oral Solution, 114 ClindropsClindamycin Hydrochloride Oral Solution114 CLTC 100 MRChlortetracycline For Medicated Feed, 237 CombicillinPenicillin G Benzathine and Penicillin G Procaine Injectable Suspension, 155 Combicillin AGPenicillin G Benzathine and Penicillin G Procaine Injectable Suspension, 155 CTC 50Chlortetracycline For Medicated Feed, 237 CTC Soluble Powder ConcentrateChlortetracycline Hydrochloride Soluble Powder, 236 DepocillinPenicillin G Procaine Injectable Suspension, 156 Derapen SQ/LAPenicillin G Procaine Injectable Suspension, 156 Dicural TabletsDioxacin Hydrochloride Tablets, 98 Dioxacin (Dicural Tablets) See Fluoroquinolones (VeterinarySystemic), 87 Tablets, 98 Dihydrostreptomycin (Ethamycin) See Aminoglycosides (VeterinarySystemic), 1 Injection, 15 Di-Methox Injection-40%Sulfadimethoxine Injection, 218 Di-Methox 12.5% Oral SolutionSulfadimethoxine Oral Solution, 216 Di-Methox Soluble PowderSulfadimethoxine Soluble Powder, 216 Duo-PenPenicillin G Benzathine and Penicillin G Procaine Injectable Suspension, 155 Duplocillin LAPenicillin G Benzathine and Penicillin G Procaine Injectable Suspension, 155 Duramycin 10Tetracycline Hydrochloride Soluble Powder, 248 Duramycin 72-200Oxytetracycline Injection (Long-Acting), 246 Duramycin 100Oxytetracycline Injection, 245 Duramycin-324Tetracycline Hydrochloride Soluble Powder, 248 DurapenPenicillin G Benzathine and Penicillin G Procaine Injectable Suspension, 155 DuricolChloramphenicol Capsules, 76 Enrooxacin (Baytril 3.23% Concentrate Solution; Baytril Injectable Solution; Baytril Injectable Solution 2.27%; Baytril 100 Injectable Solution; Baytril Tablets; Baytril Taste Tabs) See Fluoroquinolones (VeterinarySystemic), 87 Injection, 100 Oral Solution, 99 Tablets, 99 Equi-Phar EquiGlideAmikacin Sulfate Uterine Solution, 13 Erymycin-100Erythromycin Thiocyanate For Medicated Feed, 136 Erythro-36Erythromycin Intramammary Infusion, 80 Erythro-200Erythromycin Injection, 131 Erythro-Dry CowErythromycin Intramammary Infusion, 80 Erythromycin Base (Erythro-200; Gallimycin-100; Gallimycin-200) See Macrolides (VeterinarySystemic), 119 Injection, 131 Erythromycin, Intramammary (Erythro-36; Erythro-Dry Cow; Gallimycin-36; Gallimycin-Dry Cow) See Erythromycin (VeterinaryIntramammary-Local), 79 Intramammary Infusion, 80 Erythromycin Phosphate (Gallimycin; Gallimycin PFC; Gallistat) See Macrolides (VeterinarySystemic), 119 Powder For Oral Solution, 135 Erythromycin Thiocyanate (Erymycin-100; Gallimycin-50) See Macrolides (VeterinarySystemic), 119 For Medicated Feed, 136 EthamycinDihydrostreptomycin Injection, 15 ExcenelCeftiofur Sodium For Injection, 62 Excenel RTUCeftiofur Hydrochloride Injection, 62 Florfenicol (Aquaor; NuFlor) See Florfenicol (VeterinarySystemic), 81 For Medicated Feed, 84 Injection, 84 Foul Brood MixOxytetracycline Hydrochloride Soluble Powder, 241

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264 Veterinary Brand and Generic Name Index GallimycinErythromycin Phosphate Powder For Oral Solution, 135 Gallimycin-36Erythromycin Intramammary Infusion, 80 Gallimycin-50Erythromycin Thiocyanate For Medicated Feed, 136 Gallimycin-100, Gallimycin-200Erythromycin Injection, 131 Gallimycin-Dry CowErythromycin Intramammary Infusion, 80 Gallimycin PFCErythromycin Phosphate Powder For Oral Solution, 135 GallistatErythromycin Phosphate Powder For Oral Solution, 135 Garacin Piglet InjectionGentamicin Injection, 17 Garacin Pig PumpGentamicin Oral Solution, 16 Garacin Soluble PowderGentamicin Powder For Oral Solution, 17 Garasol InjectionGentamicin Injection, 17 Garasol Pig Pump Oral SolutionGentamicin Oral Solution, 16 Garasol Solution InjectableGentamicin Injection, 17 Gentamicin (AmTech GentaMax 100; AmTech Gentamicin Sulfate Pig Pump Oral Solution; AmTech Gentapoult; Garacin Piglet Injection; Garacin Pig Pump; Garacin Soluble Powder; Garasol Injection; Garasol Pig Pump Oral Solution; Garasol Solution Injectable; Gen-Gard; Genta-fuse; GentaMax 100; GentaVed 50; GentaVed 100; Gentocin; Gentocin Solution; Gentocin Solution Injectable; Gentozen; Legacy) See Aminoglycosides (VeterinarySystemic), 1 Injection, 17 Oral Solution, 16 Powder For Oral Solution, 17 Uterine Infusion, 16 Gen-GardGentamicin Powder For Oral Solution, 17 Genta-fuseGentamicin Injection, 17 GentaMax 100Gentamicin Uterine Infusion, 16 GentaVed 50Gentamicin Injection, 17 GentaVed 100Gentamicin Uterine Infusion, 16 GentocinGentamicin Injection, 17 Gentocin SolutionGentamicin Uterine Infusion, 16 Gentocin Solution InjectableGentamicin Injection, 17 GentozenGentamicin Uterine Infusion, 16 Geomycin 200Oxytetracycline Injection (Long-Acting), 246 Go-dryPenicillin G Procaine Intramammary Infusion, 150 Hetacillin (Hetacillin K Intramammary Infusion) See Aminopenicillins (VeterinaryIntramammary-Local), 33 Intramammary Infusion, 34 Hetacillin K Intramammary InfusionHetacillin Potassium Intramammary Infusion, 34 Hi-Pencin 300Penicillin G Procaine Injectable Suspension, 156 Kanamycin (Kantrim) See Aminoglycosides (VeterinarySystemic), 1 Injection, 19 KantrimKanamycin Injection, 19 Karomycin Palmitate 125, Karomycin Palmitate 250Chloramphenicol Palmitate Oral Suspension, 76 KelamycinOxytetracycline Hydrochloride Uterine Suspension, 241 LegacyGentamicin Uterine Infusion, 16 LincocinLincomycin Hydrochloride Tablets, 116 Lincocin AquadropsLincomycin Hydrochloride Syrup, 116 Lincocin InjectableLincomycin Injection, 116 Lincocin Sterile SolutionLincomycin Injection, 116 Lincomix 20 Feed Medication, Lincomix 50 Feed Medication Lincomycin Hydrochloride For Medicated Feed, 115 Lincomix InjectableLincomycin Injection, 116 Lincomix Injectable SolutionLincomycin Injection, 116 Lincomix 44 Premix, Lincomix 110 PremixLincomycin Hydrochloride For Medicated Feed, 115 Lincomix Soluble PowderLincomycin Hydrochloride Soluble Powder, 115 Lincomycin (Lincocin, Lincocin Aquadrops, Lincocin Injectable, Lincocin Sterile Solution, Lincomix 20 Feed Medication, Lincomix 50 Feed Medication, Lincomix Injectable, Lincomix Injectable Solution, Lincomix 44 Premix, Lincomix 110 Premix, Lincomix Soluble Powder, Lincomycin 44 Premix, Lincomycin 110 Premix, Lincomycin 44G Premix, Lincomycin 110G Premix, Lincosol Soluble Powder, Moormans LN 10) See Lincosamides (VeterinarySystemic), 109 For Medicated Feed, 115 Injection, 116 Soluble Powder, 115 Syrup, 116 Tablets, 116 Lincomycin 44 Premix, Lincomycin 110 Premix, Lincomycin 44G Premix, Lincomycin 110G PremixLincomycin Hydrochloride For Medicated Feed, 115 Lincosol Soluble PowderLincomycin Hydrochloride Soluble Powder, 115 Liquamycin LA-200Oxytetracycline Injection (Long-Acting), 246 LongisilPenicillin G Benzathine and Penicillin G Procaine Injectable Suspension, 155 Marbooxacin (Zeniquin Tablets) See Fluoroquinolones (VeterinarySystemic), 87 Tablets, 101 Masti-ClearPenicillin G Procaine Intramammary Infusion, 150 Maxim-100Oxytetracycline Injection, 245 Maxim-200Oxytetracycline Injection (Long-Acting), 246 MicotilTilmicosin Injection, 137 MicrocillinPenicillin G Procaine Injectable Suspension, 156 Moormans LN 10Lincomycin Hydrochloride For Medicated Feed, 115 Moxilean-50 SuspensionAmoxicillin For Oral Suspension, 40 NaxcelCeftiofur Sodium For Injection, 62 Neomycin (AmTech; Biosol Liquid; Neo-325; Neomed 325; Neomix 325; Neomix AG 325; Neomix AG 325 Medicated Premix; Neomix Soluble Powder; Neomycin 200; Neomycin 325; Neo-Sol 50; Neosol-Oral; Neosol Soluble Powder; Neoved 200; Neovet 325/100; Neovet Neomycin Oral Solution) See Aminoglycosides (VeterinarySystemic), 1 For Medicated Feed, 19 Oral Solution, 19 Powder For Oral Solution, 20 Neo-325Neomycin Sulfate Powder For Oral Solution, 20 Neomed 325Neomycin Sulfate Powder For Oral Solution, 20 Neomix 325Neomycin Sulfate Powder For Oral Solution, 20 Neomix AG 325Neomycin Sulfate Powder For Oral Solution, 20 Neomix AG 325 Medicated PremixNeomycin Sulfate For Medicated Feed, 19 Neomix Soluble PowderNeomycin Sulfate Powder For Oral Solution, 20 Neomycin 200Neomycin Sulfate Oral Solution, 19 Neomycin 325Neomycin Sulfate Powder For Oral Solution, 20 Neo-Sol 50Neomycin Sulfate Powder For Oral Solution, 20 Neosol-OralNeomycin Sulfate Oral Solution, 19 Neosol Soluble PowderNeomycin Sulfate Powder For Oral Solution, 20 Neoved 200Neomycin Sulfate Oral Solution, 19 Neovet 325/100Neomycin Sulfate Powder For Oral Solution, 20 Neovet Neomycin Oral SolutionNeomycin Sulfate Oral Solution, 19

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Veterinary Brand and Generic Name Index 265 NuFlorFlorfenicol Injection, 84 nvClindamycin CapsulesClindamycin Hydrochloride Capsules, 114 Onycin 62.5, Onycin 250, Onycin 1000Tetracycline Hydrochloride Soluble Powder, 248 OptimedSulfaquinoxaline Oral Solution, 221 Orbax TabletsOrbioxacin Tablets, 102 Orbioxacin (Orbax Tablets) See Fluoroquinolones (VeterinarySystemic), 87 Tablets, 102 Ormetoprim and Sulfadimethoxine (Primor 120; Primor 240; Primor 600; Primor 1200; Rofenaid 40; Romet 30; Romet-30) See Potentiated Sulfonamides (VeterinarySystemic), 164 For Medicated Feed, 175 Tablets, 176 OT 200Oxytetracycline Injection (Long-Acting), 246 OTC 50Oxytetracycline For Medicated Feed, 243 OXTC 50, OXTC 100, OXTC 200Oxytetracycline For Medicated Feed, 243 Oxy-110, Oxy-220, Oxy-440Oxytetracycline For Medicated Feed, 243 Oxy 250, Oxy 1000Oxytetracycline Hydrochloride Soluble Powder, 241 Oxybiotic-100Oxytetracycline Injection, 245 Oxybiotic-200Oxytetracycline Injection (Long-Acting), 246 Oxy 500 Calf Bolus, Oxy 1000 Calf BolusOxytetracycline Tablets, 245 Oxycure 100Oxytetracycline Injection, 245 Oxycure 200Oxytetracycline Injection (Long-Acting), 246 Oxy LAOxytetracycline Injection (Long-Acting), 246 Oxy LPOxytetracycline Injection, 245 Oxy-Mycin 100Oxytetracycline Injection, 245 Oxy-Mycin 200Oxytetracycline Injection (Long-Acting), 246 Oxymycine LAOxytetracycline Injection (Long-Acting), 246 Oxymycine LPOxytetracycline Injection, 245 Oxyshot LAOxytetracycline Injection (Long-Acting), 246 Oxysol-62.5, Oxysol-250, Oxysol-1000Oxytetracycline Hydrochloride Soluble Powder, 241 Oxysol-110, Oxysol-220, Oxysol-440Oxytetracycline For Medicated Feed, 243 Oxytet-250 ConcentrateOxytetracycline Hydrochloride Soluble Powder, 241 Oxytetra-AOxytetracycline Hydrochloride Soluble Powder, 241 Oxytetracycline (Agrimycin 100; Agrimycin 200; Agrimycin-343; Alamycin LA; AmTech Maxim-100; AmTech Maxim-200; AmTech Oxytetracycline HCL Soluble Powder; AmTech Oxytetracycline HCL Soluble Powder-343; Biomycin 200; Duramycin 72-200; Duramycin 100; Foul Brood Mix; Geomycin 200; Kelamycin; Liquamycin LA-200; Maxim-200; OT 200; OTC 50; OXTC 50; OXTC 100; OXTC 200; Oxy-110; Oxy-220; Oxy 250; Oxy-440; Oxy 1000; Oxybiotic-100; OxyBiotic-200; Oxy 500 Calf Bolus; Oxy 1000 Calf Bolus; Oxycure 100; Oxycure 200; Oxy LA; Oxy LP; Oxy-Mycin 100; Oxy-Mycin 200; Oxymycine LA; Oxymycine LP; Oxyshot LA; Oxysol-62.5; Oxysol-110; Oxysol-220; Oxysol-250; Oxysol-440; Oxysol-1000; Oxytet-250 Concentrate; Oxytetra-A; Oxytetracycline 50; Oxytetracycline 100; Oxytetracycline 200; Oxytetracycline 100LP; Oxy Tetra Forte; Oxytetramycin 100; Oxytet-25-S; Oxytet Soluble; Oxytet-SP; Oxytet-343 Water Soluble Powder; Oxyvet 200 LA; Oxyvet 100LP; Pennox 100 Hi-Flo Meal; Pennox 200 Hi-Flo Meal; Pennox 200 Injectable; Pennox 50 Meal; Pennox 100-MR; Pennox 343 Soluble Powder; Promycin 100; Terramycin 50; Terramycin-50; Terramycin 100; Terramycin-100; Terramycin 200; Terramycin-200; Terramycin-Aqua; Terramycin 100 For Fish; Terramycin Scours Tablets; Terramycin Soluble Powder; Terramycin-343 Soluble Powder; Terra-Vet 100; Terra-Vet Soluble Powder; Terra-Vet Soluble Powder 343; Tetradure LA 300; Tetraject LA; Tetraject LP; Tetravet-CA; Tetroxy-100; Tetroxy HCA Soluble Powder) See Tetracyclines (VeterinarySystemic), 225 For Medicated Feed, 243 Injection, 245 Injection (Long-Acting), 246 Soluble Powder, 241 Tablets, 245 Uterine Suspension, 241 Oxytetracycline 50, Oxytetracycline 100, Oxytetracycline 200Oxytetracycline For Medicated Feed, 243 Oxytetracycline 100LPOxytetracycline Injection, 245 Oxy Tetra ForteOxytetracycline Hydrochloride Soluble Powder, 241 Oxytetramycin 100Oxytetracycline Injection, 245 Oxytet-25-SOxytetracycline Hydrochloride Soluble Powder, 241 Oxytet SolubleOxytetracycline Hydrochloride Soluble Powder, 241 Oxytet-SPOxytetracycline Hydrochloride Soluble Powder, 241 Oxytet-343 Water Soluble PowderOxytetracycline Hydrochloride Soluble Powder, 241 Oxyvet 200 LAOxytetracycline Injection (Long-Acting), 246 Oxyvet 100 LPOxytetracycline Injection, 245 Panmycin AquadropsTetracycline Oral Suspension, 249 Pen-AqueousPenicillin G Procaine Injectable Suspension, 156 Pen G InjectionPenicillin G Procaine Injectable Suspension, 156 Penicillin G (Agri-cillin; Ambi-pen; Aquacillin; Benzapro; Combicillin; Combicillin AG; Depocillin; Derapen SQ/LA; Duo-Pen; Duplocillin LA; Durapen; Hi-Pencin 300; Longisil; Microcillin; Pen-Aqueous; Pen G Injection; Penmed; Penpro; Pot-Pen; Propen LA; R-Pen; Twin-pen; Ultrapen LA) See Penicillin G (VeterinarySystemic), 151 Benzathine and Procaine Injectable Suspension, 155 Potassium For Oral Solution, 154 Procaine Injectable Suspension, 156 Penicillin G, Intramammary (Go-dry; Masti-Clear) See Penicillin G (VeterinaryIntramammary-Local), 149 Intramammary Infusion, 150 PenmedPenicillin G Procaine Injectable Suspension, 156 Pennchlor 50G, Pennchlor 90GChlortetracycline For Medicated Feed, 237 Pennchlor 100 Hi-Flo MealChlortetracycline For Medicated Feed, 237 Pennchlor 50 Meal, Pennchlor 70 MealChlortetracycline For Medicated Feed, 237 Pennchlor 100 MRChlortetracycline For Medicated Feed, 237 Pennchlor 64 Soluble PowderChlortetracycline Hydrochloride Soluble Powder, 236 Pennox 100 Hi-Flo Meal, Pennox 200 Hi-Flo MealOxytetracycline For Medicated Feed, 243 Pennox 200 InjectableOxytetracycline Injection (Long-Acting), 246 Pennox 50 MealOxytetracycline For Medicated Feed, 243 Pennox 100-MROxytetracycline For Medicated Feed, 243 Pennox 343 Soluble PowderOxytetracycline Hydrochloride Soluble Powder, 241 PenproPenicillin G Procaine Injectable Suspension, 156 Pirlimycin, Intramammary (Pirsue Aqueous Gel; Pirsue Sterile Solution) See Pirlimycin (VeterinaryIntramammary-Local), 161

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266 Veterinary Brand and Generic Name Index Intramammary Infusion, 162 Pirsue Aqueous GelPirlimycin Intramammary Infusion, 162 Pirsue Sterile SolutionPirlimycin Intramammary Infusion, 162 PolyexAmpicillin For Injectable Suspension, 42 PolyOtic Soluble PowderTetracycline Hydrochloride Soluble Powder, 248 PotensulfSulfadoxine and Trimethoprim Injection, 180 Pot-PenPenicillin G Potassium For Oral Solution, 154 Powder 21Sulfamethazine and Sulfathiazole Powder For Oral Solution, 221 Primor 120, Primor 240, Primor 600, Primor 1200Ormetoprim and Sulfadimethoxine Tablets, 176 Promycin 100Oxytetracycline Injection, 245 Propen LAPenicillin G Procaine Injectable Suspension, 156 Pulmotil 90Tilmicosin For Medicated Feed, 137 Pulmotil PremixTilmicosin For Medicated Feed, 137 Pyrimethamine and Sulfaquinoxaline (Quinnoxine-S; Sulfaquinoxaline-S) See Potentiated Sulfonamides (VeterinarySystemic), 164 Oral Solution, 177 Quinnoxine-SPyrimethamine and Sulfaquinoxaline Oral Solution, 177 Robamox-V Oral SuspensionAmoxicillin For Oral Suspension, 40 Robamox-V TabletsAmoxicillin Tablets, 40 Rofenaid 40Ormetoprim and Sulfadimethoxine For Medicated Feed, 175 Romet 30Ormetoprim and Sulfadimethoxine For Medicated Feed, 175 R-PenPenicillin G Potassium For Oral Solution, 154 S-125, S-250Sulfadimethoxine Tablets, 217 SDM InjectionSulfadimethoxine Injection, 218 SDM PowderSulfadimethoxine Soluble Powder, 216 SDM SolutionSulfadimethoxine Oral Solution, 216 S-M-TSulfamethazine and Sulfathiazole Powder For Oral Solution, 221 Solu-TetTetracycline Hydrochloride Soluble Powder, 248 Solu-Tet 324Tetracycline Hydrochloride Soluble Powder, 248 Spectam InjectableSpectinomycin Hydrochloride Injection, 205 Spectam Oral SolutionSpectinomycin Hydrochloride Oral Solution, 204 Spectam Scour-HaltSpectinomycin Hydrochloride Oral Solution, 204 Spectam Soluble PowderSpectinomycin Hydrochloride Powder For Oral Solution, 204 Spectam Water SolubleSpectinomycin Hydrochloride Powder For Oral Solution, 204 Spectinomycin (Adspec Sterile Solution; AmTech Spectam Scour-Halt; Bovispec Sterile Solution; Spectam; Spectam Injectable; Spectam Oral Solution; Spectam Scour-Halt; Spectam Soluble Powder; Spectam Water Soluble) See Spectinomycin (VeterinarySystemic), 202 Hydrochloride Injection, 205 Hydrochloride Oral Solution, 204 Hydrochloride Powder For Oral Solution, 204 Sulfate Injection, 206 Streptomycin See Aminoglycosides (VeterinarySystemic), 1 Oral Solution, 21 Sulfa 25Sulfamethazine Oral Solution, 218 Sulfa 25%Sulfamethazine Oral Solution, 218 Sulfachlorpyridazine (Vetisulid Boluses; Vetisulid Injection; Vetisulid Powder) See Sulfonamides (VeterinarySystemic), 207 Injection, 215 Powder For Oral Solution, 215 Tablets, 215 Sulfadiazine and Trimethoprim (Tribrissen 30; Tribrissen 120; Tribrissen 480; Tribrissen 960; Tribrissen 24%; Tribrissen 48%; Tribrissen 400 Oral Paste; Tribrissen Piglet Suspension; Tribrissen 40% Powder; Tucoprim Powder; Uniprim Powder) See Potentiated Sulfonamides (VeterinarySystemic), 164 Injection, 179 Oral Paste, 177 Oral Powder, 177 Oral Suspension, 178 Tablets, 178 Sulfadimethoxine (Albon 12.5% Concentrated Solution; Albon Injection 40%; Albon Oral Suspension 5%; Albon SR; Albon Tablets; AmTech Sulfadimethoxine Injection-40%; AmTech Sulfadimethoxine 12.5% Oral Solution; AmTech Sulfadimethoxine Soluble Powder; Di-Methox Injection40%; Di-Methox 12.5% Oral Solution; Di-Methox Soluble Powder; S-125; S-250; SDM Injection; SDM Powder; SDM Solution; Sulfasol; Sulforal) See Sulfonamides (VeterinarySystemic), 207 Extended-Release Tablets, 217 Injection, 218 Oral Solution, 216 Oral Suspension, 216 Soluble Powder, 216 Tablets, 217 Sulfadoxine and Trimethoprim (Bimotrim; Borgal; Potensulf; Trimidox; Trivetrin) See Potentiated Sulfonamides (VeterinarySystemic), 164 Injection, 180 Sulfalean PowderSulfamethazine and Sulfathiazole Powder For Oral Solution, 221 Sulfa-Max III Calf BolusSulfamethazine Extended-Release Tablets, 220 Sulfa-Max III Cattle BolusSulfamethazine Extended-Release Tablets, 220 2 SulfamedSulfamethazine and Sulfathiazole Powder For Oral Solution, 221 Sulfamethazine (Calfspan; Sulfa 25; Sulfa 25%; Sulfa-Max III Calf Bolus; Sulfa-Max III Cattle Bolus; Sulfasure SR Calf Bolus; Sulfasure SR Calf Tablets; Sulfasure SR Cattle Bolus; Sulmet Drinking Water Solution 12.5%; Sulmet Oblets; Sulmet Soluble Powder; Suprasulfa III Calf Bolus; Suprasulfa III Cattle Bolus; Sustain III; Sustain III Calf Bolus; Sustain III Cattle Bolus) See Sulfonamides (VeterinarySystemic), 207 Extended-Release Tablets, 220 Oral Solution, 218 Powder For Oral Solution, 219 Tablets, 219 Sulfamethazine, Sulfanilamide, and Sulfathiazole (Triple Sulfa Bolus) See Sulfonamides (VeterinarySystemic), 207 Tablets, 220 Sulfamethazine and Sulfathiazole (Powder 21; S-M-T; Sulfalean Powder; 2 Sulfamed; Sulfa-MT; Sulfa 2 Soluble Powder) See Sulfonamides (VeterinarySystemic), 207 Powder For Oral Solution, 221 Sulfa-MTSulfamethazine and Sulfathiazole Powder For Oral Solution, 221 Sulfa-Q 20%Sulfaquinoxaline Oral Solution, 221

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Veterinary Brand and Generic Name Index 267 Sulfaquinoxaline (Optimed; Sulfa-Q 20%; 31.92% Sul-Q-Nox) See Sulfonamides (VeterinarySystemic), 207 Oral Solution, 221 Sulfaquinoxaline-SPyrimethamine and Sulfaquinoxaline Oral Solution, 177 SulfasolSulfadimethoxine Soluble Powder, 216 Sulfa 2 Soluble PowderSulfamethazine and Sulfathiazole Powder For Oral Solution, 221 Sulfasure SR Calf BolusSulfamethazine Extended-Release Tablets, 220 Sulfasure SR Calf TabletsSulfamethazine Extended-Release Tablets, 220 Sulfasure SR Cattle BolusSulfamethazine Extended-Release Tablets, 220 SulforalSulfadimethoxine Oral Solution, 216 Sulmet Drinking Water Solution 12.5%Sulfamethazine Oral Solution, 218 Sulmet ObletsSulfamethazine Tablets, 219 Sulmet Soluble PowderSulfamethazine Powder For Oral Solution, 219 31.92% Sul-Q-NoxSulfaquinoxaline Oral Solution, 221 Suprasulfa III Calf BolusSulfamethazine Extended-Release Tablets, 220 Suprasulfa III Cattle BolusSulfamethazine Extended-Release Tablets, 220 Sustain IIISulfamethazine Extended-Release Tablets, 220 Sustain III Calf BolusSulfamethazine Extended-Release Tablets, 220 Sustain III Cattle BolusSulfamethazine Extended-Release Tablets, 220 Terramycin 50, Terramycin 100, Terramycin 200Oxytetracycline For Medicated Feed, 243 Terramycin-AquaOxytetracycline For Medicated Feed, 243 Terramycin 100 For FishOxytetracycline For Medicated Feed, 243 Terramycin Scours TabletsOxytetracycline Tablets, 245 Terramycin Soluble PowderOxytetracycline Hydrochloride Soluble Powder, 241 Terramycin-343 Soluble PowderOxytetracycline Hydrochloride Soluble Powder, 241 Terra-Vet 100Oxytetracycline Injection, 245 Terra-Vet Soluble PowderOxytetracycline Hydrochloride Soluble Powder, 241 Terra-Vet Soluble Powder 343Oxytetracycline Hydrochloride Soluble Powder, 241 Tet-324Tetracycline Hydrochloride Soluble Powder, 248 Tetra 55, Tetra 250, Tetra 1000Tetracycline Hydrochloride Soluble Powder, 248 Tetra 4000 Tetracycline Boluses, 247 Tetracycline Uterine Tablets, 247 Tetra Bac 324Tetracycline Hydrochloride Soluble Powder, 248 Tetrabol Tetracycline Boluses, 247 Tetracycline Uterine Tablets, 247 Tetracycline (AmTech Tetracycline Hydrochloride Soluble Powder-324; Calf Scour Bolus Antibiotic; Duramycin 10; Duramycin-324; Onycin 62.5; Onycin 250; Onycin 1000; Panmycin Aquadrops; PolyOtic Soluble Powder; Solu-Tet; Solu-Tet 324; Tet-324; Tetra 55; Tetra 250; Tetra 1000; Tetra 4000; Tetra Bac 324; Tetrabol; Tetracycline 250; Tetracycline 1000; Tetracycline 250 Concentrate Soluble Powder; Tetracycline 62.5 Soluble Powder; Tetramed 250; Tetramed 1000; Tetrasol Soluble Powder; Tet-Sol 10; Tet-Sol 324; 5-Way Calf Scour Bolus) See Tetracyclines (VeterinarySystemic), 225 Boluses, 247 Oral Suspension, 249 Soluble Powder, 248 Uterine Tablets, 247 Tetracycline 250, Tetracycline 1000Tetracycline Hydrochloride Soluble Powder, 248 Tetracycline 250 Concentrate Soluble PowderTetracycline Hydrochloride Soluble Powder, 248 Tetracycline 62.5 Soluble PowderTetracycline Hydrochloride Soluble Powder, 248 Tetradure LA 300Oxytetracycline Injection (Long-Acting), 246 Tetraject LAOxytetracycline Injection (Long-Acting), 246 Tetraject LPOxytetracycline Injection, 245 Tetramed 250, Tetramed 1000Tetracycline Hydrochloride Soluble Powder, 248 Tetrasol Soluble PowderTetracycline Hydrochloride Soluble Powder, 248 Tetravet-CAOxytetracycline Hydrochloride Soluble Powder, 241 Tetroxy-100Oxytetracycline Injection, 245 Tetroxy HCA Soluble PowderOxytetracycline Hydrochloride Soluble Powder, 241 Tet-Sol 10, Tet-Sol 324Tetracycline Hydrochloride Soluble Powder, 248 Tilmicosin (Micotil; Pulmotil 90; Pulmotil Premix) See Macrolides (VeterinarySystemic), 119 For Medicated Feed, 137 Injection, 137 ToDayCephapirin Sodium Intramammary Infusion, 72 ToMorrowCephapirin Benzathine Intramammary Infusion, 72 Tribrissen 30, Tribrissen 120, Tribrissen 480, Tribrissen 960Sulfadiazine and Trimethoprim Tablets, 178 Tribrissen 24%, Tribrissen 48%Sulfadiazine and Trimethoprim Injection, 179 Tribrissen 400 Oral PasteSulfadiazine and Trimethoprim Oral Paste, 177 Tribrissen Piglet SuspensionSulfadiazine and Trimethoprim Oral Suspension, 178 Tribrissen 40% PowderSulfadiazine and Trimethoprim Oral Powder, 177 TrimidoxSulfadoxine and Trimethoprim Injection, 180 Triple Sulfa BolusSulfamethazine, Sulfanilamide, and Sulfathiazole Tablets, 220 TrivetrinSulfadoxine and Trimethoprim Injection, 180 Tucoprim PowderSulfadiazine and Trimethoprim Oral Powder, 177 Twin-penPenicillin G Benzathine and Penicillin G Procaine Injectable Suspension, 155 Tylan 10, Tylan 40, Tylan 100Tylosin Granulated, 138 Tylan 50, Tylan 200Tylosin Injection, 138 Tylan SolubleTylosin Tartrate Powder For Oral Solution, 139 Tylocine 200Tylosin Injection, 138 Tylosin Base (Tylan 50; Tylan 200; Tylocine 200; Tyloved) See Macrolides (VeterinarySystemic), 119 Injection, 138 Tylosin Phosphate (Tylan 10; Tylan 40; Tylan 100; Tylosin 10 Premix; Tylosin 40 Premix) See Macrolides (VeterinarySystemic), 119 Granulated, 138 Tylosin 10 Premix, Tylosin 40 PremixTylosin Granulated, 138 Tylosin Tartrate (Tylan Soluble) See Macrolides (VeterinarySystemic), 119

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268 Veterinary Brand and Generic Name Index Powder For Oral Solution, 139 TylovedTylosin Injection, 138 Ultrapen LAPenicillin G Procaine Injectable Suspension, 156 Uniprim PowderSulfadiazine and Trimethoprim Oral Powder, 177 Vetisulid BolusesSulfachlorpyridazine Tablets, 215 Vetisulid InjectionSulfachlorpyridazine Injection, 215 Vetisulid PowderSulfachlorpyridazine Powder For Oral Solution, 215 VicetonChloramphenicol Tablets, 77 5-Way Calf Scour BolusTetracycline Boluses, 247 Zeniquin TabletsMarbooxacin Tablets, 101

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Human Brand and Generic Name Index 269

Human Brand and Generic Name Index

Note: Only human dosage forms considered by USP Veterinary Medicine Advisory Committees to be appropriate have been included in this publication. Includes both United States and Canadian products. Achromycin VTetracycline Hydrochloride Capsules, 248 Alti-Doxycycline Doxycycline Hyclate Capsules, 239 Doxycycline Hyclate Tablets, 240 Ampicillin (Ampicin; Apo-Ampi; Novo-Ampicillin; Nu-Ampi; Omnipen; Omnipen-N; Penbritin; Polycillin-N; Principen; Totacillin; Totacillin-N) See Aminopenicillins (VeterinarySystemic), 36 Capsules, 42 For Injection, 43 AmpicinAmpicillin For Injection, 43 Ancef Cefazolin For Injection, 58 Cefazolin Injection, 58 Apo-AmpiAmpicillin Capsules, 42 Apo-Cefaclor Cefaclor Capsules, 56 Cefaclor For Oral Suspension, 57 Apo-CephalexCephalexin Tablets, 64 Apo-DoxyDoxycycline Hyclate Capsules, 239 Apo-Doxy-TabsDoxycycline Hyclate Tablets, 240 Apo-ErythroErythromycin Tablets, 130 Apo-Erythro E-CErythromycin Delayed-Release Capsules, 130 Apo-Erythro-ESErythromycin Ethylsuccinate Tablets, 133 Apo-Erythro-SErythromycin Stearate Tablets, 136 Apo-MetronidazoleMetronidazole Tablets, 146 Apo-Sulfatrim Sulfamethoxazole and Trimethoprim Oral Suspension, 180 Sulfamethoxazole and Trimethoprim Tablets, 180 Apo-Sulfatrim DSSulfamethoxazole and Trimethoprim Tablets, 180 Apo-TetraTetracycline Hydrochloride Capsules, 248 Azithromycin (Zithromax) See Macrolides (VeterinarySystemic), 119 For Injection, 129 For Oral Suspension, 128 Bactrim Sulfamethoxazole and Trimethoprim Oral Suspension, 180 Sulfamethoxazole and Trimethoprim Tablets, 180 Bactrim DSSulfamethoxazole and Trimethoprim Tablets, 180 Bactrim I.V. Sulfamethoxazole and Trimethoprim Injection, 181 Bactrim PediatricSulfamethoxazole and Trimethoprim Oral Suspension, 180 Biaxin Clarithromycin For Oral Suspension, 129 Clarithromycin Tablets, 129 Biaxin XLClarithromycin Extended-Release Tablets, 130 Cefaclor (Apo-Cefaclor; Ceclor) See Cephalosporins (VeterinarySystemic), 51 Capsules, 56 For Oral Suspension, 57 Ceclor Cefaclor Capsules, 56 Cefaclor For Oral Suspension, 57 CefadylCephapirin For Injection, 66 Cefazolin (Ancef; Kefzol) See Cephalosporins (VeterinarySystemic), 51 For Injection, 58 Injection, 58 Cexime (Suprax) See Cephalosporins (VeterinarySystemic), 51 For Oral Suspension, 59 Tablets, 59 CefotanCefotetan For Injection, 60 Cefotaxime (Claforan) See Cephalosporins (VeterinarySystemic), 51 For Injection, 60 Injection, 60 Cefotetan (Cefotan) See Cephalosporins (VeterinarySystemic), 51 For Injection. 60 Cefoxitin (Mefoxin) See Cephalosporins (VeterinarySystemic), 51 For Injection, 61 Injection, 61 Cephalexin (Apo-Cephalex; Keex; Keftab; Novo-Lexin; Nu-Cephalex; PMSCephalexin) See Cephalosporins (VeterinarySystemic), 51 Capsules, 63 For Oral Suspension, 64 Hydrochloride Tablets, 64 Tablets, 64 Cephalothin (Ceporacin; Kein) See Cephalosporins (VeterinarySystemic), 51 For Injection, 65 Cephapirin (Cefadyl) See Cephalosporins (VeterinarySystemic) For Injection, 66 Cephradine (Velosef) See Cephalosporins (VeterinarySystemic), 51 Capsules, 66 For Oral Suspension, 66 CeporacinCephalothin For Injection, 65 Chloramphenicol (Chloromycetin; Novochlorocap) See Chlorampheniol (VeterinarySystemic), 74 Capsules, 76 Sodium Succinate For Injection, 77 ChloromycetinChloramphenicol Sodium Succinate For Injection, 77 Cipro Ciprooxacin For Oral Suspension, 97 Ciprooxacin Tablets, 97 Ciprooxacin (Cipro; Cipro I.V.) See Fluoroquinolones (VeterinarySystemic), 87 For Oral Suspension, 97 Injection, 97 Tablets, 97

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270 Human Brand and Generic Name Index Cipro I.V.Ciprooxacin Injection, 97 Claforan Cefotaxime For Injection, 60 Cefotaxime Injection, 60 Clarithromycin (Biaxin; Biaxin XL) See Macrolides (VeterinarySystemic), 119 Extended-Release Tablets, 130 For Oral Suspension, 129 Tablets, 129 Cofatrim ForteSulfamethoxazole and Trimethoprim Tablets, 180 CotrimSulfamethoxazole and Trimethoprim Tablets, 180 Cotrim DSSulfamethoxazole and Trimethoprim Tablets, 180 Cotrim PediatricSulfamethoxazole and Trimethoprim Oral Suspension, 180 DaraprimPyrimethamine Tablets, 188 DoryxDoxycycline Hyclate Delayed-Release Capsules, 240 Doxycin Doxycycline Hyclate Capsules, 239 Doxycycline Hyclate Tablets, 240 Doxycycline (Alti-Doxycycline; Apo-Doxy; Apo-Doxy-Tabs; Doryx; Doxycin; Doxytec; Novo-Doxylin; Nu-Doxycycline; Vibramycin; Vibra-Tabs; Vibra-Tabs C-Pak) See Tetracyclines (VeterinarySystemic), 225 For Oral Suspension, 239 Calcium Oral Suspension, 239 Capsules, 239 Delayed-Release Capsules, 240 For Injection, 240 Tablets, 240 DoxytecDoxycycline Hyclate Capsules, 239 E-BaseErythromycin Delayed-Release Tablets, 130 E.E.S. Erythromycin Ethylsuccinate For Oral Suspension, 133 Erythromycin Ethylsuccinate Oral Suspension, 133 Erythromycin Ethylsuccinate Tablets, 133, 134 E-MycinErythromycin Delayed-Release Tablets, 130 ErybidErythromycin Delayed-Release Tablets, 130 ERYC, ERYC-250, ERYC-333Erythromycin Delayed-Release Capsules, 130 EryPed Erythromycin Ethylsuccinate For Oral Suspension, 133 Erythromycin Ethylsuccinate Tablets, 133, 134 Ery-TabErythromycin Delayed-Release Tablets, 130 Erythro Erythromycin Ethylsuccinate Oral Suspension, 133 Erythromycin Ethylsuccinate Tablets, 134 Erythrocin Erythromycin Lactobionate For Injection, 134 Erythromycin Stearate Oral Suspension, 135 Erythromycin Stearate Tablets, 136 ErythrocotErythromycin Stearate Tablets, 136 ErythromidErythromycin Tablets, 130 Erythromycin Base (Apo-Erythro; Apo-Erythro E-C; E-Base; E-Mycin; Erybid; ERYC; ERYC-250; ERYC-333; Ery-Tab; Erythromid; Ilotycin; Novo-rythro Encap; PCE) See Macrolides (VeterinarySystemic), 119 Delayed-Release Capsules, 130 Delayed-Release Tablets, 130 Tablets, 130 Erythromycin Estolate (Ilosone; Novo-rythro) See Macrolides (VeterinarySystemic), 119 Capsules, 132 Oral Suspension, 132 Tablets, 132 Erythromycin Ethylsuccinate (Apo-Erythro-ES; E.E.S.; EryPed; Erythro; Novo-Rythro) See Macrolides (VeterinarySystemic), 119 For Oral Suspension, 133 Oral Suspension, 133 Tablets, 133, 134 Erythromycin Gluceptate (Ilotycin) See Macrolides (VeterinarySystemic), 119 Sterile Erythromycin Gluceptate, 134 Erythromycin Lactobionate (Erythrocin) See Macrolides (VeterinarySystemic), 119 Erythromycin Lactobionate For Injection, 134 Erythromycin Stearate (Apo-Erythro-S; Erythrocin; Erythrocot; My-E; Novo-rythro; Wintrocin) See Macrolides (VeterinarySystemic), 119 Erythromycin Stearate Oral Suspension, 135 Erythromycin Stearate Tablets, 136 Flagyl Metronidazole Capsules, 146 Metronidazole Injection, 147 Metronidazole Tablets, 146 Flagyl I.V.Metronidazole Hydrochloride For Injection, 147 Flagyl I.V. RTUMetronidazole Injection, 147 Keex Cephalexin Capsules, 63 Cephalexin For Oral Suspension, 64 Cephalexin Tablets, 64 KeinCephalothin For Injection, 65 KeftabCephalexin Hydrochloride Tablets, 64 KefzolCefazolin For Injection, 58 Ilosone Erythromycin Estolate Capsules, 132 Erythromycin Estolate Oral Suspension, 132 Erythromycin Estolate Tablets, 132 Ilotycin Erythromycin Delayed-Release Tablets, 130 Sterile Erythromycin Gluceptate, 134 Mefoxin Cefoxitin For Injection, 61 Cefoxitin Injection, 61 Metric 21Metronidazole Tablets, 146 Metro I.V. Metronidazole Injection, 147 Metronidazole (Apo-Metronidazole; Flagyl; Flagyl I.V.; Flagyl I.V. RTU; Metric 21; Metro I.V.; Novonidazol; Protostat; Trikacide) See Metronidazole (VeterinarySystemic), 144 Capsules, 146 Hydrochloride For Injection, 147 Injection, 147 Tablets, 146 My-EErythromycin Stearate Tablets, 136 Novo-AmpicillinAmpicillin Capsules, 42 NovochlorocapChloramphenicol Capsules, 76

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Human Brand and Generic Name Index 271 Novo-Doxylin Doxycycline Hyclate Capsules, 239 Doxycycline Hyclate Tablets, 240 Novo-Lexin Cephalexin Capsules, 63 Cephalexin For Oral Suspension, 64 Cephalexin Tablets, 64 NovonidazolMetronidazole Tablets, 146 Novo-RythroErythromycin Ethylsuccinate For Oral Suspension, 133 Novo-rythro Erythromycin Estolate Capsules, 132 Erythromycin Estolate Oral Suspension, 132 Erythromycin Stearate Oral Suspension, 135 Erythromycin Stearate Tablets, 136 Novo-rythro EncapErythromycin Delayed-Release Capsules, 130 Novo-TetraTetracycline Hydrochloride Capsules, 248 Novo-Trimel Sulfamethoxazole and Trimethoprim Oral Suspension, 180 Sulfamethoxazole and Trimethoprim Tablets, 180 Novo-Trimel D.S.Sulfamethoxazole and Trimethoprim Tablets, 180 Nu-Ampi Ampicillin Capsules, 42 Nu-CephalexCephalexin Tablets, 64 Nu-Cotrimox Sulfamethoxazole and Trimethoprim Oral Suspension, 180 Sulfamethoxazole and Trimethoprim Tablets, 180 Nu-Cotrimox DSSulfamethoxazole and Trimethoprim Tablets, 180 Nu-Doxycycline Doxycycline Hyclate Capsules, 239 Doxycycline Hyclate Tablets, 240 Nu-TetraTetracycline Hydrochloride Capsules, 248 OmnipenAmpicillin Capsules, 42 Omnipen-NAmpicillin For Injection, 43 PCEErythromycin Delayed-Release Tablets, 130 PenbritinAmpicillin Capsules, 42 Penicillin G (Pzerpen) See Penicillin G (VeterinarySystemic), 151 Potassium For Injection, 156 Sodium For Injection, 157 PzerpenPenicillin G Potassium For Injection, 156 PMS-Cephalexin Cephalexin For Oral Suspension, 64 Cephalexin Tablets, 64 Polycillin-NAmpicillin For Injection, 43 PrincipenAmpicillin Capsules, 42 Pyrimethamine (Daraprim) See Pyrimethamine (VeterinarySystemic), 185 Tablets, 188 ProtostatMetronidazole Tablets, 146 RifadinRifampin Capsules, 198 Rifadin IVRifampin For Injection, 199 Rifampin (Rifadin; Rifadin IV; Rimactane; Rofact) See Rifampin (VeterinarySystemic), 191 Capsules, 198 For Injection, 199 RimactaneRifampin Capsules, 198 RofactRifampin Capsules, 198 RoubacSulfamethoxazole and Trimethoprim Tablets, 180 Septra Sulfamethoxazole and Trimethoprim Injection, 181 Sulfamethoxazole and Trimethoprim Oral Suspension, 180 Sulfamethoxazole and Trimethoprim Tablets, 180 Septra DSSulfamethoxazole and Trimethoprim Tablets, 180 Septra Grape SuspensionSulfamethoxazole and Trimethoprim Oral Suspension, 180 Septra I.V.Sulfamethoxazole and Trimethoprim Injection, 181 Septra SuspensionSulfamethoxazole and Trimethoprim Oral Suspension, 180 Sulfamethoxazole and Trimethoprim (Apo-Sulfatrim; Apo-Sulfatrim DS; Bactrim; Bactrim DS; Bactrim I.V.; Bactrim Pediatric; Cofatrim Forte; Cotrim; Cotrim DS; Cotrim Pediatric; Novo-Trimel; Novo-Trimel D.S.; NuCotrimox; Nu-Cotrimox DS; Roubac; Septra; Septra DS; Septra Grape Suspension; Septra I.V.; Septra Suspension; Sulfatrim; Sulfatrim DS; Sulfatrim Pediatric; Sulfatrim S/S; Sulfatrim Suspension) See Potentiated Sulfonamides (VeterinarySystemic), 164 Injection, 181 Oral Suspension, 180 Tablets, 180 SulfatrimSulfamethoxazole and Trimethoprim Tablets, 180 Sulfatrim DSSulfamethoxazole and Trimethoprim Tablets, 180 Sulfatrim PediatricSulfamethoxazole and Trimethoprim Oral Suspension, 180 Sulfatrim S/SSulfamethoxazole and Trimethoprim Tablets, 180 Sulfatrim SuspensionSulfamethoxazole and Trimethoprim Oral Suspension, 180 Suprax Cexime For Oral Suspension, 59 Cexime Tablets, 59 Tetracycline (Achromycin V; Apo-Tetra; Novo-Tetra; Nu-Tetra) See Tetracyclines (VeterinarySystemic), 225 Capsules, 248 TrikacideMetronidazole Capsules, 146 TotacillinAmpicillin Capsules, 42 Totacillin-NAmpicillin For Injection, 43 Velosef Cephradine Capsules, 66 Cephradine For Oral Suspension, 66 Vibramycin Doxycycline Calcium Oral Suspension, 239 Doxycycline For Injection, 240 Doxycycline For Oral Suspension, 239 Doxycycline Hyclate Capsules, 239 Vibra-TabsDoxycycline Hyclate Tablets, 240 Vibra-Tabs C-PakDoxycycline Hyclate Tablets, 240 WintrocinErythromycin Stearate Tablets, 136 Zithromax Azithromycin For Injection, 129 Azithromycin For Oral Suspension, 128

2003 Thomson MICROMEDEX

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