Final Project Levofloxacin

NEW DRUG DEVELOPMENTAL &
APPROVAL PROCESS
LEVOMAX
(Levofloxacin)
Submitted By:
Zohaib Ahmad(Roll#14) Submitted to:

Jalwaz Tihami(Roll#20) Sir Ikram Ullah Khan
B-Pharm, M.Phil,
Azeem Imam(Roll#25) MS (TQM), R.Ph.
Rizwan Rashid(Roll#43)
Ali Tariq(Roll#136)
COLLEGE OF PHARMACY
GC UNIVERSITY
FAISALABAD
CONTENTS
CHAPTER.NO.01:
INTRODUCTION
CHAPTER.NO.02:
FLOW CHART OF NEW DRUG DEVELOPMENT
CHAPTER.NO.03:
SOURCE AND SYNTHESIS
CHAPTER.NO.04:
PRECLINICAL STUDIES
CHAPTER.NO.05:
PREFORMULATION
CHAPTER.NO.06:
INVESTIGATION NEW DRUG APPLICATION
CHAPTER.NO.07:
CLINICAL TRIALS
CHAPTER.NO.08:
LONG TERM ANIMAL TOXICITY STUDIES
CHAPTER.NO.09:
PRODUCT FORMULATION
CHAPTER.NO.10:
MANUFACTURING AND CONTROL
CHAPTER.NO.11:
PACKAGE AND LABEL DESIGN
CHAPTER.NO.12:
NEW DRUG APPLICATION
CHAPTER.NO.13:
POST MARKETING SURVIELLANCE
CHAPTER.NO.14:
PRODUCT LINE EXTENTION
2
CHAPTER#01
INTRODUCTION
3
INTRODUCTION OF DRUG DISCOVERY AND
DEVELOPMENT
INTRODUCTION:
Discovering and bringing one new drug to the public typically costs a pharmaceutical
or biotechnology company nearly $900 million and takes an average of 10 to 12
years. In special circumstances, such as the search for effective drugs to treat AIDS,
the U.S. Food and Drug Administration (FDA) has encouraged an abbreviated process
for drug testing and approval called fast-tracking. The drug discovery and drug
development process is designed to ensure that only those pharmaceutical products
that are both safe and effective are brought to market. PPD provides a broad array of
drug discovery and development services and products to pharmaceutical,
biotechnology and medical device companies to expedite drug development, from
drug discovery through clinical studies and post-approval support.
Drug development is a blanket term used to define the entire process of bringing a
new drug or device to the Market. It includes Drug discovery / product development,
pre-clinical research (microorganisms/animals) and Clinical trials (on humans). Few
people still refer to the drug development as mere preclinical development.
HOW ARE NEW DRUGS DISCOVERED?
New drugs begin in the laboratory with scientists, including chemists and
pharmacologists, who identify cellular and genetic factors that play a role in specific
diseases. They search for chemical and biological substances that target these
biological markers and are likely to have drug-like effects. Out of every 5,000 new
compounds identified during the discovery process, only five are considered safe for
testing in human volunteers after preclinical evaluations. After three to six years of
further clinical testing in patients, only one of these compounds is ultimately
approved as a marketed drug for treatment. The following sequence of research
activities begins the process that results in development of new medicines:
• Target Identification. Drugs usually act on either cellular or genetic

chemicals in the body, known as targets, which are believed to be associated
with disease. Scientists use a variety of techniques to identify and isolate
4
individual targets to learn more about their functions and how they influence
disease. Compounds are then identified that have various interactions with the
drug targets that might be helpful in treatment of a specific disease.
• Target Prioritization/Validation. To select targets most likely to be useful in
the development of new treatments for disease, researchers analyze and
compare each drug target to others based on their association with a specific
disease and their ability to regulate biological and chemical compounds in the
body. Tests are conducted to confirm that interactions with the drug target are
associated with a desired change in the behavior of diseased cells. Research
scientists can then identify compounds that have an effect on the target
selected.
• Lead Identification. A lead compound or substance is one that is believed to
have potential to treat disease. Laboratory scientists can compare known
substances with new compounds to determine their likelihood of success.
Leads are sometimes developed as collections, or libraries, of individual
molecules that possess properties needed in a new drug. Testing is then done
on each of these molecules to confirm its effect on the drug target.
• Lead Optimization. Lead optimization compares the properties of various
lead compounds and provides information to help biopharmaceutical
companies select the compound or compounds with the greatest potential to be
developed into safe and effective medicines. Often during this same stage of
development, lead prioritization studies are conducted in living organisms (in
vivo) and in cells in the test tube (in vitro) to compare various lead compounds
and how they are metabolized and affect the body.
WHAT IS REQUIRED BEFORE AN INVESTIGATIONAL DRUG CAN

BE TESTED IN HUMAN VOLUNTEERS?
In the preclinical stage of drug development, an investigational drug must be tested

extensively in the laboratory to ensure it will be safe to administer to humans. Testing
at this stage can take from one to five years and must provide information about the
pharmaceutical composition of the drug, its safety, how the drug will be formulated
and manufactured, and how it will be administered to the first human subjects.
5
• Preclinical Technology. During the preclinical development of a drug,
laboratory tests document the effect of the investigational drug in living
organisms (in vivo) and in cells in the test tube (in vitro).
• Chemistry Manufacturing and Controls (CMC)/Pharmaceutics. The
results of preclinical testing are used by experts in pharmaceutical methods to
determine how to best formulate the drug for its intended clinical use. For
example, a drug that is intended to act on the sinuses may be formulated as a
time-release capsule or as a nasal spray. Regulatory agencies require testing
that documents the characteristics -- chemical composition, purity, quality and
potency -- of the drug's active ingredient and of the formulated drug.
• Pharmacology/Toxicology. Pharmacological testing determines effects of the
candidate drug on the body. Toxicology studies are conducted to identify
potential risks to humans.
Results of all testing must be provided to the FDA in the United States and/or other
appropriate regulatory agencies in order to obtain permission to begin clinical testing
in humans. Regulatory agencies review the specific tests and documentation that are
required to proceed to the next stage of development.
HOW ARE INVESTIGATIONAL DRUGS TESTED IN HUMANS?
Testing of an investigational new drug begins with submission of information about

the drug and application for permission to begin administration to healthy volunteers
or patients.
Investigational New Drug (IND)/Clinical Trial Exception (CTX)/Clinical Trial

Authorization (CTA) Applications. INDs (in the U.S.), CTXs (in the U.K.) and
CTAs (in Australia) are examples of requests submitted to appropriate regulatory
authorities for permission to conduct investigational research. This research can
include testing of a new dosage form or new use of a drug already approved to be
marketed.
In addition to obtaining permission from appropriate regulatory authorities, an

institutional or independent review board (IRB) or ethical advisory board must
approve the protocol for testing as well as the informed consent documents that
6
volunteers sign prior to participating in a clinical study. An IRB is an independent
committee of physicians, community advocates and others that ensures a clinical trial
is ethical and the rights of study participants are protected.
Clinical testing is usually described as consisting of Phase I, Phase II and Phase III
clinical studies. In each successive phase, increasing numbers of patients are tested.
• Phase I Clinical Studies. Phase I studies are designed to verify safety and
tolerability of the candidate drug in humans and typically take six to nine
months. These are the first studies conducted in humans. A small number of
subjects, usually from 20 to 100 healthy volunteers, take the investigational
drug for short periods of time. Testing includes observation and careful
documentation of how the drug acts in the body -- how it is absorbed,
distributed, metabolized and excreted.
• Phase II Clinical Studies. Phase II studies are designed to determine
effectiveness and further study the safety of the candidate drug in humans.
Depending upon the type of investigational drug and the condition it treats,
this phase of development generally takes from six months up to three years.
Testing is conducted with up to several hundred patients suffering from the
condition the investigational drug is designed to treat. This testing determines
safety and effectiveness of the drug in treating the condition and establishes
the minimum and maximum effective dose. Most Phase II clinical trials are
randomized, or randomly divided into groups, one of which receives the
investigational drug, one of which gets a placebo containing no medication
and sometimes a third group that receives a current standard treatment to
which the new investigational drug will be compared. In addition, most Phase
II studies are double-blinded, meaning that neither patients nor researchers
evaluating the compound know who is receiving the investigational drug or
placebo.
• Phase III Clinical Studies. Phase III studies provide expanded testing of
effectiveness and safety of an investigational drug, usually in randomized and
blinded clinical trials. Depending upon the type of drug candidate and the
condition it treats, this phase usually requires one to four years of testing. In
Phase III, safety and efficacy testing is conducted with several hundred to
7
thousands of volunteer patients suffering from the condition the
investigational drug treats.
New Drug Application (NDA)/Marketing Authorization Application (MAA):
NDAs (in the U.S.) and MAAs (in the U.K.) are examples of applications to market a
new drug. Such applications document safety and efficacy of the investigational drug
and contain all the information collected during the drug development process. At the
conclusion of successful preclinical and clinical testing, this series of documents is
submitted to the FDA in the U.S. or to the applicable regulatory authorities in other
countries. The application must present substantial evidence that the drug will have
the effect it is represented to have when people use it or under the conditions for
which it is prescribed, recommended or suggested in the labeling. Obtaining approval
to market a new drug frequently takes between six months and two years.
DOES TESTING CONTINUE AFTER A NEW DRUG IS APPROVED?
After the FDA (or other regulatory agency for drugs marketed outside the U.S.)
approves a new drug, pharmaceutical companies may conduct additional studies,
including Phase IIIb and Phase IV studies. Late-stage drug development studies of
approved, marketed drugs may continue for several months to several years.
• Phase IIIb/IV Studies. Phase IIIb trials, which often begin before approval,
may supplement or complete earlier trials by providing additional safety data
or they may test the approved drug for additional conditions for which it may
prove useful. Phase IV studies expand testing of a proven drug to broader
patient populations and compare the long-term effectiveness and/or cost of the
drug to other marketed drugs available to treat the same condition.
• Post-Approval Studies. Post-approval studies test a marketed drug in new

age groups or patient types. Some studies focus on previously unknown side
effects or related risk factors. As with all stages of drug development testing,
the purpose is to ensure the safety and effectiveness of marketed drugs
8
STEPS IN NEW DRUG DEVELOPMENT TILL NDA IS
FILED
9
Steps in New Drug Development till NDA is Filed
10
CHAPTER#02
FLOW CHART FOR NEW DRUG
DEVELOPMENT
FLOW CHART
11
NEW CHEMICAL ENTITY
• Organic Synthesis
• Molecular Modification
• Isolation from Plants
PRECLINICAL STUDIES
• Chemistry
• Physical Properties
• Biological Properties
ADME
Toxicology
• Preformulation
INVESTIGATIONAL NEW DRUG

APPLICATION (IND)
• Submission
• FDA Review
CLINICAL TRIALS PRECLINICAL STUDIES (Continued)

• Phase І • Long Term Animal Toxicity
• Phase І І • Product Formulation
• Phase І І І • Manufacturing and Controls
• Package and Label Design
NEW DRUG APPLICATION (NDA)

• Submission
• FDA Review
• Preapproval Plant Inspection
• FDA Action
POST MARKETING SURVEILLANCE

• Phase 4 clinical studies
• Additional Indications
• Adverse Drug Reporting
• Product Defect Reporting
• Product Line Extention
12
CHAPTER#03
SOURCE AND SYNTHESIS
13
SYNTHESIS OF LEVOFLOXACIN
Levofloxacin is a synthetic compound and is synthesized as follow;
Procedure:
1,2-Cyclic sulfamidates undergo efficient and regiospecific nucleophilic cleavage
with 2-bromophenols (and related anilines and thiophenols), followed by Pd(0)-
mediated amination to provide an entry to substituted and enantiomerically pure 1,4-
benzoxazines (and quinoxalines and 1,4-benzothiazines). This chemistry provides a
short and efficient entry to (3S)-3-methyl-1,4-benzoxazine 19, a late stage
intermediate in the synthesis of levofloxacin. This intermediate, through a series of
steps, is than converted into levofloxacin.
14
CHAPTER#04
PRECLINICAL STUDIES
Chemistry
Physical Properties
Biological Properties
• Pharmacology
• Pharmacokinetics
• Toxicity
UNIT-1:
15
CHEMISTRY OF LEVOFLOXACIN
IUPAC-Name: (S)-7-fluoro-6-(4-methylpiperazin-1-yl)-10-oxo-4-thia-1-azatricyclo
[7.3.1.05,13] trideca-5(13),6,8,11-tetraene-11-carboxylic acid
Chemical Formula: (-) - (S)- 9 fluoro- 2, 3- dihydro -3- methyl- 10- (4- methyl- 1-
piperazinyl) –7 – oxo -7H – pyrido [1, 2, 3 -de]- 1, 4 benzoxazine- 6- carboxylic acid
hemihydrate.
Empirical Formula: C18H20FN3O4 ½H2O
Routes: Oral, IV, ophthalmic
Molecular Weight: 370.38.
Stable Coordination Compounds:

Levofloxacin has the potential to form stable coordination compounds with many
metal ions. This in vitro chelation potential has the following formation order:
Al+3>Cu+2>Zn+2>Mg+2>Ca+2.
16
Structural Formula of Levofloxacin
UNIT-2:
17
PHYSICAL PROPERTIES
Appearance: Levofloxacin is a light yellowish-white to yellow-white crystal or

crystalline powder.
Stability: Stable under ordinary conditions
Melting Point: 218 ºC (http://www.chemblink.com/products/100986-85-4.htm)
Solubility: Insoluble in water

The data demonstrate that from pH 0.6 to 5.8, the solubility of levofloxacin is
essentially constant (approximately 100 mg/mL). Levofloxacin is considered soluble
to freely soluble in this pH range, as defined by USP nomenclature. Above pH 5.8, the
solubility increases rapidly to its maximum at pH 6.7 (272 mg/mL) and is considered
freely soluble in this range. Above pH 6.7, the solubility decreases and reaches a
minimum value (about 50 mg/mL) at a pH of approximately 6.9.
Physical State: crystalline powder
Odour: Odourless
UNIT 3:
18
BIOLOGICAL PROPERTIES
These biological properties are based on pre-clinical studies that are carried out in
animals.
(A) PHARMACOLOGY:
Pharmacotherapeutic Group: Quinolone Antibacterials, Fluoroquinolones
Levofloxacin is a synthetic antibacterial agent of the fluoroquinolone class and is the

S (-) enantiomer of the racemic drug substance ofloxacin.
Mechanism of action:(Chemical Basis)
Levofloxacin is a broad-spectrum antibiotic that is active against both Gram-positive

and Gram-negative bacteria. It functions by inhibiting DNA gyrase, a type II
topoisomerase, and topoisomerase iv, which is an enzyme necessary to separate
replicated DNA, thereby inhibiting cell division.
The fluoroquinolones interfere with DNA replication by inhibiting an enzyme

complex called DNA gyrase. In particular, some congeners of this drug family display
high activity not only against bacterial topoisomerases but also against eukaryotic
topoisomerases, and are toxic to cultured cells and in vivo tumor models. Although
the quinolone is highly toxic to mammalian cells in culture, its mechanism of
cytotoxic action is not known. Quinolone-induced DNA damage was first reported in
1986.
Pharmacokinetics:
Absorption:
19
Bioavailability
Approximately 99%.
Rapidly absorbed from GI tract.Peak plasma concentrations usually attained 1-2 hours
after an oral dose. Steady-state plasma concentrations attained within 48 hours with
once-daily regimen.
Distribution:
Extent
Widely distributed into body tissues and fluids, including skin, blister fluid, and lungs.
It is also distributed into CSF.
Plasma Protein Binding

24-38% bound to serum proteins.
Elimination:
Metabolism
Undergoes limited metabolism to inactive metabolites.
Elimination Route
Eliminated principally as unchanged drug in urine. Approximately 87% of an oral
dose eliminated in urine and <4% eliminated in feces.
Half-life
Terminal elimination half-life approximately 6-8 hours after oral administration.
(B) TOXICOLOGICAL STUDIES:
20
Levofloxacin, when administered orally to rats at a dose of 20 mg/kg, was absorbed
primarily from the small intestine, and the maximum serum concentration (2.5 ug/ml)
was reached 0.5 hours after administration, except for the level, in the central nervous
system and fat, levofloxacin concentration in almost all tissues of the body were
higher than the serum level, demonstrating the good transference to tissues. Drug
concentrations in the main organs were high in the kidneys and liver and lowest in the
brain.
Repeated dose toxicity:

Studies of one and six month’s duration by gavage have been carried out in the rat and
monkey. Doses were 50, 200, 800 mg/kg/day and 20, 80, 320 mg/kg/day for 1 and 6
months in the rat and 10, 30, 100 mg/kg/day and 10, 25, 62.5 mg/kg/day for 1 and 6
months in the monkey.
Signs of reactions to treatment were minor in the rat with slight effects principally at
200 mg/kg/day and above in reducing food consumption and slightly altering
haematological and biochemical parameters. The “No Observed Adverse Effect
Levels” (NOEL) in these studies were concluded to be 200 and 20 mg/kg/day after
one-and six months, respectively.
Toxicity after oral dosing in the monkey was minimal with reduced body weight at
100 mg/kg/day together with salivation, diarrhoea and decreased urinary pH in some
animals at this dose. No toxicity was seen in the 6-months study. The NOELs were
concluded to be 30 and 62.5 mg/kg/day after 1 and 6 months respectively.
The “ No Observed Adverse Effect Levels” (NOEL) in the six-month studies were
concluded to be 20 and 62.5 mg/kg/day in the rat and monkey respectively.
Subacute Toxicity:
Following 4-weeks oral administration to rats, no toxicological changes in clinical

signs, hematology, blood chemistry urinalysis and histopathology were observed in
the 50 mg/kg and 200 mg/kg administered groups. At a dose of 800 mg/kg, however,
increased M/E ratio of bone marrow cells, decreased neutrophil count and slight
degeneration of the articular cartilage of limb joint were observed. Following 4 weeks
oral administration to cynomolgus monkeys, no toxicological changes were observed
21
at doses of 10 and 30 mg/kg, but salivation, diarrhea, slight inhibition of body weight
gain and decrease in urine pH were observed at 100 mg/kg.
22
CHAPTER#05
PREFORMULATION
Bulk Characterization
Solubility Analysis
Stability Analysis
UNIT-1:
23
BULK CHARACTERIZATION
Molecular Weight: 370.38.

Method: By Mass Spectroscopic Method
Particle Size: Large

Method: By sieving method particle size is determined. it is large in size
Melting Point: 218 ºC (http://www.chemblink.com/products/100986-85-4.htm)

Method: By Hot Stage Microscopy
The melting point of a drug can be measured using three techniques:
¾ Capillary melting
¾ Hot stage microscopy
¾ Differential scanning calorimetry or thermal analysis.
Capillary Melting
Capillary melting (the observation of melting in a capillary tube in a heated metal
block) gives information about the melting range but it is difficult to assign an
accurate melting point.
Hot stage Microscopy

This is the visual observation of melting under a microscope equipped with a heated
and lagged sample stage. The heating rate is controllable and up to three transitions
can be registered. It is more precise as the phase transitions (first melt, 50% melt and
completion) can be registered on a recorder as the melting proceeds, and because of
the high magnification the values are more accurate.
Differential Scanning Calorimetry and Thermal Analysis:

Neither of the previous methods is as versatile as either differential thermal analysis
(DTA) or differential scanning calorimetry (DSC). An additional advantage is that the
sample size required is only 2-5 mg. DTA measures the temperature difference
between the sample and a reference as a function of temperature or time when heating
24
at a constant rate. DSC is similar to DTA, except that the instrument measures the
amount of energy required to keep the sample at the same temperature as the
reference, i.e. it measures the enthalpy of transition. When no physical or chemical
change occurs
within the sample then there is neither a temperature change nor input energy to
maintain an isotherm. However, when phase changes occur then latent heat
suppresses a temperature change and the isothermal energy required registers as an
electrical signal generated by thermocouples. Crystalline transitions, fusion,
evaporation and sublimation are obvious changes in state which can be quantified
(Fig. 8.3). The major concern in preformulation is polymorphism, and the
measurement of melting point and other phase changes is the primary diagnostic tool.
Confirmation by IR spectroscopy and X-ray diffraction
is usually required.
Crystal Habit: Microcrystalline

Technique: By SEM, Crystal Habit is observed
Microscopy:
The microscope has two major applications in pharmaceutical preformulation:
¾ Basic crystallography, to determine crystal morphology (structure and habit),

polymorphism and solvates
¾ Particle size analysis
Most pharmaceutical powders have crystals in the range 0.5-300 /Jim. However, the
distributions are often smaller, typically 0.5-50 /mi, to ensure good blend
homogeneity and rapid dissolution. These are the major reasons for particle size
control. A lamp-illuminated mono-objective microscope fitted with polarizing filters
above and below the stage is more than adequate. For most preformulation work a 10
x eyepiece and a 10-x objective are ideal, although occasionally, with micronized
powders and when following solid-solid and liquid-liquid transitions in
polymorphism, 10 x 20 may be required.
Crystal Purity:
25
Thermal analysis has been widely used as a method of purity determination and the
USP includes an appendix describing the methods. This is particularly pertinent at the
preformulation stage, because early samples of a new drug are inevitably 'dirty' while
Improvements in synthetic route are made. Thermal analysis is rapid and will
discriminate 0.002% of impurity.
Hygroscopicity: Hygroscopic
A substance that absorbs sufficient moisture from the atmosphere to dissolve itself is
deliquescent is called hygroscopic. A substance that loses water to form a lower
hydrate or becomes anhydrous is termed efflorescent. These are extreme cases, and
most pharmaceutical compounds are usually either impassive to the water available in
the surrounding atmosphere or lose or gain water from the atmosphere, depending on
the relative humidity (RH). Materials unaffected by RH are termed non-hygroscopic,
whereas those in dynamic equilibrium with water in the atmosphere are hygro-scopic.
Ambient RH (0% poles and desert, 55% temperate and 87% tropics) can vary widely
and continually depending on the weather and air temperature, and these cyclic
changes lead to constant variations in the moisture content of unprotected bulk drug
and excipients. The constant sinusoidal change in day and night temperatures is the
major influence. For this reason pharmaceutical air conditioning is usually set below
50% RH, and very hygroscopic products, e.g. effervescents, which are particularly
moisture sensitive, are stored and made below 40% RH.
Crystal Morphology
Crystals are characterized by repetition of atoms or molecules in a regular three-
dimensional structure, which is absent in glasses and some polymers. There are six
crystal systems (cubic, tetragonal, orthorhombic, monoclinic, triclinic and hexagonal),
which have different internal structures and spatial arrangements. Although not
changing their internal structure, which occurs with polymorphism, crystals can adopt
different external structures. This is known as crystal habit, of which five types are
recognized:
¾ Tabular: moderate expansion of two parallel faces
¾ Platy: plates
¾ Prismatic: columns
¾ Acicular: needle-like
26
¾ Bladed: flat acicular.
These occur in all six-crystal systems.
Conditions during crystallization will contribute to changes in crystal habit and may
be encountered in early batches of a new drug substance until the synthetic route has
been optimized. Crystal habit can be modified by:
¾ Excessive supersaturation, which tends to transform a prism or isodiametric
(granular) crystals to a needle shape.
¾ Cooling rate and agitation, which changes habit as it changes the degree of
supersaturation. Naphthalene gives thin plates (platy) if rapidly recrystallized
in cold ethanol or methanol, whereas slow evaporation yields prisms.
¾ The crystallizing solvent affects habit by preferential absorption on to certain
faces, inhibiting their growth. Resorcinol produces needles from benzene and
squat prisms from butyl acetate.
The addition of cosolvents or other solutes and ions which change habit by poisoning
crystal growth in one or more directions. Sodium chloride is usually cubic, but urea
produces an octahedral habit.
Powder Flow Properties:

Flow Ability: Good
Technique: Flow ability is determined by calculating angle of repose.
Angle of Repose: 22º
Explanation:
A static heap of powder, with only gravity acting upon it, will tend to form a conical
mound. One limitation exists: the angle to the horizontal cannot exceed a certain
value, and this is known as the angle of repose (0). If any particle temporarily lies
outside this limiting angle, it will slide down the adjacent surface under the influence
of gravity until the gravitational pull is balanced by the friction caused by
interparticulate forces. Accordingly, there is an empirical relationship between 6 and
the ability of the powder to flow. However, the exact value for angle of repose does
depend on the method of measurement. The angles of repose given in Table 8.14 may
be used as a guide to flow.
A simple relationship between angle of repose, Carr's index and the expected powder
flow is shown in Figure 8.6. When only small quantities of powder are available, an
alternative is to determine the 'angle of spatula' by picking up a quantity of powder on
27
a Table 8.14 Angle of repose as an indication of powder flow propertiesspatula and
estimating the angle of the triangular section of the powder heap viewed from the end
of the spatula. This is obviously crude but is useful during preformulation, when only
small quantities of drug are available.
Of primary importance when handling a drug powder is flow. When limited amounts
of drug are available this can be evaluated by measurements of bulk density and angle
of repose. These are extremely useful derived parameters to assess the impact of
changes in drug powder properties as new batches become available. Changes in
particle size and shape are generally very apparent; an increase in crystal size or a
more uniform shape will lead to a smaller angle of repose and a smaller Carr's index.
Bulk density
A simple test has been developed to evaluate the flowability of a powder by
comparing the poured (fluff) density (pBmin) and tapped density (psmax) of a powder
and the rate at which it packed down. A useful empirical guide is given by Carr's
compressibility index ('Compressibility' is a misnomer, as compression is not
involved):
28
This is a simple index that can be determined on small quantities of powder and may
be interpreted as
A similar index has been defined by Hausner (1967):
Values less than 1.25 indicate good flow (= 20% Carr), whereas greater than 1.25
indicates poor flow (= 33% Carr). Between 1.25 and 1.5, added glidant normally
improves flow. Carr's index is a one-point determination and does not always reflect
the ease or speed with which the powder consolidates. Indeed, some materials have a
high index (suggesting poor flow) but may consolidate rapidly. Rapid consolidation is
essential for uniform filling on tablet machines, when the powder flows at pBmin into
29
the die and consolidates, approaching pBmaxJ at compression. An empirical linear
relationship exists between the change in bulk density and the log number of taps in a
jolting volumeter. Non-linearity occurs up to two taps and after 30 taps when the bed
consolidates more slowly. The slope is a measure of the speed of consolidation and is
useful for assessing powders or blends with similar Carr's indices and the benefit of
glidants.
Polymorphic Forms:
Three polymorphic forms (anhydrous α, β, γ) and two pseudopolymorphic forms
(hemihydrate and monohydrate) of levofloxacin are present. Hemihydrate and
monohydrate forms are mentioned in EP 0444 678 B1 and in U.S. Patent No.
5,545,737. These two patents are directed toward processes for the preparation of
hemihydrate form free of monohydrate and for the preparation of monohydrate free of
hemihydrate.
Transformation Kinetics:
Heating the hemihydrate form resulted in a removal of the hydrated water to give
anhydrous form γ. Further heating resulted in the formation of anhydrous form β, and
then the formation of anhydrous form α. Heating of the monohydrate form resulted in
a removal of the hydrated water to give anhydrous form α. Form γ and form α
adsorbed water vapor rapidly under ordinary relative humidity conditions and
transformed into the hemihydrate and monohydrate, respectively.
Method: Transformation Kinetics are checked by differential scanning calorimetry

(DSC).
30
Unit-2:
SOLUBILITY ANALYSIS
Solubility in water:Insoluble
The data demonstrate that from pH 0.6 to 5.8, the solubility of levofloxacin is
essentially constant (approximately 100 mg/ mL). Levofloxacin is considered soluble
to freely soluble in this pH range, as defined by USP nomenclature. Above pH 5.8,
the solubility increases rapidly to its maximum at pH 6.7 (272 mg/ mL) and is
considered freely soluble in this range. Above pH 6.7, the solubility decreases and
reaches a minimum value (about 50 mg/ mL) at a pH of approximately 6.9.
Partion Coefficient: Pka value is 6.8 ± 0.3

Method: Shake flask method is used to determine Pka
Membrane Permeabiliy: High permeability drug

Permeability classification of representative fluoroquinolones by a cell culture
method:
This study was undertaken to categorize representative fluoroquinolone drug
substance permeability based on the methods outlined in the Food and Drug
Administration's biopharmaceutic classification system (BCS) Guidance for Industry.
The permeability of ciprofloxacin, levofloxacin, lomefloxacin, and ofloxacin was
measured in an in vitro
Caco-2 assay with previously demonstrated method suitability. The permeability class
and efflux potential were ascertained by comparing test drug results with standard
compounds (metoprolol, atenolol, labetalol, and rhodamine-123). All 4 quinolones
drugs demonstrated concentration-dependent permeability, indicating active drug
transport. In comparing absorptive versus secretive in vitro transport, the tested
fluoroquinolones were found to be subject to efflux in varying degrees (ciprofloxacin
> lomefloxacin > rhodamine 123 > levofloxacin > ofloxacin). Based on comparison to
31
labetalol, the high permeability internal standard, ciprofloxacin was classified as a
low permeability drug, whereas lomefloxacin, levofloxacin, and ofloxacin were
classified as high permeability drugs. The in vitro permeability results matched
human in vivo data based on absolute bioavailabilities. This laboratory exercise
demonstrated the applicability of an in vitro permeability method for classifying drugs
as outlined in the BCS Guidance.
Dissolution: Drug exhibit good dissolution properties.

Method and Equipment: Rotating Basket Apparatus is used.
Drug is placed in the Rotating Basket Apparatus and the dissolution of compound is
determined
32
UNIT-3:
STABILITY ANALYSIS
Hydrolysis: There is no effect of moisture.

Stability-indicating RP-HPLC method for levofloxacin in the presence of
degradation products, its process related impurities and identification of
oxidative degradant
The objective of current study was to develop a validated specific stability indicating
reversed-phase liquid chromatographic method for the quantitative determination of
levofloxacin as well as its related substances determination in bulk samples,
pharmaceutical dosage forms in the presence of degradation products and its process
related impurities. Forced degradation studies were performed on bulk sample of
levofloxacin as per ICH prescribed stress conditions using acid, base, oxidative, water
hydrolysis, thermal stress and photolytic degradation to show the stability indicating
power of the method.
RESULT:
Significant degradation was observed during oxidative stress and the degradation
product formed was identified by LCMS/MS, slight degradation in acidic stress and
no degradation was observed in other stress conditions. The chromatographic method
was optimized using the samples generated from forced degradation studies and the
impurity spiked solution. Good resolution between the peaks corresponds to process
related impurities and degradation products from the analyte were achieved on ACE
C18 column using the mobile phase consists a mixture of 0.5% (v/v) triethyl amine in
sodium dihydrogen orthophosphate dihydrate (25 mM; pH 6.0) and methanol using a
simple linear gradient. The detection was carried out at 294 nm. The limit of detection
and the limit of quantitation for the levofloxacin and its process related impurities
were established. The stressed test solutions were assayed against the qualified
working standard of levofloxacin and the mass balance in each case was in between
99.4 and 99.8% indicating that the developed LC method was stability indicating.
Validation of the developed LC method was carried out as per ICH requirements. The
developed LC method was found to be suitable to check the quality of bulk samples
33
of levofloxacin at the time of batch release and also during its stability studies (long
term and accelerated stability).
34
CHAPTER#06
INVESTIGATIONAL NEW DRUG
APPLICTION
35
Documents required by Ministry of Health for the approval of Clinical Trials in
Pakistan
Documents
Investigator Brochure.
Final protocol.
Informed Consent (English and Urdu )Form
Fees 5000.
(Head of Account)
C-Non Tax Revenue
C02- Receipts from Civil Administration and other Functions.
C028-Social Services.
C02841-Health-Other Receipts
List of participating countries.
Phase of Trial
Quantity of drug to be imported on Form 4 of Drugs Import & Export Rules 1976
along with the sites where trial is to be conducted.
CV’s of Investigators.
Ethics committee approval of sites, with complete composition of committee i.e names
and designation of members.
GMP Certificate along with CPP/Free Sale Certificate of Country of Origin.
Pre- clinical/ Clinical data/ Safety studies.
Summary of the Protocol
Summary of the IB ( for quick review on drug).
Adverse Event Reporting Form .
Number patients to be enrolled in each center
Name of Monitors/ Clinical Research Associate
Evidence of registration in country of origin
Copy of registration letter if drug is registered in Pakistan
Sample of label of drug
Duration of Trial
36
CHAPTER#07
CLINICAL TRIALS
37
CLINICAL TRIALS
Our product is converted into a suitable dosage form. Than we submitted

investigational to FDA. All preclinical studies mentioned and took permission for
clinical trials.
PHASE-1 CLINICAL TRIALS:

Aims:
To study the safety of the drug in healthy volunteers
No. of Patients:
We selected 20-100 healthy voluntaries for phase 1 trials.
Procedure:
We administered 1/10 of no effect dose of animals. This purloins gets stable so we
increased the dose gradually and checked the response. In this phase, Parmacokinetics
and Pharmacodynamic studies of a drug are undertaken to determine its toxicity,
metabolism, absorption, distribution and elimination and pharmacological action
preferred route of administration and safe dosage.
Duration:
Phase-1 survives usually for 1-2 years.
Results:
We conducted study under careful circumstances by personals trained in clinical
pharmacology. The clinical research on ranitidine is preceded to phase-2 because
phase 1 studies showed promise and no drug reaction, which became evident.
PHASE-2 CLINICAL TRIALS:
Phase II studies are sometimes divided into Phase IIA and Phase IIB.
¾ Phase IIA is specifically designed to assess dosing requirements (how much

drug should be given).
38
¾ Phase IIB is specifically designed to study efficacy (how well the drug works
at the prescribed dose(s)).
Aims:
¾ This trial aims to demonstrate conclusively efficacy of drug in relation to its
safety.
¾ Pharmacokinetics of a drug should be investigated in patients because they
may handle it differently from healthy people. Variation may occur due to the
following reasons:
• Effect of disease
• Age as compared with that of the volunteers studies that
in phase-1 trials.
No. of Patients:
We recruited hundred of patients for the conformation of phase-1 trials.
Duration:
It took 1-2 years for its completion.
A STUDY TO EVALUATE THE PHARMACOKINETICS AND SAFETY OF

LEVOFLOXACIN IN PATIENTS WITH VARYING DEGREES OF RENAL
FUNCTION
PURPOSE:
The primary objective was to evaluate the pharmacokinetics and safety of two dosing
regimens of Levofloxacin in patients with varying degrees of renal function.
Condition Intervention Phase

Renal Diseases Drug: Levofloxacin Phase 2
Study Type Interventional
Study Design Treatment, Randomized, Open Label, Parallel Assignment,

Pharmacokinetics Study
Official Title An Open-Label Randomized Multiple-Dose Study to

Evaluate Levofloxacin Steady-State Pharmacokinetics and
Safety in Subjects With Varying Degrees of Renal Function
39
FURTHER STUDY DETAILS AS PROVIDED
Primary Outcome Measures:
Evaluation of the pharmacokinetics of two dosing regimens of Levofloxacin in

renally impaired and dialysis patients.
Secondary Outcome Measures:
Safety of two dosing regimens of Levofloxacin in renally impaired and dialysis

patients.
Estimated Enrollment: 60
Study Start Date: October 2007
Study Completion Date: April 2009
Detailed Description:
In this multiple-dose study conducted at 4 centers, the pharmacokinetics of two dosing

regimens of levofloxacin were assessed in medically stable men and women with
varying degree of renal function. The study consisted of a 21 day pretreatment
screening phase, a 7-day open label treatment phase, and a 7 day posttreatment phase
(or a follow-up phase for subjects with early study withdrawal). Patients were
randomized into 1 of 10 treatment groups, for a total of 6 patients per group, based on
degree of renal function to ensure that creatinine clearance values within each group
represented the full range of values defined in the Food and Drug Administration's
(FDA) 1998 guideline for pharmacokinetic studies in patients with impaired renal
function. Fifty-nine patients were enrolled in the study. All patients received a single
750-mg dose of levofloxacin on Day 1; subsequent doses of either 250, 500, or 750
mg of levofloxacin (q24h or q48h) were based on renal function. Blood samples were
collected from each patient from Day 1 to Day 14 for pharmacokinetic evaluation.
Urine was collected on Days 1 and 7 before dosing and over specific time intervals up
to 24 or 48 hours postdosing depending on the patient's dosing regimen. Dialysate
samples were collected on Day 7 from HD patients immediately before dosing (as
40
dialysis began) and at the end of the dialysis treatment. Patients were confined
overnight at the study unit on Days 0, 1, 6, and 7, and remained confined until the 24
hour blood samples were collected on Days 2 and 8. Safety was based on the
incidence, relationship to therapy, and severity of treatment-emergent adverse events
and on changes in clinical laboratory values (hematology, chemistry, and urinalysis),
vital sign measurements, electrocardiograms (ECGs), and physical examination
findings.
Single 750-mg dose of levofloxacin on Day 1; subsequent doses of Levofloxacin 250

milligram (mg), 500 mg, and 750 mg tablets administered every 24 hours for 7 days or
every 48 hours for 7 days
Eligibility Criteria:
Ages Eligible for Study: 18 Years to 65 Years

Genders Eligible for Study: Both
Accepts Healthy Volunteers: No
Inclusion Criteria:
¾ BMI between 18 and 35 kg/m2
¾ No prescription or over-the-counter medications for previous 7 days
¾ Negative tests for drug and alcohol abuse, HIV, hepatitis B and hepatitis C
¾ Medically stable based on medical history, physical examination, 12-lead

electrocardiograms, toxicology, antigen, and antibody screens, and clinical
laboratory evaluations
¾ Stable renal function based on calculated creatine clearance for non-dialysis

patients and the same dialysis treatment for at least 6 months prior to screening
for dialysis patients
¾ Patients with creatinine clearance ≤80 mL/min who require treatment for renal
impairment or other chronic disease (e.g., well-controlled diabetes,
hypertension) must be on a stable treatment plan (medicines, doses, and
regimens) for at least 2 months prior to Day 1 and during the entire study
¾ Hematocrit (hct) within the normal range based on patients' renal function at
screening.
41
Exclusion Criteria:
¾ Allergic reaction to quinolones
¾ Known or suspected allergy to heparin
¾ Clinically significant ECG or clinical laboratory abnormalities
¾ Creatinine clearance <80 mL/min whose medical condition was unstable
¾ Creatinine clearance >= 80 mL/min who required concomitant medication

during the study
¾ Poorly controlled type 1 or type 2 diabetes
¾ Patients with creatinine clearance >= 50 mL/min with screening blood

pressure outside the normal range (sitting systolic blood pressure <90 or >140
mm mercury [Hg] or diastolic blood pressure <60 or >90 mm Hg)
¾ Patients with CLCR <50 mL/min who had sitting systolic blood pressure <90
or >160 mm Hg, or diastolic blood pressure <60 or >90 mm Hg
¾ Required immunosuppressive medications for treatment of immune-mediated

renal disease or kidney transplant
¾ Pregnant or breastfeeding
Results:
We conducted study under careful circumstances by personals trained in clinical

pharmacology. The clinical research on ranitidine is preceded to phase-3 because
phase-2 studies showed promise and no drug reaction, which became evident.
Phase-3 Clinical Trials:
The phase-3 studies are intended to assess the drug-s safety, effectiveness and most
desirable dosage in treating a specific disease in a large group of subjects. Basically
phase-3 involves the comparison between the existing therapies of a particular disease
and the new drug.
We conducted following phase-3 clinical studies
42
A Study of the Safety and Effectiveness of Levofloxacin Compared With
Ceftriaxone Sodium or Cefuroxime Axetil in the Treatment of Adults With
Pneumonia
Purpose:
The purpose of this study is evaluation of the safety and effectiveness of levofloxacin,
an antibiotic, compared with ceftriaxone sodium or cefuroxime axetil in the treatment
of adults with pneumonia.

Pneumonia Drug: levofloxacin Phase II
Phase III
Study Type: Interventional
Study Design: Treatment, Randomized, Open Label, Active Control, Parallel

Assignment, Safety/Efficacy Study
Official Title: A Multicenter, Active-Controlled, Randomized Study To Evaluate

The Safety And Efficacy Of Levofloxacin Versus Ceftriaxone
Sodium Or Cefuroxime Axetil In The Treatment Of Community-
Acquired Pneumonia In Adults
Further study details as provided
Clinical response rate (reduction in signs and symptoms, improvement in x-ray

findings) at post-therapy (5 - 7 days after the last dose of study drug).
Rate of elimination of disease-causing bacteria, by patient, and by type of bacteria;

incidence of adverse events; changes in physical examination and laboratory tests
after treatment with study drug
43
Estimated Enrollment: 528
Study Start Date: September 2005
Estimated Study Completion Date: January 2007
This is a randomized, open-label, parallel group, multicenter study to determine the

safety and effectiveness of levofloxacin (500 mg once daily by mouth) compared with
ceftriaxone sodium (1 - 2 grams administered into a vein or muscle once daily or in
divided doses twice daily for 7 - 14 days) or cefuroxime axetil (500 mg by mouth
twice daily for 7 - 14 days) in adults with community-acquired pneumonia. The study
consists of 4 visits: one visit for screening and enrollment, and 3 visits for assessment
of safety and effectiveness (one visit on Day 2 - 4 [on-therapy], one visit [post-
therapy] 5 - 7 days after the last dose of the study drug, and one visit [post-study] 21 -
28 days after the last dose of the study drug). The total duration of patient
participation in the study is approximately 6 weeks. Levofloxacin is an antibacterial
agent used for the treatment of many types of infections in adults. The purpose of this
study is to compare the safety and effectiveness of levofloxacin with other frequently
used antibiotics (ceftriaxone sodium or cefuroxime axetil) in the treatment of adults
with pneumonia acquired in the community. The primary efficacy assessment is the
clinical response 5 - 7 days after the last dose of study drug, (categorized as cured,
improved, or failed) based upon changes in signs and symptoms, and changes in x-ray
findings, Safety evaluations (incidence of adverse events, physical examination, and
laboratory tests) are performed throughout the study. Cost-effectiveness is also
assessed for the study drugs. The study hypothesis is that treatment with levofloxacin
will be at least as effective as ceftriaxone sodium or cefuroxime axetil in treating
patients with pneumonia acquired in the community, and that it will be well tolerated.
Levofloxacin 500 mg by mouth once daily; ceftriaxone sodium (1 - 2 grams

administered into a vein or muscle once daily or in divided doses twice daily); or
cefuroxime axetil (500 mg by mouth twice daily). Treatment duration is 7 - 14 days.
44
Ages Eligible for Study: 18 Years and older

Inclusion Criteria:
¾ Diagnosis of pneumonia based upon clinical signs and symptoms of a lower

respiratory tract infection including at least 2 of the following: fever, cough,
greenish-yellow mucus produced on coughing, chest pain, shortness of breath,
or evidence of decreased lung function during the physical examination
¾ Has chest x-ray findings consistent with acute pneumonia
¾ Previously received antibiotics for pneumonia if the duration of therapy was

<= 24 hours, or if greater than 24 hours, but without improvement or
stabilization with that therapy
Exclusion Criteria:
¾ Previous allergic or serious adverse reaction to any antibiotic similar to those

used in this study or to penicillin
¾ Collection of pus in the cavity between the lung and the membrane that
surrounds it
¾ Has cystic fibrosis
¾ Has a lung infection due to fungus, bacteria, or virus known prior to the start
of the study to be resistant to any of the study drugs
¾ Has severe kidney failure, decrease in white blood cell count, seizure disorder,
or an unstable psychiatric condition.
Results:
Levofloxacin 500 mg by mouth once daily is more efficacious as compared to

ceftriaxone sodium (1 - 2 grams administered into a vein or muscle once daily or in
divided doses twice daily); or cefuroxime axetil (500 mg by mouth twice daily)
45
A Study to Compare the Safety and Effectiveness of 2 Doses of Levofloxacin
Given for Different Time Periods in Patients With Pneumonia
Purpose:
The purpose of this study is to evaluate the effectiveness and safety of two antibiotic
regimens in the treatment of community-acquired pneumonia in non-hospitalized
adult patients. A 5-day course of 750 milligrams of levofloxacin given once daily will
be compared to a 10-day course 500 milligrams of levofloxacin given once daily.

Pneumonia Drug: levofloxacin Phase III
Study Type: Interventional
Study Design: Treatment, Randomized, Double-Blind, Parallel Assignment,

Safety/Efficacy Study
Official Title: Multicenter, Double-Blind Randomized Study to Compare the

Safety and Efficacy of Levofloxacin 750 mg Once Daily for Five
Days vs. Levofloxacin 500 mg Once Daily for 10 Days in the
Treatment of Mild to Severe Community-Acquired Pneumonia in
Adults
Further study details as provided
Clinical response rates based on signs and symptoms at posttherapy visit.
Microbiologic eradication rates at posttherapy visit; Clinical response rates (chest x-

ray findings and signs/symptoms) and microbiologic eradication rates at poststudy;
Incidence of adverse events.
46
Enrollment: 530
Study Start Date: March 2007
Study Completion Date: June 2009
Levofloxacin is an antibiotic that is approved by the FDA for the treatment of

sinusitis, chronic bronchitis, skin infections, urinary tract infections, and community-
acquired pneumonia. This multicenter, double-blind (neither the patient nor the study
doctor will know the dose of levofloxacin being administered) study evaluates the
effectiveness and safety of two antibiotic regimens in the treatment of community-
acquired pneumonia in adult patients. A 5-day course of 750 milligrams of
levofloxacin given once daily will be compared to a 10-day course 500 milligrams of
levofloxacin given once daily. Patients receive levofloxacin by mouth or through a
vein depending on the severity of their pneumonia. Patients are assessed after 3 days
of treatment; treatment is discontinued if no significant improvement is noted.
Patients showing signs of improvement continue in the study, with assessments on
study days 12-16, and 17-21 (posttherapy visits), and 31-38 (poststudy visit).
Effectiveness is assessed by measuring the ability of the study drug to eliminate
bacteria causing pneumonia and to reduce the signs and symptoms of pneumonia.
Chest x-rays and laboratory tests for presence of bacteria are performed during the
study. Safety evaluations (incidence of adverse events, physical examinations,
laboratory tests) are performed throughout the study. The study hypothesis is that
levofloxacin administered at a higher dose for a shorter duration is at least as effective
as levofloxacin administered at a lower dose for a longer duration in the treatment of
community-acquired pneumonia and is generally well-tolerated.
Levofloxacin, 500 milligrams (mg) by mouth or through vein daily for 10 days or 750
mg by mouth or slowly through a vein daily for 5 days
47
Ages Eligible for Study: 18 Years and older

Inclusion Criteria:
¾ Diagnosis of community-acquired pneumonia as follows: clinical signs and

symptoms of a lower respiratory tract infection and chest-x-ray findings
consistent with pneumonia within 24 hours before entry into the study
¾ At least one of the following: abnormal temperature (high or low) or abnormal

white blood cell count
¾ Previous antibiotic treatment <= 24 hours or, if the duration of treatment was
>= 72 hours and that therapy failed based on at least 2 of the following: fever
within 12 hours of entry into the study, chest x-ray findings have worsened
compared to the initial chest-x-ray, white blood cell count is significantly
increased, respiratory rate higher than at the start of treatment and >= 20
breaths per minute or need for supplemental oxygen if not previously needed
¾ Patients whose infection is acquired in the community or, if in a nursing home,

who had been living there < 14 days
¾ Fine Class (rating scale used to assess patients' overall condition which
includes information such as age, gender, other diseases, physical examination
and laboratory findings) score <= 130 upon admission (patients with Fine
Class scores > 70 but < = 130 must initially be hospitalized
¾ Patients with scores of <= 70 may be treated as outpatients or hospitalized at

the discretion of the investigator)
Exclusion Criteria:
¾ Pneumonia known or suspected to be due to a bacteria resistant to levofloxacin
¾ Previous allergic or serious reaction to or failed therapy with levofloxacin or

similar drugs
¾ Life expectancy < 72 hours
48
¾ Hospitalized within 2 weeks before entry in the study or within 1 month
before entry in the study if treated with antibiotics
¾ Pneumonia acquired in a hospital
¾ Cystic fibrosis or other lung disorders
¾ Receiving chronic steroid treatment
¾ Received assistance from a machine to breathe within the previous month
Results:
Levofloxacin, 500 milligrams (mg) by mouth or through vein daily for 10 days show
better results than 750 mg by mouth or slowly through a vein daily for 5 days.
WE GIVE CONSTANT REPORTS ON PROGRESS OF EACH

PHASE TO THE AUTHORITY.
49
CHAPTER#08
LONG TERM ANIMAL TOXICITY
STUDIES
LONG TERM ANIMAL TOXICITY STUDIES
Levofloxacin, when administered orally to rats at a dose of 20 mg/kg, was absorbed

primarily from the small intestine, and the maximum serum concentration (2.5 ug/ml)
50
was reached 0.5 hours after administration, except for the level, in the central nervous
system and fat, levofloxacin concentration in almost all tissues of the body were
higher than the serum level, demonstrating the good transference to tissues. Drug
concentrations in the main organs were high in the kidneys and liver and lowest in the
brain
Long term toxicity studies show following results;
Repeated dose toxicity:

Studies of one and six month’s duration by gavage have been carried out in the rat and
monkey. Doses were 50, 200, 800 mg/kg/day and 20, 80, 320 mg/kg/day for 1 and 6
months in the rat and 10, 30, 100 mg/kg/day and 10, 25, 62.5 mg/kg/day for 1 and 6
months in the monkey.
Signs of reactions to treatment were minor in the rat with slight effects principally at
200 mg/kg/day and above in reducing food consumption and slightly altering
haematological and biochemical parameters. The “No Observed Adverse Effect
Levels” (NOEL) in these studies were concluded to be 200 and 20 mg/kg/day after
one-and six months, respectively.
Toxicity after oral dosing in the monkey was minimal with reduced body weight at
100 mg/kg/day together with salivation, diarrhoea and decreased urinary pH in some
animals at this dose. No toxicity was seen in the 6-months study. The NOELs were
concluded to be 30 and 62.5 mg/kg/day after 1 and 6 months respectively.
The “ No Observed Adverse Effect Levels” (NOEL) in the six-month studies were
concluded to be 20 and 62.5 mg/kg/day in the rat and monkey respectively.
Subacute Toxicity:
Following 4-weeks oral administration to rats, no toxicological changes in clinical

signs, hematology, blood chemistry urinalysis and histopathology were observed in
the 50 mg/kg and 200 mg/kg administered groups. At a dose of 800 mg/kg, however,
increased M/E ratio of bone marrow cells, decreased neutrophil count and slight
degeneration of the articular cartilage of limb joint were observed. Following 4 weeks
oral administration to cynomolgus monkeys, no toxicological changes were observed
at doses of 10 and 30 mg/kg, but salivation, diarrhea, slight inhibition of body weight
gain and decrease in urine pH were observed at 100 mg/kg.
51
Chronic Toxicity:
Following 26 weeks oral administration to rats, no toxicological changes were
observed at a dose of 20 mg/kg, but salivation and high urinary pH were observed at
doses of 80 and 320 mg/kg. In addition, at a dose of 320 mg/kg, increased feces and
enlargement of goblet cells in cecal mucosa were seen. Following 26-weeks oral
administration to cynomolgus monkeys, no toxicological changes were observed at
doses of 10, 25 and 62.5 mg/kg
Genotoxicity:
Levofloxacin did not induce gene mutations in bacterial or mammalian cells but did
induce chromosome aberrations in Chinese hamster lung (CHL) cells in vitro at or
above 100 μg/ml, in the absence of metabolic activation.
In-vivo tests (micronucleus, sister chromatid exchange, unscheduled DNA synthesis,
dominant lethal tests) did not show any genotoxic potential.
Reproductive studies:
¾ Fertility study : No effects were observed on fertility in either sex or on

fetuses after oral administration to rats at upto 360 mg/kg.
¾ Teratogenic study: No effects were observed on fetuses or neonates after oral
administration to rats upto 90 mg/kg. Moreover lethal effect to
embryos and fetuses, growth retardation in fetuses and neonates or
teratogenesis were not observed in rabbits after oral administration at 50
mg/kg.
¾ Prenatal & postnatal study: No effects Were observed on maternal
parturition and nursing or on neonates in rats after oral administration of upto
360 mg/kg.
Antigenicity:
No specific antibody to levofloxacin was produced in mice, guinea pigs, and rabbits
concurrently treated with adjuvants. In PCA test
using serum of experimentally sensitized animals, mice showed positive reaction, but
52
guinea pigs and rabbits were negative, and systemic anaphylactic reactions were not
observed in guinea pigs.
Mutagenicity:
Chromosomal aberration test and sister chromatid exchange test using cultured
Chinese hamster cell showed positive results.
However, in vivo studies for the same items, mouse bone marrow micronucleus test
and sister chromatid exchange test results were
negative. Moreover, the reverse mutation test, induced mutation frequency test,
HGPRT test, in vivo unscheduled DNA synthesis
test, and dominant lethal test were negative.
Effect on kidneys:
Following oral administration of upto 120 mg/kg to rabbits for 10 days, no
abnormalities were observed in renal function and morphology.
Effect on eyes:
Eye toxicity tests in pigmented rats orally administered 100 mg/kg/day for 14 days
showed no changes in electroretiongram, ophthalmological examination and
histopathology.
Effect on articular cartilage:

When levofloxacin was orally administered to juvenile rats (3 to 4 weeks of age) and
beagle dogs (4 months) for 7 days, lesions were seen in the articular cartilage in rats at
300 mg/kg or more and in dogs at 10 mg/kg or more. Juvenile dogs were more
susceptible to the chondrotoxicity. When levofloxacin was orally administered to
young adult dogs (13 months of age) for 7 days, very mild toxicity was observed at 40
mg/kg. However, in adult dogs aged 18 months in which the drug was administered
for 14 days, no toxicity was observed at a high dose of 30 mg/kg.
Phototoxicity test:
53
Albino mice were orally given levofloxacin and subsequently irradiated with UVA
(wave length 320-400nm), and auricular thickness was measured. Phototoxicity
(increase in thickness) was not shown at 200 mg/kg.
54
CHAPTER#09
PRODUCT FORMULATION
55
PRODUCT FORMULATION
Levomax 500mg tablets:

Each film-coated tablet of Levomax contains 500mg of levofloxacin as active
ingredient corresponding to 512.46mg of levofloxacin hemihydrate.
List of excipients:
Levomax 500mg film-coated tablets contain the following excipients for a weight of
630mg respectively.
Tablet core
Crospovidone
Methylhydroxypropylcellulose
Microcristalline cellulose
Sodium stearyl fumarate
Tablet coating
Methylhydroxypropylcellulose
Titanium dioxide
Talc
Polyethylene glycol (E 171)
Yellow ferric oxide (E 172)
Red ferricoxide (E 172).
56
Machinery and Equipments:
¾ Weighing Balance
¾ Glen Mixer
¾ Fitzpatrick Mill
¾ Stainless Steel Spatula
¾ Multiple Punching Machine
¾ Fluidized Bed Dryer
¾ Trolleys
57
CHAPTER#10
MANUFACTURING PROCESS
QUALITY CONTROLS
58
MANUFACTURING PROCESS
Levomax tablets of the same dosage amount are manufactured in batches. After
careful weighing, the necessary ingredients are mixed and compressed into units of
granular mixture called slugs. The slugs are than filtered to remove air and lumps, and
are compressed again into numerous individual tablets. Documentation on each batch
is kept throughout the manufacturing process and finished tablets undergo several
tests before they are bottled and packaged for distribution.
The procedure for manufacturing levomax tablets, known as dry granulation or

slugging, is as follows:
Weighing:
The active ingredient-levofloxacin, the lubricant-sodium steryl fumerate and other
excepients are weighed separately in sterile canisters to determine if the ingredients
meet pre-determined specifications for the batch size and dosage amount.
Mixing:
Sodium steryl fumerate is dispensed into cold purified water, than heated and stirred
until a translucent paste forms. The active ingredient, the microcrystalline cellulose, a
part of binder-methyl hydroxypropyl cellulose and a part of lubricant -sodium steryl
fumerate are next poured into one sterile canister, and the canister is wheeled to a
mixing machine called Glen Mixer. Mixing blends the ingredients as well as expels
air from the mixture.
Slugging:
The mixture is than mechanically separated into units, which are generally from 7/8 to
1 inches (2.22 to 2.54 cm) in size. These units are called slugs.
Dry Screening:
Next, small batches of slugs are forced through a mesh screen by a handle-held
stainless steel spatula. Large batches in sizable manufacturing outlets are filtered
59
through machine called Fitzpatrick mill. The remaining lubricant is added to the
mixture, which is blended gently in a rotary granulator and sifter. The lubricant keeps
the mixture from sticking to the tablet machine during the compression process.
Compression:
The mixture is compressed into tablets either by a single punch machine (for small
batches) or by a rotary tablet machine (for large scale production).
On single punch machines, the mixture is fed into one tablet mold (called a die cavity)
by a feed shoe. After this, the powder is compressed into tablet with the help of a
punch. This punch descends into the die compressing the mixture into a tablet.
On a rotary tablet machine, the mixture runs through a feed line into a number of die
cavities that are situated on a large steel plate. The plate revolves as the mixture is
dispensed through the feed line, rapidly filling each die cavity. Punches, both above
and below the die cavities, rotate in sequence with the rotation of the die cavities.
Rollers on top of upper punches press the punches down onto the die cavities,
compressing the mixture into tablets, while roller-activated punches beneath the die
cavities lift up and eject the tablets from the die platform.
Coating:
Film coating;
The optimization of film coating may be necessary to improve adhesion of the coating
to the core, to decrease bridging of intagliations, to increase coating hardness or to
improve any other property that the formulator deems deficient. The development
scientist has to consider three major factor which affect the film quality –tensile
strength of the film coating formulation, elasticity of the resultant film and the film
tablet surface interaction. Due to these considerations, it becomes very important to
use the most optimized coating formulation in order to get the best results.
Film coating involves the deposition, usually by a spray method, of a thin film of
polymer formulation around each tablet core. It is possible to use conventional
panning equipment but usually specialized equipment is employed to take advantage
of the fast coating times and higher degree of automation possible.
The coating liquid contains a polymer in suitable liquid medium together with other
ingredient such as pigments and plastesizers. This solution is sprayed on a rotating,
60
mixed tablet bed. The drying condition results in the removal of the solvent leaving a
thin deposit of a coating material around each tablet core.
Film Coating Parameters:
Inlet Air Temperature 50°C

Exhaust Air Temperature 60°C
Air Flow 245 CMH
Spray Rate 06 g/min
Atomization Air 2.0 bar
Pan Speed 20 RPM
Pattern Air 2.0 bar
61
QUALITY CONTROL TESTS
¾ Disintegration Test
¾ Dissolution Test
¾ Tablet Hardness and Friability
¾ Tablet Weight and Weight Variation Test
¾ Content Uniformity Test
¾ Tablet Thickness
Disintegration Test:
Disintegration test determines whether tablet disintegrate within the prescribed time
when placed in a liquid medium. Disintegration is considered to be achieved when;
¾ No residue remain on screen
¾ If there is a residue, it consist of a soft mass having no palpably firm,
unmoisture core sieve only fragments of coating remain on screen.
Test:
a) A riged basket rack assembly supporting six cylindrical transperant tubes 75-
80 mm long, 21.5 mm in internal diameter. Wall thickness is about 2mm.
b) A cylindrical disk for each tube, each 20.55-20.85 mm in diameter and 9.35-
9.65 mm thick, made for transparent plastic with a related density of 1.18-
1.20, weighing 2.8-3.2g pierced with 5 holes, one in the center and other four
spaced equally on the circle of radius 6 mm from the center of the disc.
c) The tubes are held vertically by two separate and superimposed rigid plastic
plates 90mm in diameter and 6 mm thick.
d) The plates are held rigidly in position and 77.5mm apart by vertical metal rod
at the periphery and metal rod is also fixed to center of upper plate to enable
the assembly to be attached to a mechanical device capable of raising and
lowering it smoothly through a distance of 50-60 mm at a constant frequency
of between 25-30 cpm.
e) The assembly is suspended in a specific liquid medium. The volume of liquid
is such that when the assembly is in highest position, the wire mesh is atleast
15mm below the surface liquid and when the assembly is in lowest position,
62
wire mesh is at least 25mm above the bottom of the beaker and the upper open
ends of the tubes remain above the surface of the liquid.
Method:
Unless otherwise stated in the individual monograph, introduce one tablet into each of
the 6 tubes and, if prescribed, add the disc to each tube. Suspend the assembly in the
beaker containing the specified liquid and operate the apparatus for the specified
time. Remove the assembly from the liquid. The tablet has passed the tst if all 6 have
disintegrated.
Disintegration Test:
Apparatus:
Basket Rack Assembly

Description:
The basket rack assembly consist of six open glass tubes each 7.75±0.25cm long
having inside diameter of approximately 21.5mm and wall approximately 2mm thick.
The tubes are held in vertical position by two plastic plates, each about 9mm in
diameter and 6mm in thickness, with 6 holes each about 24mm in diameter
equidistant from the center of the plates and equally spaced from one another.
Procedure:
1. Replace the 10 mesh stainless steel cloth in the basket rake assembly with 40
mesh and also to the top of the assembly to provide for the insertion in the
dissolution medium.
2. Adjust the apparatus so that it descends to 1±0.1cm from the bottom of the
vessel on the downward stroke.
3. Use the medium as specified and proceed as directed in the individual
monograph.
Tablet Hardness and Friability:

It is fairly common for a tablet press to exert as little as 3000 and as much as 4000 lb
of force in production of tablet. Generally the greater the pressure applies, the harder
the tablet is. Although the granulation also have a baring on hardness. In general
tablets should be sufficiently hard to resist breaking during normal handling and yet
soft enough to disintegrate properly after swallowing. Special dedicated hardness
63
tester or multifunctional systems are used to measure the degree of force required to
break the tablet. Multifunctional automated equipments can determine weight,
thickness, hardness and diameter of the tablet.
Tablet Weight and USP Weight Variation Test:

The quantity of fill in a die of a tablet press determines the weight of the tablet. The
volume fill is adjusted with the first few tablets to yield the desired weight and
content. During production, sample tablets are periodically removed for visual
inspection and automated physical measurement.
The USP contain a test for determination of dosage form uniformity by weight
variation for uncoated tablets. In this test, 10 tablets are weighed individually and the
average weight calculated. The tablets are assayed and the contents of active
ingredient in each of the 10 tablets are calculated assuming homogeneous drug
distribution.
Content Uniformity:
By the USP method, 10 dosage units are individually assayed for their content
according to the method described in the individual monograph. Unless otherwise
stated in the monograph, the requirements for content uniformity are met if the
amount of active ingredient in each dosage units lies within range of 85%-115% of
the label claim and the standard deviation is less than 6%. If one or more units don’t
meet these criteria, additional tests as prescribed in the USP are required.
Tablet Thickness:
The thickness of a tablet is determined by
¾ The diameter of the die,
¾ The amount of fill permitted to enter the die,
¾ The compaction characteristics of the fill material and
¾ The force or pressure applied during compression
To produce tablets of uniform thickness during and between batch productions for the
same formulation, care must be exercised to employ the same factors ogf fill, die and
pressure. The degree of pressure affects not only thickness but also hardness of the
tablets; hardness is perhaps the more important criteria, since it can affect
64
disintegration and dissolution. Thus, for tablets of uniform thickness and hardness, it
is doubly important to control pressure. Tablet thickness can be measured by hand
gauge during production or by automated equipment
65
CHAPTER#11
66
PACKAGE DESIGN
PRIMARY PACKAGING:
Tablets after manufacturing was packed into aluminum foil. Other
specifications are given below;
Packaging Material Aluminium Foil
Length 10.4cm
Width 6.5cm
No. of Tablets per Blister 10
Tablet Strength 500 mg
Batch No. 271186
Registration No. 51536
Manufacturing Date 11-12-2009
Expiry Date 11-12-2011
Manufactured by Kenstars Pharmaceuticals
Secondary Packaging:
Folding Cartons:
Provide excellent secondary protection for individually packaged multiple unit
packs. For multiple unit packs, the carton can be designed as a dispenser carton by
including a perforated area into the carton. The user exposes the product for easy
removal by their customer using the perforated section.
There are a great many styles of folding cartons available at numerous

specialized features that can be added to these designs styles. Although some simple
styles dcan be ordered as of –the- shelf items, the vast majority of folding cartons
used for medical products are custom designed to fit the product and to incorporate
the specialized features which enhance the product presentation.
67
Packaging Specifications for Unit Carton
Dimensions:
Dimensions are described based on the opening of an assembled box. The opening
can be located on the top or the side, depending on how the product will load into the
box.
Length of Carton 14.5 cm
Width of Carton 7.7 cm
Length of Front Flap 7.6 cm
Width of Front Flap 2.2 cm
Width of Folding Flap (top) 0.7cm
Width of Folding Flap (bottom) 0.7cm
Length of Folding Flap 7.6cm
Cut of Lock 1 cm
Length of Side Flap 11cm
Width of side Flap (top) 1.5 cm
Width of side Flap (bottom) 1cm
Text:
AS PER REFERENCE
68
69
LABEL DESIGN
Levomax (Levofloxacin)
500mg Tablet
DESCRIPTION:
Levomax (levofloxacin) is a synthetic broad spectrum anti-bacterial agent.
Chemically, levofloxacin, a chiral fluorinated carboxyquinolone, is the pure (-)-(S)-
enanciomer of the racmic drug substance ofloxacin.
Qualitative and quantitative composition:

Levomax(levofloxacin) is available for oral administration in film coated tablets as:
Levofloxacin………………………….500mg
CLINICAL PHARMACOLOGY:
MMa acchhaanniissm
mO Off A Accttiioonn::
It involves the inhibition of DNA Gyrase, which is essential in the reproduction of
bacterial DNA. It is often bactericidal at concentration equal to or slightly greater than
inhibitory concentration.
PPhhaarrmmaaccookkiinneettiiccss::
Absorption:
It is rapidly and essentially completely absorbed after oral administraion. Peak plasma
concentration is attained 1-2 hours after oral dosing.
Distribution:
Mean volume of distribution ranges from 74-112 litres after single and multiple
dosing.
Metabolism and Elimination:
It undergo limited metabolism in body and mainly eliminated from body in
unchanged drug in urine.
THERAPUTIC INDICATION:
Lev
Levomax (levofloxacin) ta
tablets are indicated for the treatment of community acquired
Pneumonia and nosocomial Pneumonia.
DOSAGE AN AND AD ADMINISTRATION:

Lev
Le v o ma x ( l e vofloxacin) 500mg tablets are administered once daily. The duration of
treatment depends on the type and severity of the infection and the sensitivity of the
pathogen.
In case of community acquired Pneumonia and nosocomial Pneumonia, levomax
tablet
let is adm
administered once daily for 07-14 days.
ADVERSE REACTIONS:
Allergic reaction may include: Rash, Swallowing, Breathing Problems, Swelling of
70
Your Lips, Face, Throat, or Tongue; Feeling Sick (nausea) and Diarrhea; Skin rash
and Itching; Drowseness; Sleeping Problems; Paresthesia; Arthralgia; Nausea and
Diarrhea.
CONTRAINDICATIONS:
Levomax is contraindicated in children, adolescents and in patients with a history of
hypersensitivity to this drug.
PREGNENCY:
There are no adequate and well-controlled studies in pregnant women.
NURSING MOTHERS:
No adequate and well-controlled studies.
PRECAUTIONS:
Tablet should be swallowed without crushing.
It should be taken taken with sufficient amount of water.
It may be taken during meal and between meals.
It should not be administered with antacids. Should be taken two hours before or after
antacids.
It should be discontinue if the patient experiences pain, inflammation or rupture of a
tendon during therapy.
STORAGE:
Store below 30ºC.
Protect from sunlight and moisture.
Keep out of the reach of children.
PLEASE READ THE CONTENTS CAREFULLY BEFORE USE.
MANUFACTURED BY:
Kenstars Pharmaceuticals
Industrial area, Fsd.
LOGO:
71
CHAPTER#12
NEW DRUG APPLICATION (NDA)
72
The Secretory,
Drug Registration Board,
Government of Pakistan,
Islamabad.
Subject: Application for Registration of a Drug for Local Manufacturer
Dear Sir,
We, Kenstars Pharmaceuticals (Pvt) Ltd., Lahore, hereby apply for registration of
drug namely LEVOMAX, details of which are enclosed.
Treasury Challan of Rs. 8000/- being fee of registration is enclosed.
Thanking You.
Yours Truly,
Kenstar Pharmaceuticals (Pvt) Ltd., Lahore,
Director
73
UNDERTAKING
We, Kenstars Pharmaceuticals (Pvt) Ltd., Lahore, do hereby declare that the
Label/Carton/Color Scheme and printed Matter of LEVOMAX is not a
copy/counterfeit of any other registered drug in Pakistan. We also declare that the
name of LEVOMAX bears no resemblance to any other registered drug in Pakistan.
Director
74
FORM 5-D
[See rule 26 (1)]
APPLICATION FORM FOR REGISTRATION OF A DOSAGE FORM

CONTAINING A NEW DRUG MOLECULE OR A NEW COMBINATION /
DOSAGE FORM, FOR LOCAL MANUFACTURE.
I / We Kenstars Pharmaceuticals (Pvt) Ltd., Lahore hereby apply for registration

of the drug, namely Levomax Tablet containing a new drug molecule for a local
manufacturer.
Details of which are enclosed.
Date: 27.11.2009 Signed:

Place: Lahore
ENCLOSURES OF THE APPLICATION FOR REGISTRATION OF A NEW

DRUG OR A NEW COMBINATION / DOSAGE FORM
Dosage Form:Tablet
1. Name and address of the manufacturer:

2. Brand (Proprietary) name of the drug:

Levomax
3. The chemical name(s) and, as appropriate and available, the

established (generic) and synonyms of the drug:
Levofloxacin
4. Strength of active ingredient(s) per unit, e.g. each tablet or

5 ml, etc. contains:
75
Each film-coated tablet of Levomax contains 500mg of levofloxacin as active
ingredient corresponding to 512.46mg of levofloxacin hemihydrate.
5. Pharmacological group:
Flouroquinolone Antibiotic
6. Proposed route of administration:

Oral
7. Composition (actives & excepients) including statement of

the quantitative composition, giving the weight or measure
for each active substance used in the manufacture of the
dosage form.
Formulation:
As given on page#56 of chapter-09
Manufacturing:
As given on page#58 of chapter-10
8. Recommended clinical use.

For the treatment of Pneumonia in adult patients.
9. Full description of the specifications and analytical

methods necessary to assure the identity, strength, quality,
purity and homogeneity through out the shelf life of the
drug product.
RAW MATERIAL SPECIFICATIONS
Quality Control Laboratory
General Profile
Name Levofloxacin
Category Flouroquinolone Antibiotic
Formula C18H20FN3O4 ½H2O
Molecular Weight 370.38
76
Characteristics/Parameters Description/Limits
Physical state Light yellowish-white to yellow-
white crystal or crystalline powder,
Insoluble in water
Identification Positive
Acidity and Alkalinity Complies to B.P
Halogenated Compounds Complies to B.P
Heavy Metals 20ppm
Storage Stable under ordinary conditions,
Store in air tight contained, Protect
from light
FINISHED GOODS SPECIFICATIONS

Quality Control Laboratory
Brand Name Levomax
Generic Name Levofloxacin
Dasage Form Tablet
Shelf Life 2 years
Characteristics/Parameters Description/Limits
Physical inspection Light yellowish-white to yellow-
white in colour
Identification Positive for levofloxacin
Strength 500 mg
10. Labeling and prescribing information (to be mentioned

on the pack/leaflet) specimen or draft shall be submitted.
LEAFLET
Levomax® 500 mg tablets
Levofloxacin
Read all of this leaflet carefully before you start taking this medicine.
¾ Keep this leaflet. You may need to read it again.
¾ If you have any further questions, ask your doctor or your pharmacist.
¾ This medicine has been prescribed for you.
77
¾ Do not pass it on to others. It may harmthem, even if their symptoms are the
same as yours.
¾ If any of the side effects gets serious, or if you notice any side effects not
listed in this leaflet, please tell your doctor or pharmacist.
What Tavanic tablets are and what they are used for:
The name of your medicine is Levomax tablets. Levomax tablets contain a medicine
called levofloxacin. This belongs to a group of medicines called antibiotics.
Levofloxacin is a ‘quinolone’ antibiotic. It works by killing the bacteria that cause
infections in your body.
Tavanic tablets can be used to treat infections of the:
¾ Sinuses
¾ Lungs, in people with long-term breathing problems or pneumonia
¾ Urinary tract, including your kidneys or bladder
¾ Prostate gland, where you have a long lasting infection
¾ Skin and underneath the skin, including muscles. This is sometimes called
‘soft tissue’
Before you take Levomax tablets
Do not take this medicine and tell yourdoctor if:
¾ You are allergic to levofloxacin, any other quinolone antibiotic such as
moxifloxacin, ciprofloxacin or ofloxacin or any of the other ingredients of
Levomax tablets (listed in Section 6 below) Signs of an allergic reaction
include: a rash, swallowing or breathing problems, swelling of your lips, face,
throat or tongue
¾ You have ever had epilepsy
¾ You have ever had a problem with your tendons such as tendonitis that was
related to treatment with a ‘quinolone antibiotic'. A tendon is the cord that
joins your muscle to your skeleton
¾ You are a child or a growing teenager
¾ You are pregnant, might become pregnant or think you may be pregnant
¾ You are breast-feeding
¾ Do not take this medicine if any of the above apply to you. If you are not sure,
talk to your doctor or pharmacist before taking Levomax tablets.
78
Take special care with Levomax tablets. Check with your doctor or
pharmacistbefore taking your medicine if:
¾ You are 65 years of age or older
¾ You are using corticosteroids, sometimes called steroids (see “Taking other
medicines” below)
¾ You have ever had a fit (seizure)
¾ You have had damage to your brain due to a stroke or other brain injury
¾ You have kidney problems
¾ You have something known as ‘glucose – 6 – phosphate dehydrogenase
deficiency’. You are more likely to have serious problems with your blood
when taking this medicine
¾ You have ever had mental health problems
¾ You have ever had heart problems
¾ You are diabetic
¾ You have ever had liver problems
¾ If you are not sure if any of the above applies to you, talk to your doctor or
pharmacist before taking Levomax tablets.
Taking other medicines
Please tell your doctor or pharmacist if you are taking or have recently taken any
other medicines.
This includes medicines you buy without a prescription, including herbal medicines.
This is because Levomax tablets can affect the way some other medicines work. Also
some medicines can affect the way Levomax tablets work.
In particular, tell your doctor if you are taking any of the following medicines.
This is because it can increase the chance of you getting side effects, when taken
with Levomax tablets:
¾ Corticosteroids, sometimes called steroids – used for inflammation. You may
be more likely to have inflammation and/or breakage of your tendons.
¾ Warfarin - used to thin the blood. You may be more likely to have a bleed.
Your doctor may need to take regular blood tests to check how well your
blood clot.
¾ Theophylline - used for breathing problems. You are more likely to have afit
(seizure) if taken with Levomax tablets
79
¾ Non-steroidal anti-inflammatory drugs (NSAIDS) - used for pain and
inflammation such as aspirin, ibuprofen, fenbufen, ketoprofen and
indomethacin. You are more likely to have a fit (seizure) if taken with
Levomax tablets
¾ Ciclosporin - used after organ transplants. You may be more likely to get the
side effects of Ciclosporin
¾ Medicines known to affect the way your heart beats. This includes medicines
used for abnormal heart rhythm (antiarrhythmics such as quinidine and
amiodarone), for depression (tricyclic antidepressants such as amitriptylineand
imipramine) and for bacterial infections (‘macrolide’ antibiotics such as
erythromucin, azithromycin and Clarithromycin).
¾ Probenecid - used for gout, and cimetidine - used for ulcers and heartburn.
Special care should be taken when taking either of these medicines with
Levomax. If you have kidney problems, your doctor may want to give you a
lower dose.
Do not take Levomax tablets at the same time as the following medicines. This is
because it can affect the way Levomax tablets work:
Iron tablets (for anemia), magnesium or aluminum-containing antacids (for acid or
heartburn) or sulcralfate (for stomach ulcers).
Urine tests for opiates
Urine tests may show ‘false-positive’ results for strong painkillers called ‘opiates’ in
people taking Levomax tablets. If your doctor is due to take a urine test, tell them you
are taking Levomax tablets.
Pregnancy and breast-feeding
Do not take this medicine if:
¾ You are pregnant, might become pregnant or think you may be pregnant
¾ You are breast-feeding or planning to breast-feed Ask your doctor or
pharmacist for advice before taking any medicine if you are pregnant or
breast-feeding.
Driving and using machines
You may get side effects after taking this medicine, including feeling dizzy, sleepy, a
spinning feeling (vertigo) or changes to your eyesight. Some of these side effects can
affect you being able to concentrate and your reaction speed. If this happens, do not
drive or carry out any work that requires a high level of attention
80
How to take Levomax tablets
Always take Levomax tablets exactly as your doctor has told you. You should check
with your doctor or pharmacist if you are not sure.
Taking this medicine
¾ Take this medicine by mouth
¾ Swallow the tablets whole with a drink of water
¾ The tablets may be taken during meals or at any time between meals
Protect your skin from sunlight
Keep out of direct sunlight while taking this medicine. This is because your skin will
become much more sensitive to the sun and may burn, tingle or severely blister if you
do not take the following precautions:
¾ Make sure you use high factor sun cream
¾ Always wear a hat and clothes which cover your arms and legs
¾ Avoid sun beds
If you are already taking iron tablets, antacids or sulcralfate
¾ Do not take these medicines at the same time as Levomax. Take your dose at
least 2 hours before or after Levomax tablets
How much to take
¾ Your doctor will decide on how many
¾ Levomax tablets you should take
¾ The dose will depend on the type of infection you have and where the
infection is in your body
¾ The length of your treatment will depend on how serious your infection is
¾ If you feel the effect of your medicine is too weak or strong, do not change the
dose yourself, but ask your doctor
Adults and the elderly
Sinuses
¾ One tablet of Levomax 500 mg, once each day
Lungs, in people with long-term breathing problems
¾ 1/2 tablet or one tablet of Levomax 500 mg, once each day
Pneumonia
¾ One tablet of Levomax 500 mg, once or twice each day
Urinary tract, including your kidneys or bladder
81
¾ 1/2 tablet of Levomax 500 mg, each day
Prostate gland
¾ One tablet of Levomax 500 mg, once each day
Skin and underneath the skin, including muscles
¾ ½ tablet or one tablet of Levomax 500 mg, once or twice each day
Adults with kidney problems
Your doctor may need to give you a lower dose.
Children and Teenagers
This medicine must not be given to children or teenagers.
If you take more Levomax tablets than you should
If you accidentally take more tablets thanyou should, tell a doctor or get other medical
advice straight away. Take the medicine pack with you.
This is so the doctor knows what you have taken. The following effects may happen:
convulsive fits (seizures), feeling confused, dizzy, less conscious and heart problems -
leading to uneven heart beats as well as feeling sick (nausea).
If you forget to take Levomax tablets
If you forgot to take a dose, take it as soon as you remember unless it is nearly time
for your next dose. Do not double-up the next dose to make up for the missed dose.
If you stop taking Levomax tablets
Do not stop taking Levomax tablets just because you feel better. It is important that
you complete the course of tablets that your doctor has prescribed for you. If you stop
taking the tablets too soon, the infection may return, your condition may get worse or
the bacteria may become resistant to the medicine.
If you have any further questions on the use of this medicine, ask your doctor or
pharmacist.
Possible side effects
Like all medicines, Levomax can cause side effects, although not everybody gets
them. These effects are normally mild or moderate and often disappear after a short
time.
Stop taking Levomax tablets and see a doctor or go to a hospital straight away if
you notice the following side effect:
Very rare (affects less than 1 person in 10,000)
¾ You have an allergic reaction. The signs may include: a rash, swallowing or
breathing problems, swelling of your lips, face, throat, or tongue
82
Stop taking Levomax tablets and see a doctor straight away if you notice any of
the following serious side effects – you may need urgent medical treatment:
Rare (affects less than 1 person in 1000)
¾ Watery diarrhoea which may have blood in it, possibly with stomach cramps
and a high temperature. These could be signs of a severe bowel problem
¾ Pain and inflammation in your tendons.
¾ The Achilles tendon is affected most often and in some cases, the tendon could
break
¾ Fits (convulsions)
¾ Burning, tingling, pain or numbness. These may be signs of something called
‘neuropathy’
Other :
¾ Severe skin rashes which may include blistering or peeling of the skin around
your lips, eyes, mouth, nose and genital• Loss of appetite, skin and eyes
becoming yellow in colour, dark-coloured urine, itching, or tender stomach
(abdomen).
¾ These may be signs of liver problems
Tell your doctor if any of the following side effects gets serious or lasts longer
than a few days:
Common (affects less than 1 person in 10)
¾ Feeling sick (nausea) and diarrhoea
¾ Increase in the level of some liver enzymes in your blood
Uncommon (affects less than 1 person in 100)
¾ Itching and skin rash
¾ Loss of appetite, stomach upset or in digestion (dyspepsia), being sick
(vomiting) or pain in your stomach area, feeling bloated (flatulence) or
constipation
¾ Headache, feeling dizzy, a spinning feeling (vertigo), feeling sleepy, sleeping
problems or feeling nervous
¾ Blood tests may show unusual results due to liver or kidney problems
¾ Changes in the number of white blood cells shown up in the results of some
blood tests
83
¾ General weakness
¾ Changes in the number of other bacteria or fungi may increase, which may
need to be treated
Rare (affects less than 1 person in 1,000)
¾ Tingly feeling in your hands and feet (paraesthesia) or trembling
¾ Feeling stressed (anxiety), depressed, mental problems, feeling restless
(agitation) or feeling confused
¾ Unusual fast beating of your heart or low blood pressure
¾ Joint pain or muscle pain
¾ Bruising and bleeding easily due to a lowering in the number of blood
platelets
¾ Low number of white blood cells (called neutropenia)
¾ Difficulty breathing or wheezing (bronchospasm)
¾ Shortness of breath (dyspnoea)
¾ Severe itching or hives (called urticaria)
¾ Increased sensitivity of your skin to sun and ultraviolet light
¾ Lowering of your blood sugar levels (hypoglycaemia). This is important for
people that have diabetes
¾ Problems with your hearing or eyesight or changes in the way things taste and
smell
¾ Seeing or hearing things that are not there (hallucinations), change in your
opinion and thoughts (psychotic reactions) with a chance of having suicidal
thoughts or actions
¾ Loss of circulation (anaphylactic like shock)
¾ Muscle weakness. This is important in people with myasthenia gravis (a rare
disease of the nervous system)
¾ Inflammation of the liver, changes in the way your kidney works and
occasional kidney failure which may be due to an allergic kidney reaction
called interstitial nephritis
¾ Fever, sore throat and a general feeling of being unwell that does not go away.
This may be due to a lowering in the number of white blood cells
¾ Fever and allergic lung reactions
84
Other side effects include:
¾ Lowering in red blood cells (anemia). This can make the skin pale or yellow
due to damage of the red blood cells and lowering in the number of all types of
blood cells
¾ Exaggerated immune response (hypersensitivity)
¾ Sweating too much (hyperhidrosis)
¾ Pain, including pain in the back, chest and extremities
¾ Problems moving and walking
¾ Attacks of porphyria in people who already have porphyria (a very rare
metabolic disease)
¾ Inflammation of your tubes that carry blood around your body (vessels) due to
an allergic reaction
If any of the side effects gets serious, or if you notice any side effects not listed in
this leaflet, please tell your doctor or pharmacist.
How to store Levomax tablets

¾ Keep out of the reach and sight of children.
¾ This medicine does not require any special storage conditions but it is best to
keep Levomax tablets in the original strips and box in a dry place.
¾ Do not use Levomax tablets after the expiry date (EXP) which is stated on the
carton and foil.
¾ Medicines should not be disposed of via wastewater or household waste. Ask
your pharmacist how to dispose of medicines no longer required. These
measures will help to protect the environment
Further information
What Levomax tablets contain
The active ingredient is levofloxacin. Each tablet of Levomax 500 mg tablets contains
500 mg of levofloxacin.
The other ingredients are:
¾ For the tablet core: crospovidone, hypromellose, microcrystalline cellulose
and sodium stearyl fumarate
¾ For the tablet coating: hypromellose, titanium dioxide, talc, macrogol, yellow
ferric oxide and red ferric oxide
85
What Levomax tablets look like and contents of the pack
Levomax tablets are film-coated tablets for oral use.
For Levomax 500 mg, the tablets are provided in pack sizes of 10 tablets.
This leaflet does not contain all the information about your medicine. If you have
any questions or are not sure about anything, ask your doctor or pharmacist.
11. Proposed dosage:

Oral route
500mg OD for pneumonia
12. Proposed shelf life of the drug:

01 years
13. Unit price of the drug, e.g. per tablet, per capsule, per
5ml, etc.
Price of 500 mg tablet= 19 Rs
14. Proposed storage conditions of finished product.

¾ Store in dry cool place
¾ Protect from sun, light and heat
¾ Store away from children
15. Persons under whose direct supervision and control

the drug applied for registration shall be manufactured with
the following details, namely:-
a. Total number of technical staff

08 personnals
b. Name, qualification and designation of the persons
directly supervising the manufacture of the drug applied
for registration, and any change shall be properly
documented and record maintained by the manufacturer.
86
Zohaib Ahmad
17- Name of equipments that will be used in the

manufacture of the applied drug:
LIST OF EQUIPMENTS
Oral Tablet Manufacturing Section
Sr. No. Name of Machinery and Equipments Quantity
1 Weighing Balance 1
2 Glen Mixer 1
3 Fitzpatrick Mill 1
4 Stainless Steel Spatula 1
5 Multiple Punching Machine 4
6 Fluidized Bed Dryer 4
7 Trolleys 2
Oral Tablet Packaging Section

1 Turn Table (after air blowing) 1
2 Air Blower 1
3 Conveyer (before filling and after filling) 1
4 Turn Table (after filling and sealing) 1
5 Labeling Machine 1
6 Conveyer (packing) 1
Over Printing Section

1 Printing Machine (Local) 1
2 Printing Machine (Manual) 2
3 Printing Machine (Automatic) K 420 1
4 Printing Machine (Automatic) K 550 2
87
18- Name, qualification and designation of the persons
who will be responsible for the quality control of the
drug.
Following will be responsible for the completion of various steps,
under their supervision.
a) Q.A Incharge
Zohaib Ahmad (Senior Q.A officer)
b) Q.C Incharge
Jalwaz Tihami (Senior Q.C officer)
c) Person for physical testing

Rizwan Rashid (Analyst)
d) Person for chemical testing

Azeem Imam (Analyst)
e) Person for microbiological and pharmacological testing

Ali Tariq (Microbiologist)
19-Description of the equipment to be used for the

quality control of the active raw material and the
finished products.
Sr. No. Name of Equipments

01. H.P.L.C (Spectra physics U.S.A)
02. Infrared Spectrophotometer(FTIR)
03. Melting Point Apparatus (Gallenkamp U.K)
04. Moisture Analyzer (Mitsubishi Japan)
05. Precision Balance (Sartorioue)
06. Drying Oven (Mamart)
07. Fludized Bed Dryer (China)
08. pH Meter (Micro processor)
88
09. Glass Apparatus
10. Autoclave
11. Incubator
12. Sterile Filtration System
13. U-2800 Double Beam Spectrophotometer (Hitachi
Japan)
14. Moisture Balance MB-45 (Ohaus U.S.A)
15. Automatic Titrator GT-100 (Mitsubishi Japan)
16. Conductivity / TDS Meter (Jenway 4510 England)
20- Facility of the water processing with specifications.

We donnot use water in our preparation because it is insoluble in water.
21-Environment control processing with details.

Floor Polishing:
¾ After washing allow the floor to air dry.
¾ Apply the polish/cream properly on floor with clean cloth.
¾ Use the polishing machine to polish the floor.
Floor Moping:
¾ Squeezed the clean mop and moist it with potable water.
¾ Use this moist mop accordingly to clean the floor.
¾ If required use the detergent to remove the spots on the floor for
proper cleaning.
¾ Clean the mod after use with potable water.
Insecticide Spray:
¾ Acoording to the sop for pest control and disinfection.
Drainage and Sewerage:

¾ Clean the inside and outsidethe plant drainage and sewerage
points by using germicidal agents.
89
¾ Following points of outer sewerage are cleaned.
• In the washing area of tablet section.
• Outside the raw material in corridor.
• Inside syrup manufacturing area.
• Inside base preparation room.
22-Attach the last Inspection Report conducted by the

Ministry of Health.
N/A
23-Clinical data (along with data of clinical trials

conducted and safety data of the drug, with reported
side effects and adverse drug reactions in the
indigenous community).
As given in Chapter-07
24. Clinical justification.

Clinically it is a better option because it is more efficacious and less
hazards.
25. Dosage form stability profile:
Levofloxacin is film-coated and packed in aluminium foil to protect it
from heat light and moisture.
26-Any other relevant information that may be required
by the Board.
N/A
90
UNDERTAKING
I / We hereby undertake that the above given information is true and correct to the
best of my / our knowledge and belief.
Zohaib Ahmad Jalwaz Tihami

Production Manager Quality Control Manager.
91
CHAPTER#13
92
Phase 4 clinical trials:

The data from phase 3 clinical trials may lead to a conditional approval of the drug
and require further monitoring of drug in phase 4 clinical trials.
No. of Patients:
These trials are undertaken in larger population, may exceeding 10,000 patients.
Phase 4 trials should be constructed to demonstrate;
¾ Drug efficacy in prolonged use where perhaps the natural course of disease
may be modified over a period of several months or year
¾ Adverse reactions which may only occur with long term use
¾ Detailed examination of non-responders
¾ Assessment of overdose and misuse or abuse liability
¾ New dosage forms
¾ New indications
¾ Drug interactions
INTERACTIONS WITH OTHER MEDICAMENTS AND OTHER FORMS OF

INTERACTION
Levofloxacin interact with many other drugs through different machanisims such as
¾ Inhibition or activation of cytochrome P450 enzymes
¾ Complexation with other drugs
¾ Alteration of gartric pH and
¾ Compitition for renal tubular secretion
Following interactions have been reported during post marketing surveillance;
Iron salts, Magnesium-or Aluminum-containing Antacids:

Levofloxacin absorption is significantly reduced when iron salts, or magnesium-or
aluminum-containing antacids are administered concomitantly with Levomax tablets.
It is recommended that preparations containing divalent cations such as iron salts, or
magnesium-or aluminum-containing antacids should not be taken 2 hours before or
93
after Levomax tablet administration. No interaction was found with calcium
carbonate.
Sucralfate:
The bioavailability of Levomax tabltes is significantly reduced when administered
together with sucralfate. If the patient is to receive both sucralfate and Levomax, it is
best to administer sucralfate 2 hours after the Levomax tablet administration.
Theophylline, Fenbufen or Similar Non-Steroidal Anti-Inflammatory Drugs:

No pharmacokinetic interactions of levofloxacin were found with theophylline in a
clinical study. However a pronounced lowering of the cerebral seizure threshold may
occur when quinolones are given concurrently with theophylline, nonsteroidal anti-
inflammatory drugs, or other agents that lower the seizure threshold.
Levofloxacin concentrations were about 13% higher in the presence of fenbufen than
when administered alone.
Probenecid and Cimetidine:

Probenecid and cimetidine had a statistically significant effect on the elimination of
levofloxacin. The renal clearance of levofloxacin was reduced by cimetidine (24%)
and probenecid (34%). This is because both drugs are capable of blocking the renal
tubular secretion of levofloxacin. However, at the tested doses in the study, the
statistically significant kinetic differences are unlikely to be of clinical relevance.
Caution should be exercised when levofloxacin is coadministered with drugs that
affect the tubular renal secretion such as probenecid and cimetidine, especially in
renally impaired patients.
Cyclosporin:
The half life of cyclosporin was increased by 33% when coadministered with
levofloxacin.
Vitamin K antagonist:
Increased coagulation tests (PT/INR) and/or bleeding, which may be severe, have
been reported in patients treated with levofloxacin in combination with a vitamin K
94
antagonist (e.g. warfarin). Coagulation tests, therefore, should be monitored in
patients treated with vitamin K antagonists.
Meals:
There is no clinically relevant interaction with food. Levomax tablets may therefore
be administered regardless of food intake.
Other relevant information:

Clinical pharmacology studies were carried out to investigate possible
pharmacokinetic interactions between levofloxacin and some commonly prescribed
drugs. The pharmacokinetics of levofloxacin were not affected to any clinically
relevant extent when levofloxacin was administered together with the following
drugs: calcium carbonate, digoxin, glibenclamide, ranitidine, warfarin.
PATIENT MONITORING
Following parameters should be monitored during therapy;
¾ Obtain patient history, including drug history and any known allergies.
¾ Obtain baseline CBC, renal, and liver function tests, and electrolytes.
¾ Obtain baseline vital signs. Monitor vital signs at least bid while administering
medication.
¾ Assess for any skin rashes. Notify physician if skin rash occurs.
¾ Monitor for signs of anaphylaxis (eg, pharyngeal or facial edema, dyspnea,
urticaria, itching).
¾ Monitor patterns of elimination and stool consistency.
¾ Monitor for signs of superinfection.
¾ Encourage fluid intake.
¾ Frequently assess patency of IV site and observe for signs of phlebitis during
therapy.
¾ Notify physician if vomiting, fatigue, lymphocytopenia, increased liver
function test results, seizures, or vital disturbances occur.
¾ Notify physician if symptoms of pseudomembranous colitis occur (eg, loose
or foul-smelling stools) or if symptoms of CNS stimulation occur (eg, tremor,
restlessness, confusion).
95
SIDE-EFFECTS/UNDESIRABLE EFFECTS
The information given below is based on data from clinical studies in more than 5000
patients and on extensive post marketing experience. The following frequency rating
has been used:
¾ Very common - more than 10%
¾ Common - 1 to 10%
¾ Uncommon - 0.1 to 1%
¾ Rare - 0.01 to 0.1%
¾ Very rare - less than 0.01%
¾ Isolated cases
Allergic Reactions:
¾ Uncommon: pruritus, rash,
¾ Rare: urticaria, bronchospasm/dyspnoea,
¾ Very rare: angio-oedema, hypotension, anaphylactic-like shock;
photosensitisation
¾ Isolated cases: severe bullous eruptions such as Stevens Johnson syndrome,
toxic epidermal necrolysis (Lyell’s syndrome) and erythema exsudativum
multiforme. Muco-cutaneous, anaphylactic/-oid reactions may sometimes
occur even after the first dose.
Gastro-Intestinal, Metabolism:
¾ Common: nausea, diarrhoea,
¾ Uncommon: anorexia, vomiting, abdominal pain, dyspepsia,
¾ Rare: bloody diarrhoea which in very rare cases may be indicative of
enterocolitis, including pseudomembranous colitis,
¾ Very rare: hypoglycaemia,particularly in diabetic patients.
Neurological:
¾ Uncommon: headache,dizziness/vertigo, drowsiness, insomnia,
¾ Rare: depression, psychotic reactions (with e.g. hallucinations), paraesthesia,
tremor, anxiety, agitation, confusion, convulsions,
96
¾ Very rare: hypoaesthesia, visual and auditory disturbances, disturbances of
taste and smell,
¾ Isolated cases: Psychotic reactions with self endangering behaviour including
suicidal ideation or acts.
Cardiovascular:
¾ Rare: tachycardia, hypotension
¾ Very rare: shock (anaphylactic)
¾ Isolated cases: QT-interval prolongation
Musculo-Skeletal:
¾ Rare: arthralgia, myalgia, tendon disorders including tendinitis (e.g. Achilles
tendon),
¾ Very rare: tendon rupture (e.g. Achilles tendon), as with other
fluoroquinolones this undesirable effect may occur within 48 hours of starting
treatment and may be bilateral ; Muscular weakness, which may be of special
importance in patients with myasthenia gravis,
¾ Isolated cases: rhabdomyolysis.
Liver, Kidney:
¾ Common: increased liver enzyme levels (e.g. ALT, AST),
¾ Uncommon: increase in bilirubin, increase in serum creatinine,
¾ Very rare: liver reactions such as hepatitis ; acute kidney failure (e.g. due to
interstitial nephritis)
Blood
¾ Uncommon: eosinophilia, leukopenia,
¾ Rare: neutropenia, thrombocytopenia,
¾ Very rare: agranulocytosis,
¾ Isolated cases: haemolytic anaemia, pancytopenia
Others
¾ Uncommon: asthenia, fungal overgrowth and proliferation of other resistant
microorganisms,
97
¾ Very rare: allergic pneumonitis, fever.
¾ Psychotic reactions such as acute confusional states and depressive mood
changes (these reactions may occur even after the first dose),
¾ Extrapyramidal symptoms and other disorders of muscular coordination,
hypersensitivity vasculitis,
¾ Attacks of porphyria in patients with porphyria
PRECAUTIONS
Pregnancy:
Reproductive studies in animals did not raise specific concerns. However in
the absence of human data and due to the experimental risk of damage by
fluoroquinolones to the weight-bearing cartilage of the growing organism, Levomax
tablets must not be used in pregnant women.
Lactation:
In the absence of human data and due to the experimental risk of damage by
fluoroquinolones to the weight-bearing cartilage of the growing organism, Levomax
tablets must not be used in breast-feeding women.
Effects on ability to drive and use machines:

Some undesirable effects (e.g. dizziness/vertigo, drowsiness, visual disturbances) may
impair the patient’s ability to concentrate and react, and therefore may constitute a
risk in situations where these abilities are of special importance (e.g. driving a car or
operating machinery).
CONTRAINDICATIONS
Hypersensitivity to Fluoroquinolones, Quinolone antibiotics, or any product

component; tendonitis or tendon rupture associated with Quinolone use.
CLINICAL PHARMACOLOGY/ TOXICOLOGY
Not Reported
PRODUCT DEFECT REPORTING
Not Reported
98
CHAPTER#14
99
Levomax Infusion:
Levomax infusion will available in 100ml unit dose colorless glass bottle.
Each ml contains 5 mg of levofloxacin.
100
REFERENCES
¾ Pharmaceutical Manufacturing Encyclopedia; 3rd Edition; Wlliam Andrew
Publishing ; Norwich, NY, USA
¾ Handbook of Pharmaceutical Manufacturing Formulations; Compressed Solid
Products;
¾ Volker Buhler; Generic Drug Formulations; 2nd edition
¾ Pharmaceutical Preformulations and Formuation; A practical guide for
candidate drug selection to commercail dosage form: Editor: Mark Gibson;
IHS, Health Group
¾ Handbook of Pharmaceutical Excipients, 5th Edition; Editors: Raymond C
Rowe, Paul J Sheskey & Sian C Owen; PhP Pharmaceutical Press
¾ Reynolds JEF, editor; Martindale, The Extra Pharmacopoeia; 29th Edition; PhP
Pharmaceutical Press
¾ AMA Drug Evaluation; 6th Edition; Chicago; American Medical Association.
¾ Product Package
¾ http://www.clinicaltrail.gov/
¾ http://www.clinicaltrail.gov/ct2/show/NCT00645437?term=levefloxacin&rank
=5
=10
=26
¾ http://emc.medicines.org.uk
101
¾ http://emc.medicines.org.uk/medicine/12796/SPC/Tavanic+500mg+tablets/
¾ http://emc.medicines.org.uk/medicine/3090/XPIL/Tavanic+250mg%2c+500m
g+tablets/
¾ http://www.chemblink.com/products/100986-85-4.htm
¾ http://www.druginfosys.com
¾ http://www.drugguide.com
¾ http://www.drugs.com
¾ http://www.pharmascience.com
¾ http://www.pharmainfo.net
102

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NEW DRUG DEVELOPMENTAL &

Zohaib Ahmad(Roll#14) Submitted to:

HOW ARE NEW DRUGS DISCOVERED?

• Target Identification. Drugs usually act on either cellular or genetic

WHAT IS REQUIRED BEFORE AN INVESTIGATIONAL DRUG CAN

In the preclinical stage of drug development, an investigational drug must be tested

HOW ARE INVESTIGATIONAL DRUGS TESTED IN HUMANS?

Testing of an investigational new drug begins with submission of information about

Investigational New Drug (IND)/Clinical Trial Exception (CTX)/Clinical Trial

In addition to obtaining permission from appropriate regulatory authorities, an

New Drug Application (NDA)/Marketing Authorization Application (MAA):

DOES TESTING CONTINUE AFTER A NEW DRUG IS APPROVED?

• Post-Approval Studies. Post-approval studies test a marketed drug in new

INVESTIGATIONAL NEW DRUG

CLINICAL TRIALS PRECLINICAL STUDIES (Continued)

NEW DRUG APPLICATION (NDA)

POST MARKETING SURVEILLANCE

Empirical Formula: C18H20FN3O4 ½H2O

Routes: Oral, IV, ophthalmic

Molecular Weight: 370.38.

Stable Coordination Compounds:

Appearance: Levofloxacin is a light yellowish-white to yellow-white crystal or

Stability: Stable under ordinary conditions

Melting Point: 218 ºC (http://www.chemblink.com/products/100986-85-4.htm)

Solubility: Insoluble in water

Physical State: crystalline powder

Pharmacotherapeutic Group: Quinolone Antibacterials, Fluoroquinolones

Levofloxacin is a synthetic antibacterial agent of the fluoroquinolone class and is the

Mechanism of action:(Chemical Basis)

Levofloxacin is a broad-spectrum antibiotic that is active against both Gram-positive

The fluoroquinolones interfere with DNA replication by inhibiting an enzyme

Plasma Protein Binding

(B) TOXICOLOGICAL STUDIES:

Repeated dose toxicity:

Following 4-weeks oral administration to rats, no toxicological changes in clinical

Molecular Weight: 370.38.

Particle Size: Large

Melting Point: 218 ºC (http://www.chemblink.com/products/100986-85-4.htm)

Hot stage Microscopy

Differential Scanning Calorimetry and Thermal Analysis:

Crystal Habit: Microcrystalline

¾ Basic crystallography, to determine crystal morphology (structure and habit),

Powder Flow Properties:

Method: Transformation Kinetics are checked by differential scanning calorimetry

Partion Coefficient: Pka value is 6.8 ± 0.3

Membrane Permeabiliy: High permeability drug

Dissolution: Drug exhibit good dissolution properties.

Hydrolysis: There is no effect of moisture.

Our product is converted into a suitable dosage form. Than we submitted

PHASE-1 CLINICAL TRIALS:

PHASE-2 CLINICAL TRIALS:

¾ Phase IIA is specifically designed to assess dosing requirements (how much

A STUDY TO EVALUATE THE PHARMACOKINETICS AND SAFETY OF

Condition Intervention Phase

Study Type Interventional

Study Design Treatment, Randomized, Open Label, Parallel Assignment,

Official Title An Open-Label Randomized Multiple-Dose Study to

Primary Outcome Measures:

Evaluation of the pharmacokinetics of two dosing regimens of Levofloxacin in

Secondary Outcome Measures:

Safety of two dosing regimens of Levofloxacin in renally impaired and dialysis

Study Start Date: October 2007