Doripenem Monograph

National PBM Drug Monograph Doripenem (DoribaxTM) January 2008 VHA Pharmacy Benefits Management Service and the Medical Advisory Panel
The purpose of VACO PBM-SHG drug monographs is to provide a comprehensive drug review for making formulary decisions. These documents will be updated when new data warrant additional formulary discussion. Documents will be placed in the Archive section when the information is deemed to be no longer current.

Executive Summary Doripenem is the most recent addition to the class of carbapenem antibiotics. It received FDAapproval for the treatment of complicated intra-abdominal infections and complicated urinary tract infections, including pyelonephritis. Doripenem displays potent in vitro activity against a variety of Gram-positive and Gram-negative aerobic and anaerobic organisms. Doripenem has a similar spectrum of activity to meropenem and imipenem although doripenem demonstrates more potent activity against P. aeruginosa than imipenem. The efficacy of doripenem for the treatment of complicated intra-abdominal infections has been demonstrated in two pivotal, Phase III, randomized, double-blind clinical trials. Doripenem was found to be non-inferior to meropenem in the treatment of complicated intra-abdominal infections. Similarly, the efficacy of doripenem for the treatment of complicated urinary tract infections including pyelonephritis was demonstrated in a Phase III, randomized double-blind clinical trial. Doripenem was found to be non-inferior to levofloxacin for the treatment of complicated urinary tract infections, including pyelonephritis. Doripenem appeared to be well tolerated in clinical trials. The most common adverse reactions occurring in 5% of patients included headache, phlebitis, nausea, diarrhea, and rash. Similar to other carbapenems, hypersensitivity reactions have been reported as well as drug-drug interaction with valproic acid. The recommended dosage of doripenem is 500mg by intravenous infusion every 8 hours. Dosage adjustments are recommended in renal impairment (CrCL >10 to 50 mL/min); however, prescribing information does not provide recommendations for renal dosing for patients with severe renal dysfunction including those undergoing hemodialysis. Place in therapy: Doripenem provides an alternative to currently available antipseudomonal carbapenems (i.e., imipenem, meropenem). It is FDA approved for the treatment of complicated intra-abdominal and urinary tract infections. The NDA application for treatment of nosocomial pneumonia is being reviewed by the FDA. Introduction The purposes of this monograph are to (1) evaluate the available evidence of safety, efficacy, cost, and other pharmaceutical issues that would be relevant to evaluating doripenem for possible addition to the VA National Formulary; (2) define its role in therapy; and (3) identify parameters for its rational use in the VA.` Pharmacology1-4 Doripenem, similar to other carbapenems, display bactericidal activity by inhibiting bacterial cell wall biosynthesis. More specifically, carbapenems bind to penicillin binding proteins (PBPs) and inhibit cross-linking of the peptidoglycan structure. The binding affinity of the carbapenems to PBPs can vary among bacterial species. In addition, individual carbapenem antibiotics (e.g., doripenem vs. imipenem) demonstrate varying affinities for PBPs and such differences may account for the more potent in vitro activity of doripenem against P. aeruginosa compared to imipenem.
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Doripenem Monograph

Pharmacokinetics1 Doripenem, similar to meropenem and ertapenem, are stable from hydrolysis by the renal dehydropeptidase-I. The pharmacokinetics of doripenem are linear (only evaluated with dosing between 500mg to 1g) and dependent on renal clearance. Single-dose studies conducted in subjects with varying degree of renal dysfunction including hemodialysis demonstrated that higher plasma exposure was seen in subjects with moderate or severe renal dysfunction. Dosage adjustments are recommended for patients with CrCL <50 mL/min (Refer to Dose and Administration). The pharmacokinetics of doripenem in the central nervous system (CNS) has not been studied. Table 1. Pharmacokinetics of Doripenem in Healthy Adult Subjects Parameter Doripenem Cmax 23 mcg/mL Tmaxss NA AUC0- 36.3 mcghr/mL T1/2 (terminal) ~ 1 hour Vd 16.8L (range 8.09 55.5 L) Protein Binding 8.1% to plasma proteins Metabolism Via dehydropeptidase-I to inactive metabolite Elimination Urine: 70% (unchanged drug) and 15% (inactive metabolite)
NA=not available

Microbiology1,5--19 Doripenem displays potent in vitro activity against a variety of Gram-Positive and Gram-Negative aerobic and anaerobic organisms. The MIC susceptibility breakpoints differ for doripenem and the other carbapenems (Table 2). The in vitro activity of doripenem, imipenem, meropenem, and ertapenem against a selected group of pathogens is provided in Table 3. The table presents the minimum concentration (mcg/mL) of antibiotic required to inhibit growth at 50% (MIC50) of the tested strains and 90% (MIC90) of the strains. Multiple references were utilized for the MIC ranges (minimal 25 isolates for each organism was required for inclusion); therefore, the isolates represent a heterogeneous patient population. Against Enterobacteriaceae isolates (n=9639) collected during 2005-2007, doripenem and meropenem exhibit identical MIC50 (0.03mcg/mL) and MIC90 (0.12mcg/mL) values. In comparison, the MIC50 and MIC90 of imipenem are 0.25mcg/mL and 2mcg/mL, respectively. High susceptibility rates have been seen with the carbapenems against fluoroquinolone-resistant Enterobacteriaceae (FQRE) isolated in the Phase III nosocomial pneumonia clinical trials. Both doripenem and meropenem inhibited 100% of FQRE at 0.5mcg/mL while imipenem and ertapenem inhibited 91% and 83% of FQRE at 0.5mcg/mL, respectively. However, it is important to note that these agents have different susceptibility breakpoints for Enterobacteriaceae and dosage regimens (Refer to Table 2). Therefore, one should relate the MIC values to pharmacokinetics, PK/PD surrogate markers, and susceptibility breakpoints of the individual agent. Doripenem and meropenem generally exhibit similar MICs against P. aeruginosa. In comparison, these agents are typically several doubling dilutions more potent than imipenem against P. aeruginosa. A surveillance study that collected 1660 isolates of P. aeruginosa during 2005-2007 reports that doripenem has similar in vitro activity to meropenem (MIC50/MIC90: 0.25/4mcg/mL vs MIC50/MIC90: 0.5/8mcg/mL, respectively) and more potent in vitro activity than imipenem (MIC50/MIC90: 2/8mcg/mL). Similar results have been seen in P. aeruginosa isolates (n=107) collected from patients enrolled in the phase III nosocomial pneumonia clinical trials (MIC50/MIC90 of doripenem: 0.25/4mcg/mL; MIC50/MIC90 of meropenem: 0.5/8mcg/mL; MIC50/MIC90 of imipenem: 1/16mcg/mL). Of the 53 P. aeruginosa isolates
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Doripenem Monograph

obtained from patients enrolled in the ventilator-associated pneumonia clinical trial (DORI-10), seven isolates (13.2%) were resistant to imipenem (>4mcg/mL) while none of the isolates had a MIC > 4mcg/mL for doripenem (however, note that the doripenem MIC breakpoint for susceptibility is 2). Doripenem, meropenem, and imipenem display similar MIC50 and MIC90 against Acinetobacter baumannii isolates (n=47) collected in the nosocomial pneumonia trials. The MIC50 is within onedoubling dilution (MIC of doripenem and meropenem was 0.5 mcg/mL vs 0.25mcg/mL for imipenem) while the MIC90 is 64mcg/mL with all three agents. Similar to other carbapenems, doripenem exhibits in vitro activity against methicillin-sensitive Staphylococcus aureus while it is inactive against methicillin-resistant strains. Doripenem also displays in vitro activity against Streptococcus species including S. pneumoniae. High susceptibility rates are seen with the carbapenems against anaerobes. A recent surveillance study that collected ~400 anaerobe strains reported MIC50/MIC90 (mcg/mL) of 0.25/1 for both doripenem and ertapenem, 0.12/0.5 for meropenem, and 0.12/1 for imipenem. Table 2. Susceptibility Breakpoints for the Carbapenems Ertapenem 2 Enterobacteriaceae NA Pseudomonas aeruginosa Acinetobacter baumannii NA Haemophilus spp. 0.5 Staphylococcus spp. 2 Streptococcus pneumoniae 1 Streptococcus spp. other than 1 NA S. pneumoniae Streptococcus agalactiae and 4 0.5 NA NA Streptococcus pyogenes Streptococcus anginosus group 0.12 4 NA NA Anaerobes 1 4 4 4 a Susceptibility breakpoint is provided for aerobic and anaerobic bacteria (not specific to organism) b Susceptibility breakpoint refers to Acinetobacter spp. c Susceptibility breakpoint is specific for H. influenzae d Susceptibility breakpoint is specific for S. aureus Doripenem 0.5 2 1 NA NA NA MIC (mcg/mL) Imipenema Meropenem 4 4 4 4 4 4b 4 0.5c 4 4d 4 0.12 4 NA

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Doripenem Monograph

Table 3. In Vitro Activity Profiles of Carbapenems Doripenem Imipenem MIC50 MIC90 MIC50 MIC90 mcg/mL mcg/mL mcg/mL mcg/mL Gram-Negatives A. baumannii 0.5 4-16 0.5 2->8 Enterobacter spp. Ceftazidime resistant E. coli ESBL producing K. pneumonia ESBL producing P. mirabilis Indole-positive P. aeruginosa Carbapenem resistant Serratia spp. Gram-Positives E. faecalis E. faecium Staphylococcus aureus (MS) Coagulase-neg staphylococci (MS) -haemolytic streptococci Streptococcus pneumoniae Penicillinresistant Viridans group streptococci Anaerobes Bacteroides fragilis Bacteroides thetaiotaomicron Clostridium spp.
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Meropenem MIC50 MIC90 mcg/mL mcg/mL 1-2 0.030.06 0.12 0.06 0.06 0.030.06 0.06 0.06 0.06 0.25-0.5 >8 0.030.06 NA >16 0.12 0.12 0.008 0.0160.12 0.5 0.06 8->8 0.060.12 0.25 0.06 0.06 0.060.12 0.12 0.06 0.12 1-16 >8 0.060.12 NA >16 0.12 0.12

Ertapenem MIC50 MIC90 mcg/mL mcg/mL 4-8 0.030.06 0.5 0.0150.06 0.06 0.015 0.06 0.06 0.06 4-8 >32 0.06 >8->32 0.25-1 4 0.0150.06 0.25 0.03 0.25-0.5 0.06 0.06 >8-16 >32 0.060.12 >32 >8 0.25 0.5 0.06 0.5 2 1

0.030.06 0.06 0.0150.03 0.0150.03 0.030.06 0.030.06 0.12 0.12 0.25-0.5 8 0.12

0.060.12 0.12 0.0150.03 0.030.06 0.030.12 0.060.12 0.25 0.5 0.5-8 >32 0.25-0.5

0.5 0.25 0.120.5 0.120.5 0.120.25 0.120.5 1 2 1 >8 0.5-2

0.5-1 1 0.250.5 0.5 0.25-0.5 0.250.5 2 4 2- >8 >8 1-4

4 >16 0.030.06 0.03 0.008 0.0160.06 0.5 0.03

16 >16 0.06 0.06

1 >8 0.0160.5 0.5 0.5 0.060.5 0.5 0.5

4 >8 0.030.5 0.5 0.5 0.5-1 1 0.5

16 >8 0.12 0.25 0.06 0.06 1 0.12

0.03 0.5-1 1 0.5

0.06 0.5-1 1 0.5

0.25-0.5 0.25-0.5 1

1 0.5-1 2

0.1250.25 0.25-0.5 2

0.25-0.5 0.5-1 8

0.12 0.25 1

0.5-1 0.5 2

0.25 0.5 2

0.5-2 1-2 8

MS: methicillin-susceptible

Doripenem Monograph

Selection of resistance3-4,20-21 In vitro studies have demonstrated that doripenem selected less frequently for resistant mutations than meropenem and imipenem. Cross-resistance among carbapenems is expected if resistance is due to hydrolysis from carbapenemases. However, doripenem and meropenem display slightly different resistance profiles than imipenem from other circulating mechanisms of resistance (e.g., efflux). FDA Approved Indications1 1) Doripenem is indicated as a single agent for the treatment of complicated intra-abdominal infections caused by Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa, Bacteroides caccae, Bacteroides fragilis, Bacteroides thetaiotaomicron, Bacteroides uniformis, Bacteroides vulgatus, Streptococcus intermedius, Streptococcus constellatus, and Peptostreptococcus micros. 2) Doripenem is indicated as a single agent for the treatment of complicated urinary tract infections, including pyelonephritis caused by E. coli including cases with concurrent bacteremia, K. pneumoniae, Proteus mirabilis, P. aeruginosa, and Acinetobacter baumannii. Current VA National Formulary Alternatives Other formulary options include ampicillin/sulbactam, cefepime, cefotaxime, ceftazidime, ciprofloxacin, ertapenem, imipenem/cilastatin, levofloxacin, metronidazole, moxifloxacin, and piperacillin/tazobactam. Dosage and Administration1 The recommended dosage in adults ( 18 years old) is 500mg every 8 hours by intravenous infusion over one hour. According to the PI, the recommended duration of therapy is 5 14 days for complicated intraabdominal infection and 10 days for complicated UTI including pyelonephritis. However, these timeframes includes a possible switch to an oral agent if clinical improvement has been demonstrated and after a minimum of 3 days of parenteral therapy. Duration of complicated UTI can be extended to 14 days for patients with concurrent bacteremia. Renal Impairment: Dosage adjustments are recommended in renal impairment (Table 4). Table 4. Dosage Recommendations Estimated CrCL (mL/min) Recommended dosage regimen > 50 30 to 50 > 10 to < 30 End-stage renal disease on hemodialysis 500mg intravenously infused over one hour every 8 hours 250mg intravenously infused over one hour every 8 hours 250mg intravenously infused over one hour every 12 hours Doripenem is hemodialyzable; however, insufficient information to provide recommendation.

Hepatic Impairment: The pharmacokinetics of doripenem has not been adequately evaluated in individuals with hepatic impairment. However, since doripenem does not undergo hepatic metabolism, the pharmacokinetics are not expected to be affected by hepatic impairment. Pediatric: The pharmacokinetics, safety and effectiveness has not be evaluated in patients <18 years of age. Stability1 Doripenem provides extended stability at room and refrigeration temperatures (Table 5). Table 5. Stability Times of Doripenem Infusion Solutions
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Doripenem Monograph

Stability Time at Room Temperaturea Normal Saline 5% Dextrose

a

Stability Time at 2-8C (Refrigeration)a 24 hours 24 hours

8 hours 4 hours

Timeframe includes storage and infusion time

Efficacy Treatment of complicated intra-abdominal infections: doripenem versus meropenem22-24 Two identical Phase III clinical trials were utilized to receive FDA approval for treatment of complicated intra-abdominal infections. The combined results of the two clinical trials have only been published in abstract/poster form. In these multi-center, randomized, double-blind, double-dummy clinical trials, doripenem was compared to meropenem for treatment of complicated intra-abdominal infections in adults. Randomization occurred in 1:1 ratio for doripenem and meropenem with stratification by primary infection site, severity of illness (APACHE II score 10 vs >10) and geographic region. Doripenem was administered 500mg IV infusion over 60 minutes every 8 hours while meropenem was administered 1gm IV bolus over 3 to 5 minutes every 8 hours. The protocol allowed for both IV doripenem and meropenem to be switched to oral amoxicillin/clavuanate (875/125 orally twice daily) in patients that received at least 9 doses of IV therapy and met criteria for clinical improvement. The study protocol allowed total duration of antibiotic therapy (IV only or combination of IV and PO) between 5 to 14 days. Inclusion and exclusion were not specified in the abstract/poster. The studies were designed as non-inferiority efficacy trials. Non-inferiority was declared if lower limit of the 2-sided 95% confidence interval for the treatment difference in patients with clinical cures of -15%. Four populations were evaluated as endpoints. Intent-to-treat (ITT) was defined as all randomized patients who took at least one dose of study drug. Microbiologically modified ITT (mMITT) was defined as all randomized patients who took at least one dose of study drug and evidence of an intra-abdominal infection with a bacterial pathogen identified at study entry. Clinically evaluable (CE) was defined as population with evidence of an intra-abdominal infection who adhered to protocol including compliance and had a measurable outcome at the test of cure (TOC) visit (21-60 days after the final dose of the drug therapy). Microbiologically evaluable (ME) was defined as all randomized patients who had evidence of intra-abdominal infection with an intra-abdominal bacterial pathogen isolated at study entry that was susceptible to study medications. In addition, the ME patient population adhered to protocol including compliance to study medications and had a measureable outcome at TOC. Endpoints: Primary efficacy endpoints: o Clinical cure rates in the ME population at TOC visit o Clinical cure rates in the mMITT population up to 60 days after the last dose of the study drug. Secondary efficacy endpoints: o Clinical cure rates in the CE patient population o Microbiological cure rates in ME population Of the 946 patients in the ITT population, 477 patients were administered doripenem and 469 were administered meropenem. The demographics of the doripenem-treated patients (ME population =325 persons) include mean age of 45.8 years old, 89.2% APACHE II score 10, and 51.1% from South America (27.7% North America vs 21.2% Europe). In comparison, the demographics of the meropenemJanuary 2008 Updated versions may be found at www.pbm.va.gov or vaww.pbm.va.gov 6

Doripenem Monograph

treated patients (ME population=309 persons) include mean age of 45.7 years old, 91.6% APACHE II score 10, and 47.9% from South America (28.8% North America vs 23.3% Europe). The primary site of infection was complicated appendicitis in 34.5% doripenem-treated and 33.3% meropenem-treated patients. The major anatomic site of the infection was appendix (62.5% vs 61.2%) followed by colon perforation (20.0% vs 20.1%), biliary-cholecystitis (5.2% vs 4.9%), and small bowel perforation (5.2% vs 4.9%). Similarly, the infection process included generalized peritonitis (46.2% vs 43.4%) followed by single abscess (23.7% vs 24.9%), localized infection (25.8% vs 27.2%), and multiple abscesses (3.4% vs 4.9%). In the primary efficacy endpoints, doripenem was non-inferior to meropenem in clinical cure for both the ME and mMITT patient populations (Table 6). Similarly, secondary endpoints appear comparable for doripenem and meropenem. Microbiological cure rates were similar for doripenem and meropenem against a variety of pathogens isolated (Table 7). In conclusion, doripenem was non-inferior to meropenem in clinical cure for the treatment of complicated intra-abdominal infections. Table 6. Efficacy Endpoints Doripenem Primary Efficacy Endpoints: Clinical cure rates in the ME population at TOC visit Clinical cure rates in the mMITT population Secondary Efficacy Endpoints: Clinical cure rates in CE population at TOC visit Microbiological cure rates in ME population 275/325 (84.6%) 301/395 (76.2%) proportion NA (85.3%) 274/325 (84.3%) Meropenem 260/309 (84.1%) 290/375 (77.3%) proportion NA (86.2%) 281/309 (84.5%) 95% CI (%) -5.5, 6.4 -7.4,5.1

NA NA

ME: Microbiologically evaluable; mMITT: Microbiologically modified intent-to-treat; CE: Clinically evaluable; NA: not available

Table 7. Microbiological Cure Rates for Baseline Pathogens (30 patients in doripenem arm) Doripenem Meropenem 95% CI (%) Gram-Negatives aerobes Enterobacteriaceae 271/315 234/274 -5.4, 6.6 (86.0%) (85.4%) E. coli 189/216 168/199 -4.1, 10.3 (87.5%) (84.4%) K. pneumoniae 25/32 19/20 NA (78.1%) (95.0%) P. aeruginosa 34/40 24/32 -11.5, 31.5 (85.0%) (75.0%) Gram-Positives aerobes Viridans group streptococci 93/109 71/90 -5.3,18.2 (85.3%) (78.9%) S. intermedius 30/36 21/29 -12.5, 34.4 (83.3%) (72.4%) Anaerobes B. fragilis group 152/173 152/181 -3.9, 11.7 (87.9%) (84.0) B. fragilis 56/67 54/68 -10.4,18.7
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B. thetaiotaomicron Gram-positives anaerobes

NA: not available

(83.6%) 30/34 (88.2%) 61/73 (83.6%)

(79.4%) 32/36 (88.9%) 62/82 (75.6%)

-18.4, 17.1 -5.9, 21.8

Intravenous therapy with doripenem versus levofloxacin with an option for oral-step down therapy in the treatment of complicated urinary tract infection and pyelonephritis25 This study was the pivotal, Phase III trial utilized to receive FDA-approved indication for treatment of complicated urinary tract infections, including pyelonephritis. The results of this clinical trial have only been published in abstract/poster form. In this multi-center, randomized, double-blind, double-dummy clinical trial, doripenem was compared to levofloxacin for treatment complicated UTI including pyelonephritis in adults. Doripenem was administered 500mg IV infusion over 60 minutes every 8 hours while levofloxacin was administered 250mg IV infusion over 60 minutes every 24 hours. The protocol allowed for both IV doripenem and levofloxacin to be switched to oral levofloxacin (250mg orally every 24 hours) in patients that received at least 3 days of IV therapy and met criteria for clinical and microbiological improvement. Inclusion and exclusion were not specified in the abstract/poster. This study was designed as a non-inferiority efficacy trial. Non-inferiority was declared if lower limit of the 2-sided 95% confidence interval for the treatment difference in patients with microbiological cures of -10%. Four populations were evaluated as endpoints. Intent-to-treat (ITT) was defined as all randomized patients who took at least one dose of study drug. Microbiologically modified ITT (mMITT) was defined as all randomized patients who took at least one dose of study drug and had a positive urinary culture identified at study entry. Microbiologically evaluable (ME) was defined as all randomized patients who had clinical signs and symptoms of UTI with a positive urinary culture identified at study entry. In addition, the ME patient population adhered to protocol including compliance to study medications and had a follow-up urine culture test of cure (TOC) window (6 to 11 days after the final dose of the drug therapy). Lastly, clinically evaluable (CE) was defined similar to ME patient population with the exception that assessment of clinical outcome replaced follow-up urine culture at TOC. Endpoints: Primary efficacy endpoints: o Microbiological cure rate defined as eradication of baseline pathogens (<104 CFU/mL) in the ME population at TOC visit and in the mMITT population. Secondary efficacy endpoints: o Microbiological cure rate in ME population with infections caused by E. coli o Clinical cure rate in CE population at the TOC visit Of the 748 patients in the ITT population, 372 patients were administered doripenem and 376 were administered levofloxacin. The demographics were similar between doripenem-treated and levofloxacintreated groups in both the ME (n=545) and mMITT (n=648) population. Overall, 61% of ME patients were female with a mean age of 51.6 years. Of the doripenem-treated patients (ME = 280 persons), the baseline diagnosis including complicated lower UTI (51.8%) and pyelonephritis (48.2%) compared with 49.4% and 50.6% of levofloxacin-treated patients, respectively. There were 7.1% doripenem- and 8.7% levofloxacin-treated patients with concurrent bacteremia.

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Doripenem Monograph

In the primary efficacy endpoint, doripenem was non-inferior to levofloxacin in microbiological cure in both the ME and mMITT patient population (Table 8). In the secondary efficacy endpoints, microbiological cures were similar between doripenem- and levofloxacin-treated patients in ME population with UTI caused by E. coli. However, clinical cure rates were higher in patients treated with doripenem compared to levofloxacin. In subgroup analysis, patients infected with a levofloxacin-resistant E. coli at study entry had a higher eradication rate when treated with doripenem (11/20, 55%) compared to levofloxacin (6/21, 29%). In conclusion, doripenem was found to be non-inferior to levofloxacin for the treatment of UTI. Table 8. Efficacy Endpoints Doripenem Primary Efficacy Endpoints: Microbiological cure rates in ME population Microbiological cure rates in mMitt Secondary Efficacy Endpoints: Microbiological cure rates in ME population with UTI caused by E. coli Clinical cure rates in CE population at the TOC visit ME: Microbiologically evaluable mMITT: Microbiologically modified intent-to-treat 230/280 (82.1%) 259/327 (79.2%) 168/199 (84.4%) 272/286 (95.1%) Levofloxacin 221/265 (83.4%) 251/321 (78.2%) 184/211 (87.2%) 240/266 (90.2%) 95% CI (%) -8.0, 5.5 -5.6, 7.6

-10.0, -4.5 0.2, 9.6

Treatment of nosocomial pneumonia: doripenem vs piperacillin/tazobactam (DORI-9)26-27 This study was one of the pivotal, Phase III clinical trial submitted to the FDA for the indication of treatment of nosocomial pneumonia. The FDA should announce their decision by April 2008. The results of this clinical trial have only been published in abstract form. In this multi-center, prospective, open-label clinical trial, doripenem was compared to piperacillintazobactam for treatment of nosocomial pneumonia. Randomization occurred in 1:1 ratio for doripenem and piperacillin-tazobactam with stratification by ventilator-associated pneumonia (VAP) vs non-VAP, severity of illness (APACHE II score 15 vs >15) and geographic region. Doripenem was administered 500mg IV infusion over 60 minutes every 8 hours while piperacillin-tazobactam was administered 4.5g IV infusion over 30 minutes every 6 hours. If the physician suspected P. aeruginosa or MRSA as a causative pathogen, the protocol allowed the use of aminoglycoside and vancomycin, respectively. The protocol allowed for both IV doripenem and piperacillin-tazobactam to be switched to oral levofloxacin (750mg once daily) in patients that received at least 3 days of IV therapy. Inclusion and exclusion were not specified in the abstract. This study was designed as a non-inferiority efficacy trial. Similar to the studies cited above, the authors evaluated four populations (clinical modified intent-to-treat, microbiological modified intent-to-treat, clinically evaluable, and microbiologically evaluable). Endpoints: Primary o Clinical cure in clinically evaluable patients o Clinical cure in clinical modified intent-to-treat (cMITT) patients.

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Doripenem Monograph

Of the 253 clinically evaluable patients, 134 patients were administered doripenem and 119 were administered piperacillin-tazobactam. The demographics of the doripenem-treated patients include mean age of 57.5 years old, 78.4% non-VAP, 73.1% APACHE II score 15, and 52.2% from Eastern Europe (30.6% South America vs 14.2% North America). In comparison, the demographics of the piperacillintazobactam-treated patients include mean age of 59.3 years old, 78.2% non-VAP, 76.5% APACHE II score 15, and 52.1% from Eastern Europe (31.1% South America vs 14.3% North America). In co-primary efficacy endpoints, doripenem was non-inferior to piperacillin-tazobactam in clinical cure in clinically evaluable and clinical modified ITT (Table 9). Clinical cure rates by stratified groups were provided in percents (Refer to Table 10); higher clinical cure rates were seen in patients diagnosed with non-VAP and lower APACHE II scores. In this study with the majority of the patients diagnosed with non-VAP nosocomial pneumonia and less severely ill, doripenem was non-inferior to piperacillintazobactam. Table 9. Efficacy Endpoints Doripenem Primary Efficacy Endpoints: Clinical cure rates in clinically evaluable Clinical cure rates in modified ITT Piperacillintazobactam 95/119 (79.8%) 134/209 (64.1%) 95% CI (%)

109/134 (81.3%) 148/213 (69.5%)

-9.1%, 12.1% -4.1, 14.8%

Table 10. Efficacy Endpoints Subgroup Clinical cure rates by disease type Non-VAP Early-onset VAP Clinical cure rates by APACHE II score 15 >15 Clinical cure rates by Region South America North America Eastern Europe
NA: not available

Doripenem

Piperacillintazobactam 86.0% 57.7% 83.5% 67.9% 67.6% 82.4% 87.1%

95% CI (%)

84.8% 69.0% 89.9% 57.1% 68.3% 73.7% 91.4%

NA

NA

NA

Treatment of ventilator-associated pneumonia (VAP): doripenem vs imipenem (DORI-10)19 This study was one of the pivotal, Phase III trial submitted to the FDA for the indication of the treatment of nosocomial pneumonia. The results of this clinical trial have only been published in abstract/poster form. In this multi-center, prospective, randomized, open-label clinical trial, doripenem was compared to imipenem for treatment of VAP in adults. Randomization occurred in 1:1 ratio for doripenem and imipenem with stratification by duration of ventilation (early-onset defined as < 5days vs late-onset VAP defined as 5days), severity of illness (APACHE II score 15 vs >15) and geographic region. Doripenem was administered 500mg IV infusion over 4 hours every 8 hours while imipenem was administered either 500mg IV infusion over 30 minutes every 6 hours or imipenem 1g IV infusion over 60 minutes every 8 hours. Imipenem dosage regimen was based upon standard of practice at local facility. If the physician
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Doripenem Monograph

suspected P. aeruginosa or MRSA as a causative pathogen, the protocol allowed the use of aminoglycoside and vancomycin, respectively. This study was designed as a non-inferiority efficacy trial. Non-inferiority was declared if lower limit of the 2-sided 95% confidence interval for the treatment difference in patients with clinical cures of -20%. Four populations were evaluated as endpoints: clinical modified intent-to-treat, microbiological modified intent-to-treat, clinically evaluable, and microbiologically evaluable. Clinical modified ITT (cMITT) population was defined patients who met the clinical and radiographical definition of pneumonia and received at least one dose of study drug. Other populations were not defined in abstract/poster. Endpoints: Primary efficacy endpoints: o Clinical cure rates in cMITT and CE at TOC visit. Of the 525 patients in the IIT population, 262 patients were administered doripenem and 263 were administered imipenem. However, only 126 doripenem-treated and 122 imipenem-treated patients were considered CE at TOC visit. Most of exclusions were due to violations with concomitant antibacterials, timeframe of TOC, and indeterminate clinical assessment. The demographics of the doripenem-treated patients include mean age of 50.7 years old, 38.1% early-onset VAP, 46.8% APACHE II score 15, and 42.1% from North America (37.3% Europe vs 20.6% other). In comparison, the demographics of the imipenem-treated patients include mean age of 50.3 years old, 40.2% early-onset VAP, 50.0% APACHE II score 15, and 41% from North America (38.5% Europe vs 20.5% other). In co-primary efficacy endpoint, doripenem was non-inferior to imipenem in clinical cure in clinically evaluable and clinical modified ITT (Table 10). No significant differences were noted in clinical cure rates in CE patients at TOC based upon subgroups (Table 11). In patients with APACHE II score 20, higher percent of doripenem-treated patients achieved clinical cure compared to imipenem-treated patients; however, a low number of patients were enrolled in each group. In the microbiologically evaluable population, 73.3% of doripenem-treated patients and 67.3% of imipenem-treated patients achieved microbiological cure (95% CI -6.8, 18.8). Table 10. Efficacy Endpoints Doripenem Primary Efficacy Endpoints: Clinical cure rates in clinically evaluable Clinical cure rates in cMITT 86/126 (68.3%) 144/244 (59%) Imipenem 79/122 (64.8%) 144/249 (57.8%) 95% CI (%) -9.1, 16.1 -7.9, 10.3

Table 11. Efficacy Endpoints Subgroup Clinical cure rates by duration of ventilation Late-onset VAP Early-onset VAP Clinical cure rates by APACHE II score 15 16-20 20 Clinical cure rates by region (%) North America
January 2008

Doripenem 58/78 (74.4%) 28/48 (58.3%) 40/59 (67.8%) 27/40 (67.5%) 19/27 (70.4%) 40/53 (75.5%)

Imipenem 52/73 (71.2%) 27/49 (55.1%) 42/61 (68.9%) 22/35 (62.9%) 15/26 (57.7%) 29/50 (58.0%)

95% CI (%) -12.4, 18.7 -18.5, 25.0 -19.1, 17.3 -19.6, 28.9 NA -2.4, 37.3
11

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Doripenem Monograph

Europe Other

31/47 (66.0%) 15/26 (57.7%)

34/47 (72.3%) 16/25 (64.0%)

-27.1, 14.4 NA

In conclusion, doripenem and imipenem were non-inferior for the treatment of VAP. In comparison to the nosocomial pneumonia clinical trial, the VAP trial had a higher percent of patients with APACHE II 15 and utilized a prolonged infusion of 4 hours with doripenem. This dosage regimen optimizes T>MIC with minimizing drug expenditure. Adverse Events (Safety Data)1,28 Incidence of adverse events was assessed in 853 patients treated with doripenem in three, pivotal phase III clinical trials. Overall, doripenem appeared to be well tolerated with few patients discontinuing for adverse events [nausea (0.2%), vulvuomycotic infection (0.1%), and rash (0.1%)]. The most common adverse reactions occurring in 5% of patients included headache, phlebitis, nausea, diarrhea, and rash (Table 12). Hypersensitivity reactions have been reported in <1% in Phase III clinical trials. No seizures were reported in these 3 clinical trials. In postmarketing experience of doripenem in other countries, adverse events reported include anaphylaxis, Stevens Johnson Syndrome, toxic epidermal necrolysis, interstitial pneumonia, and seizure. Compared to imipenem, doripenem has low potential for convulsive activity in animal models as well as demonstrated low affinity for GABA receptors. Table 12. Adverse Events/Reactions Phase III Clinical Trial: UTI
Doripenem (n=376) 16% 4% 4% 6% 2% <1% <1% 1% 2% 1% 2% Levofloxacin (n=372) 15% 4% 6% 10% 1% 0% 1% 1% 3% 0% 1%

Phase III Clinical Trial: Intra-abdominal

Doripenem (n=477) 4% 8% 12% 11% 10% 1% 3% 5% 1% 1% 1% Meropenem (n=469) 5% 6% 9% 11% 5% <1% 2% 2% 3% 2% <1%

Headache Phlebitis Nausea Diarrhea Anemia Renal impairment/renal failure Pruritus Rash Hepatic enzyme elevation Oral candidiasis Vulvomycotic infection

p-values were not provided. Contraindications/precautions1 Contraindications Known serious hypersensitivity to doripenem or to other drugs in the same class or in patients who have demonstrated anaphylactic reactions to beta-lactams. Warnings and Precautions Hypersensitivity reactions: Serious hypersensitivity reactions including fatal cases and serious skin reactions have been reported in patients receiving beta-lactam antibiotics. If doripenem is to be administered to a beta-lactam-allergic patient, caution should be exercised because crosshyperreactivity among beta-lactam antibiotics has been clearly documented. Interaction with sodium valproate: Carbapenems may reduce serum valproic concentrations, which can lead to subtherapeutic levels and loss of seizure control. Clostridium difficile-associated diarrhea (CDAD): CDAD has been reported with most antibacterial agents. The signs and symptoms may range from mild diarrhea to fatal colitis.
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Doripenem Monograph

Development of drug-resistant bacteria: In the absence of a proven or strongly suspected bacterial infection, administration doripenem is unlikely to provide benefit to the patient; however, it may increase the risk of development of drug-resistant bacteria. Pneumonitis with inhalational use: Pneumonitis has been reported when doripenem has been administered investigationally via inhalation. Doripenem should not be administered by this route.

Pregnancy/Nursing Mothers Pregnancy category B It is not known if doripenem is excreted in human breast milk. Caution should be exercised when doripenem is administered to a nursing mother. Look-alike / Sound-alike (LA / SA) Error Risk Potential The VA PBM and Center for Medication Safety is conducting a pilot program which queries a multiattribute drug product search engine for similar sounding and appearing drug names based on orthographic and phonologic similarities, as well as similarities in dosage form, strength and route of administration. Based on similarity scores as well as clinical judgment, the following drug names may be potential sources of drug name confusion: Doripenem LA/SA: Ertapenem 1gm injectable, imipenem 500mg injectable, doxapram hydrochloride 20mg intravenous, dolophine hydrochloride 10mg injection (high alert drug per ISMP), dopram 20mg injection, meropenem 1gm injection, dipentum 250mg capsule, daraprim 25mg tablet, dyrenium 100mg capsule. DoribaxTM: Doryx 100mg tablet, dolorex 300mg capsule, cerebyx 50mg injection (high alert drug per ISMP), dostinex 0.5mg tablet, zovirax 500mg injection, rubex 50mg injection (high alert drug per ISMP), dexrazoxane 500mg injectable, diamox 500mg injection, didrex 50mg tablet, diuril 500mg injectable, dryvax kit intradermal, duomax 1200mg tablet, durabac 325mg capsule, duramax 45mg tablet, varivax 1350mg powder for injection, zithromax 500mg injectable. Drug-Drug Interactions1,29 Doripenem is not expected to impact the pharmacokinetics of co-administered agents. It is not an inhibitor or inducer of the major CYP450 isoenzymes. It also does not appear to induce uridine diphosphate glucuronosyl transferase 1A1 isozyme (UGT1A1). As mentioned in the warning section, carbapenems may reduce serum valproic concentrations. Researchers have hypothesized that the carbapenems inhibit the enzyme that enables the hydrolysis of valproic acid glucoronide to valproic acid. The inhibition of this hydrolytic enzyme can lead to subtherapeutic levels of valproic acid and loss of seizure control. The prescribing information states that clinicians should monitor serum valproic acid concentrations during the co-administration of a carbapenem and valproic acid. Clinicians should also consider switching to an alternative antibiotic or anticonvulsant therapy if the patient experiences a seizure or therapeutic concentrations are not maintained. The co-administration of probenecid is not recommended with doripenem. Probenecid competes with doripenem for active renal tubular secretion; the co-administration results in an increased doripenem AUC by 75% and half-life by 53%.

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Doripenem Monograph

Acquisition Costs Table 11. Cost of Antimicrobial Agents

Drug & Strength Doripenem (500mg vial) Ampicillin/sulbactam Cefepime Dosage Regimen 500mg every 8 hours by intravenous infusion 3g every 4-6 hours by intravenous infusion 1-2gm every 12 hours by intravenous infusion Cost Dose ($) $21.72 $7.21 (FSS) VIAL (BIG4) 1gm $10.72 2gm $21.28 ADD-VANTAGE 1gm $11.14 2gm $21.70 $2.27 (FSS) $5.57 (FSS) $4.30 (FSS) $4.51 (FSS) VIAL $34.29 (Big 4) ADD-VANTAGE $36.81 (Big 4) VIAL $14.13 (Big 4) ADD-VANTAGE $19.75 (Big 4) 500mg $10.82 (Big 4) 750mg $11.61 (Big 4) Big 4 $26.93 $1.20 (FSS) FSS $8.75 FROZEN $10.37 (Big 4) VIAL
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Cost/ 14 day course ($) $912 $404-606

$300 $596

Cefotaxime Ceftazidime Ceftriaxone Ciprofloxacin Ertapenem

1gm every 8 hours by intravenous infusion 1gm every 8 hours by intravenous infusion 1gm every 24 hours by intravenous infusion 400mg every 12 hours by intravenous infusion 1gm every 24 hours by intravenous infusion

$312 $608 $95 $234 $60 $126

$480

$515 $791

Imipenem cilastatin (500mg)

500mg every 6 hours by intravenous infusion

Levofloxacin Meropenem (1gm) (Non-formulary) Metronidazole Moxifloxacin Piperacillin/tazobactam

500-750mg every 24 hours by intravenous infusion 1gm every 8 hours by intravenous infusion 500mg every 8 hours by intravenous infusion 400mg every 24 hours by intravenous infusion 3.375g every 6 hours by intravenous infusion

$1106 $152 $163 $1131 $50 $123

$581

Doripenem Monograph

$10.48 (Big 4) Prices from Feb 2008

$587

Conclusions Doripenem is an antipseudomonal carbapenem that received FDA approval for the treatment of complicated intra-abdominal and urinary tract infections including pyelonephritis. The indication for nosocomial pneumonia is currently being reviewed by the FDA and the decision should be announced by July 2008. Doripenem has a spectrum of activity similar to imipenem and meropenem. Doripenem demonstrated more potent activity against P. aeruginosa than imipenem. Cross-resistance among carbapenems is expected if resistance is due to hydrolysis from carbapenemases. However, doripenem and meropenem display slightly different resistance profiles than imipenem from other circulating mechanisms of resistance (e.g., efflux). In the Phase III clinical trials, doripenem was found to be noninferior to meropenem for treatment of complicated intra-abdominal. Similarly, doripenem was found to be non-inferior to levofloxacin in Phase III clinical trial for complicated urinary tract infections. Doripenem appears to be well-tolerated in the clinical trials. The most common adverse reactions occurring in 5% of patients included headache, phlebitis, nausea, diarrhea, and rash. Hypersensitivity reactions (<1%) have been reported in phase III clinical trials and the potential of cross-hyperreactivity may occur with other beta-lactams. In vivo studies have shown that doripenem has minimal seizure potential. With a half-life of approximately one hour, the recommended dosage of doripenem is 500mg by intravenous infusion over one hour every 8 hours. Dosage adjustments are recommended in renal impairment (CrCL >10 to 50 mL/min); however, prescribing information does not provide recommendations for renal dosing for patients with severe renal dysfunction including those undergoing hemodialysis or CVVH. The VAP clinical trial utilized a dosage recommendation that optimized the T>MIC by administering 500mg by IV infusion over 4 hours every 8 hours. The stability of doripenem in normal saline is 8 hours at room temperature, which enables this to be feasible from a stability perspective. Recommendations Doripenem provides an alternative to currently available antipseudomonal carbapenems (i.e., imipenem, meropenem). It is FDA approved for the treatment of complicated intra-abdominal and urinary tract infections. The NDA application for treatment of nosocomial pneumonia is being reviewed by the FDA.

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Doripenem Monograph

References 1. DoribaxTM (Doripenem) package insert, Ortho-McNeil Pharmaceutical. October 2007. 2. Davies TA, Shang W, Bush K, Flamm RK. Binding of doripenem and comparators to penicillinbinding proteins in Escherichia coli and Pseudomonas aeruginosa. 46th ICAAC, September 27-30, San Francisco, California. 3. Lister PD. Carbapenems in the USA: focus on doripenem. Expert Rev Anti Infect Ther 2007;5:793809. 4. Zhanel GG, Wiebe R, Dilay L, et al. Comparative review of the carbapenems. Drugs 2007;67:10271052. 5. Ge Y et al. In vitro antimicrobial activity of doripenem, a new carbapenem. AAC 2004;4:1384-1396. 6. Mushtaq, Ge Y, and Livermore DM. Comparative activities of doripenem versus isolates, mutants, and transconjugants of Enterobacteriaceae and Acinetobacter spp. with characterized beta-lactamases. AAC 2004;48:1313-1319. 7. Jones RN, Huynh HK, Biedenbach DJ. Activities of doripenem (S-4661) against drug-resistant clinical pathogens. AAC 2004;48:3136-3140. 8. Jones, Huynh HK, Biedenbach DJ. Doripenem (S-4661), a novel carbapenem: comparative activity against contemporary pathogens including bactericidal action and preliminary in vitro methods evaluations. JAC 2004;54:144-154. 9. Wexler HM, Engel AE, Glass D, Li C. In vitro activities of doripenem and comparator agents against anerobic clinical isolates. AAC 2005;49:4413-4417. 10. Fritsche TR, Stilwell MG, Jones RN. Antimicrobial activity of doripenem (S-4661): a global surveillance report (2003). Clin Microbiol Infect 2005;11:974-84. 11. Credito KL, Ednie LM, Appelbaum PC. Comparative anti-anerobic activity of doripenem by MIC and Time-kill analysis. AAC 2007 Oct 15; [Epub ahead of print] 12. Brown SD, Traczewski MM. Comparative in vitro antimicrobial activity of a new carbapenem, doripenem: tentative disc diffusion criteria and quality control. JAC 2005;55:944-949. 13. Kaniga K, Prokocimer P, Llorens L, Friedland I. Prevalence of ESBL and fluoroquinolone-resistant isolates from Phase 3 trials of nosocomial pneumonia and their susceptibility to doripenem. Abstract E265. 47th ICAAC, September 17-20, Chicago, Illinois. 14. Pillar CM, Aranza-Torres MK, Shah D. Sahm DF. Analysis of doripenem activity, relative to other carbapenems, against target Gram-Negative pathogens isolated form specific infection sites. Abstract E262. 47th ICAAC, September 17-20, Chicago, Illinois.

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Doripenem Monograph

15. Ge Y, Wikler MA, Sahm DF, et al. In vitro antimicrobial activity of doripenem, a new carbapenem. AAC:48;1384-1396. 16. Invanz (Ertapenem) package insert, Merck & Co, Inc. December 2007. 17. Primaxin (Imipenem-cilastatin) package insert, Merck & Co, Inc. October 2007 18. Merrem (Meropenem) package insert, AstraZeneca Pharmaceuticals LP, February 2007. 19. Chastre J, Wunderink R, Prokocimer P, et al. Efficacy and safety of doripenem versus imipenem for ventilator-associated pneumonia. Abstract/Poster L-486. 46th ICAAC, September 27-30, San Francisco, California. 20. Mushtaq S, Ge Yigong, Livermore DM. Doripenem versus Pseudomonas aeruginosa In vitro: activity against characterized isolates, mutants, and transconjugants and resistance selection potential AAC 2004;48:3086-3092. 21. Sakyo S. Tomita H, Tanimoto K, et al. Potency of carbapenems for the prevention of carbapenemresistant mutants of Pseudomonas aeruginosa. The high potency of a new carbapenem doripenem. 22. Solomkin J. Umeh O, Jiang J,Kaniga K, Friedland I. Doripenem versus meropenem with an option for oral step-down therapy in the treatment of complicated intra-abdominal infections. Abstract/Poster L487. 47th ICAAC, September 17-20, Chicago, Illinois. 23. Malafaia O, Umeh O, Jiang. Doripenem versus meropenem for the treatment of complicated intraabdominal infections. Abstract/poster L-1564b. 46th ICAAC, September 27-30, San Francisco, California. 24. Lucasti C, Jasovich A, Umeh O, Jiang J, Kaniga K. Treatment of complicated intra-abdominal infections: doripenem versus meropenem. Abstract/poster P834. ECCMID 2007. 25. Naber K, Redman R, Llorens L, Kaniga K. Intravenous therapy with doripenem versus levofloxacin with an option for oral step-down therapy in the treatment of complicated urinary tract infection and pyelonephritis. ECCMID 2007. 26. Rea-Neto et al. Doripenem for the treatment of nosocomial pneumonia. Abstract L-731. 47th ICAAC, September 17-20, Chicago, Illinois. . 27. Data on File, Ortho-McNeil Pharmaceutical. 28. Horiuchi M, Kimura M, Tokumura M et al. Absence of convulsive liability of doripenem, a new carbapenem antibiotic, in comparison with -lactam antibiotics. Toxicology 2006;222:114-124. 29. Nakajima Y, Mizobuchi M, Nakamura M, et al. Mechanism of the drug interaction between valproic acid and carbapenem antibiotics in monkeys and rats. Drug Metab Dispos 2004;32:1383-1391. Prepared 1/08 by Melinda Neuhauser, PharmD_______________________________________

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