Summary Basis of Decision for Doribax
Review decision
The Summary Basis of Decision explains why the product was approved for sale in Canada. The document includes regulatory, safety, effectiveness and quality (in terms of chemistry and manufacturing) considerations.
Product type:
Doribax
Doripenem monohydrate, 500 mg/vial, Powder for solution, Intravenous (IV)
Janssen-Ortho Inc.
Submission control no: 113640
Date issued: 2010-01-07
Foreword
Health Canada's Summary Basis of Decision (SBD) documents outline the scientific and regulatory considerations that factor into Health Canada regulatory decisions related to drugs and medical devices. SBDs are written in technical language for stakeholders interested in product-specific Health Canada decisions, and are a direct reflection of observations detailed within the evaluation reports. As such, SBDs are intended to complement and not duplicate information provided within the Product Monograph.
Readers are encouraged to consult the 'Reader's Guide to the Summary Basis of Decision - Drugs' to assist with interpretation of terms and acronyms referred to herein. In addition, a brief overview of the drug submission review process is provided in the Fact Sheet entitled 'How Drugs are Reviewed in Canada'. This Fact Sheet describes the factors considered by Health Canada during the review and authorization process of a drug submission. Readers should also consult the 'Summary Basis of Decision Initiative - Frequently Asked Questions' document.
The SBD reflects the information available to Health Canada regulators at the time a decision has been rendered. Subsequent submissions reviewed for additional uses will not be captured under Phase I of the SBD implementation strategy. For up-to-date information on a particular product, readers should refer to the most recent Product Monograph for a product. Health Canada provides information related to post-market warnings or advisories as a result of adverse events (AE).
For further information on a particular product, readers may also access websites of other regulatory jurisdictions. The information received in support of a Canadian drug submission may not be identical to that received by other jurisdictions.
Other Policies and Guidance
Readers should consult the Health Canada website for other drug policies and guidance documents. In particular, readers may wish to refer to the 'Management of Drug Submissions Guidance'.
1 Product and submission information
Brand name:
Manufacturer/sponsor:
Medicinal ingredient:
International non-proprietary Name:
Strength:
Dosage form:
Route of administration:
Drug identification number(DIN):
- 02332906
Therapeutic Classification:
Non-medicinal ingredients:
Submission type and control no:
Date of Submission:
Date of authorization:
* All trademark rights used under license.
2 Notice of decision
On September 2, 2009, Health Canada issued a Notice of Compliance to Janssen-Ortho Inc. for the drug product Doribax.
Doribax contains the medicinal ingredient doripenem, as doripenem monohydrate, which is an antibacterial agent.
- Doribax is indicated for the treatment of adults (18 years and older) with the following infections when caused by susceptible strains of the designated microorganisms:
- Nosocomial Pneumonia, including Ventilator-Associated Pneumonia caused by Staphylococcus aureus (methicillin-susceptible strains only), Streptococcus pneumoniae, Enterobacter cloacae, Escherichia coli, Klebsiella pneumoniae, Haemophilus influenzae and Pseudomonas aeruginosa.
- Complicated Intra-Abdominal Infections caused by Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa, Bacteroides fragilis, Bacteroides thetaiotaomicron, Bacteroides caccae, Bacteroides uniformis, Bacteroides vulgatus, Streptococcus intermedius, Streptococcus constellatus and Peptostreptococcus micros.
- Complicated Urinary Tract Infections, including Pyelonephritis caused by Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa, Proteus mirabilis, and Acinetobacter baumannii.
Doripenem is a synthetic, beta-lactam carbapenem antibacterial agent with in vitro antibacterial activity against aerobic and anaerobic gram-positive and gram-negative bacteria. Doripenem exerts its bactericidal activity by inhibiting bacterial cell wall biosynthesis.
The market authorization was based on quality, non-clinical, and clinical information submitted. Two pivotal Phase III non-inferiority studies were submitted to support each indication. Doribax demonstrated non-inferiority to the appropriate comparative drugs used for each indication.
Doribax (500 mg/vial, doripenem, as doripenem monohydrate) is presented as a powder for solution for intravenous infusion. The recommended dose of Doribax for patients aged 18 years and older is 500 mg administered every 8 hours by one-hour intravenous infusion. For patients with late onset Ventilator-Associated Pneumonia (>5 days ventilation) who are at risk for infection with less susceptible pathogens, four-hour infusions are recommended. The Product Monograph provides the recommended dosage, infusion time, and duration by indication. Dosage adjustments are required for patients with moderate to severe renal impairment. Dosing guidelines are available in the Product Monograph.
Doribax is contraindicated in patients with known hypersensitivity to doripenem monohydrate or to other drugs in the same class or in patients who have demonstrated anaphylactic reactions to beta-lactams. Doribax should be administered under the conditions stated in the Product Monograph taking into consideration the potential risks associated with the administration of this drug product. Detailed conditions for the use of Doribax are described in the Product Monograph.
Based on the Health Canada review of data on quality, safety, and efficacy, Health Canada considers that the benefit/risk profile of Doribax is favourable for the indications stated above.
3 Scientific and Regulatory Basis for Decision
A New Drug Submission (NDS) for Doribax (doripenem monohydrate) was filed with Health Canada on September 24, 2007. Upon review, Health Canada concluded that the data and analyses as presented did not support Doribax as monotherapy in the treatment of nosocomial pneumonia, including ventilator-associated pneumonia. On July 15, 2008, the submission received a Notice of Deficiency (NOD). A response to the NOD was received on October 9, 2008. The issues pertaining to the data to support the indication for nosocomial pneumonia, including ventilator-associated pneumonia were satisfactorily resolved. A Notice of Compliance (NOC) was subsequently issued for Doribax on September 2, 2009.
3.1 Quality Basis for Decision
3.1.1 Drug Substance (Medicinal Ingredient)
General Information
Doripenem monohydrate, the medicinal ingredient of Doribax, is an antibacterial agent. Doripenem is a synthetic, beta-lactam carbapenem antibacterial agent with in vitro antibacterial activity against aerobic and anaerobic gram-positive and gram-negative bacteria. Doripenem exerts its bactericidal activity by inhibiting bacterial cell wall biosynthesis.
Manufacturing Process and Process Controls
The drug substance is synthetically derived.
The manufacturing process is considered to be adequately controlled within justified limits.
Characterization
The structure of doripenem monohydrate has been adequately elucidated and the representative spectra have been provided. The spectroscopic analysis confirms the proposed drug substance structure.
Impurities and degradation products arising from manufacturing and/or storage were reported and characterized. The proposed limits are considered adequately qualified [that is (i.e.) within International Conference on Harmonisation (ICH) limits and/or qualified from toxicological studies]. Control of the impurities and degradation products is therefore considered acceptable.
Control of Drug Substance
Copies of the analytical methods and, where appropriate, validation reports were provided and are considered satisfactory for all analytical procedures used for release and stability testing of doripenem monohydrate.
Batch analysis results were reviewed and all results comply with the specifications and demonstrate consistent quality of the batches produced.
The drug substance packaging is considered acceptable.
Stability
Based on the long-term, real-time, accelerated, and stress stability data submitted, the proposed re-test period and shelf-life storage conditions for the drug substance were supported and are considered to be satisfactory.
3.1.2 Drug Product
Description and Composition
Doribax (the drug product) consists of sterile drug substance (doripenem monohydrate) aseptically filled into a container closure without any excipient or further processing at the manufacturing site. Doribax is supplied as sterile, single-use, clear, 20 mL glass vials containing 500 mg (on an anhydrous basis) of sterile doripenem powder. The drug substance, doripenem monohydrate is a white to slightly yellowish, off-white crystalline powder.
Pharmaceutical Development
Changes to the manufacturing process and formulation made throughout the pharmaceutical development are considered acceptable upon review.
Manufacturing Process and Process Controls
The method of manufacturing is considered acceptable and the process is considered adequately controlled within justified limits.
Control of Drug Product
Doribax is tested to verify that its identity, appearance, assay, chromatographic purity, water content, weight, particulates, bacterial endotoxins, and sterility are within acceptance criteria. The test specifications and analytical methods are considered acceptable; the shelf-life and the release limits, for individual and total degradation products, are within acceptable limits.
Validation studies have been completed for both the production of the finished product and sterility assurance. No deficiencies were identified.
The test specifications are considered acceptable to control the drug product, and the impurity limits were set according to ICH recommendations.
Data from final batch analyses were reviewed and are considered to be acceptable according to the specifications of the drug product.
Stability
Based on the long-term and accelerated stability data submitted, the proposed shelf-life of 36 months is considered acceptable for Doribax when stored at 15°C - 30°C.
Adequate data were provided in the drug submission to qualify the packaging materials.
3.1.3 Facilities and Equipment
The design, operations, and controls of the facility and equipment that are involved in the production of Doribax are considered suitable for the activities and products manufactured. The site is rated Good Manufacturing Practices (GMP) compliant for the manufacturing activities.
3.1.4 Adventitious Agents Safety Evaluation
No excipients of animal or human origin are used in manufacture of Doribax; therefore, there is no risk of bovine spongiform encephalopathy (BSE)/ Transmissible Spongiform Encephalopathy (TSE).
3.1.5 Conclusion
The Chemistry and Manufacturing information submitted for Doribax has demonstrated that the drug substance and drug product can be consistently manufactured to meet the approved specifications. Proper development and validation studies were conducted, and adequate controls are in place for the commercial processes.
3.2 Non-Clinical Basis for Decision
3.2.1 Microbiology
The microbiology of doripenem was comprehensively characterized in the submission and review process, comprising of studies and analysis of in vitro activity (surveillance, clinical trial data and effects of culture conditions), mechanism of action, synergy, antagonism, resistance development, in vivo activity, pharmacokinetic-pharmacodynamics, target attainment analysis, susceptibility interpretive criteria development, quality control and clinical trial microbiology methods. Also, solicited information regarding issues raised by other regulatory agencies was checked. The key features and data relating to doripenem's microbiology are listed in the Product Monograph and are considered acceptable.
Doripenem is a synthetic broad spectrum beta-lactam carbapenem antibacterial agent with in vitro antibacterial activity against aerobic and anaerobic gram-positive and gram-negative bacteria. Doripenem shares the bactericidal mode of action of other beta-lactams by targeting penicillin-binding proteins (PBPs) to inhibit the biosynthesis of the bacterial wall, and has a high affinity for multiple major PBPs of susceptible species. The pharmacokinetic-pharmacodynamic index (PK/PD index) that best correlated with efficacy in a neutropenic murine thigh infection model was established to be the time (% of the dosing interval) that the plasma concentration of free doripenem exceeds the minimum inhibitory concentration of the infecting organism (%ƒT>MIC), similar to other beta-lactam antimicrobial agents.
Dilution testing interpretive criteria were evaluated based on data from the pivotal clinical studies, the PK-PD target, target attainment analysis and minimum inhibitory concentration (MIC) frequency distributions, since final interpretive criteria were pending from the Clinical Laboratory Standards Institute (CLSI). The clinical study data for the three proposed indications comprised of six Phase III studies, of which 5/6 used a 1-hour infusion and 1/6 used a 4-hour infusion (Study Dori-10). Study Dori-10 had low numbers of microbiologically evaluable baseline isolates with MICs of 2 and 4 µg/mL, so the predicted effectiveness of a 4-hour infusion had limited clinical testing. The PK-PD targets used in simulations (25%, 30%, 35%) did not cover the higher ranges of PK-PD index (38 to 54%ƒT>MIC) resulting from the neutropenic murine thigh infection studies, which also did not include representation for Enterococcus faecalis and Acinetobacter baumannii proposed pathogens with substantially higher MIC frequency distributions. Investigators in recent literature have used the upper PK-PD targets (maximal bactericidal) for target attainment analysis (40% for doripenem). The probability of target attainment interpreted to be supportive of efficacy ranges 80 to 90% in literature, with limited confirmatory clinical data, and little consensus. Based on human pharmacokinetic modeling and simulations, extending the infusion time to 4 hours generally increased the %ƒT>MIC for the recommended dose. The %ƒT>MIC was highly dependent on renal function, as doripenem undergoes rapid renal excretion, and for pathogens having MIC of 2 to 4 µg/mL, target attainment is not always predicted, even with a 4-hour infusion. These data limitations were the basis for requesting doripenem susceptibility interpretive criteria to be revised to ≤1 µg/mL from the proposed ≤4 µg/mL.
3.2.2 Pharmacodynamics
A core battery of safety pharmacology studies were conducted to characterize the non-microbiological actions of doripenem. In rats, doripenem did not exhibit any central nervous system (CNS) or respiratory effects up to a dose of 300 mg/kg administered intravenously. In dogs, no cardiovascular effects (heart rate, blood pressure, and electrocardiogram) were reported at a dose level of 100 mg/kg, a doripenem plasma concentration 20x higher than the therapeutic concentration. Doripenem had no effects on HERG (the Human Ether-à-go-go Related Gene) currents in cells expressing HERG channels, and no effects on action potential in dog Purkinje fibers. Doripenem also showed no effects on renal function.
Beta-lactam antibiotics are known to induce convulsions in humans and animals. It has been suggested that this effect may be due to inhibition of gamma aminobutyric acid (GABA) mediated inhibitory transmission. Doripenem has a lower affinity for GABA receptor in mouse synaptic membranes as compared to imipenem, meropenem, panipenem and cefazolin. Additional animal studies demonstrated that doripenem had a lower potential to induce seizures or to enhance seizures induced by external stimuli, compared to drugs like imipenem or meropenem.
3.2.3 Pharmacokinetics
The non-clinical pharmacokinetic (PK) studies with doripenem have been conducted in mice, rats, rabbits, dogs, and monkeys. The lyophilized form of doripenem was the drug product used in the majority of the non-clinical absorption, distribution, metabolism, and excretion studies, before crystalline doripenem monohydrate was developed. The physical form of doripenem (lyophilized or crystalline powder) is not a concern as the drug product was formulated for IV injection by dissolution in physiological saline.
Absorption
In all the species studied, the increases in maximum plasma concentration (Cmax) and the area under the concentration-time curve (AUC) were dose-proportional. The plasma half-life associated with the terminal slope (t1/2) of doripenem in all tested species was relatively short, amounting to 1 hour or less.
Distribution
Tissue distribution of doripenem was rapid but limited, in conformity with the low volume of distribution. In mice, the tissue concentration was highest in the kidneys, followed by the liver, lungs, heart, and spleen. In rats, the tissue distribution of doripenem was reported in the previously mentioned tissues, as well as in the bone, trachea, and skin. Doripenem was transferred to the foetus when administered to pregnant rats but the concentrations were low.
The protein-binding rates of doripenem in various animal plasmas were 10.2% to 35% for the mice, rats, rabbits, and dogs.
Metabolism
In pooled human liver microsomes, no metabolism of doripenem (100 μM) could be detected, cytochrome P450 (CYP)-mediated or otherwise, in the presence or absence of NADPH (nicotinamide adenine dinucleotide phosphate).
A study in liver, kidney, and lung homogenates from rats, dogs, and monkeys suggests that dehydropeptidase-I (DHP-I) is the enzyme responsible for the hydrolysis of doripenem to its carboxylic acid metabolite (doripenem-M-1).
In rats, doripenem was rapidly metabolized and plasma levels of the doripenem-M-1 metabolite were equal to those of the parent compound within five minutes. In contrast, this metabolism was far less extensive in dogs and monkeys. In humans, the extent of metabolism of doripenem to doripenem dicarboxylic acid was more similar to that of the dog and monkey than the rat.
Excretion
Doripenem was primarily excreted in the urine of rats, dogs, and monkeys. Excretion of doripenem into the bile was minimal. A study with lactating rats reported that doripenem was excreted in milk.
3.2.4 Toxicology
Single-Dose Toxicity
The approximate lethal dose of doripenem in dogs and rats was >2000 mg/kg. The primary target organs of toxicity were the kidney and gastrointestinal tract.
Repeat-Dose Toxicity
In the one- and three-month toxicity studies in rats, an increase in cecal weight and/or dilatation of cecum was observed at doses of 100 mg/kg/day or higher without any evident histologic changes in the gastrointestinal tract. These changes have been attributed to changes in the intestinal flora caused by the antimicrobial effects of doripenem. In the one- and three-month toxicity studies in dogs, no gastrointestinal effects were observed in the 100 mg/kg/day group.
In one-month toxicity studies in rats and dogs, doripenem administration led to an increase in kidney weight. This was associated with vacuolization of the renal proximal tubular epithelium. Single-dose toxicity in rabbits indicated that the high dose of doripenem (400 mg/kg and higher), resulted in an increase in serum urea nitrogen and creatine, necrosis of the renal cortical tubular epithelium and dilatation of the renal cortical tubules. However, with lower doses of doripenem (200 mg/kg) in the repeat-dose studies, these changes were not observed. It is concluded that the renal toxicity of doripenem is comparable to that of meropenem but weaker than that of biapenem. There was evidence of immunostimulation with splenomegaly and hypertrophy of germinal centers in rats and dogs in the repeat-dose toxicity studies. The hypertrophy of the germinal center of the white pulp was mild and reversible and has been attributed to an immune response to repeated administration of doripenem which may be secondary to either the weak antigenicity of the drug or a response to alterations in gut microflora. The changes in spleen and germinal centers are not unique to doripenem, but are also known to be associated with meropenem and impipenem/cilastin. The hypertrophy of the germinal center of the white pulp is considered as a normal physiologic response and is a mild and reversible condition that resolves and lacks toxicologic significance.
Genotoxicity/ Mutagenicity
Doripenem is not genotoxic and did not induce any genetic mutation or chromosomal anomalies.
Carcinogenicity
Carcinogenicity studies have not been performed because the period of use in the clinic is expected to be relatively short, not more than 14 days.
Reproductive and Developmental Toxicity
The reproductive toxicity studies did not demonstrate any adverse effects of doripenem on pregnancy or the development of the embryo or foetus. No teratogenic effects have been observed with doripenem.
Antigenicity Studies
In the antigenicity studies in mice and guinea pigs, no immunologic reactivity was produced by immunization with doripenem alone. However, sensitizing antigenicity of doripenem was observed in combination with adjuvant in both animal species and was comparable to imipenem. The weak antigenicity of doripenem observed in these studies suggests a possible allergic reaction in some patients in clinical studies.
3.2.5 Conclusion
The non-clinical studies for this drug submission are considered suitable. Doripenem has demonstrated in vitro and in vivo activity against the microorganisms listed in the indication. The safety pharmacology studies and toxicity data support its safe use in humans as described in the labelling. There are no pharmacological/toxicological issues within the submission which preclude the intended clinical usage for doripenem.
3.3 Clinical basis for decision
3.3.1 Pharmacodynamics
A thorough QT/QTc pharmacodynamic (PD) study was performed to assess the effects of doripenem (therapeutic and supratherapeutic doses) on the QT/QTc interval duration in healthy adults. The effect of doripenem on QTc prolongation is considered negative.
3.3.2 Pharmacokinetics
Absorption
Doripenem pharmacokinetics demonstrated dose-proportionality for doses ranging from 125 mg to 1000 mg in healthy adults. Consistent with the short terminal elimination half-life of doripenem, steady-state was attained by the second dose when administered every 8 hours. Doripenem did not accumulate after multiple-dose administration in healthy subjects.
Distribution
The in vitro protein binding of doripenem to human plasma proteins was minimal (8.1%). The majority of the drug remains unbound in plasma and therefore potentially available for tissue and fluid penetration. Doripenem penetrates well into various body tissues and fluids, generally reaching the concentrations needed to inhibit most susceptible bacteria. The volume of distribution of doripenem in healthy subjects is approximately equal to the extracellular fluid volume. This suggests that intracellular penetration of doripenem does not occur to an appreciable extent.
Metabolism
The major metabolic pathway was the cleavage of the beta-lactam ring of doripenem towards its dicarboxylic acid metabolite, doripenem-M-1. Subsequent metabolism of doripenem-M-1 resulted in the formation of the taurine and glycine conjugates of doripenem dicarboxylic acid. Doripenem-M-1 lacks microbiological activity. The metabolism of doripenem was characterized in healthy men after a single 500 mg radiolabelled dose of doripenem. Unchanged doripenem accounted for the majority (81%) of circulating dose-related radioactivity in plasma, and doripenem-M-1 comprised about 13% of the total radioactivity in plasma.
Excretion
Doripenem was excreted mainly unchanged in urine. Approximately 70% and 15% of the administered dose was recovered in urine as doripenem and doripenem-M-1, respectively. Doripenem renal clearance exceeds the glomerular filtration rate in humans indicating that both glomerular filtration and active tubular secretion are involved in its renal excretion.
Drug Interactions
During concurrent administration of doripenem and valproic acid, serum valproic acid levels fell below the therapeutic range. Reports also showed that concomitant administration of probenecid and doripenem resulted in increased drug exposure of doripenem. The pharmacokinetic interactions of doripenem with valproate and probenecid have been captured in the Product Monograph.
Doripenem is not metabolized in the liver and has little propensity for cytochrome P450-mediated drug interactions.
Special Populations
An increase in drug exposure was reported in elderly subjects compared to younger subjects however, these differences were mainly attributed to age-related changes in renal function. The increase in exposure to doripenem by the elderly population was similar to what was reported for subjects with mild renal impairment, for which no dosage adjustments are recommended. No significant effect of gender on the PK of doripenem, were observed in the population PK analysis. The systemic exposure to doripenem significantly increased in subjects with moderate and severe renal impairment therefore dosage adjustments are required for this population. The pharmacokinetics of doripenem was not studied in subjects with hepatic impairment.
3.3.3 Clinical Efficacy
Phase III non-inferiority studies were submitted to support the use of Doribax for the treatment of nosocomial pneumonia, including ventilator-associated pneumonia; complicated intra-abdominal infections; and complicated urinary tract infections, including pyelonephritis.
Nosocomial Pneumonia Including Ventilator-Associated Pneumonia
The two Phase III non-inferiority studies (DORI-09 and DORI-10) conducted to support the indication for nosocomial pneumonia (NP), including ventilator-associated pneumonia (VAP), were open-label (with in-house blinding), randomized, multicentre, controlled studies, where the efficacy of Doribax therapy was compared to that of piperacillin/tazobactam (DORI-09) and imipenem (DORI-10). These are considered to be appropriate comparator drugs for this indication. A total of 444 patients were enrolled in DORI-09 and 525 patients in DORI-10. In Study DORI-09, a 1-hour infusion of Doribax 500 mg (q8h) was compared to piperacillin/tazobactam [4.5 g infused over 30 minutes every 6 hours (q6h)] in subjects with NP either not associated with mechanical ventilation (non-VAP) or with early-onset VAP (<5 days of mechanical ventilation). In Study DORI-10, a 4-hour infusion of the same dosage of Doribax (q8h) was compared to imipenem [500 mg (infused over 30 minutes q6h) or 1 g (infused over 1 hour q8h)] in subjects with VAP, including those at higher risk for less susceptible pathogens (such as subjects with late-onset VAP). As for other carbapenems, in vivo efficacy of Doribax is most closely related to %T >MIC, hence the 4-hour infusion duration for the treatment of less susceptible pathogens.
The primary analysis set was clinically evaluable patients at test of cure (TOC), which is appropriate. Both studies independently met their non-inferiority margin for the primary endpoint: DORI-09 81.3% (Doribax) versus 79.8% (piperacillin/tazobactam) with a 2-sided 95% confidence interval (CI) of -9.1% to 12.1%; DORI-10 68.3% (Doribax) versus 64.8% (imipenem) (95% CI -9.1; 16.1).
Therapy for NP is generally initiated empirically, before culture results are known. In these studies, adjunctive therapy for suspected methicillin-resistant Staphylococcus aureus (with vancomycin) was allowed at the discretion of the investigator. Regarding adjunctive therapy for suspected Pseudomonas aeruginosa, initial amikacin therapy was required (with some allowed exceptions) in DORI-09; and 78% of Doribax-treated patients and 85% piperacillin/tazobactam-treated patients in the DORI-09 clinically evaluable patients at TOC analysis set received adjunctive antipseudomonal therapy. Only 29 clinically evaluable patients in the Doribax arm of DORI-09 did not receive any adjunctive antipseudomonal coverage, while 105 clinically-evaluable patients in the Doribax arm received at least one dose of anti-pseudomonal adjunctive therapy. In DORI-10, where adjunctive therapy was optional, only 20% and 25% of Doribax- and imipenem-treated subjects, respectively, received adjunctive antipseudomonal therapy.
Study data from DORI-09 and DORI-10 could not be pooled due to variations in the study design. However, after resolution of the issues raised in the NOD of July 2008, it can be concluded that each study independently supports the indication as requested, with data (clinical trial data and PK/PD modelling) provided in support of both the one-hour and four-hour infusion durations. Clinical practice dictates in which situations a drug such as Doribax would be used as monotherapy versus as combination therapy in the treatment of a serious infection such as nosocomial pneumonia with /without ventilator associated pneumonia. This cannot be labelled for in the Product Monograph, and is at the discretion of the treating physician.
Nosocomial pneumonia, when caused by susceptible strains of Staphylococcus aureus (methicillin-susceptible strains only), Streptococcus pneumoniae, Enterobacter cloacae, Escherichia coli, Klebsiella pneumoniae, Haemophilus influenzae or Pseudomonas aeruginosa, may be treated with Doribax 500 mg infused every eight hours over a period of one or four hours. One-hour infusions are generally recommended for treatment of patients with nosocomial pneumonia. For patients with late onset of ventilator-associated pneumonia (>5 days ventilation) who are at risk for infection with less susceptible pathogens, four-hour infusions are recommended. Treatment duration is 7 to 14 days.
Complicated Intra-Abdominal Infections
Two pivotal, Phase III, multicentre, randomized, double-blind, non-inferiority studies (DORI-07 and DORI-08) were submitted to support the indication for complicated intra-abdominal infections (cIAI). Both studies were identical in study design. Patients were treated with 500 mg doripenem infused over 1 hour q8h or 1 g of meropenem infused over 3-5 minutes q8h, for 5 to 14 days. Both regimens allowed for a switch to oral amoxicillin/clavulanate therapy (875/125 mg twice daily) after 9 or more doses of IV study drug therapy if protocol-specified criteria indicating sufficient clinical improvement were met. A total of 471 patients were enrolled in DORI-07 and 475 patients in DORI-08. Both studies enrolled patients with localized or generalized peritonitis secondary to appendix perforation, small or large bowel perforation, cholecystitis, or parenchymal (e.g., liver or spleen) abscesses. The primary efficacy endpoint was the clinical cure rate at the TOC visit in the microbiologically evaluable (ME) patients with cIAI.
In DORI-07, the clinical cure rate in the ME with cIAI at TOC analysis set was 85.9% in the Doribax arm compared with 85.3% in the meropenem arm. The difference between the clinical cure rates (Doribax minus meropenem) was 0.6% with a 2-sided 95% CI of -7.7% to 9.0% indicating that Doribax was non-inferior to meropenem in the treatment of IAI. In DORI-08, the clinical cure rates in the ME at TOC analysis were 83.3% in the Doribax arm and 83.0% in the meropenem arm with a difference between the clinical cure rates (Doribax minus meropenem) of 0.3%, with a 2-sided 95% CI of -8.6% to 9.2% indicating that Doribax was non-inferior to meropenem in the treatment of IAI.
From the pooled efficacy data of DORI-7 and DORI-08, clinical cure rates in the ME at TOC showed 84.6% for the Doribax arm and 84.1% for the meropenem arm. At the TOC visit, the per-patient microbiological cure rates were similar between the two treatment arms, 84.3% (Doribax) vs. 84.5% (meropenem). Microbiological cure rates were noted for the following pathogens: Escherichia coli, 189/216-87.5%; Klebsiella pneumoniae, 25/32-78.1%; Pseudomonas aeruginosa, 34/40-85%; Bacteroides fragilis, 56/67-83.6%; Bacteroides thetaiotaomicron, 30/34-88.2%; Bacteroides caccae, 23/25-92.0%; Streptococcus intermedius, 30/36-83.3%; Bacteroides uniformis, 19/22-86.4%; Bacteroides vulgatus, 11/11-100%; Streptococcus constellatus, 9/10-90%; Peptostreptococcus micros, 11/13-84.6%; Enterococcus faecalis, 16/20-80%. The use of Doribax is not recommended for treatment of cIAIs caused by Enterococcus faecalis because of the MIC level, the limited North American experience, the success rate of 60% eradication in the microbiological modified intent-to-treat population, and the 75% eradication in the ME.
Complicated Urinary Tract Infections, Including Pyelonephritis
Three studies (DORI-03, DORI-05, and DORI-06) were submitted to support the use of Doribax for complicated urinary tract infections (cUTIs) including pyelonephritis. DORI-03 was not regarded as a "pivotal" study for review purposes.
DORI-05 was a Phase III, randomized, double-blind study comparing Doribax with levofloxacin for the treatment of patients aged 18 years or older with cUTIs, including pyelonephritis. This study was designed to establish that Doribax (at a dose of 500 mg infused IV over 1 hour q8h) was not inferior to levofloxacin (at a dose of 250 mg infused IV over 1 hour q24h) as assessed by the microbiological cure rate at the TOC visit (5 to 11 days after the last dose of study drug therapy) in patients identified as being ME at TOC. Patients were allowed (but were not required) to be switched to oral antibiotic therapy (levofloxacin) to complete a 10-day (IV plus oral) treatment course. Increasing the dose of levofloxacin to 500 mg q24h was permitted only for patients in whom bacteremia was verified and they may have received study drug therapy (IV plus oral) for a total of 10 to 14 days. Microbiological cure rates at the TOC visit among patients in the ME at TOC analysis set were 82.1% and 83.4% in the Doribax versus levofloxacin treatment arms, respectively. Statistically, Doribax met the protocol definition of non-inferiority.
Study DORI-06 was a Phase III, multicentre, prospective, open-label study of Doribax infusions (500 mg q8h) in the treatment of cUTI in adults. This study was designed to provide an independent confirmation of the response rate for Doribax observed in DORI-05. The microbiological cure rate in the final ME at TOC analysis set was 83.6% in the Doribax treatment arm compared with 83.4% in the DORI-05 levofloxacin treatment arm. Again, Doribax was non-inferior to levofloxacin in the treatment of cUTIs.
The efficacy data from DORI-05 and DORI-06 were pooled. The inclusion/exclusion and evaluability criteria were identical for the two studies, and both studies enrolled similar types of patients and employed similar methodologies. For both studies, similar results at TOC for the ME were noted for the Doribax treatment arms. The per baseline uropathogen eradication rates in the ME at TOC analysis set at the TOC visit for the pooled data from DORI-05 and DORI-06 are noted only for those pathogens isolated from at least 10 Doribax-treated patients. Doripenem 500 mg q8h was effective in eradicating: Escherichia coli 313/357 (87.7%), Klebsiella pneumoniae 26/33 (78.8%), Pseudomonas aeruginosa 19/27 (70.4%), Proteus mirabilis 22/30 (73.3%), and Acinetobacter baumannii 8/10 (80%). Doribax 500 mg q8h was less effective in eradicating: Enterococcus faecalis 8/12 (66.7%),and Enterobacter cloacae 18/28 (64.3%).
3.3.4 Clinical Safety
A total of 1, 817 subjects were evaluated for safety and received the standard dose (500 mg) of Doribax in the Phase II and Phase III studies included in the original drug submission for Doribax. The data obtained provides a substantial database from which to draw conclusions regarding the safety of doripenem. Postmarketing data from Europe and the United States were also available. Furthermore, there was a large experience in a Japanese population, albeit frequently using a lower dose of doripenem.
Detailed safety evaluations from numerous studies demonstrated similarity of doripenem compared to the comparator agents (i.e., levofloxacin, meropenem, piperacillin/tazobactam, and imipenem), which have known safety profiles and a positive benefit/risk ratio for named indications. Adverse events (AEs) identified in the Phase II and Phase III studies were generally similar to those associated with agents in the carbapenem class. These were generally mild to moderate in severity, and reversible. Doripenem may have a greater propensity to cause skin rash than the other carbapenems. The most common AEs in patients treated with Doribax were diarrhoea, headache, phlebitis, nausea, vomiting, and rash. Elevations in serum hepatic enzymes were also noted. Increases in liver enzymes have been associated with beta-lactam antibiotics.
The mortality rate was low in the complicated urinary tract infection studies and complicated intra-abdominal infection studies, and at the lower end of the range reported in literature in the nosocomial pneumonia studies. No deaths were reported as being related to Doribax therapy. Drug-related discontinuations occurred in 1.2% of the patients in the Phase III studies.
In patients with severe or moderate renal impairment, adjustment of the dose of Doribax is required. Doribax is not recommended for patients with a creatinine clearance of ≤10 mL/min or patients on any type of dialysis.
Patients with seizure disorders controlled with valproic acid or sodium valproate may be at an increased risk for breakthrough seizures when treated with Doribax concomitantly.
Post-market AEs included: neutropenia, anaphylaxis, toxic epidermal necrolysis, and Stevens-Johnson syndrome. The following treatment-emergent AEs (known to occur with beta-lactams including carbapenems) were also reported: interstitial pneumonia, agranulocytosis, leukopenia, and seizure. Hemolytic anemia and pancytopenia have been reported during treatment with carbapenems. The AEs seen in the clinical studies and in the post-marketing period have been labelled appropriately in the Product Monograph.
3.4 Benefit/Risk Assessment and Recommendation
3.4.1 Benefit/Risk Assessment
Doribax is a broad-spectrum antibacterial drug proven statistically to be non-inferior to comparators in the treatment of nosocomial pneumonia, including ventilator-associated pneumonia; complicated intra-abdominal infections; and complicated urinary tract infections including pyelonephritis. The safety profile is similar to the comparators chosen. The overall risks are similar to those of widely-used standard therapies. Overall, the benefit to risk profile is favourable and supports the use of Doribax for the proposed indications.
3.4.2 Recommendation
Based on the Health Canada review of data on quality, safety and efficacy, Health Canada considers that the benefit/risk profile of Doribax is favourable for the treatment of adults (18 years and older) with the following infections when caused by susceptible strains of the designated microorganisms:
- Nosocomial Pneumonia, Including Ventilator-Associated Pneumonia caused by Staphylococcus aureus (methicillin-susceptible strains only), Streptococcus pneumoniae, Enterobacter cloacae, Escherichia coli, Klebsiella pneumoniae, Haemophilus influenzae and Pseudomonas aeruginosa.
- Complicated Intra-Abdominal Infectionscaused by Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa, Bacteroides fragilis, Bacteroides thetaiotaomicron, Bacteroides caccae, Bacteroides uniformis, Bacteroides vulgatus, Streptococcus intermedius, Streptococcus constellatus and Peptostreptococcus micros.
- Complicated Urinary Tract Infections, Including Pyelonephritis caused by Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa, Proteus mirabilis, and Acinetobacter baumannii.
The NDS complies with the requirements of sections C.08.002 and C.08.005.1 and therefore Health Canada has granted the NOC pursuant to section C.08.004 of the Food and Drug Regulations.
4 Submission Milestones
Submission Milestones: Doribax
| Submission Milestone | Date |
|---|---|
| Submission filed: | 2007-09-24 |
| Screening 1 | |
| Screening Acceptance Letter issued: | 2007-11-14 |
| Review 1 | |
| Quality Evaluation complete: | 2008-07-09 |
| Notice of Deficiency issued by Director General (efficacy issues): | 2008-07-15 |
| Response filed: | 2008-10-09 |
| Screening 2 | |
| Screening Acceptance Letter issued: | 2008-11-06 |
| Review 2 | |
| Quality Evaluation complete: | 2009-08-31 |
| Clinical Evaluation complete: | 2009-08-20 |
| Labelling Review complete: | 2009-08-31 |
| Notice of Compliance issued by Director General: | 2009-09-02 |