Summary Basis of Decision for Eraxis
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:
Eraxis
Anidulafungin, 100 mg/vial, powder for solution, Intravenous
Pfizer Canada Inc.
Submission control no: 110202
Date issued: 2008-04-16
Health Products and Food Branch
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Health Products and Food Branch
Également disponible en français sous le titre : Sommaire des motifs de décision (SMD), PrERAXIS*, anidulafungine, 100 mg/flacon, poudre pour solution,
Pfizer Canada Inc., No de contrôle de la présentation 110202
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):
- 02302160
Therapeutic Classification:
Non-medicinal ingredients:
Diluent: Dehydrated alcohol and Water for Injection
Submission type and control no:
Date of Submission:
Date of authorization:
™ Vicuron Pharmaceuticals Inc.
Pfizer Canada Inc., Licensee
2 Notice of decision
On November 14, 2007, Health Canada issued a Notice of Compliance to Pfizer Canada Inc. for the drug product, Eraxis.
Eraxis contains the medicinal ingredient anidulafungin which is an antifungal agent.
Eraxis is indicated for treatment of invasive candidiasis/candidemia in adult non-neutropenic patients. Anidulafungin selectively inhibits 1,3-β-D glucan synthase, an enzyme present in fungal, but not mammalian cells. This results in inhibition of the formation of 1,3-b-D-glucan, an essential component of the fungal cell wall.
The market authorization was based on quality, non-clinical, and clinical information submitted. In a single, Phase III active control study, Eraxis was significantly better than the reference standard, fluconazole, in the treatment of patients with candidemia and other invasive candidiasis. Eraxis has not been studied in endocarditis, osteomyelitis, or meningitis due to Candida. Infections caused by C. krusei have not been studied. Neutropenic patients have not been studied in sufficient numbers to determine the efficacy of the drug in this group. The overall safety profile of Eraxis was comparable to that of fluconazole.
Eraxis (anidulafungin, 100 mg/vial) is presented as a powder for solution for intravenous infusion. A single 200 mg loading dose should be administered on Day 1, followed by 100 mg daily thereafter. Duration of treatment should be based on the patient's clinical response. In general, antifungal therapy should continue for at least 14 days after the last positive culture. Dosing guidelines are available in the Product Monograph.
Eraxis is contraindicated for patients with known hypersensitivity to anidulafungin, any component of Eraxis, or other echinocandins. Eraxis 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 Eraxis are described in the Product Monograph.
Based on the Health Canada review of data on quality, safety, and effectiveness, Health Canada considers that the benefit/risk profile of Eraxis is favourable for the treatment of invasive candidiasis/candidemia in adult non-neutropenic patients.
3 Scientific and Regulatory Basis for Decision
3.1 Quality Basis for Decision
3.1.1 Drug Substance (Medicinal Ingredient)
General Information
Anidulafungin, the medicinal ingredient of Eraxis, is an antifungal agent. Anidulafungin selectively inhibits 1,3-β-D glucan synthase, an enzyme present in fungal, but not mammalian cells. This results in inhibition of the formation of 1,3-b-D-glucan, an essential component of the fungal cell wall.
Manufacturing Process and Process Controls
The drug substance is manufactured by a fermentation and synthetic process. The manufacturing process is considered to be adequately controlled within justified limits.
Characterization
The established structure of anidulafungin is consistent with the method of synthesis and all analytical and spectroscopic data obtained.
Impurities and degradation products arising from manufacturing and/or storage were reported and characterized. These products were found to be within ICH established limits and/or were qualified from batch analysis or toxicological studies and therefore, are considered to be acceptable.
Control of Drug Substance
Copies of the analytical methods and, where appropriate, validation reports are considered satisfactory for all analytical procedures used for release and stability testing of anidulafungin.
The specifications are considered acceptable for the drug substance. Data from batch analyses were reviewed and are within the proposed acceptance criteria.
The drug substance packaging is considered acceptable.
Stability
Based on the stability data submitted, the proposed retest period and storage conditions for the drug substance are supported and considered to be satisfactory.
3.1.2 Drug Product
Description and Composition
Eraxis (anidulafungin) is a sterile, lyophilized powder in a 30 mL Type 1 glass vial with an elastomeric stopper, aluminium seal, and a flip-off cap. Each vial of product contains 100 mg lyophile. The non-medicinal ingredients (excipients) include fructose, mannitol, polysorbate 80, tartaric acid, and sodium hydroxide and/or hydrochloric acid for pH adjustment.
Eraxis is reconstituted with the companion diluent; 30 mL of 20% (w/w) dehydrated alcohol in Water for Injection in a Type 1 glass vial with an elastomeric stopper, aluminium seal, and a flip-off cap.
All excipients found in the drug product are acceptable for use in drugs according to the Food and Drug Regulations. The compatibility of anidulafungin with the excipients is demonstrated by the stability data presented on the proposed commercial formulation.
Pharmaceutical Development
Changes to the manufacturing process and formulation made throughout the pharmaceutical development are considered acceptable upon review.
Manufacturing Process and Process Controls
Eraxis is manufactured by a standard aseptic process. The equipment utilized to manufacture Eraxis is standard aseptic equipment. The method of manufacturing is considered acceptable and the process is considered adequately controlled within justified limits.
The validated process is capable of consistently generating product that meets release specifications.
Control of Drug Product
Eraxis is tested to verify that the identity, appearance, content uniformity, reconstitution time, and levels of degradation products, microbiological impurities, water content, and pH 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. The validation process is considered to be complete. Results of batch analysis indicate that all testing parameters met the specifications.
The proposed specifications for the glass vials, stopper, and seal contain appropriate tests to control the identity and dimensions of each packaging component. The packaging system is considered acceptable.
Stability
Based on the stability data submitted, the proposed 36-month shelf-life at 15-30°C for the drug product, Eraxis, is considered acceptable.
3.1.3 Facilities and Equipment
The design, operations and controls of the facilities and equipment that are involved in the production are considered suitable for the activities and products manufactured.
3.1.4 Adventitious Agents Safety Evaluation
Not applicable. The excipients used in the drug product formulation are not from animal or human origin.
3.1.5 Conclusion
The Chemistry and Manufacturing information submitted for Eraxis 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 Pharmacodynamics
The efficacy of Eraxis (anidulafungin) against a variety of Candida isolates, including those that demonstrated resistance to other antifungals, was demonstrated in the primary pharmacodynamic (PD) studies. Anidulafungin reduced the organ burden of C.albicans in a disseminated infection model in persistently neutropenic rabbits and immunosuppressed rabbits.
The safety pharmacology studies demonstrated an anti-diuretic effect with decreased urine volume and decreased urine sodium excretion, at doses of 20 mg/kg anidulafungin (a dose 4.9-fold greater than the human therapeutic dose). Rats that received 20 mg/kg also experienced a decrease in arterial pressure which occurred immediately after dosing. Two safety pharmacology studies revealed hemodynamic changes when anidulafungin was administered to rats.
3.2.2 Pharmacokinetics
Pharmacokinetic (PK) studies of anidulafungin were conducted in rats and monkeys following single and multiple intravenous (IV) doses of anidulafungin. In general, anidulafungin concentrations and exposures were dose-proportional for the clinically relevant dose levels. Steady-state levels were achieved in less than a week when daily dosing did not include a loading dose on Day 1. If a loading dose was used (double the normal daily dose) steady-state was obtained after the second dose. Anidulafungin had a rapid distribution phase followed by a prolonged elimination phase when dosed intravenously. It was widely distributed in all species with a volume of distribution approximately equivalent to the total body fluid content. Maximum anidulafungin concentrations and exposures in rat liver, spleen, kidney, and lung were greater than the observed plasma concentration; drug exposure in these tissues were approximately 10-fold greater compared to plasma. Anidulafungin was primarily eliminated by slow chemical degradation, with less than 10% of the drug eliminated in feces as intact drug. Virtually no elimination of either anidulafungin or radiolabelled degradation products occurred via urine. The half-life of anidulafungin was approximately 1-2 days, with once daily dosing. Repeated dosing did not influence distribution or clearance. Volume of distribution, plasma clearance, and half-life were dose-independent in the animal species tested.
3.2.3 Toxicology
Single-Dose Toxicity
The median lethal dose (LD50) was 71 mg/kg in rats and >100 mg/kg in mice. The maximum non-lethal dose in rats was 50 mg/kg and the minimal lethal dose in this species was 100 mg/kg. The maximum non-lethal dose in mice was not identified as no deaths were observed at the highest dose tested.
In rats, clinical signs of histamine-mediated infusion-related reactions occurred shortly after dosing in the low (20 mg/kg) and mid-dose (50 mg/kg) groups.
Repeat-Dose Toxicity
In rats and monkeys, repeat doses of anidulafungin produced hepatotoxic effects. The histologic effects in both species included mild to moderate morphological changes in the liver including single cell hepatocellular necrosis, hepatocellular hypertrophy and increased liver weights, accompanied by increases in hepatic enzymes and cholesterol. Hepatocellular hypertrophy was still noted one month after three months of dosing in both species.
Infusion-related reactions were reported in rats that received repeat exposure of anidulafungin by intravenous infusion. The infusion reactions occurred during the first 10-20 minutes of the infusion or 1 hour after dosing. These reactions generally subsided after 1-5 days of dosing. The clinical signs observed were red ears, swollen snout, hypoactivity, and sternal recumbence. Similar reactions were not observed in monkeys.
At higher doses of anidulafungin (30 mg/kg/day), anemia and reticuloendothelial system changes were also reported.
Genotoxicity
Anidulafungin was not genotoxic in the in vitro bacterial reverse mutation assays and the chromosome aberration assay with Chinese hamster ovary cells. Anidulafungin was not genotoxic in mice using the in vivo micronucleus assay.
Mutagenicity
Mutagenicity tests, including the chromosome aberration assay with Chinese hamster ovary cells and the mutation assay with mouse lymphoma cells, did not demonstrate mutagenic potential.
Carcinogenicity
Long-term carcinogenicity studies were not performed.
Reproductive and Developmental Toxicity
Although anidulafungin was shown to be excreted in the milk of lactating animals, the animal data (rats and rabbits) did not reveal developmental toxicities. Fertility and embryonic development studies showed no impact on fertility or reproductive performance.
3.2.4 Conclusion
The non-clinical studies within this submission have demonstrated no pharmacological/toxicological issues which preclude authorization of the product for the requested indication.
3.3 Clinical basis for decision
3.3.1 Pharmacodynamics
Anidulafungin selectively inhibits 1,3-β-D glucan synthase, an enzyme responsible for the assembly of the fungal cell wall, resulting in lysis of the cell and cell death. Anidulafungin has shown fungicidal activity against Candida species and activity against regions of active cell growth of the hyphae of Aspergillus fumigatus.
3.3.2 Pharmacokinetics
Systemic exposure of anidulafungin was found to be dose proportional, with extensive tissue distribution and high protein binding. The exposure kinetics of anidulafungin in healthy subjects were comparable to population pharmacokinetic estimates in patients having fungal infections, in HIV-patients, and in HIV-positive patients with fungal infections. Maximum plasma exposure kinetics of anidulafungin were achieved with the proposed dose regimen. Non-enzymatic chemical degradation into the feces was the main mechanism of elimination. The half-life of anidulafungin was approximately one day, and therefore supports daily intravenous dosing.
Drug interaction studies of medicinal products likely to be co-administered with anidulafungin (e.g. cyclosporine, voriconazole, tacrolimus) revealed no significant interactions; nor were effects reported by population PK analysis involving amphotericin B and rifampin (the latter a potent cytochrome P450 inducer). The overall population pharmacokinetic analyses demonstrated no interactions between anidulafungin and concomitant medications known to be metabolic substrates, inhibitors, or inducers of cytochrome P450 isoenzymes. Population PK modelling analyses were also done in order to predict possible additional drug-drug interactions. The model predicted no interactions with substrates, inducers or inhibitors of hepatic cytochrome P450 isozymes.
No dosage adjustments are required for patients with hepatic or renal impairment.
Although no information was provided in a placebo-controlled, randomized, Phase I study with a positive control arm to assess the effect of anidulafungin on QT prolongation, the majority of the clinical studies, performed with candidemia patients, revealed no effects of anidulafungin on the QTc interval changes from baseline.
3.3.3 Clinical Efficacy
A pivotal Phase III, randomized, double-blind, multicentre study was conducted to evaluate the efficacy and safety of Eraxis compared to fluconazole (the current standard of care) for the treatment of patients with candidemia and/or other forms of invasive candidiasis. Additional safety and efficacy data were obtained from two supporting non-pivotal studies, an open-label study and a dose-ranging study. The information reported in the supporting clinical studies confirmed the observations and conclusions of the pivotal study.
In the pivotal study, patients (n=256) were randomized to receive once-daily, intravenous (IV) doses of Eraxis (200 mg loading dose followed by 100 mg maintenance dose) or IV doses of fluconazole (800 mg loading dose followed by 400 mg maintenance dose). Treatment was administered for at least 14 days and not more than 42 days. Patients in both treatment arms were permitted to switch to oral fluconazole after at least 10 days of intravenous therapy, provided that they were able to tolerate oral medication, were afebrile for at least 24 hours, and the most recent blood cultures were negative for Candida species.
The two treatment arms were well balanced in terms of the patient population. Patients had proven fungal infection with a positive baseline blood culture or positive culture from a specimen from a normally sterile site (microbiological intent-to-treat [Micro-ITT] population). Most patients (~90% in each treatment arm) had candidemia, and the population was seriously ill with a mean Apache II score of 15 in the Eraxis arm and 14.4 in the fluconazole arm. The most frequent species isolated at baseline were C. albicans, followed by C. glabrata, C. parapsilosis, and C. tropicalis. Patients with Candida endocarditis, osteomyelitis or meningitis, or those with infection due to C. krusei, were excluded from the study.
The primary efficacy endpoint was the Global Response (combined clinical and microbiological response) in the Micro-ITT population at the end of IV therapy. In the Eraxis arm, 96 patients (75.6%) had global success versus 71 patients (60.2%) in the fluconazole arm. The data reported in the pivotal report confirmed the results of the Eraxis dose-ranging study where 70.7% of the patients in the Micro-ITT had global success at the end of therapy.
In the pivotal study, the between-group difference in global success rate (Eraxis minus fluconazole) was 15.42% (95% CI: 3.85, 26.99). The lower limit of the confidence interval for the treatment difference between Eraxis and fluconazole was greater than zero; however, due to the nature of the study, Eraxis is considered non-inferior to fluconazole. The one pivotal study was a small clinical study with results indicating marginal superiority to fluconazole, with lower limits of the 95% confidence interval barely above zero.
In all secondary efficacy analyses, Eraxis was superior to, or at least as effective as, fluconazole, consistent with the primary efficacy analysis. Eraxis-treated patients had higher rates of global, clinical, and microbiological success at all time points on therapy and at the end of therapy. It was also noted that more patients in the Eraxis group had global success at the end of IV therapy for catheter-related infections when the catheter was not removed compared with the fluconazole group, although the number of patients was small.
The striking difference in global success rates by pathogen for C. albicans (81.1% vs. 62.3%) may reflect the fungicidal activity of Eraxis as compared to the fungistatic effect of fluconazole. Compared with those in the fluconazole arm, patients treated with Eraxis had a numerically higher global success rate for every pathogen except C. parapsilosis, for which the absolute number of isolates was small. Two of 4 patients in the Eraxis arm, and 1 of 2 patients in the fluconazole arm, had persistent C. parapsilosis at the end of IV therapy. Only 2 of 7 patients in the Eraxis arm had a documented persistent C. glabrata at the end of IV therapy compared with 6 of 11 patients in the fluconazole arm. Overall, at the end of IV therapy, only 6.3% of patients treated with Eraxis had a documented persistent Candida infection compared with 14.4% of patients treated with fluconazole. At all timepoints, a greater proportion of Eraxis patients than fluconazole patients had eradication of Candida species.
3.3.4 Clinical Safety
In the pivotal study (described in section 3.3.3 Efficacy), both Eraxis and fluconazole were well tolerated by patients with invasive candidiasis and/or candidemia. The median exposure to IV study drug was 14 days for Eraxis and 11 days for fluconazole (ITT population). AEs were reported by 130 (99.2%) patients in the Eraxis arm and 122 (97.6%) patients in the fluconazole arm. The AEs were typically mild to moderate in severity and seldom led to discontinuation.
Most patients did not experience AEs related to study medication. The two most common related AEs for Eraxis were hypokalemia (3.1%) and diarrhea (3.1%). For fluconazole, the two most common related AEs were increased levels of hepatic enzymes (7.2%) and increased levels of blood alkaline phosphatase (4.0%).
The proportion of patients with related adverse events (AEs) was similar in the two treatment arms (approximately 25%). Fewer Eraxis-treated patients (15, 11.5%) than fluconazole-treated patients (27, 21.6%) experienced an AE that led to discontinuation of study drug. Serious adverse events (SAEs) were reported by 49.6% of patients in the Eraxis arm and 56.8% of patients in the fluconazole arm; however, SAEs were considered related to treatment for only 2 patients in each study arm. Fewer Eraxis-treated patients (30, 22.9%) than fluconazole-treated patients (39, 31.2%) died during and shortly after the study.
Infusion-related AEs were reported with Eraxis, including rash, urticaria, flushing, pruritus, dyspnea, and hypotension. These events can be minimized by infusing anidulafungin at a rate that does not exceed 1.1 mg/minute.
No cases of hepatic failure, anaphylaxis, or QT prolongation occurred in the two treatment arms. Clinical laboratory results yielded no clinically meaningful trends and do not suggest toxicity. The safety data show that Eraxis at a dose of 100 mg IV daily has a safety profile similar to and, in some instances, more favourable than that of fluconazole 400 mg IV daily.
Although Eraxis was well-tolerated, there are areas for which limited information is available as well as safety risks that should be considered. These include the identified risks of infusion-associated reactions and hepatobiliary events and a hypothetical risk of convulsion. The sponsor has provided a Risk Management Plan to monitor infusion-related reactions, hepatobiliary effects, convulsion, and QT prolongation, and to provide information on AEs in areas of currently limited knowledge (e.g. pediatric and adolescent patients, patients with neutropenia, pregnant patients, and elderly patients).
3.4 Benefit/Risk Assessment and Recommendation
3.4.1 Benefit/Risk Assessment
The market authorization of Eraxis and its availability as primary therapy for fungal infections would give the treating physician an additional choice of therapy when confronted with invasive candidiasis/candidemia infections of adult non-neutropenic patients. Primary endpoint analyses from the single comparative pivotal study showed results of global success favouring Eraxis when compared to the reference standard of fluconazole. The favourable results were also supported by the secondary endpoint analyses confirming significance in favour of Eraxis.
The overall safety profile of Eraxis was not found to be inferior to fluconazole. The overall safety profile of Eraxis appears to be similar to those of other Echinocandins (caspofungin and micafungin).
The lack of drug-drug interactions demonstrated in the reported clinical studies and the population PK-PD results is an additional benefit of Eraxis. The results of these studies revealed no drug-drug interaction effects with voriconazole, rifampin, tacrolimus, cyclosporine, and amphotericin B. This is a significant advantage as potential drug interaction effects usually involve the cumbersome procedure of dose adjustment. The lack of drug interaction can also be considered a benefit when combination therapies are involved. The lack of drug interaction with substrates, inducers, or inhibitors of hepatic cytochrome P450 isozymes means that Eraxis can be safely administered with a number of other drugs such as HIV therapies.
No dose adjustment is required when treating patients with renal or hepatic insufficiency. Other drugs, such as caspofungin, require dose adjustment when treating patients with moderate hepatic insufficiency.
The risks associated with the use of anidulafungin involve infusion-related reactions, hepatic concerns, and reports of convulsions which currently have not been considered to be related to medication. However, the sponsor will follow-up on these reactions during the post-approval process. These concerns are clearly identified in the Risk Management Plan submitted.
In conclusion, the benefits of Eraxis as an antifungal agent seem to outweigh the risks. The clinical and non-clinical information provided in the submission support the safety, quality, and efficacy of Eraxis for the treatment of invasive candidiasis/candidemia in adult non-neutropenic patients.
3.4.2 Recommendation
Based on the Health Canada review of data on quality, safety and effectiveness, Health Canada considers that the benefit/risk profile of Eraxis is favourable in the treatment of invasive candidiasis/candidemia in adult non-neutropenic patients. The New Drug Submission complies with the requirements of sections C.08.002 and C.08.005.1 and therefore Health Canada has granted the Notice of Compliance pursuant to section C.08.004 of the Food and Drug Regulations.
4 Submission Milestones
Submission Milestones: Eraxis
| Submission Milestone | Date |
|---|---|
| Submission filed | 2006-11-30 |
| Screening 1 | |
| Screening Acceptance Letter issued | 2007-01-18 |
| Review 1 | |
| Quality Evaluation complete | 2007-11-13 |
| Clinical Evaluation complete | 2007-10-23 |
| Labelling Review complete | 2007-11-14 |
| NOC issued by Director General | 2007-11-14 |