Summary Basis of Decision for Mycamine ®
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:
Mycamine®
Micafungin sodium, 25 mg/vial and 50/mg/vial, Powder for solution, Intravenous
Astellas Pharma Canada Inc.
Submission control no: 078577
Date issued: 2008-01-10
Health Products and Food Branch
Our mission is to help the people of Canada maintain and improve their health.
Health Canada
HPFB's Mandate is to take an integrated approach to managing the health-related risks and benefits of health products and food by:
- minimizing health risk factors to Canadians while maximizing the safety provided by the regulatory system for health products and food; and,
- promoting conditions that enable Canadians to make healthy choices and providing information so that they can make informed decisions about their health.
Health Products and Food Branch
Également disponible en français sous le titre : Sommaire des motifs de décision (SMD), PrMYCAMINEMD micafungine sodique, 25 mg/flacon et 50 mg/flacon, poudre pour solution, Astellas Pharma Canada Inc. No de contrôle de la présentation 078577
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):
- 02294214
- 02294222
Therapeutic Classification:
Non-medicinal ingredients:
Submission type and control no:
Date of Submission:
Date of authorization:
2 Notice of decision
On May 22, 2007, Health Canada issued a Notice of Compliance to Astellas Pharma Canada Inc. for the drug product Mycamine.
Mycamine contains the medicinal ingredient micafungin sodium which is an antifungal drug.
Mycamine is indicated for the treatment of patients with esophageal candidiasis, and for prophylaxis of Candida infections in patients undergoing hematopoietic stem cell transplantation. Micafungin, the medicinal ingredient of Mycamine, inhibits the synthesis of 1, 3-β-D-glucan, an essential component of fungal cell walls.
The market authorization was based on submitted data from quality (chemistry and manufacturing) studies, as well as data from non-clinical and clinical studies. Mycamine was evaluated in a Phase 3, randomized, double-blind study which compared Mycamine 150 mg/day (n=260) to intravenous fluconazole 200 mg/day (n=258) in untreated HIV infected adults with endoscopically-proven esophageal candidiasis. Endoscopic cure, clinical cure, overall therapeutic cure, and mycological eradication were comparable for patients in the Mycamine and fluconazole treatment groups. In another study with hematopoietic stem cell transplant recipients, successful prophylaxis (defined as the absence of a proven, probable, or suspected systemic fungal infection through the end of therapy (usually 18 days), and the absence of a proven or probable systemic fungal infection through the end of the 4-week post-therapy period) was documented in 80.7% of the recipients who received Mycamine, and in 73.7% of the recipients who received fluconazole. The efficacy of Mycamine against infections caused by fungi other than Candida has not been established.
Mycamine (25 mg/vial and 50 mg/vial, micafungin sodium) is presented as sterile, lyophilized powder for intravenous infusion. The recommended dose is 150 mg/day for the treatment of esophageal candidiasis, and 50 mg/day for prophylaxis of Candida infections in patients undergoing hematopoietic stem cell transplantation. Dosing guidelines are available in the Product Monograph.
Mycamine is contraindicated for patients with hypersensitivity to any component of this product. Mycamine 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 Mycamine 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 Mycamine is favourable for the treatment of patients with esophageal candidiasis, and for prophylaxis of Candida infections in patients undergoing hematopoietic stem cell transplantation.
3 Scientific and Regulatory Basis for Decision
A New Drug Submission for micafungin sodium was filed with Health Canada in June 2002. The submission did not contain enough evidence to support any of the three indications requested, therefore the submission was recommended for a Notice of Non-compliance (NON) on April 22, 2004. The sponsor submitted a response to the NON in August 2004 and post-hoc analysis resulted in a NON-Withdrawal issued on March 15, 2005. A Level I appeal followed on April 12, 2005 and was denied December 08, 2005. This appeal was denied based on the methodological problems in the post hoc-analysis of un-blinded data for the prophylaxis indication, and on the inadequacy of the representativeness of data for the treatment of esophageal candidiasis.
On February 10, 2006, the Request for a Second Level of Appeal was accepted by the Office of Science in the Therapeutic Drug Directorate (TPD) in Health Canada. An Appeal Panel was convened, consisting of three Canadian Infectious Disease experts. The Panel, sponsor's staff, Scientific Advisory Committee, manufacturer's staff and representatives from TPD met on September 15, 2006 in Ottawa. The adequacy of the data to support the sponsor's requested indications for Mycamine was critiqued in detail in a presentation to the panel by TPD staff. The composite endpoint in the pivotal prophylaxis study (including "suspicion of infection") was a particularly difficult issue. There was active discussion and questioning by panel members. Shortly after the meeting, the panel made recommendations in favour of the sponsor's requested indications for the use of Mycamine. These recommendations have been accepted by the Office of Science and the Director General's Office. The appeal process has been duly respected. The NON-Withdrawal letter has thus been rescinded. A Product Monograph consistent with available scientific information on Mycamine has been negotiated with the manufacturer, and a Notice of Compliance was recommended.
The timeline of these events are reported in section 4 Submission Milestones. Discussions regarding the efficacy of Mycamine appear in sections 3.3.4 Clinical Efficacy.
3.1 Quality Basis for Decision
3.1.1 Drug Substance (Medicinal Ingredient)
General Information
Micafungin sodium, the medicinal ingredient of Mycamine, is an antifungal agent which inhibits the synthesis of 1,3-β-D-glucan, an essential component of fungal cell walls.
Manufacturing Process and Process Controls
Micafungin sodium is synthesized by a chemical modification of a fermentation product of Coleophoma empetri F-11899. Materials used in the manufacture of the drug substance are considered suitable and/or meet standards appropriate for their intended use. The manufacturing process is considered to be adequately controlled within justified limits.
Characterization
The structure of micafungin sodium is considered to be adequately elucidated. 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 and therefore, considered to be acceptable.
Control of Drug Substance
Validation reports are considered satisfactory for all analytical procedures used for in-process and release testing of micafungin sodium. The specifications are considered acceptable for the drug substance. Data from the batch analyses were reviewed and were within the proposed acceptance criteria.
Stability
Based on the real-time and accelerated stability data submitted, the proposed shelf-life, storage and shipping conditions for micafungin sodium were supported and considered to be satisfactory.
3.1.2 Drug Product
Description and Composition
Mycamine (micafungin sodium) is available as a sterile, non-pyrogenic, lyophilized powder for intravenous infusion containing 25 mg or 50 mg of micafungin sodium per vial. Non-medicinal ingredients include lactose, citric acid and/or sodium hydroxide.
Mycamine is supplied in 10mL USP Type 1 glass vials that are packaged in individual cartons of ten. The glass vials are covered with a light protective film.
All excipients (non-medicinal ingredients) found in Mycamine are acceptable for use in drugs according to the Food and Drug Regulations. The compatibility of micafungin sodium 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 development are considered acceptable upon review.
Manufacturing Process and Process Controls
The manufacturing process for Mycamine incorporates standard pharmaceutical practices. All manufacturing equipment, in-process manufacturing steps and detailed operating parameters were adequately described in the submitted documentation and are found to be acceptable. The manufacturing process is considered to be adequately controlled within justified limits.
Control of Drug Product
The test specifications are considered acceptable to control the drug product, and the impurity limits were set according to ICH recommendations.
Copies of the analytical methods and, where appropriate, validation reports are considered satisfactory for all analytical procedures used for release and stability testing of Mycamine.
Data from final batch analyses were reviewed and considered to be acceptable according to the specification of the drug product.
Although impurities and degradation products arising from manufacturing and/or storage were reported and characterized, these were found to be within ICH established limits and/or were qualified from batch analysis and therefore, considered to be acceptable.
Stability
Based on the real-time and accelerated stability study data submitted, the proposed 24-month shelf-life at 15-30 °C for Mycamine is considered acceptable, when the product is protected from light.
3.1.3 Facilities and Equipment
The design, operations and controls of the facility and equipment that are involved in the production are considered suitable for the activities and products manufactured.
3.1.4 Adventitious Agents Safety Evaluation
N/A
3.1.5 Summary and Conclusion
The Chemistry and Manufacturing information submitted for Mycamine 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 pharmacodynamic properties of Mycamine (micafungin sodium) were evaluated with in vitro and in vivo animal studies.
Micafungin displayed fungicidal activity against various Candida species. Micafungin exhibited in vitro activity against C. albicans, C. glabrata, C. krusei, C. parapsilosis, and C. tropicalis. The antifungal activity of micafungin was comparable or slightly inferior to that of amphotericin (AMPH-B) and superior to fluconazole (FLCZ) and itraconazole (ITCZ). The mechanism of action was the inhibition of fungal cell wall synthesis. Micafungin inhibited 1,3-β-D-glucan synthesis, an essential component of fungal cell walls, in a concentration-dependent manner. Micafungin also showed a high protein-binding capacity for human serum albumin and the minimal inhibitory concentration (MIC) of micafungin was elevated by the addition of human serum or human serum albumin. These results indicate that in vivo efficacy of micafungin is influenced by its high protein binding capacity.
Therapeutic effects on oropharyngeal and esophageal candidiasis were observed in mice treated with micafungin. Results showed significant decreases in viable colony counts in the tongues and esophagi, compared with the control group. After an 8-day untreated period, markedly decreased counts were still observed in the 5 and 10 mg/kg dose groups, while increased counts were observed in the 2 mg/kg dose group.
Mice in the 100 mg/kg dose group experienced decreased spontaneous motor activity. Rats in the 32 mg/kg dose group had increased plasma histamine levels and increased heart rates. Rats treated with 100 mg/kg had decreased blood pressure and increased urinary excretion of electrolytes. Doses of 100 mg/kg in the rat also resulted in overt signs such as tremor, hypotonia, and loss of reflexes (righting, corneal, pinna, startle). In almost all the in vivo and in vitro tests, effects occurred at 100 mg/kg and at concentrations of more than 1x10E-4 g/mL. Clinical use of micafungin sodium should exercise caution with respect to possible effects on the cardiovascular and blood systems.
3.2.2 Pharmacokinetics
Absorption and Bioavailability
In mice, rats and dogs, plasma concentrations of micafungin declined biexponentially with a terminal half-life of approximately 4-6 hours. There were no statistically significant differences in parameters among doses, indicating linear pharmacokinetics over the dose range studied.
The ratio of unchanged substance to plasma radioactivity was 100% at 5 minutes, 92% at 2 hours, 72% at 4 hours, 64% at 6 hours, 53% at 8 hours, and 13% at 24 hours post-injection. These results indicate that the major part of radioactivity in the plasma existed as unchanged drug during the early period after dosing, and metabolites were both formed slowly and eliminated slowly from the plasma.
Distribution
Distribution of micafungin was rapid. In tissues, at 5 minutes post-dose, the highest levels of radioactivity were found in the lung and kidney (tissue/plasma concentration ratio were 1.86 and 1.09, respectively). The ratios ranged from 0.17 to 0.86 in the other tissues except the brain, eyeball, white fat, and testes where the radioactivity was very low and was ≤ 0.08 times the plasma concentration. In the thymus, liver, skin and testis, the highest tissue concentrations were obtained at 6 hours post-dosing and thereafter the radioactivity declined slowly. Whole-body radiography performed in one animal per group revealed that radioactivity was distributed rapidly into tissues, consistent with findings obtained from tissue homogenates.
At a concentration of 10 µg/mL, protein binding was >99% for each species. In human serum, micafungin was primarily bound to albumin (99.6%); however, alpha-1-acid glycoproteins also showed a capacity to bind micafungin (72.5%).
Micafungin was found in the gestational tissue of pregnant rats and in the milk of lactating rats.
Metabolism
Micafungin was primarily metabolized by the liver. Following the IV administration of 1 mg/kg of micafungin to male rats, six metabolites in urine, bile, feces and/or plasma (M-1, M-2, M-3, M-5, S-1, S-2) were detected by thin layer chromatography. In rats, the primary metabolites were M-1 and M-2 in the rat liver, M-5 in urine and M-6 and M-10 in bile. Results showed that 22% of the administered radioactivity was recovered as parent drug in bile 48 hours post-dose and in feces 96 hours post-dose. The composition of metabolites differed between rats and dogs. In dogs, the primary metabolites were M-4 and M-6 (plasma and feces), and M-4 and M-5 (urine).
Oxidative metabolism of micafungin appears to be mediated by multiple human CYP isozymes. The relevance of this in vitro activity to in vivo events is unknown.
Excretion
In rats and dogs, the unchanged drug and its metabolites were excreted in the feces via the bile.
Drug-Drug Interactions
The combinations of micafungin with commercially available antifungal agents showed some positive interactions.
3.2.3 Toxicology
Acute Toxicity
In rats, the lethal dose of micafungin was approximately 125 mg/kg for males and 250 mg/kg for females.
Doses of 100 mg/kg and 200 mg/kg did not cause lethal effects in dogs. The characteristic findings by single dosing with micafungin in dogs were swelling of the palpebra, its surrounding area and limb, increased liver enzymes, and decreased erythrocytic parameters.
Long-Term Toxicity
In the two-week study, rats were administered micafungin at 3.2, 10, and 32 mg/kg/day, or physiological saline for control animals. Adverse findings attributable to treatment were only found in the high dose group, 32 mg/kg/day. In the liver of the males and females, single cell necrosis and nuclear hypertrophy in hepatocytes, associated with vacuolation and acidophilic body were noted. Some animals showed mitosis in hepatocytes, suggesting regeneration. Reflecting these histopathological changes, both males and females had increased levels of transaminase and alkaline phosphatase activity, and decreased total protein and alpha1-globulin fraction. In males, there were increased levels of beta-globulin and in females there were increased levels of cholesterol and phospholipids and decreased levels of inorganic phosphorus and relative weight of the liver. An increase in the relative weight of the kidney was noted in both males and females, but there were no histopathological changes thought to be attributable to the study drug. Cystitis in the urinary bladder was noted in females. The incidence of perivascular hemorrhage at the injection site was slightly higher in males in the high dose group than in the control.
In the four-week study with rats at doses of 3.2, 10, and 32 mg/kg/day, no deaths were reported and there were no abnormal changes in body weight, food consumption, ophthalmology, or gross pathology in any treatment group.
Significant findings were found in the hematology, chemistry, organ weight analysis and liver histopathology results:
- Significant decreases in erythrocytes and increases in red blood cell indices (MCV, MCH, MCHC) and reticulocyte rates were observed in the males of the 32 mg/kg/day group. A significant shortening of activated partial thromboplastin time, decrease in lymphocyte rate, and increase in segmented neutrophil rate were also observed in these animals. The reticulocyte rate increased significantly in the females of this group.
- Increased blood enzyme activity of the liver was observed (AST, ALT, LDH, ALP, total bilirubin, and potassium) in the males and females of the 32 mg/kg/day group. Blood urea nitrogen and the alpha2-globulin rate increased significantly, while the alpha1-globulin rate decreased significantly in the males of the 32 mg/kg/day group.
- Actual and relative spleen weights increased significantly in the males of the 32 mg/kg/day group.
- In the 32 mg/kg/day group, the liver histopathology results included reports of slight to moderate single-cell necrosis. Hepatocytes were reported to have slight to moderate acidophilic bodies, slight nuclear hypertrophy, slight or moderate vacuolation, and/or mild mitosis. In one male of the 3.2 mg/kg/day group, slight or mild round cell infiltration/accumulation in the sinusoid was observed.
Carcinogenicity
Carcinogenic studies were not conducted with micafungin sodium.
Mutagenicity
No mutagenic potential was observed in the standard battery of in vitro and in vivo tests (i.e., bacterial reversion, chromosomal aberration, IV mouse micronucleus). Reproductive and Developmental Toxicity
In rats, doses of approximately twice the recommended clinical dose (based on body surface area comparisons) resulted in higher epididymis weights and reduced numbers of sperm cells. No impairment of fertility was reported in the animal studies with micafungin sodium.
Doses of 32 mg/kg/day (seven times the recommended clinical dose) administered to pregnant rabbits (IV dosing on days 6-18 of gestation) resulted in visceral abnormalities and abortion. Visceral abnormalities included abnormal lobation of the lung, levocardia, retrocaval ureter, anomalous right subclavian artery, and dilatation of the ureter.
3.2.4 Summary and Conclusion
Micafungin sodium, the medicinal ingredient of Mycamine, displayed fungicidal activity against various Candida species. The mechanism of action was the inhibition of the synthesis of 1,3-β-D-glucan, an essential component of fungal cell walls.
In the animal studies, high doses of micafungin sodium have been associated with irreversible changes to the liver when administered for prolonged periods. Reproductive toxicity was also reported. The results of the non-clinical studies as well as the potential risks to humans have been included in the Product Monograph. In view of the intended use of Mycamine, there are no pharmacological/toxicological issues within this submission which preclude authorization of the product for the requested indication.
3.3 Clinical basis for decision
3.3.1 Pharmacodynamics
Micafungin exhibited a broad range of activity against several Candida species and was more active than amphotericin B, fluconazole and itraconazole against most of the Candida species tested.
Micafungin was inactive against Cryptococcus neoformans, Trochosporon cutaneum, Trichosporon asahii, Pseudallescheria boydii and the zygomycetes including Absidia corymbifera, Cunninghamella elegans, Rhizopus oryzae and Rhizopus microsporus.
3.3.2 Pharmacokinetics
The pharmacokinetics of micafungin were studied over a wide dose range (up to 896 mg per day) in 179 healthy volunteers and 254 patients. The pharmacokinetic results were consistent across all of the studies.
Steady-state was rapidly achieved, generally within 4-5 days. Mean plasma concentrations at clinically relevant daily dosages (50-100 mg in adults or 1-2 mg/kg in pediatric patients) exceed the minimum inhibitory concentrations of a wide spectrum of Candida species and these concentrations are maintained for 24 hours. There was no evidence of systemic accumulation of micafungin or non-linear kinetics.
Micafungin was highly protein bound, but protein binding was demonstrated in vitro to be independent of micafungin concentration over the range of 10-100 µg/mL. Micafungin binds primarily to albumin; however, micafungin does not displace bilirubin binding to albumin at clinically relevant concentrations and, therefore, would not be expected to cause kernicterus.
Based on the results of the in vitro studies, the oxidative metabolism of micafungin appears to be mediated by multiple CYP isozymes, with CYP1A2, 2B6, 2C, and 3A4 enzymes identified as being involved in M5 formation by human liver microsomes. Whether all, some, or one of these isozymes contribute(s) to the in vivo disposition of micafungin in a predominant role is not known. The plasma concentrations of metabolites following administration of micafungin to humans have been shown to be minimal, a fraction of the parent compound.
None of the three metabolites of micafungin found in human plasma (M1, m2, M5) are expected to contribute to the therapeutic antifungal effectiveness of micafungin. While the in vitro spectrum and activity of m2 is similar to that of the parent compound and M1 had moderate activity against C. neoformans and T. cutaneum (strains that were not inhibited by the parent compound), their plasma concentrations in man are too low to contribute to the antifungal activity of micafungin. A third metabolite, M5, demonstrated more than a hundred-fold less in vitro activity than its parent compound. Therefore, the antifungal efficacy of micafungin appears to be solely due to the parent drug.
All evidence suggests that it is unlikely that micafungin at clinically relevant concentrations would affect (induce or inhibit) cytochrome P450 isozyme-mediated metabolism of concomitantly-administered drugs. Micafungin, at clinically relevant concentrations, does not inhibit major cytochrome P450 isozymes and would not be expected to have clinically significant interactions with warfarin, diazepam, salicylic acid, methotrexate, terfenadine, astemizole, cyclosporine, or tacrolimus. The absence of any clinically significant pharmacokinetic interaction between micafungin and either tacrolimus or cyclosporine (both extensively metabolized primarily by CYP3A) has been demonstrated in healthy volunteers. Concomitant administration of micafungin and fluconazole did not affect the pharmacokinetics of either drug in adult cancer (bone marrow transplant/peripheral stem cell transplant) patients. Therefore, micafungin would not be expected to have clinically significant interactions with drugs commonly co-administered in the target patient population.
Elimination of micafungin was primarily non-renal. The excretion of radioactivity following a single intravenous dose of 14C-micafungin sodium for injection (25 mg) was evaluated in healthy volunteers. At 28 days after administration, mean urinary and fecal recovery of total radioactivity accounted for 82.5% (76.4 to 87.9%) of the administered dose. Fecal excretion was the major route of elimination (total radioactivity at 28 days was 71.0% of the administered dose).
In conclusion, the pharmacokinetic profile of micafungin in a variety of subject populations over a large dose range does not suggest any potential clinical issues or safety concerns. The data suggest that dosage adjustment based on age, gender, race, renal impairment, or hepatic dysfunction is not necessary.
3.3.3 Clinical Efficacy
The indications for Mycamine are for the treatment of patients with esophageal candidiasis, and for prophylaxis of Candida infections in patients undergoing hematopoietic stem cell transplantation
For the treatment of patients with esophageal candidiasis, the primary support for the efficacy of micafungin was based on the pivotal Phase III Study 03-7-005, a randomized, double-blind study which compared Mycamine 150 mg/day (n=260) to fluconazole 200 mg/day (n=258). Most patients in this study had HIV infection, with CD4 cell counts <100 cells/mm3. Outcome was assessed by endoscopy and by clinical response at the end of treatment. Clinical cure was defined as complete resolution in clinical symptoms of esophageal candidiasis (dysphagia, odynophagia, and retrosternal pain). Overall therapeutic cure was defined as both clinical and endoscopic cure. Mycological eradication was determined by culture, and by histological or cytological evaluation of esophageal biopsy or brushings obtained endoscopically at the end of treatment. Endoscopic cure, clinical cure, overall therapeutic cure, and mycological eradication were comparable for patients in the Mycamine and fluconazole treatment groups. There was no statistically significant difference in relapse rates at either 2 weeks or through 4 weeks post-treatment for patients in the Mycamine and fluconazole treatment groups. The efficacy data to support the second indication (prophylaxis of Candida infections in patients undergoing hematopoietic stem cell transplantation) was provided by a randomized, double-blind study. Mycamine (50 mg IV once daily) was compared to fluconazole (400 mg IV once daily) in 882 patients undergoing an autologous/syngeneic (46%) or allogeneic (54%) stem cell transplant. Successful prophylaxis [defined as the absence of a proven, probable, or suspected systemic fungal infection through the end of therapy (usually 18 days), and the absence of a proven or probable systemic fungal infection through the end of the 4-week post-therapy period] was documented in 80.7% of the recipients who received Mycamine, and in 73.7% of the recipients who received fluconazole.
Concerns were previously raised about the study designs of the prophylaxis Study 98-0-050 where the endpoint largely consisted of "suspected" fungal infections, and the treatment Study 03-7-005 where the study population was considered to be non-representative of the intended target population. The outcome of these concerns resulted in the issuance of a NON-Withdrawal (March 15, 2005), as well as a decision to deny a Level 1 appeal (December 08, 2005). The studies were considered not adequately powered to support credible evidence of efficacy and safety, and the study population (untreated HIV-infected patients in South America and Africa) was regarded as not being representative of or comparable to the target Canadian population where the majority of the patients are treated with highly active antiretrovial therapy (HAART). Adequate individual drug interaction studies were not performed with antiretroval agents, and this was believed to be a potential safety concern for the target patient population where antiretroviral drugs are commonly prescribed.
On February 10, 2006, the sponsor requested a Second Level of Appeal and this was accepted by the Office of Science. A panel of three infectious disease experts convened on September 15, 2006 and provided affirmative answers and rationales that were supportive of the appeal.
The panel regarded the primary endpoint as favourable, the statistical approach as meeting international standards, and the study having solid diagnostic and outcome criteria with test results that were clinically meaningful. The panel believed that the results could be extrapolated from the HIV-infected study population with esophageal candidiasis to other Canadian (HIV positive or negative) patients with esophageal candidiasis. The panel also believed that the HIV-infected study population with esophageal candidiasis was sufficiently similar to the Canadian HIV-infected population to be used in a pivotal trial. Approximately 85% of individuals presented with esophageal candidiasis in Canada are not on HAART. It was also noted that there is seldom a clinical imperative to initiate HAART within the first few days following the diagnosis of esophageal candidiasis. To the best of their knowledge, there is no data to suggest any concerns regarding extrapolating South African and South American patient data to Canada based on the natural history of disease of HIV infection, ethnicity, social context or response to therapy.
The panel reviewed the pharmacokinetic interaction data presented. The metabolic path used by Mycamine (CYP3A4) does not appear to have a significant overlap with, or impact on any of the commonly used antiretroviral agents or with drugs used to treat concurrent infections likely to be occurring in this population. Further, extensive use of this agent in Japan and the United States has not resulted in the identification of any unsuspected drug-drug interactions.
3.3.4 Clinical Safety
The clinical safety of Mycamine was based on Study 03-7-005, a pivotal Phase III, randomized, double-blind study of Mycamine vs. fluconazole. Initially, the study population was considered non-representative of the intended immunocompromised population (see section 3.3.3 Clinical Efficacy). The lack of drug-interaction data was thought to pose a potential safety risk for the targeted Canadian population, and the safety data available from thisstudy was considered inferior to that of the comparatorfluconazole.
In Study 03-7-005, a total of 202/260 (77.7%) patients that received Mycamine 150 mg/day and 186/258 (72.1%) patients who received intravenous fluconazole 200 mg/day experienced an adverse event (AE). The number of discontinuations, and the incidence of drug-related AEs were higher in patients receiving Mycamine. Drug-related AEs resulting in discontinuation were reported in six (2.3%) of the Mycamine-treated patients and in two (0.8%) of the fluconazole-treated patients. AEs considered to be drug-related occurred in 72 (27.7%) and 55 (21.3%) patients in the Mycamine and fluconazole treatment groups, respectively. The incidence of allergic/histamine drug-related AEs, as well as phlebitis/injection site AEs were significantly higher in patients treated with Mycamine. Rash and delirium were the most common drug-related AEs that resulted in Mycamine discontinuation.
The panel that evaluated the Second Level of Appeal felt that the studies supported the safety of Mycamine at a dose of 150 mg daily. They concluded that the submitted study populations were reasonably representative of the target Canadian population and that the results can be deemed valid for the use of the agent within the Canadian context (see section 3.3.3 Efficacy). The panel felt that the risk of disease and its associated morbidity in all of the situations presented outweighed the AEs that were reported.
A complete list of the drug-related AEs is included in the Product Monograph. Warnings and cautionary statements have been incorporated within the labelling and Product Monograph to address the identified safety concerns.
3.4 Benefit/Risk Assessment and Recommendation
3.4.1 Benefit/Risk Assessment
Esophageal candidiasis is a growing concern in immunocompromised populations such as HIV-infected patients, cancer patients, and other hospitalized patients on antibiotic therapies. Current standard of treatment of mucosal candidiasis consists of fluconazole but resistance is common. Availability of new drugs with a different mechanism of action would be beneficial to the patients. Micafungin is a 1,3-β-D-glucan synthesis inhibitor which exhibits antifungal activity against various Candida species.
In a double-blind, controlled clinical trial, micafungin has been shown to be non-inferior to fluconazole in the treatment of esophageal candidiasis in severely immunocompromised, untreated HIV-infected adult patients, with no concomitant use of antiretroviral medications. This study population is reasonably representative of the target Canadian population and the results can be deemed valid for the use of the drug within the Canadian context.
Drug-related adverse events are common with the use of Mycamine, however the benefits associated with the use of Mycamine for the proposed indications outweigh the potential risks.
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 Mycamine is favourable for the treatment of patients with esophageal candidiasis, and for prophylaxis of Candida infections in patients undergoing hematopoietic stem cell transplantation. 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: Mycamine®
| Submission Milestone | Date |
|---|---|
| Request for priority status | |
| Filed | 2002-06-03 |
| Rejection issued by Dr. Jacques Bouchard | 2002-07-05 |
| Submission filed | 2002-06-27 |
| Screening 1 | |
| Screening Acceptance Letter issued | 2002-08-06 |
| Review 1 | |
| Quality Evaluation complete | 2003-07-22 |
| Clinical Evaluation complete | 2004-04-19 |
| NON issued by Director General (efficacy issues) | 2004-04-22 |
| Response filed | 2004-07-28 |
| Screening 2 | |
| Screening Acceptance Letter issued | 2004-08-20 |
| Review 2 | |
| NON/W issued by Director General (efficacy issues) | 2005-03-15 |
| Level 1 Appeal | |
| Filed | 2005-06-10 |
| Rejection issued by Dr. Bryan Garber. | 2005-12-08 |
| Level 2 Appeal | |
| Filed | 2006-01-10 |
| Scientific Advisory Committee meeting held? | 2006-09-15 |
| Grant issued by Director General | 2007-01-08 |
| NOC issued by Director General | 2007-05-22 |
Related Drug Products
| Product name | DIN | Company name | Active ingredient(s) & strength |
|---|---|---|---|
| MYCAMINE | 02294222 | ASTELLAS PHARMA CANADA INC | MICAFUNGIN SODIUM 50 MG / VIAL |