Antifungal

Astellas Pharma Canada, Inc. Markham, Ontario L3R 0B8

Control # 117047

(r) Registered Trademark

Date of Revision: September 2, 2008

Product Monograph - Mycamine(r) Page 1 of 31

TABLE OF CONTENTS

PART I: HEALTH PROFESSIONAL INFORMATION 3

SUMMARY PRODUCT INFORMATION 3 INDICATIONS AND CLINICAL USE 3 CONTRAINDICATIONS 3 WARNINGS AND PRECAUTIONS 4 ADVERSE REACTIONS 6 DRUG INTERACTIONS 12 DOSAGE AND ADMINISTRATION 13 OVERDOSAGE 15 ACTION AND CLINICAL PHARMACOLOGY 15 STORAGE AND STABILITY 17 SPECIAL HANDLING INSTRUCTIONS 18 DOSAGE FORMS, COMPOSITION AND PACKAGING 18

PART II: SCIENTIFIC INFORMATION 19

PHARMACEUTICAL INFORMATION 19 CLINICAL TRIALS 20 DETAILED PHARMACOLOGY 27 MICROBIOLOGY 27 TOXICOLOGY 28 REFERENCES 29

PART III: CONSUMER INFORMATION. 30

PrMycamine(r) Micafungin sodium for injection

PART I: HEALTH PROFESSIONAL INFORMATION SUMMARY PRODUCT INFORMATION

CONTRAINDICATIONS

Mycamine is contraindicated in patients with hypersensitivity to micafungin, echinocandins or any component of this drug product (For a complete listing, see the Dosage Forms, Composition and Packaging section of the product monograph).

WARNINGS AND PRECAUTIONS

General

Isolated cases of serious hypersensitivity (anaphylaxis and anaphylactoid) reactions (including shock) have been reported in patients receiving Mycamine. If these reactions occur, Mycamine infusion should be discontinued and appropriate treatment administered.

Carcinogenesis, Mutagenesis, Impairment of Fertility

Hepatic carcinomas and adenomas were observed in a 6-month intravenous toxicology study with an 18-month recovery period of micafungin sodium in rats designed to assess the reversibility of hepatocellular lesions. Rats administered micafungin sodium for 3 months at 32 mg/kg/day (corresponding to 8 times the highest recommended human dose [150 mg/day], based on AUC comparisons), exhibited colored patches/zones, multinucleated hepatocytes and altered hepatocellular foci after 1 or 3 month recovery periods, and adenomas were observed after 20-month recovery period. Rats administered micafungin sodium at the same dose for 6 months exhibited adenomas after a 12- month recovery period; after an 18-month recovery period, an increased incidence of adenomas was observed, and additionally, carcinomas were detected. A lower dose of micafungin sodium (equivalent to 5 times the human AUC) in the 6-month rat study resulted in a lower incidence of adenomas and carcinomas following 18 months recovery. The duration of micafungin dosing in these rat studies (3 or 6 months) exceeds the usual duration of Mycamine dosing in patients, which is typically less than 1 month for treatment of esophageal candidiasis, but dosing may exceed 1 month for Candida prophylaxis. Although the increase in carcinomas in the 6-month rat study did not reach statistical significance, the persistence of altered hepatocellular foci subsequent to micafungin dosing, and the presence of adenomas and carcinomas in the recovery periods suggest a causal relationship between micafungin sodium, altered hepatocellular foci, and hepatic neoplasms. Whole-life carcinogenicity studies of Mycamine in animals have not been conducted, and it is not known whether the hepatic neoplasms observed in treated rats also occur in other species, or if there is a dose threshold for this effect.

Hepatic Insufficiency

Laboratory abnormalities in liver function tests have been seen in healthy volunteers and patients treated with Mycamine. In some patients with serious underlying conditions who were receiving Mycamine along with multiple concomitant medications, clinical hepatic abnormalities have occurred, and isolated cases of significant hepatic dysfunction, hepatitis, or worsening hepatic failure have been reported. Patients who develop abnormal liver function tests during Mycamine therapy should be monitored for evidence of worsening hepatic function and evaluated for the risk/benefit of continuing Mycamine therapy.

Renal Insufficiency

Elevations in BUN and creatinine, and isolated cases of significant renal dysfunction or acute renal failure have been reported in patients who received Mycamine. In fluconazole- controlled trials, the incidence of drug-related renal adverse events was 0.4% for Mycamine treated patients and 0.5% for fluconazole treated patients. Patients who develop abnormal renal function tests during Mycamine therapy should be monitored for evidence of worsening renal function.

Hematological Effects

Acute intravascular hemolysis and hemoglobinuria were seen in a healthy volunteer during infusion of Mycamine (200 mg) and oral prednisolone (20 mg). This event was transient, and the subject did not develop significant anemia. Isolated cases of significant hemolysis and hemolytic anemia have also been reported in patients treated with Mycamine. Patients who develop clinical or laboratory evidence of hemolysis or hemolytic anemia during Mycamine therapy should be monitored closely for evidence of worsening of these conditions and evaluated for the risk/benefit of continuing Mycamine therapy.

Sexual Function/Reproduction

Male rats treated intravenously with micafungin sodium for 9 weeks showed vacuolation of the epididymal ductal epithelial cells at or above 10 mg/kg (about 0.6 times the recommended clinical dose for esophageal candidiasis, based on body surface area comparisons). Higher doses (about twice the recommended clinical dose, based on body surface area comparisons) resulted in higher epididymis weights and reduced numbers of sperm cells. In a 39-week intravenous study in dogs, seminiferous tubular atrophy and decreased sperm in the epididymis were observed at 10 and 32 mg/kg, doses equal to about 2 and 7 times the recommended clinical dose, based on body surface area comparisons. There was no impairment of fertility in animal studies with micafungin sodium.

Special Populations

Pregnant Women:

No adequate, well-controlled studies have been conducted in pregnant women. Mycamine should be used during pregnancy only if the benefits outweigh the potential risks.

Micafungin sodium administration to pregnant rabbits (intravenous dosing on days 6 to 18 of gestation) resulted in visceral abnormalities and abortion at 32 mg/kg, a dose equivalent to about four times the recommended dose based on body surface area comparisons. Visceral abnormalities included abnormal lobation of the lung, levocardia, retrocaval ureter, anomalous right subclavian artery, and dilatation of the ureter. However, animal studies are not always predictive of human response.

Nursing Women:

It is not known whether micafungin is excreted in human milk. Micafungin was found in the milk of lactating, drug-treated rats. Caution should be exercised when Mycamine is administered to a nursing woman.

Pediatrics (< 16 years):

The safety and efficacy of Mycamine has not been established in pediatric patients below the age of 16 years.

Geriatrics ( > 65 years of age):

A total of 418 subjects in clinical studies of Mycamine were 65 years of age and older, and 124 subjects were 75 years of age and older. No overall differences in safety or effectiveness were observed between these subjects and younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

DRUG INTERACTIONS

Drug-Drug Interactions

A total of 14 clinical drug-drug interaction studies were conducted in healthy volunteers to evaluate the potential for interaction between Mycamine and amphotericin B, mycophenolate mofetil, cyclosporine, tacrolimus, prednisolone, sirolimus, nifedipine, fluconazole, itraconazole, voriconazole, ritonavir, or rifampin. In these studies, no interaction that altered the pharmacokinetics of micafungin was observed. Co-administration of Mycamine and amphotericin B deoxycholate was associated with a 30% increase in amphotericin B deoxycholate exposure. The clinical significance of this increase is unclear however this co-administration should only be used when the benefits clearly outweigh the risks, with close monitoring of amphotericin B deoxycholate toxicities. Co-administration of voriconazole with Mycamine was associated with approximately 20% reduction of voriconazole exposure on average. In the same study co-administration of placebo and voriconazole was associated with a similar reduction of voriconazole exposure. When the effect of Mycamine was corrected for the effect of placebo, there was no significant effect of Mycamine on the pharmacokinetics of voriconazole. There was no effect of a single dose or multiple doses of Mycamine on mycophenolate mofetil, cyclosporine, tacrolimus, prednisolone, voriconazole and fluconazole pharmacokinetics. Sirolimus AUC was increased by 21% with no effect on Cmax in the presence of steady-state Mycamine compared with sirolimus alone. Nifedipine AUC and Cmax were increased by 18% and 42%, respectively, in the presence of steady-state Mycamine compared with nifedipine alone. Itraconazole AUC and Cmax were increased by 22% and 11%, respectively, in the presence of steady-state Mycamine compared with itraconazole alone. Patients receiving sirolimus, itraconazole or nifedipine in combination with Mycamine should be monitored for sirolimus, itraconazole or nifedipine toxicity. The sirolimus, itraconazole or nifedipine dosage should be reduced if necessary. Micafungin is not an inhibitor of P-glycoprotein and, therefore, would not be expected to alter P- glycoprotein-mediated drug transport activity.

Drug-Food Interactions

Interactions with food have not been established.

Drug-Herb Interactions

Interactions with herbs have not been established.

Drug-Laboratory Test Interactions

Interactions with laboratory tests have not been established.

DOSAGE AND ADMINISTRATION

Dosing Considerations

Do not mix or co-infuse Mycamine with other medications

. Mycamine has been shown to precipitate when mixed directly with a number of other commonly used medications.

Mycamine should be administered by a slow intravenous infusion over the period of 1 hour. More rapid infusions may result in more frequent histamine mediated reactions.

NOTE: An existing intravenous line should be flushed with 0.9% Sodium Chloride Injection, USP, prior to infusion of Mycamine.

Recommended Dose and Dosage Adjustment

1. In patients treated successfully for candidemia and other Candida infections, the mean duration of treatment was

15 days (range 10-47 days)

In hematopoietic stem cell transplant (HSCT) recipients who experienced success of prophylactic therapy, the mean duration of prophylaxis was 19 days (range 6-51 days)

In patients treated successfully for esophageal candidiasis, the mean duration of treatment was 15 days (range 10-

30 days).

A loading dose is not required; typically, 85% of the steady-state concentration is achieved after three daily Mycamine doses. No dosing adjustments are required based on age, race, gender, or in patients with severe renal dysfunction or mild-to-moderate hepatic insufficiency. The effect of severe hepatic impairment on micafungin pharmacokinetics has not been studied. (See Action And Clinical Pharmacology - Special Populations.) No dose adjustment for Mycamine is required with concomitant use of mycophenolate mofetil, cyclosporine, tacrolimus, prednisolone, sirolimus, nifedipine, fluconazole, voriconazole, itraconazole, amphotericin B, ritonavir, or rifampin. (See Drug Interactions).

Reconstitution

Please read this entire section carefully before beginning reconstitution. The diluent to be used for reconstitution and dilution is 0.9% Sodium Chloride Injection, USP (without a bacteriostatic agent). Alternatively, 5% Dextrose Injection, USP, may be used for reconstitution and dilution of Mycamine. Solutions for infusion are prepared as follows:

Mycamine 25 mg vial

Aseptically add 5 mL of 0.9% Sodium Chloride Injection, USP (without a bacteriostatic agent) to each 25 mg vial to yield a preparation containing approximately 5 mg micafungin/mL.

Mycamine 50 mg vial

Aseptically add 5 mL of 0.9% Sodium Chloride Injection, USP (without a bacteriostatic agent) to each 50 mg vial to yield a preparation containing approximately 10 mg micafungin/mL.

Mycamine 100 mg vial

Aseptically add 5 mL of 0.9% Sodium Chloride Injection, USP (without a bacteriostatic agent) to each 100 mg vial to yield a preparation containing approximately 20 mg micafungin/mL. To minimize excessive foaming, GENTLY dissolve the Mycamine powder by swirling the vial.

DO NOT VIGOROUSLY SHAKE THE VIAL.

As with all parenteral drug products, reconstituted Mycamine should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Do not use material if there is any evidence of precipitation or foreign matter. Aseptic technique must be strictly observed in all handling since no preservative or bacteriostatic agent is present in Mycamine or in the materials specified for reconstitution and dilution.

Dilution

The diluted solution should be protected from light. It is not necessary to cover the infusion drip chamber or the tubing.

For treatment of Candidemia and other Candida infections: Reconstitution

add 100 mg of reconstituted Mycamine (see

) into 100 mL of 0.9% Sodium Chloride Injection, USP or 100 mL of 5% Dextrose Injection, USP.

For prophylaxis of Candida infections: Reconstitution

add 50 mg of reconstituted Mycamine (see

) into 100 mL of 0.9% Sodium Chloride Injection, USP or 100 mL of 5% Dextrose Injection, USP.

For treatment of esophageal candidiasis: Reconstitution

add 150 mg of reconstituted Mycamine (see

) into 100 mL of 0.9% Sodium Chloride Injection, USP or 100 mL of 5% Dextrose Injection, USP.

Mycamine is preservative-free. Discard partially used vials.

OVERDOSAGE

For management of a suspected drug overdose, please contact your regional Poison Control Centre. Mycamine is highly protein bound and, therefore, is not dialyzable. No cases of Mycamine overdosage have been reported. Repeated daily doses up to 8 mg/kg (maximum total dose of 896 mg) in adult patients have been administered in clinical trials with no reported dose-limiting toxicity. The minimum lethal dose of Mycamine is 125 mg/kg in rats, equivalent to 8.1 times the recommended human clinical dose for esophageal candidiasis based on body surface area comparisons.

ACTION AND CLINICAL PHARMACOLOGY

Mechanism of Action

Micafungin is a semisynthetic lipopeptide (echinocandin) compound synthesized by a chemical modification of a fermentation product of Coleophoma empetri F-11899. Micafungin is a member of a class of antifungal drugs known as echinocandins. It inhibits the synthesis of 1,3-b-D glucan, an essential component of fungal cell walls, which is not present in mammalian cells.

Pharmacokinetics

The pharmacokinetics of micafungin were determined in healthy subjects, hematopoietic stem cell transplant recipients, and patients with esophageal candidiasis or invasive candidiasis up to a maximum daily dose of 8 mg/kg body weight. The relationship of area under the concentration-time curve (AUC) to micafungin dose was linear over the daily dose range of 50 mg to 150 mg and 3 mg/kg to 8 mg/kg body weight. Steady-state pharmacokinetic parameters in relevant patient populations after repeated daily administration are presented in Table 5.

HIV=human immunodeficiency virus; EC = esophageal candidiasis; HSCT = hematopoietic stem cell transplant;

IC=Candidemia and other Candida infections; a= n for Cmax and T1/2; b= n for AUC 0-24 and Cl

* AUC 0-infinity is presented for day 1 and AUC 0-24 is presented for steady state. Distribution: The mean +- standard deviation volume of distribution of micafungin at terminal phase was 0.39 +- 0.11 L/kg body weight when determined in adult patients with esophageal candidiasis at the dose range of 50 mg to 150 mg. Micafungin is highly (>99%) protein bound in vitro, independent of plasma concentrations over the range of 10 to 100 mcg/mL. The primary binding protein is albumin; however, micafungin, at therapeutically relevant concentrations, does not competitively displace bilirubin binding to albumin. Micafungin also binds to a lesser extent to a1-acid-glycoprotein. Metabolism: Micafungin is metabolized to M-1 (catechol form) by arylsulfatase, with further metabolism to M-2 (methoxy form) by catechol-O-methyltransferase. M-5 is formed by hydroxylation at the side chain (o-1 position) of micafungin catalyzed by cytochrome P450 (CYP) isozymes. Even though micafungin is a substrate for and a weak inhibitor of CYP3A in vitro, hydroxylation by CYP3A is not a major pathway for micafungin metabolism in vivo. Micafungin is neither a P-glycoprotein substrate nor inhibitor in vitro. In four healthy volunteer studies, the ratio of metabolite to parent exposure (AUC) at a dose of 150 mg/day was 6% for M-1, 1% for M-2, and 6% for M-5. In patients with esophageal candidiasis, the ratio of metabolite to parent exposure (AUC) at a dose of 150 mg/day was 11% for M-1, 2% for M-2, and 12% for M-5. Excretion: 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 is the major route of elimination (total radioactivity at 28 days was 71.0% of the administered dose).

Special Populations

Mycamine disposition has been studied in a variety of populations as described below.

Geriatric:

The exposure and disposition of a 50 mg Mycamine dose administered as a single 1- hour infusion to 10 healthy subjects aged 66-78 years were not significantly different from those in 10 healthy subjects aged 20-24 years. No dose adjustment is necessary for the elderly.

Race and Gender:

No dose adjustment of Mycamine is required based on gender or race. After 14 daily doses of 150 mg to healthy subjects, micafungin AUC in women was greater by approximately 23% compared with men, due to smaller body weight. No notable differences among white, black, and Hispanic subjects were seen. The micafungin AUC was greater by 26% in Japanese subjects compared to blacks, due to smaller body weight.

Renal Insufficiency: Mycamine does not require dose adjustment in patients with renal impairment. A single 1-hour infusion of 100 mg Mycamine was administered to 9 subjects with severe renal dysfunction (creatinine clearance <30 mL/min) and to 9 age-, gender-, and weight- matched subjects with normal renal function (creatinine clearance >80 mL/min). The maximum concentration (Cmax) and AUC were not significantly altered by severe renal impairment. Since micafungin is highly protein bound, it is not dialyzable. Supplementary dosing should not be required following hemodialysis. Hepatic Insufficiency: A single 1-hour infusion of 100 mg Mycamine was administered to 8 subjects with moderate hepatic dysfunction (Child-Pugh score 7-9) and 8 age-, gender-, and weight-matched subjects with normal hepatic function. The Cmax and AUC values of micafungin were lower by approximately 22% in subjects with moderate hepatic insufficiency. This difference in micafungin exposure does not require dose adjustment of Mycamine in patients with moderate hepatic impairment. The pharmacokinetics of Mycamine have not been studied in patients with severe hepatic insufficiency.

STORAGE AND STABILITY

Stability and Storage Recommendations

Unopened vials of lyophilized material should be stored, protected from light, at controlled room temperature, 15-30deg C.

Storage of Reconstituted Product Concentrate

The reconstituted product may be stored in the original vial for up to 24 hours at room temperature, 25deg C.

Storage of Diluted Product

The diluted infusion should be protected from light and may be stored for up to 24 hours at room temperature, 25deg C.

Note: Mycamine is preservative-free. Discard partially used vials.

SPECIAL HANDLING INSTRUCTIONS

Not Applicable.

DOSAGE FORMS, COMPOSITION AND PACKAGING

Mycamine for Injection (micafungin sodium) is available as a sterile, non-pyrogenic, lyophilized powder for intravenous infusion containing 25 mg, 50 mg or 100 mg of micafungin sodium per vial. Non-medicinal ingredients include lactose, citric acid and/or sodium hydroxide (used for pH adjustment). Following reconstitution with 0.9% Sodium Chloride for Injection, USP, the resulting pH of the solution is between 5.0-7.0. 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.

PART II: SCIENTIFIC INFORMATION

PHARMACEUTICAL INFORMATION

Drug Substance

Proper name: micafungin sodium Chemical name: Pneumocandin A0, 1-[(4R,5R)-4,5-dihydroxy-N2-[4-[5-[4- (pentyloxy)phenyl]-3- isoxazolyl]benzoyl]-L-ornithine]-4-[(4S)-4-hydroxy- 4-[4-hydroxy-3-(sulfooxy)phenyl]-L-threonine]-, monosodium salt. Molecular formula: C56H70N9NaO23S Molecular mass: 1292.26 Structural formula: Physicochemical properties: Physical Form: Micafungin sodium is a light-sensitive, hygroscopic white powder that is freely soluble in water, isotonic sodium chloride solution, N,N-dimethylformamide and dimethylsulfoxide, slightly soluble in methyl alcohol, and practically insoluble in acetonitrile, ethyl alcohol (95%), acetone, diethyl ether and n-hexane.

pH:

The pH of the reconstituted solution, with 0.9% Sodium Chloride Injection, USP, is between 5.0-7.0.

CLINICAL TRIALS

Treatment of Candidemia and Other Candida Infections

Study demographics and trial design

* Administration of study drug could be prolonged up to a maximum of 8 weeks for patients with chronic disseminated candidiasis, Candida osteomyelitis or Candida endocarditis.

+A dose of 2mg/kg was used for patients weighing < 40kg. Dose increases of 200mg/day (patients weighing > 40kg) or 4mg/kg/day (patients weighing < 40kg) were permitted.

++ Administration of study drug could be prolonged up to a maximum of 8 weeks for patients with chronic disseminated candidiasis, Candida osteomyelitis or Candida endocarditis.

In the presentation of the Efficacy Analysis for study FG-463-21-08 (Table 8), the Independent Data Review Board modified Full Analysis Set (IDRB-mFAS) was used. The IDRB-mFAS population was N=248 for Mycamine and

N=246 for AmBisome.

Two dose levels of Mycamine were evaluated in a phase III, randomized, double-blind study to determine the efficacy and safety versus caspofungin in patients with invasive candidiasis and candidemia. Patients were randomized to receive once daily intravenous infusions (IV) of Mycamine, either 100 mg/day or 150 mg/day or caspofungin (70 mg loading dose followed by 50 mg maintenance dose). Patients were stratified by APACHE II score (<= 20 or >20) and by geographic region. Patients with Candida endocarditis were excluded from this analysis. Outcome was assessed by overall treatment success based on clinical (complete resolution or improvement in attributable signs and symptoms and radiographic abnormalities of the Candida infection and no additional antifungal therapy) and mycological (eradication or presumed eradication) response at the end of IV therapy. Deaths that occurred during IV study drug therapy were treated as failures. In this study, 111/578 (19.2 %) of the patients had baseline APACHE II scores of >20, and 50/578 (8.7%) were neutropenic at baseline (absolute neutrophil count less than 500 cells/mm3). Outcome, relapse and mortality data are shown for the recommended dose of Mycamine (100 mg/day) and caspofungin in Table 7.

70 mg loading dose on day 1 followed by 50 mg/day thereafter (caspofungin)

1. All patients who received at least one dose of study medication and had documented invasive candidiasis or candidemia. Patients with Candida endocarditis were excluded from the analyses.

2. A patient may have had >1 organ of dissemination

3. A patient may have had >1 baseline infection species

4. All patients who had a culture confirmed relapse or required systemic antifungal therapy in the post treatment period for a suspected or proven Candida infection. Also includes patients who died or were not assessed in follow-up.

In a second phase III, randomized, double-blind, parallel group study, the efficacy and safety of Mycamine versus AmBisome were determined in non-neutropenic and neutropenic (absolute neutrophil count [ANC] < 500 cells/mcL) patients with invasive candidiasis or candidemia. Patients received an initial dose of IV micafungin 100 mg qd (2.0 mg/kg for patients weighing

<=

40 kg) or IV AmBisome 3 mg/kg by 1-hour infusion in a blinded manner.

The primary endpoint was success based on clinical (complete or partial) and mycological (eradication or presumed eradication) response at the end of IV therapy and no additional systemic antifungal therapy. Deaths that occurred during IV study drug therapy were treated as failures. In this study a total of 32/248 (12.9%) of patients in the micafungin group and 25/246 (10.2%) of patients in the AmBisome group were neutropenic at baseline (absolute neutrophil count less than 500 cells/mcL). A baseline APACHE II score of >20 was recorded for 61/226 (27.0%) of patients in the micafungin group and 53/219 (24.2%) in the AmBisome group. Outcome, relapse and mortality data are shown for the recommended dose of Mycamine (100 mg/day) and AmBisome in Table 8.

1. Success is defined as a positive clinical response (complete or partial) and a positive microbiological response (eradication or presumed eradication) at the end of blinded therapy. Patients that died during treatment (first dose

through last dose day +1), missed evaluation, or met one of following 3 criteria of systemic antifungal therapy were considered a failure: i. pre-treatment (within 72 hours of study drug administration) systemic (IV, PO, CIV) antifungal

use for therapeutic, non-prophylaxis purposes for > 2 days; ii. any on study treatment systemic antifungal use for >1 day; or iii. post-treatment systemic antifungal use for therapeutic purposes initiated within 48 hours of discontinuation

of study therapy.

Micafungin 100 - AmBisome. 95% CI for difference based on the Cochran-Mantel-Haenszel method controlling for baseline neutropenia status.

Neutropenia was assessed by Investigator

1. A patient may have had more than one baseline fungal infection species.

2. Death Day > Last dose day+1

3. IV therapy duration is from first dose day through last dose day +1

Treatment of Esophageal Candidiasis

Study results

In two controlled trials involving 763 patients with esophageal candidiasis, 445 adults with endoscopically-proven candidiasis received Mycamine, and 318 received fluconazole for a median duration of 14 days (range 1-33 days). Mycamine was evaluated in a phase III, randomized, double-blind study which compared Mycamine 150 mg/day (n=260) to intravenous fluconazole 200 mg/day (n=258) in adults with endoscopically-proven esophageal candidiasis. 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. Endoscopic cure was defined as endoscopic grade 0, based on a scale of 0-3. 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. As shown in Table 10 below, endoscopic cure, clinical cure, overall therapeutic cure, and mycological eradication were comparable for patients in the Mycamine and fluconazole treatment groups.

*Endoscopic and clinical outcome were measured in modified intent-to-treat population, including all randomized

patients who received >= 1 dose of study treatment. Mycological outcome was determined in the per protocol (evaluable) population, including patients with confirmed esophageal candidiasis who received at least 10 doses of

study drug, and had no major protocol violations.

+calculated as Mycamine - fluconazole

Most patients (96%) in this study had Candida albicans isolated at baseline. The efficacy of Mycamine was evaluated in less than 10 patients with Candida species other than C. albicans, most of which were isolated concurrently with C. albicans. Relapse was assessed at 2 and 4 weeks post-treatment in patients with overall therapeutic cure at end of treatment. Relapse was defined as a recurrence of clinical symptoms or endoscopic lesions (endoscopic grade > 0). 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, as shown in Table 11 below.

*calculated as Mycamine - fluconazole; N=number of patients with overall therapeutic cure (both clinical and

endoscopic cure at end-of-treatment);

+Relapse included patients who died or were lost to follow-up, and those who received systemic anti-fungal therapy in the post-treatment period

In this study, 459 of 518 (88.6%) patients had oropharyngeal candidiasis in addition to esophageal candidiasis at baseline. At the end of treatment 192/230 (83.5%) Mycamine treated patients and 188/229 (82.1%) of fluconazole treated patients experienced resolution of signs and symptoms of oropharyngeal candidiasis. Of these, 32.3% in the Mycamine group, and 18.1% in the fluconazole group (treatment difference = 14.2%; 95% confidence interval [5.6, 22.8]) had symptomatic relapse at 2 weeks post-treatment. Relapse included patients who died or were lost to follow-up, and those who received systemic antifungal therapy during the post-treatment period. Cumulative relapse at 4 weeks post-treatment was 52.1% in the Mycamine group and 39.4% in the fluconazole group (treatment difference 12.7%, 95% confidence interval [2.8, 22.7]).

Prophylaxis of Candida Infections in Hematopoietic Stem Cell Transplant Recipients

Study demographics and trial design

Study Results

In 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 or syngeneic (46%) or allogeneic (54%) stem cell transplant. The status of the patients' underlying malignancy at the time of randomization was: 365 (41%) patients with active disease, 326 (37%) patients in remission, and 195 (22%) patients in relapse. The more common baseline underlying diseases in the 476 allogeneic transplant recipients were: chronic myelogenous leukemia (22%), acute myelogenous leukemia (21%), acute lymphocytic leukemia (13%), and non-Hodgkin's lymphoma (13%). In the 404 autologous and syngeneic transplant recipients the more common baseline underlying diseases were: multiple myeloma (37.1%), non-Hodgkin's lymphoma (36.4%), and Hodgkin's disease (15.6%). During the study, 198 of 882 (22.4%) transplant recipients had proven graft-versus-host disease; and 475 of 882 (53.9%) recipients received immunosuppressive medications for treatment or prophylaxis of graft-versus-host disease. Study drug was continued until the patient had neutrophil recovery to an absolute neutrophil count (ANC) of >= 500 cells/mm3 or up to a maximum of 42 days after transplant. The average duration of drug administration was 18 days (range 1 to 51days). Successful prophylaxis was 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. A suspected systemic fungal infection was diagnosed in patients with neutropenia (ANC <500 cells/mm3); persistent or recurrent fever (while ANC <500 cells/mm3) of no known etiology; and failure to respond to at least 96 hours of broad spectrum antibacterial therapy. A persistent fever was defined as four consecutive days of fever greater than 38oC. A recurrent fever was defined as having at least one day with temperatures >= 38.5 oC after having at least one prior temperature > 38 oC; or having two days of temperatures > 38 oC after having at least one prior temperature > 38oC. Transplant recipients who died or were lost to follow-up during the study were considered failures of prophylactic therapy. Successful prophylaxis was documented in 80.7% of recipients who received Mycamine, and in 73.7% of recipients who received fluconazole (7.0% difference [95% CI = 1.5, 12.5]), as shown in Table 13, along with other study endpoints. The use of systemic antifungal therapy post-treatment was 42% in both groups. The number of proven breakthrough Candida infections was 4 (0.9%) in the Mycamine and 2 (0.4%) in the fluconazole group. The efficacy of Mycamine against infections caused by fungi other than Candida has not been established.

* Defined as the absence of Proven, Probable or Suspected fungal infections through the end of therapy and the absence of a proven

or probable infection the end of the 4-week post-treatment period. Difference (Mycamine - Fluconazole): +7.0% [95% CI=1.5, 12.5]

1 Through end-of-study (4 weeks post- therapy) 2 Through end-of-therapy.

DETAILED PHARMACOLOGY

Human pharmacokinetics of micafungin were determined in healthy subjects, hematopoietic stem cell transplant recipients and patients with esophageal candidiasis up to a maximum of daily dose of 8 mg/kg body weight. The relationship of area under the curve (AUC) to micafungin dose was linear over the daily dose range of 50 mg to 150 mg and 3 mg/kg to 8 mg/kg body weight. Detailed pharmacokinetics in relevant patient groups and special populations are described previously in the Action and Clinical Pharmacology section.

MICROBIOLOGY

Activity In Vitro

Micafungin exhibited in-vitro activity against C. albicans, C. glabrata, C. guilliermondii, C. kefyr,

krusei, C. lusitaniae, C. parapsilosis, C. pelliculosa and C. tropicalis. Standardized susceptibility testing methods for 1,3- b-D-glucan synthesis inhibitors have not been established, and the results of susceptibility studies do not correlate with clinical outcome.

Activity In Vivo

Micafungin sodium has shown activity in both mucosal and disseminated murine models of candidiasis. Micafungin sodium, administered to immunosuppressed mice in models of disseminated candidiasis prolonged survival and/or decreased the mycological burden.

Drug Resistance

Mutants of Candida with reduced susceptibility to micafungin have been identified in some patients during treatment suggesting a potential for the development of drug resistance. The incidence of drug resistance by various clinical isolates of Candida species is unknown.

TOXICOLOGY

High doses of micafungin sodium (5 to 8 times the highest recommended human dose, based on AUC comparisons) have been associated with irreversible changes to the liver when administered for 3 or 6 months, and these changes may be indicative of pre-malignant processes.

Carcinogenesis, Mutagenesis and Impairment of Fertility

Hepatic carcinomas and adenomas were observed in a 6-month intravenous toxicology study with an 18-month recovery period of micafungin sodium in rats designed to assess the reversibility of hepatocellular lesions. Rats administered micafungin sodium for 3 months at 32 mg/kg/day (corresponding to 8 times the highest recommended human dose [150 mg/day], based on AUC comparisons), exhibited colored patches/zones, multinucleated hepatocytes and altered hepatocellular foci after 1 or 3 month recovery periods, and adenomas were observed after 20-month recovery period. Rats administered micafungin sodium at the same dose for 6 months exhibited adenomas after a 12- month recovery period; after an 18-month recovery period, an increased incidence of adenomas was observed, and additionally, carcinomas were detected. A lower dose of micafungin sodium (equivalent to 5 times the human AUC) in the 6-month rat study resulted in a lower incidence of adenomas and carcinomas following 18 months recovery. The duration of micafungin dosing in these rat studies (3 or 6 months) exceeds the usual duration of Mycamine dosing in patients, which is typically less than 1 month for treatment of esophageal candidiasis, but dosing may exceed 1 month for Candida prophylaxis. Although the increase in carcinomas in the 6-month rat study did not reach statistical significance, the persistence of altered hepatocellular foci subsequent to micafungin dosing, and the presence of adenomas and carcinomas in the recovery periods suggest a causal relationship between micafungin sodium, altered hepatocellular foci, and hepatic neoplasms. Whole-life carcinogenicity studies of Mycamine in animals have not been conducted, and it is not known whether the hepatic neoplasms observed in treated rats also occur in other species, or if there is a dose threshold for this effect. Micafungin sodium was not mutagenic or clastogenic when evaluated in a standard battery of in- vitro and in-vivo tests (i.e., bacterial reversion - S. typhimurium, E. coli; chromosomal aberration; intravenous mouse micronucleus). Male rats treated intravenously with micafungin sodium for 9 weeks showed vacuolation of the epididymal ductal epithelial cells at or above 10 mg/kg (about 0.6 times the recommended clinical dose for esophageal candidiasis, based on body surface area comparisons). Higher doses (about twice the recommended clinical dose, based on body surface area comparisons) resulted in higher epididymis weights and reduced numbers of sperm cells. In a 39-week intravenous study in dogs, seminiferous tubular atrophy and decreased sperm in the epididymis were observed at 10 and 32 mg/kg, doses equal to about 2 and 7 times the recommended clinical dose, based on body surface area comparisons. There was no impairment of fertility in animal studies with micafungin sodium.

REFERENCES

1. De Wet NT, Bester AJ, Viljoen JJ. et al., A randomized, double blind, comparative trial of micafungin (FK463) vs. fluconazole for the treatment of oesophageal candidiasis. Aliment Pharmacol Ther 2005; 21: 899-907

2. De Wet N, Llanos-Cuentas A, Suleiman J. et al., A Randomized, Double-Blind, Parallel- Group, Dose-Response Study of Micafungin Compared with Fluconazole for the Treatment of Esophageal Candidiasis in HIV-Positive Patients. Clinical Infectious Diseases 2004; 39:842-9

3. Kuse ER, Chetchotisakd P, da Cunha CA, et al. Micafungin versus liposomal amphotericin B for candidaemia and invasive candidosis: a phase III randomized double-blind trial. Lancet. 2007 May 5; 369(9572):1519-27.

4. Pappas PG, Rotstein CMF, Betts RF, et al., Micafungin versus Caspofungin for Treatment of Candidemia and Other Forms of Invasive Candidiasis. Clinical Infectious Diseases 2007 Oct 1; 45(7):883-93.

5. van Burik JA, Ratanatharathorn V, Stepan D, et al., Micafungin versus Fluconazole for Prophylaxis against Invasive Fungal Infections during Neutropenia in Patients Undergoing Hematopoietic Stem Cell Transplantation. Clinical Infectious Diseases 2004; 39:1407-16

PART III: CONSUMER INFORMATION

PrMycamine(r)

Micafungin sodium for injection

This leaflet is part III of a three-part "Product Monograph" published when Mycamine was approved for sale in Canada and is designed specifically for Consumers. This leaflet is a summary and will not tell you everything about Mycamine. Contact your doctor or pharmacist if you have any questions about the drug.

ABOUT THIS MEDICATION

What the medication is used for:

Your doctor has prescribed Mycamine to treat one of several types of fungal infections described below.

• Mycamine is used to treat certain fungal infections of the esophagus (food tube connecting the mouth to the stomach). These infections are called esophageal candidiasis and are caused by Candida (fungus). Healthy individuals usually have Candida in their mouth and throat without any ill effects. An infection occurs when the body's resistance is lowered.

• Mycamine is used to treat patients with certain fungal infections caused by Candida including Candidemia and other Candida infections as determined by the doctor.

• Mycamine is used to help prevent fungal infections caused by Candida in patients who are undergoing a stem cell transplant.

Mycamine has not been studied for the treatment of other types of fungal infections.

What it does:

Mycamine is an antifungal drug that belongs to a class of drugs called echinocandins. Mycamine interferes with the production

of a component (glucan polysaccharide) of the fungal cell wall that is necessary if the fungus is to continue living and growing.

Fungal cells exposed to Mycamine have incomplete or defective cell walls, making them fragile and unable to grow.

When it should not be used:

Do not use Mycamine if you are allergic to it, another echinocandin or any of the ingredients in Mycamine (see What the non-medical ingredients are).

Use in children:

• Mycamine should not be used in patients under 18 years of

age.

What the medicinal ingredient is:

Micafungin sodium

What the important nonmedicinal ingredients are:

Lactose, citric acid and/or sodium hydroxide

This is a complete listing of all non-medicinal ingredients.

What dosage forms it comes in:

Mycamine for Injection (micafungin sodium) is available as a sterile powder for injection containing 25 mg, 50 mg or 100 mg

micafungin sodium per vial.

WARNINGS AND PRECAUTIONS

Serious Warnings and Precautions:

The use of Mycamine may sometimes cause severe allergic reactions including shock (see Side Effects).

Serious liver problems including liver inflammation or worsening of liver failure (see Side Effects).

Mycamine may cause kidney problems, kidney failure, and abnormal kidney function tests.

Mycamine may cause destruction of red blood cells called hemolysis or hemolytic anemia.

Use in pregnancy and breast-feeding:

Mycamine has not been studied in pregnant women. Mycamine should not be used in pregnancy unless the doctor decides the

potential benefit justifies the potential risk to the fetus.

It is not known if Mycamine is excreted in breast milk. You and your doctor will discuss this.

Use in patients with liver problems:

Patients with liver problems may require extra vigilance by their doctor to monitor liver function. Be sure to tell your doctor if

you have had or now have liver problems.

BEFORE you use Mycamine talk to your doctor or pharmacist if:

You are taking or plan to take other medications, including those obtained without a prescription.

You have liver problems

You are pregnant

You are breast feeding

You are allergic to any component of Mycamine.

INTERACTIONS WITH THIS MEDICATION

Mycamine and other medicines may interact with each other. Tell your healthcare professional about all the medicines you take including prescription and non-prescription medicines, vitamins, and herbal supplements. Especially, tell your healthcare professional if you take:

• sirolimus (Rapamune)

• nifedipine (Adalat)

• itraconazole (Sporanox)

• amphotericin B

The doses of these medicines may need to be reduced while you are receiving Mycamine.

PROPER USE OF THIS MEDICATION

Usual Adult dose:

The treatment schedule and dosage will be set by your doctor, who will monitor your response and condition. Mycamine should be administered once daily by slow intravenous infusion of approximately 1 hour.

SIDE EFFECTS AND WHAT TO DO ABOUT THEM

Any medicine may have unintended or undesirable effects, so- called side effects.

Common side effects of Mycamine include rash, mental confusion, nausea, vomiting, itching, facial swelling, diarrhea, fever, fatigue and relaxing of blood vessels (vasodilation). Mycamine may also cause injection site reactions such as inflammation of the veins.

Other reported medication-related undesirable effects include: anemia, low white blood cells count, abdominal pain, injection site pain, itching, trouble breathing, swelling of the hands, ankles, or feet, impaired liver function, sleep problems, and alterations in some laboratory blood tests. Life-threatening allergic reactions have been reported rarely during administration of Mycamine.

Other side effects may also occur rarely; and, as with any prescription medication, some side effects may be serious. Ask your doctor or pharmacist for more information. Tell your doctor promptly about these or any other unusual symptoms.

This is not a complete list of side effects. For any unexpected effects while taking Mycamine contact your doctor.

HOW TO STORE IT

Store between 15-30deg C. Protect from light.

REPORTING SUSPECTED SIDE EFFECTS

To monitor drug safety, Health Canada through the Canada Vigilance Program collects information on serious and unexpected side effects of drugs. If you suspect you have had a serious or unexpected reaction to this drug you may notify Canada Vigilance:

By toll-free telephone: 1-866-234-2345 By toll-free fax: 1-866-678-6789

Online: www.healthcanada.gc.ca/medeffect By email: CanadaVigilance @hc-sc.gc.ca

By regular mail:

Canada Vigilance National Office Marketed Health Products Safety and Effectiveness Information Bureau Marketed Health Products Directorate Health Products and Food Branch Health Canada

Tunney's Pasture, AL 0701C Ottawa ON K1A 0K9

or

Astellas Pharma Canada, Inc. by: Toll-free telephone: 1-888-338-1824

Toll-free fax: 1-866-493-3419 By regular mail:

Astellas Pharma Canada, Inc.

675 Cochrane Drive, Suite 500, West Tower Markham, Ontario L3R 0B8

NOTE: Should you require information related to the management of the side effect, please contact your health care provider before notifying Canada Vigilance. The Canada Vigilance Program does not provide medical advice.

MORE INFORMATION

This document plus the full product monograph, prepared for health professionals can be found at: http://www.astellas.com/ca/

or by contacting the sponsor, Astellas Pharma Canada, Inc., at: 1-888-338-1824

This leaflet was prepared by Astellas Pharma Canada, Inc. Last revised: September 2, 2008

Mycamine is a Registered Trademark of Astellas Pharma, Inc.