Micafungin

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Product Details

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.

DESCRIPTION

Micafungin sodium is a sterile, lyophilized product for intravenous (IV) infusion that contains micafungin sodium. Micafungin sodium is a semisynthetic lipopeptide (echinocandin) synthesized by a chemical modification of a fermentation product ofColeophoma empetri F-11899. Micafungin inhibits the synthesis of 1, 3-β-D-glucan,an integral component of the fungal cell wall.Each single-use vial contains 50 mg or 100 mg micafungin sodium, 200 mg lactose,with citric acid and/or sodium hydroxide (used for pH adjustment). MYCAMINE mustbe diluted with 0.9% Sodium Chloride Injection, USP, or 5% Dextrose Injection,USP (see DOSAGE AND ADMINISTRATION). Following reconstitution with 0.9%Sodium Chloride Injection, USP, the resulting pH of the solution is between 5.0-7.0.Micafungin sodium is chemically designated as:

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.The empirical/molecular formula is C56H70N9NaO23S and the formula weight is 1292.26.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.

CLINICAL PHARMACOLOGY

Pharmacokinetics

The pharmacokinetics of micafungin were determined in healthy subjects,hematopoietic stem cell transplant recipients, and patients with esophageal 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 the table below.

Distribution

The mean ± standard deviation volume of distribution of micafungin at terminalphase was 0.39 ± 0.11 L/kg body weight when determined in adult patients withesophageal candidiasis at the dose range of 50 mg to 150 mg.Micafungin is highly (>99%) protein bound in vitro, independent of plasmaconcentrations over the range of 10 to 100 mcg/mL. The primary binding protein is albumin; however, micafungin, at therapeutically relevant concentrations, does notcompetitively displace bilirubin binding to albumin. Micafungin also binds to a lesser.extent to α1-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 (ω-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.

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.

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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.

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.

MICROBIOLOGY

Mechanism of Action

Micafungin, the active ingredient in MYCAMINE, inhibits the synthesis of 1,3-β-Dglucan,

an essential component of fungal cell walls, which is not present in

mammalian cells.

Activity In Vitro

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

parapsilosis, and C. tropicalis. Standardized susceptibility testing methods for 1,3-

β-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

The potential for development of drug resistance is not known.

INDICATIONS AND USAGE

MYCAMINE is indicated for:

• Treatment of patients with esophageal candidiasis (see CLINICAL

STUDIES, MICROBIOLOGY)

• Prophylaxis of Candida infections in patients undergoing hematopoietic stem

cell transplantation (see CLINICAL STUDIES, MICROBIOLOGY).

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NOTE: The efficacy of MYCAMINE against infections caused by fungi other than

Candida has not been established.

CONTRAINDICATIONS

MYCAMINE is contraindicated in patients with hypersensitivity to any component of

this product.

WARNINGS:

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.

PRECAUTIONS

Hepatic Effects

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 Effects

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

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 was 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.

Drug Interactions

A total of 11 clinical drug-drug interaction studies were conducted in healthy

volunteers to evaluate the potential for interaction between MYCAMINE and

mycophenolate mofetil, cyclosporine, tacrolimus, prednisolone, sirolimus, nifedipine,

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fluconazole, ritonavir, and rifampin. In these studies, no interaction that altered the

pharmacokinetics of micafungin was observed.

There was no effect of a single dose or multiple doses of MYCAMINE on

mycophenolate mofetil, cyclosporine, tacrolimus, prednisolone, 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. Patients receiving sirolimus or

nifedipine in combination with MYCAMINE should be monitored for sirolimus or

nifedipine toxicity and sirolimus 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.

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 a 21-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

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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.

Pregnancy Category C

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, adequate, well-controlled studies were not conducted in pregnant

women. Animal studies are not always predictive of human response; therefore,

MYCAMINE should be used during pregnancy only if clearly needed.

Nursing Mothers

Micafungin was found in the milk of lactating, drug-treated rats. It is not known

whether micafungin is excreted in human milk. Caution should be exercised when

MYCAMINE is administered to a nursing woman.

Pediatric Use

The safety and efficacy of MYCAMINE in pediatric patients has not been

established in clinical studies.

Geriatric Use

A total of 186 subjects in clinical studies of MYCAMINE were 65 years of age and

older, and 41 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.

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ADVERSE REACTIONS

General

Possible histamine-mediated symptoms have been reported with MYCAMINE,

including rash, pruritus, facial swelling, and vasodilatation.

Injection site reactions, including phlebitis and thrombophlebitis have been reported,

at MYCAMINE doses of 50-150 mg/day. These events tended to occur more often

in patients receiving MYCAMINE via peripheral intravenous administration.

Clinical Adverse Experiences

Because clinical trials are conducted under widely varying conditions, adverse

reaction rates observed in clinical trials of MYCAMINE cannot be directly compared

to rates in clinical trials of another drug and may not reflect the rates observed in

practice. The adverse reaction information from clinical trials does provide a basis

for identifying adverse events that appear to be related to drug use and for

approximating rates.

Esophageal Candidiasis

In a phase 3, randomized, double-blind study for treatment of esophageal

candidiasis, a total of 202/260 (77.7%) patients who received MYCAMINE 150

mg/day and 186/258 (72.1%) patients who received intravenous fluconazole 200

mg/day experienced an adverse event. Adverse events considered to be drugrelated

occurred in 72 (27.7%) and 55 (21.3%) patients in the MYCAMINE and

fluconazole treatment groups, respectively. Drug-related adverse events resulting

in discontinuation were reported in 6 (2.3%) MYCAMINE treated patients; and in 2

(0.8%) fluconazole treated patients. Rash and delirium were the most common

drug-related adverse events resulting in MYCAMINE discontinuation. Drug-related

adverse experiences occurring in ≥0.5% of the patients in either treatment group.

Packaging

The packaging can be customized, normally, 1kgs/Tin, or 5kgs/Tin or per drums