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, 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
Two, 2-year female rat studies were conducted with micafungin sodium at daily doses of 20 mg/kg (5-times clinical exposure) and 32 mg/kg (8-times clinical exposure). In the one study, animals received intravenous micafungin sodium for 6 months, followed by 18 months of observation and in the other study, animals received intravenous micafungin sodium for 3 months, followed by 21 months of observation.
In the 6-month treatment study, the incidence of hepatocellular adenoma was significantly increased in the 32 mg/kg treatment group at the end of the 18-month recovery period. The incidence of hepatocellular carcinoma was not significantly increased at the end of the 18-month recovery in either treatment group. In the 3-month treatment study, the number of animals bearing hepatocellular adenoma (incidence) was not significantly increased in the 32 mg/kg group, however, the number of hepatocellular adenomas in the 32 mg/kg group was significantly increased as compared to the control group at the end of the 21-month recovery period. No carcinomas were observed in the 3-month treatment study.
In a 13-week intravenous dog study with 4-week recovery (doses to 10 times clinical exposure), liver discoloration, cellular infiltration and hypertrophy remained visible at the end of the 4-week recovery period.
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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