Micafungin sodium
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Gloria Picoy [2]
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Overview
Micafungin sodium is an echinocandin that is FDA approved for the treatment of candidemia, acute disseminated candidiasis, candida peritonitis and abscesses, and esophageal Candidiasis; prophylaxis of Candida Infections in Patients Undergoing Hematopoietic Stem Cell Transplantation. Common adverse reactions include diarrhea, nausea, vomiting, pyrexia, thrombocytopenia, and headache.
Adult Indications and Dosage
FDA-Labeled Indications and Dosage (Adult)
- Treatment of patients with candidemia, acute cisseminated candidiasis, candida peritonitis and abscesses
- Dosage: 100 mg once daily
- Treatment of patients with esophageal candidiasis
- Dosage: 150 mg once daily
- Prophylaxis of candida infections in patients undergoing hematopoietic stem cell transplantation
- Dosage: 50 mg once daily
Off-Label Use and Dosage (Adult)
Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Micafungin sodium in adult patients.
Non–Guideline-Supported Use
- Invasive aspergillosis
- Prophylaxis against invasive aspergillosis in high-risk patients
- Candida endophthalmitis
- Candida infection of the cardiovascular system
- Candida osteoarticular infections
- Chronic disseminated candidiasis
- Empiric antifungal therapy for suspected candidiasis in nonneutropenic patients
- Oropharyngeal candidiasis in patients with HIV
- Prophylaxis of invasive fungal infections
- Oropharyngeal candidiasis
- Chronic necrotizing or cavitary pulmonary aspergillosis
Pediatric Indications and Dosage
FDA-Labeled Indications and Dosage (Pediatric)
Micafungin sodium is indicated in pediatric patients 4 months and older for:
- Treatment of patients with candidemia, acute cisseminated candidiasis, candida peritonitis and abscesses
- Dosage: 2 mg/kg once daily
- Treatment of patients with esophageal candidiasis
- Dosage for 30 kg or less: 3 mg/kg once daily
- Dosage for greater than 30 kg: 2.5 mg/kg once daily
- Prophylaxis of candida infections in patients undergoing hematopoietic stem cell transplantation
- Dosage: 1 mg/kg once daily
Off-Label Use and Dosage (Pediatric)
Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Micafungin sodium in pediatric patients.
Non–Guideline-Supported Use
- Invasive aspergillosis
- Prophylaxis of invasive fungal infections
Contraindications
Micafungin sodium is contraindicated in persons with known hypersensitivity to micafungin, any component of micafungin sodium, or other echinocandins.
Warnings
Hypersensitivity Reactions
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.
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 reaction 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.
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 impairment, hepatitis, and 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 impairment or acute renal failure have been reported in patients who received Mycamine. In fluconazole-controlled trials, the incidence of drug-related renal adverse reactions 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.
Adverse Reactions
Clinical Trials Experience
In all clinical trials with Mycamine, 2497/2748 (91%) adult patients experienced at least one treatment-emergent adverse reaction.
Candidemia and Other Candida Infections
In a randomized, double-blind study for treatment of candidemia and other Candida infections, treatment-emergent adverse reactions occurred in 183/200 (92%), 187/202 (93%) and 171/193 (89%) patients in the Mycamine 100 mg/day, Mycamine 150 mg/day, and caspofungin (a 70 mg loading dose followed by a 50 mg/day dose) treatment groups, respectively. Selected treatment-emergent adverse reactions, those occurring in 5% or more of the patients and more frequently in a Mycamine treatment group, are shown in TABLE 3.
In a second, supportive, randomized, double-blind study for treatment of candidemia and other Candida infections, treatment-emergent adverse reactions occurred in 245/264 (93%) and 250/265 (94%) patients in the Mycamine (100 mg/day) and AmBisome (3 mg/kg/day) treatment groups, respectively. The following treatment-emergent adverse reactions in the Mycamine treated patients at least 16 years of age were notable: nausea (10% vs. 8%); diarrhea (11% vs. 11%), vomiting (13% vs. 9%), abnormal liver function tests (4% vs. 3%); increased aspartate aminotransferase (3% vs. 2%), and increased blood alkaline phosphatase (3% vs. 2%), in the Mycamine and AmBisome treatment groups, respectively.
Esophageal Candidiasis
In a randomized, double-blind study for treatment of esophageal candidiasis, a total of 202/260 (78%) patients who received Mycamine 150 mg/day and 186/258 (72%) patients who received intravenous fluconazole 200 mg/day experienced an adverse reaction. Treatment-emergent adverse reactions resulting in discontinuation were reported in 17 (7%) Mycamine treated patients; and in 12 (5%) fluconazole treated patients. Selected treatment-emergent adverse reactions, those occurring in 5% or more of the patients and more frequently in the Mycamine group, are shown in TABLE 4.
Prophylaxis of Candida Infections in Hematopoietic Stem Cell Transplant Recipients
A double-blind study was conducted in a total of 882 patients scheduled to undergo an autologous or allogeneic hematopoietic stem cell transplant. The median duration of treatment was 18 days (range 1 to 51 days) in both treatment arms.
All adult patients who received Mycamine (382) or fluconazole (409) experienced at least one adverse reaction during the study. Treatment-emergent adverse reactions resulting in Mycamine discontinuation were reported in 15 (4%) adult patients; while those resulting in fluconazole discontinuation were reported in 32 (8%). Selected adverse reactions, those reported in 15% or more of adult patients and more frequently on the Mycamine treatment arm, are shown in TABLE 5.
Other selected adverse reactions reported at less than 5% in adult clinical trials are listed below:
- Blood and lymphatic system disorders: coagulopathy, pancytopenia, thrombotic thrombocytopenic purpura
- Cardiac disorders: cardiac arrest, myocardial infarction, pericardial effusion
- General disorders and administration site conditions: infusion reaction, injection site thrombosis
- Hepatobiliary disorders: hepatocellular damage, hepatomegaly, jaundice, hepatic failure
- Immune disorders: hypersensitivity, anaphylactic reaction
- Nervous system disorders: convulsions, encephalopathy, intracranial hemorrhage
- Psychiatric disorders: delirium
- Skin and subcutaneous tissue disorders: urticaria
Clinical Trials Experience in Pediatric Patients
The overall safety of Mycamine was assessed in 479 patients 3 days through 16 years of age who received at least one dose of Mycamine in 11 separate clinical studies. The mean treatment duration was 24.8 days. A total of 246 patients received at least one dose of Mycamine 2 mg/kg or higher.
Of the 479 pediatric patients, 264 (55%) were male, 319 (67%) were Caucasians, with the following age distribution: 116 (24%) less than 2 years, 108 (23%) between 2 and 5 years, 140 (29%) between 6 years and 11 years, and 115 (24%) between 12 and 16 years of age.
In all pediatric studies with Mycamine, 439/479 (92%) patients experienced at least one treatment-emergent adverse reaction.
Two studies that included pediatric patients were randomized, double-blind, and active-controlled: The invasive candidiasis and candidemia study investigated the efficacy and safety of Mycamine (2 mg/kg/day for patients weighing 40 kg or less and 100 mg/day for patients weighing greater than 40 kg) compared to AmBisome (3 mg/kg/day) in 112 pediatric patients. Treatment-emergent adverse reactions occurred in 51/56 (91%) of patients in the Mycamine group and 52/56 (93%) of patients in the AmBisome group. Treatment-emergent adverse reactions resulting in Mycamine discontinuation were reported in 2 (4%) pediatric patients; while those resulting in AmBisome discontinuation were reported in 9 (16%).
The prophylaxis study in patients undergoing HSCT investigated the efficacy of Mycamine (1 mg/kg/day for patients weighing 50 kg or less and 50 mg/day for patients weighing greater than 50 kg) as compared to fluconazole (8 mg/kg/day for patients weighing 50 kg or less and 400 mg/day for patients weighing greater than 50 kg). All 91 pediatric patients experienced at least one treatment-emergent adverse reaction. Three (7%) pediatric patients discontinued Mycamine due to adverse reaction; while one (2%) patient discontinued fluconazole.
The selected treatment-emergent adverse reactions, those occurring in 15% or more of the patients and more frequently in a Mycamine group, for all Mycamine pediatric studies and for the two comparative studies (candidemia and prophylaxis) described above are shown in TABLE 6.
Other clinically significant adverse reactions reported at less than 15% in pediatric clinical trials are listed below:
- Hepatobiliary disorders: hyperbilirubinemia
- Investigations: liver function tests abnormal
- Renal Disorders: renal failure
Postmarketing Experience
The following adverse reactions have been identified during the post-approval use of micafungin sodium for injection. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency.
- Blood and lymphatic system disorders: disseminated intravascular coagulation
- Hepatobiliary disorders: hepatic disorder
- Renal and urinary disorders: renal impairment
- Skin and subcutaneous tissue disorders: Stevens-Johnson syndrome, toxic epidermal necrolysis
- Vascular disorders: shock
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, and rifampin. In these studies, no interaction that altered the pharmacokinetics of Mycamine was observed.
There was no effect of a single dose or multiple doses of Mycamine on mycophenolate mofetil, cyclosporine, tacrolimus, prednisolone, fluconazole, and voriconazole 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.
Patients receiving sirolimus, nifedipine or itraconazole in combination with Mycamine should be monitored for sirolimus, nifedipine or itraconazole toxicity and the sirolimus, nifedipine or itraconazole dosage should be reduced if necessary.
Micafungin is neither a substrate nor an inhibitor of P-glycoprotein and, therefore, would not be expected to alter P-glycoprotein-mediated drug transport activity.
Use in Specific Populations
Pregnancy
Pregnancy Category (FDA): C There are no adequate and well-controlled studies of Mycamine in pregnant women. Animal reproduction studies in rabbits showed visceral abnormalities and increased abortion at 4 times the recommended human dose. However, animal studies are not always predictive of human response. Mycamine should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
When pregnant rabbits were given 4 times the recommended human dose, there were increased abortion and visceral abnormalities including abnormal lobation of the lung, levocardia, retrocaval ureter, anomalous right subclavian artery, and dilatation of the ureter.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Micafungin sodium in women who are pregnant.
Labor and Delivery
There is no FDA guidance on use of Micafungin sodium during labor and delivery.
Nursing Mothers
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
Safety and effectiveness in pediatric patients younger than 4 months of age have not been established.
Safety and effectiveness of Mycamine in pediatric patients 4 months of age and older have been demonstrated based on the evidence from adequate and well-controlled studies in adult and pediatric patients and additional pediatric pharmacokinetic and safety data. Two randomized, double-blind, active control studies investigated the safety and efficacy of Mycamine in both adult and pediatric patients: one for the treatment of invasive candidiasis and candidemia and the other for prophylaxis of Candida infections in patients undergoing HSCT.
Geriatic Use
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 and 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.
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.
Gender
No dose adjustment of Mycamine is required based on gender. 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
Race
No dose adjustment of Mycamine is required based on race. No notable differences among white, black, and Hispanic subjects were seen. The micafungin AUC was greater by 19% in Japanese subjects compared to blacks, due to smaller body weight.
Renal Impairment
Mycamine does not require dose adjustment in patients with renal impairment. Supplementary dosing should not be required following hemodialysis.
Hepatic Impairment
Dose adjustment of Mycamine is not required in patients with mild, moderate, or severe hepatic impairment.
Females of Reproductive Potential and Males
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.
Immunocompromised Patients
There is no FDA guidance one the use of Micafungin sodium in patients who are immunocompromised.
Administration and Monitoring
Administration
Intravenous
Monitoring
There is limited information regarding Micafungin sodium Monitoring in the drug label.
IV Compatibility
There is limited information regarding the compatibility of Micafungin sodium and IV administrations.
Overdosage
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, up to 6 mg/kg in pediatric patients 4 months of age and older, and up to 10 mg/kg in pediatric patients less than 4 months of age 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 times the recommended highest adult clinical dose (150 mg) and approximately 7 times the highest pediatric clinical dose (3 mg/kg), based on body surface area comparisons.
Pharmacology
There is limited information regarding Micafungin sodium Pharmacology in the drug label.
Mechanism of Action
Micafungin inhibits the synthesis of 1, 3-beta-D-glucan, an essential component of fungal cell walls, which is not present in mammalian cells.
Structure
The chemical structure of micafungin sodium is:
Pharmacodynamics
There is limited information regarding Micafungin sodium Pharmacodynamics in the drug label.
Pharmacokinetics
Adults
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 TABLE 7.
Pediatric Patients 4 months of age and older
Micafungin pharmacokinetics in 229 pediatric patients 4 months through 16 years of age were characterized using population pharmacokinetics. Micafungin exposure was dose proportional across the dose and age range studied.
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 (greater than 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 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% of the administered dose).
Nonclinical Toxicology
Drug abuse and dependence
There has been no evidence of either psychological or physical dependence or withdrawal or rebound effects with Mycamine.
Drug Resistance
There have been reports of clinical failures in patients receiving Mycamine therapy due to the development of drug resistance. Some of these reports have identified specific mutations in the FKS protein component of the glucan synthase enzyme that are associated with higher MICs and breakthrough infection.
Activity In Vitro and In Clinical Infections
Micafungin has been shown to be active against most isolates of the following Candida species, both in vitro and in clinical infections:
- Candida albicans
- Candida glabrata
- Candida guilliermondii
- Candida krusei
- Candida parapsilosis
- Candida tropicalis
Carcinogenesis and Mutagenesis
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 Mycamine 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).
Animal Toxicology and/or Pharmacology
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.
Clinical Studies
There is limited information regarding Micafungin sodium Clinical Studies in the drug label.
How Supplied
- cartons of 10 individually packaged 50 mg single-use vials (NDC 0469-3250-50).
- cartons of 10 individually packaged 100 mg single-use vials (NDC 0469-3211-99).
Storage
Stored at 25°C (77°F)
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Patient Counseling Information
Patients should be advised of the potential benefits and risks of Mycamine. Patients should be informed about the serious adverse effects of Mycamine including hypersensitivity reactions (anaphylaxis and anaphylactoid reactions including shock), hematological effects (acute intravascular hemolysis, hemolytic anemia and hemoglobinuria), hepatic effects (abnormal liver function tests, hepatic impairment, hepatitis or worsening hepatic failure) and renal effects (elevations in BUN and creatinine, renal impairment or acute renal failure). Patients should be instructed to inform their health care provider if they develop any unusual symptom, or if any known symptom persists or worsens. Patients should be instructed to inform their health care provider of any other medications they are currently taking with Mycamine, including over-the-counter medications.
Precautions with Alcohol
Alcohol-Micafungin sodium interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
Brand Names
- Mycamine
Look-Alike Drug Names
There is limited information regarding Micafungin sodium Look-Alike Drug Names in the drug label.
Drug Shortage Status
Price
References
The contents of this FDA label are provided by the National Library of Medicine.