Micafungin sodium
- 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
- 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
- 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
- Prophylaxis of invasive fungal infections
Isolated cases of serious hypersensitivity (anaphylaxis and anaphylactoid) reactions (including shock) have been reported in patients receiving micafungin sodium. If these reactions occur, micafungin sodium infusion should be discontinued and appropriate treatment administered.
Acute intravascular hemolysis and hemoglobinuria was seen in a healthy volunteer during infusion of micafungin sodium (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 micafungin sodium. Patients who develop clinical or laboratory evidence of hemolysis or hemolytic anemia during micafungin sodium therapy should be monitored closely for evidence of worsening of these conditions and evaluated for the risk/benefit of continuing micafungin sodium therapy.
Laboratory abnormalities in liver function tests have been seen in healthy volunteers and patients treated with micafungin sodium. In some patients with serious underlying conditions who were receiving micafungin sodium 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 micafungin sodium therapy should be monitored for evidence of worsening hepatic function and evaluated for the risk/benefit of continuing micafungin sodium therapy.
Elevations in BUN and creatinine, and isolated cases of significant renal impairment or acute renal failure have been reported in patients who received micafungin sodium. In fluconazole-controlled trials, the incidence of drug-related renal adverse reactions was 0.4% for micafungin sodium treated patients and 0.5% for fluconazole treated patients. Patients who develop abnormal renal function tests during micafungin sodium therapy should be monitored for evidence of worsening renal function.
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 micafungin sodium 100 mg/day, micafungin sodium 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 micafungin sodium 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 micafungin sodium (100 mg/day) and AmBisome (3 mg/kg/day) treatment groups, respectively. The following treatment-emergent adverse reactions in the micafungin sodium 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 micafungin sodium and AmBisome treatment groups, respectively.
In a randomized, double-blind study for treatment of esophageal candidiasis, a total of 202/260 (78%) patients who received micafungin sodium 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%) micafungin sodium treated patients; and in 12 (5%) fluconazole treated patients.
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 micafungin sodium (382) or fluconazole (409) experienced at least one adverse reaction during the study. Treatment-emergent adverse reactions resulting in micafungin sodium 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 micafungin sodium 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
The overall safety of micafungin sodium was assessed in 479 patients 3 days through 16 years of age who received at least one dose of micafungin sodium in 11 separate clinical studies. The mean treatment duration was 24.8 days. A total of 246 patients received at least one dose of micafungin sodium 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 micafungin sodium, 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 micafungin sodium (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 micafungin sodium group and 52/56 (93%) of patients in the AmBisome group. Treatment-emergent adverse reactions resulting in micafungin sodium 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 micafungin sodium (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 micafungin sodium 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 micafungin sodium group, for all micafungin sodium pediatric studies and for the two comparative studies (candidemia and prophylaxis) described above are shown in TABLE 6.
- Hepatobiliary disorders: hyperbilirubinemia
- Investigations: liver function tests abnormal
- Renal Disorders: renal failure
- 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
There was no effect of a single dose or multiple doses of micafungin sodium 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 micafungin sodium compared with sirolimus alone. Nifedipine AUC and Cmax were increased by 18% and 42%, respectively, in the presence of steady-state micafungin sodium compared with nifedipine alone. Itraconazole AUC and Cmax were increased by 22% and 11%, respectively.
Patients receiving sirolimus, nifedipine or itraconazole in combination with micafungin sodium 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.
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.
Safety and effectiveness of micafungin sodium 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 micafungin sodium 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.
The exposure and disposition of a 50 mg micafungin sodium 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.
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.
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.
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 1-acid-glycoprotein.
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 (-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.
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).
There has been no evidence of either psychological or physical dependence or withdrawal or rebound effects with micafungin sodium.
There have been reports of clinical failures in patients receiving micafungin sodium 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.
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
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 , 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 micafungin sodium 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 sodium 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 micafungin sodium 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).
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.
Two dose levels of micafungin sodium were evaluated in a 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 micafungin sodium, either 100 mg/day or 150 mg/day or caspofungin (70 mg loading dose followed by 50 mg maintenance dose).  Patients in both study arms were permitted to switch to oral fluconazole after at least 10 days of intravenous therapy, provided they were non-neutropenic, had improvement or resolution of clinical signs and symptoms, had a Candida isolate which was susceptible to fluconazole, and had documentation of 2 negative cultures drawn at least 24 hours apart. Patients were stratified by APACHE II score (20 or less or greater than 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 greater than 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 micafungin sodium (100 mg/day) and caspofungin in TABLE 11.
In two cases of ophthalmic involvement assessed as failures in the above table due to missing evaluation at the end of IV treatment with micafungin sodium, therapeutic success was documented during protocol-defined oral fluconazole therapy.
In two controlled trials involving 763 patients with esophageal candidiasis, 445 adults with endoscopically-proven candidiasis received micafungin sodium, and 318 received fluconazole for a median duration of 14 days (range 1-33 days).
micafungin sodium was evaluated in a randomized, double-blind study which compared micafungin sodium 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 less than 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 12, endoscopic cure, clinical cure, overall therapeutic cure, and mycological eradication were comparable for patients in the micafungin sodium and fluconazole treatment groups.
Most patients (96%) in this study had Candida albicans isolated at baseline. The efficacy of micafungin sodium 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 greater than 0). There was no statistically significant difference in relapse rates at either 2 weeks or through 4 weeks post-treatment for patients in the micafungin sodium and fluconazole treatment groups, as shown in TABLE 13.
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%) micafungin sodium 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 micafungin sodium group, and 18.1% in the fluconazole group (treatment difference = 14.2%; 95% confidence interval ) 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 micafungin sodium group and 39.4% in the fluconazole group (treatment difference 12.7%, 95% confidence interval ).
In a randomized, double-blind study, micafungin sodium (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. All pediatric patients, except 2 per group, received allogeneic transplants. 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-Hodgkins 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 greater or up to a maximum of 42 days after transplant. The average duration of drug administration was 18 days (range 1 to 51 days). Duration of therapy was slightly longer in the pediatric patients who received micafungin sodium (median duration 22 days) compared to the adult patients who received micafungin sodium (median duration 18 days).
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 less than 500 cells/mm3); persistent or recurrent fever (while ANC less than 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 38.5oC or higher after having at least one prior temperature higher than 38oC; or having two days of temperatures higher than 38oC after having at least one prior temperature higher than 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 adult and pediatric micafungin sodium recipients, and in 73.7% of adult and pediatric patients who received fluconazole (7.0% difference ), as shown in TABLE 14, 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 in the micafungin sodium and 2 in the fluconazole group.
The efficacy of micafungin sodium against infections caused by fungi other than Candida has not been established.
- cartons of 10 individually packaged 100 mg single-use vials (NDC 0469-3211-99).
-  "FDA LABEL: MYCAMINE- micafungin sodium injection, powder, lyophilized, for solution"..mw-parser-output cite.citation{font-style:inherit}.mw-parser-output q{quotes:"\"""\"""'""'"}.mw-parser-output code.cs1-code{color:inherit;background:inherit;border:inherit;padding:inherit}.mw-parser-output .cs1-lock-free a{background:url("")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-limited a,.mw-parser-output .cs1-lock-registration a{background:url("")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-subscription a{background:url("")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration{color:#555}.mw-parser-output .cs1-subscription span,.mw-parser-output .cs1-registration span{border-bottom:1px dotted;cursor:help}.mw-parser-output .cs1-hidden-error{display:none;font-size:100%}.mw-parser-output .cs1-visible-error{display:none;font-size:100%}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration,.mw-parser-output .cs1-format{font-size:95%}.mw-parser-output .cs1-kern-left,.mw-parser-output .cs1-kern-wl-left{padding-left:0.2em}.mw-parser-output .cs1-kern-right,.mw-parser-output .cs1-kern-wl-right{padding-right:0.2em}