Mycamine Information
Mycamine (Micafungin sodium) Indications And Usage
Mycamine (Micafungin sodium) is indicated for:
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Mycamine (Micafungin sodium) has not been adequately studied in patients with endocarditis, osteomyelitis
and meningitis due to infections.
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NOTE: The efficacy of Mycamine (Micafungin sodium) against infections caused by fungi other than has not been established.
Mycamine (Micafungin sodium) Dosage And Administration
Do not mix or co-infuse Mycamine (Micafungin sodium) with other medications. Mycamine (Micafungin sodium) has been shown to precipitate when mixed directly with a number of other commonly used medications.
A loading dose is not required. Typically, 85% of the steady-state concentration is achieved after three daily Mycamine (Micafungin sodium) doses.
No dosing adjustments are required based on race, gender, or in patients with severe renal impairment or in patients with mild, moderate, or severe hepatic impairment [].
No dose adjustment for Mycamine (Micafungin sodium) is required with concomitant use of mycophenolate mofetil, cyclosporine, tacrolimus, prednisolone, sirolimus, nifedipine, fluconazole, voriconazole, itraconazole, amphotericin B, ritonavir, or rifampin [].
Mycamine (Micafungin sodium) Dosage Forms And Strengths
50 mg and 100 mg single-use vials
Mycamine (Micafungin sodium) Contraindications
Mycamine (Micafungin sodium) is contraindicated in persons with known hypersensitivity to micafungin, any component of Mycamine (Micafungin sodium) , or other echinocandins.
Mycamine (Micafungin sodium) Adverse Reactions
Possible histamine-mediated symptoms have been reported with Mycamine (Micafungin sodium) , including rash, pruritus, facial swelling, and vasodilatation.
Injection site reactions, including phlebitis and thrombophlebitis have been reported, at Mycamine (Micafungin sodium) doses of 50-150 mg/day. These reactions tended to occur more often in patients receiving Mycamine (Micafungin sodium) via peripheral intravenous administration.
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in clinical trials of Mycamine (Micafungin sodium) 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.
In a randomized, double-blind study for treatment of candidemia and other infections, treatment emergent adverse events occurred in 183/200 (91.5%), 187/202 (92.6%) and 171/193 (88.6%) patients in the Mycamine (Micafungin sodium) 100 mg/day, Mycamine (Micafungin sodium) 150 mg/day, and caspofungin (70/50 mg/day) treatment groups, respectively. Treatment emergent adverse events occurring in ≥5% of the patients in any treatment study groups are shown in .
In a second, supportive, randomized, double-blind study for treatment of candidemia and other infections, treatment emergent adverse events occurred in 245/264 (92.8%) and 250/265 (94.3%) patients in the Mycamine (Micafungin sodium) (100 mg/day) and AmBisome (3 mg/kg/day) treatment groups, respectively. The most common treatment emergent adverse events occurring in ≥5% of the Mycamine (Micafungin sodium) -treated patients at least 16 years of age were: pyrexia (15.2% vs. 17%); hypokalemia (16.7% vs. 20.8%); nausea (9.5% vs. 8.3%); diarrhea (10.6% vs. 11.3%) and vomiting (12.9% vs. 9.4%), in the Mycamine (Micafungin sodium) and AmBisome treatment groups, respectively. Other important treatment emergent adverse events that occurred at
In a randomized, double-blind study for treatment of esophageal candidiasis, a total of 202/260 (77.7%) patients who received Mycamine (Micafungin sodium) 150 mg/day and 186/258 (72.1%) patients who received intravenous fluconazole 200 mg/day experienced an adverse event. Treatment emergent adverse events resulting in discontinuation were reported in 17 (6.5%) Mycamine (Micafungin sodium) treated patients; and in 12 (4.7%) fluconazole treated patients. Treatment emergent adverse events occurring in ≥5% of the patients in either treatment group are shown in .
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 patients who received Mycamine (Micafungin sodium) (425) and all patients who received fluconazole (457) experienced at least one adverse event during the study. Treatment emergent adverse events resulting in Mycamine (Micafungin sodium) discontinuation were reported in 18 (4.2%) patients; while those resulting in fluconazole discontinuation were reported in 33 (7.2%). Treatment emergent adverse events occurring in ≥15% of the patients in either treatment group are shown in .
The overall safety of Mycamine (Micafungin sodium) was assessed in 3083 patients and 501 volunteers in 41 clinical studies, including the invasive candidiasis, esophageal candidiasis and prophylaxis studies, who received single or multiple doses of Mycamine (Micafungin sodium) , ranging from 12.5 mg to ≥150 mg/day. Treatment emergent adverse events which occurred in ≥5% of all patients who received Mycamine (Micafungin sodium) in these trials are shown in .
Overall, 2810 of 3083 (91.1%) patients who received Mycamine (Micafungin sodium) experienced an adverse event.
Clinically significant adverse events regardless of causality or incidence which occurred in these trials are listed below:
Mycamine (Micafungin sodium) Drug Interactions
A total of 14 clinical drug-drug interaction studies were conducted in healthy volunteers to evaluate the potential for interaction between Mycamine (Micafungin sodium) 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 micafungin was observed.
There was no effect of a single dose or multiple doses of Mycamine (Micafungin sodium) on mycophenolate mofetil, cyclosporine, tacrolimus, prednisolone, fluconazole, and voriconazole pharmacokinetics.
Sirolimus AUC was increased by 21% with no effect on C in the presence of steady-state Mycamine (Micafungin sodium) compared with sirolimus alone. Nifedipine AUC and C were increased by 18% and 42%, respectively, in the presence of steady-state Mycamine (Micafungin sodium) compared with nifedipine alone. Itraconazole AUC and C were increased by 22% and 11%, respectively.
Patients receiving sirolimus, nifedipine or itraconazole in combination with Mycamine (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.
Mycamine (Micafungin sodium) Use In Specific Populations
Pregnancy Category C. There are no adequate and well-controlled studies of micafungin 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. Micafungin 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 [].
A total of 418 subjects in clinical studies of Mycamine (Micafungin sodium) 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 (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.
Mycamine (Micafungin sodium) Drug Abuse And Dependence
There has been no evidence of either psychological or physical dependence or withdrawal or rebound effects with Mycamine (Micafungin sodium) .
Mycamine (Micafungin sodium) Overdosage
Mycamine (Micafungin sodium) is highly protein bound and, therefore, is not dialyzable. No cases of Mycamine (Micafungin sodium) 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 (Micafungin sodium) 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.
Mycamine (Micafungin sodium) Description
Mycamine (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 of 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 (Micafungin sodium) must be diluted with 0.9% Sodium Chloride Injection, USP, or 5% Dextrose Injection, USP []. Following reconstitution with 0.9% Sodium Chloride Injection, USP, the resulting pH of the solution is between 5-7.
Micafungin sodium is chemically designated as:
Pneumocandin A0,1-[(4,5)-4,5-dihydroxy- -[4-[5-[4-(pentyloxy)phenyl]-3-isoxazolyl]benzoyl]-L-ornithine]-4-[(4)-4-hydroxy-4-[4-hydroxy-3-(sulfooxy)phenyl]-L-threonine]-, monosodium salt.
The chemical structure of micafungin sodium is:
The empirical/molecular formula is CHNNaOS 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.
Mycamine (Micafungin sodium) Clinical Pharmacology
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.
Mycamine (Micafungin sodium) does not require dose adjustment in patients with renal impairment. A single 1-hour infusion of 100 mg Mycamine (Micafungin sodium) was administered to 9 subjects with severe renal impairment (creatinine clearance 80 mL/min). The maximum concentration (C) 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.
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 , 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.
Micafungin is metabolized to M-1 (catechol form) by arylsulfatase, with further metabolism to M-2 (methoxy form) by catechol-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 , hydroxylation by CYP3A is not a major pathway for micafungin metabolism . Micafungin is neither a P-glycoprotein substrate nor inhibitor .
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 C-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).
Micafungin inhibits the synthesis of 1,3-β-D-glucan, an essential component of fungal cell walls, which is not present in mammalian cells.
Micafungin exhibited activity against andStandardized susceptibility testing methods for 1,3-β-D-glucan synthesis inhibitors have recently been proposed by the CLSI, however, the correlation between the results of susceptibility studies and clinical outcome has not been established.
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.
Mutants of with reduced susceptibility to micafungin have been identified in some patients during treatment suggesting a potential for development of drug resistance. The incidence of drug resistance by various clinical isolates of species is unknown.
Mycamine (Micafungin sodium) Nonclinical Toxicology
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 (Micafungin sodium) dosing in patients, which is typically less than 1 month for treatment of esophageal candidiasis, but dosing may exceed 1 month for 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 (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 and tests (i.e., bacterial reversion - ; 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.
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 [].
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.
Mycamine (Micafungin sodium) Clinical Studies
Two dose levels of Mycamine (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 Mycamine (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 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 > 20) and by geographic region. Patients with 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 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/mm). Outcome, relapse and mortality data are shown for the recommended dose of Mycamine (Micafungin sodium) (100 mg/day) and caspofungin in .
In two cases of ophthalmic involvement assessed as failures in the above table due to missing evaluation at the end of IV treatment with Mycamine (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 Mycamine (Micafungin sodium) , and 318 received fluconazole for a median duration of 14 days (range 1-33 days).
Mycamine (Micafungin sodium) was evaluated in a randomized, double-blind study which compared Mycamine (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
Most patients (96%) in this study had isolated at baseline. The efficacy of Mycamine (Micafungin sodium) was evaluated in less than 10 patients with species other than , most of which were isolated concurrently with
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 (Micafungin sodium) and fluconazole treatment groups, as shown in .
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 (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 Mycamine (Micafungin sodium) 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 (Micafungin sodium) group and 39.4% in the fluconazole group (treatment difference 12.7%, 95% confidence interval [2.8, 22.7]).
In a randomized, double-blind study, Mycamine (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. 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/mm or up to a maximum of 42 days after transplant. The average duration of drug administration was 18 days (range 1 to 51 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 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 (Micafungin sodium) , and in 73.7% of recipients who received fluconazole (7.0% difference [95% CI = 1.5, 12.5]), as shown in , along with other study endpoints. The use of systemic antifungal therapy post-treatment was 42% in both groups.
The number of proven breakthrough infections was 4 in the Mycamine (Micafungin sodium) and 2 in the fluconazole group.
The efficacy of Mycamine (Micafungin sodium) against infections caused by fungi other than has not been established.
Mycamine (Micafungin sodium) How Supplied/storage And Handling
Mycamine (Micafungin sodium) is available in:
Unopened vials of lyophilized material must be stored at room temperature, 25° C (77° F); excursions permitted to 15°-30°C (59°-86°F). [See USP Controlled Room Temperature.]
The reconstituted product may be stored in the original vial for up to 24 hours at room temperature, 25° C (77° F).
The diluted infusion should be protected from light and may be stored for up to 24 hours at room temperature, 25° C (77° F).
Mycamine (Micafungin sodium) Patient Counseling Information
Patients should be advised of the potential benefits and risks of Mycamine (Micafungin sodium) . Patients should be informed about the common adverse effects of Mycamine (Micafungin sodium) 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 (Micafungin sodium) , including over-the-counter medications.
Mycamine (Micafungin sodium)
Mycamine (Micafungin sodium) Principal Display Panel
Mycamine (Micafungin sodium) Principal Display Panel
