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Mechanism of Action
Micafungin is a member of the echinocandin class of antifungal agents [see Microbiology].
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.
Table 6. Pharmacokinetic Parameters of Micafungin in Adult
|Population||n||Dose (mg)||(Mean ± Standard Deviation)|
| Patients with IC† [Day 1]
|20||100||5.7 ± 2.2||83 ± 51||14.5 ± 7.0||0.359 ± 0.179|
|20||100||10.1 ± 4.4||97 ± 29||13.4 ± 2.0||0.298 ± 0.1 15|
| HTV‡- Positive Patients with EC§
|20||50||4.1 ± 1.4||36 ± 9||14.9 ± 4.3||0.321 ± 0.098|
|20||100||8.0 ± 2.4||108 ± 31||13.8 ± 3.0||0.327 ± 0.093|
|14||150||11.6 ± 3.1||151 ± 45||14.1 ± 2.6||0.340 ± 0.092|
|[Day 14 or 21]||20||50||5.1 ± 1.0||54 ± 13||15.6 ± 2.8||0.300 ± 0.063|
|20||100||10.1 ± 2.6||115 ± 25||16.9 ± 4.4||0.301 ± 0.086|
|14||150||16.4 ± 6.5||167 ± 40||15.2 ± 2.2||0.297 ± 0.081|
|Recipients [Day 7]||8||3||21.1 ± 2.84||234 ± 34||14.0 ± 1.4||0.214 ± 0.031|
|10||4||29.2 ± 6.2||339 ± 72||14.2 ± 3.2||0.204 ± 0.036|
|8||6||38.4 ± 6.9||479 ± 157||14.9 ± 2.6||0.224 ± 0.064|
|8||8||60.8 ± 26.9||663 ± 212||17.2 ± 2.3||0.223 ± 0.081|
| * AUC0-infinity is presented for day 1; AUC0-24
is presented for steady state.
† candidemia or other Candida Infections
‡ human immunodeficiency virus
§ esophageal candidiasis
¶ hematopoietic stem cell transplant
Patients with Renal Impairment
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 impairment (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.
Patients with Hepatic Impairment
- A single 1-hour infusion of 100 mg Mycamine was administered to 8 subjects with moderate hepatic impairment (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 impairment compared to normal subjects. This difference in micafungin exposure does not require dose adjustment of Mycamine in patients with moderate hepatic impairment.
- A single 1-hour infusion of 100 mg Mycamine was administered to 8 subjects with severe hepatic impairment (Child-Pugh score 10-12) and 8 age-, gender-, ethnic- and weight-matched subjects with normal hepatic function. The mean Cmax and AUC values of micafungin were lower by approximately 30% in subjects with severe hepatic impairment compared to normal subjects. The mean Cmax and AUC values of M-5 metabolite were approximately 2.3-fold higher in subjects with severe hepatic impairment compared to normal subjects; however, this exposure (parent and metabolite) was comparable to that in patients with systemic Candida infection. Therefore, no micafungin dose adjustment is necessary in patients with severe hepatic impairment.
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 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 ctl-acid-glycoprotein.
Micafungin is metabolized to M-l (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 (ϖ-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-l, 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-l, 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).
Mechanism of Action
Activity In Vitro
Micafungin exhibited in vitro activity against C. albicans, C. glabrata, C. guilliermondii, C. krusei, C. parapsilosis and C. tropicalis. Standardized 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.
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.
Mutants of Candida 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 Candida species is unknown.
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 [see Nonclinical Toxicology].
Reproductive Toxicology Studies
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.
Treatment of Candidemia and Other Candida Infections
Two dose levels of Mycamine 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, 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 > 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 > 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 Mycamine (100 mg/day) and caspofungin in Table 7.
Table 7. Efficacy Analysis: Treatment Success in Patients
in Study 03-0-192 with Candidemia and other Candida Infections
| Mycamine 100 mg/day
% treatment difference
| Caspofungin 70/50 mg/day*
|Treatment Success at End of IV Therapy†|| 135/191 (70.7)
|Success in Patients with Neutropenia at Baseline||14/22 (63.6)||5/11(45.5)|
|Success by Site of Infection Candidemia||116/163(71.2)||103/161 (64)|
|Abscess||4/5 (80)||5/9 (55.6)|
|Acute Disseminated‡||6/13 (46.2)||5/9 (55.6)|
|Peritonitis||4/6 (66.7)||2/5 (40)|
|Success by Organism§|
|C. albicans||57/81 (70.4)||45/73 (61.6)|
|C. glabrata||16/23 (69.6)||19/31 (61.3)|
|C. tropicalis||17/27 (63)||22/29 (75.9)|
|C. parapsilosis||21/28 (75)||22/39 (56.4)|
|C. krusei||5/8 (62.5)||2/3 (66.7)|
|C. lusitaniae||2/3 (66.7)||2/2|
|Relapse through 6 Weeks¶|
|Culture confirmed relapse||5||4|
|Required systemic antifungal therapy||11||5|
|Died during follow-up||17||16|
|Overall study mortality||58/200 (29)||51/193 (26.4)|
|Mortality during IV therapy||28/200 (14)||27/193 (14)|
| * 70 mg loading dose on day 1 followed by 50 mg/day thereafter
†All patients who received at least one dose of study medication and had documented invasive candidiasis or candidemia.
Patients with Candida endocarditis were excluded from the analyses.
‡ A patient may have had > 1 organ of dissemination
§ A patient may have had > 1 baseline infection species
¶All patients who had a culture confirmed relapse or required systemic antifungal therapy in the post treatment period for a suspected or proven Candida infection. Also includes patients who died or were not assessed in follow-up.
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, therapeutic success was documented during protocol-defined oral fluconazole therapy.
Treatment of Esophageal Candidiasis
In two controlled trials involving 763 patients with esophageal candidiasis, 445 adults with endoscopically-proven candidiasis received Mycamine, and 318 received fluconazole for a median duration of 14 days (range 1-33 days).
Mycamine was evaluated in a randomized, double-blind study which compared Mycamine 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 < 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 8, endoscopic cure, clinical cure, overall therapeutic cure, and mycological eradication were comparable for patients in the Mycamine and fluconazole treatment groups.
Table 8. Endoscopic, Clinical, and Mycological Outcomes for
Esophageal Candidiasis at End-of-Treatment
|Treatment Outcome*|| Mycamine
| % Difference†
|Endoscopic Cure||228 (87.7%)||227 (88.0%)||-0.3% (-5.9, +5.3)|
|Clinical Cure||239(91.9%)||237 (91.9%)||0.06% (-4.6, +4.8)|
|Overall Therapeutic Cure||223 (85.8%)||220 (85.3%)||0.5% (-5.6, +6.6)|
|Mycological Eradication||141/189 (74.6%)||149/192 (77.6%)||-3.0% (-11.6, +5.6)|
|* Endoscopic and clinical outcome were measured in modified
intent-to-treat population, including all randomized patients who received
> 1 dose of study treatment. Mycological outcome was determined in the
per protocol (evaluable) population, including patients with confirmed esophageal
candidiasis who received at least 10 doses of study drug, and had no major
† Calculated as Mycamine - fluconazole
Most patients (96%) in this study had Candida albicans isolated at baseline. The efficacy of Mycamine 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 > 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 and fluconazole treatment groups, as shown in Table 9.
Table 9. Relapse of Esophageal Candidiasis at Week 2 and
through Week 4 Post-Treatment in Patients with Overall Therapeutic Cure at the
End of Treatment
| % Difference*
|Relapse† at Week 2||40 (17.9%)||30 (13.6%)||4.3% (-2.5, 11.1)|
|Relapse† Through Week 4 (cumulative)||73 (32.7%)||62 (28.2%)||4.6% (-4.0, 13.1)|
|*Calculated as Mycamme - fluconazole; N=number of patients
with overall therapeutic cure (both clinical and endoscopic cure at end-of-treatment);
† Relapse included patients who died or were lost to follow-up, and those who received systemic anti-fungal therapy in the post-treatment period
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 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 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 group and 39.4% in the fluconazole group (treatment difference 12.7%, 95% confidence interval [2.8,22.7]).
Prophylaxis of Candida Infections in Hematopoietic Stem Cell Transplant Recipients
In a randomized, double-blind study, Mycamine (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 lymphocyric 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/mm3 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 < 500 cells/mm3); persistent or recurrent fever (while ANC < 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 38°C. A recurrent fever was defined as having at least one day with temperatures ≥ 38.5°C after having at least one prior temperature > 38°C; or having two days of temperatures > 38°C after having at least one prior temperature > 38°C. 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, and in 73.7% of recipients who received fluconazole (7.0% difference [95% CI = 1.5, 12.5]), as shown in Table 10, 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 Mycamine and 2 in the fluconazole group.
The efficacy of Mycamine against infections caused by fungi other than Candida has not been established.
Table 10. Results from Clinical Study of Prophylaxis of Candida
Infections in Hematopoietic Stem Cell Transplant Recipients
|Outcome of Prophylaxis|| Mycamine
|Success*||343 (80.7%)||337 (73.7%)|
|Failure:||82 (19.3%)||120 (26.3%)|
|All Deaths†||18 (4.2%)||26 (5.7%)|
|Proven/probable fungal infection prior to death||1 (0.2%)||3 (0.7%)|
|Proven/probable fungal infection (not resulting in death)†||6 (1.4%)||8 (1.8%)|
|Suspected fungal infection‡||53 (12.5%)||83 (18.2%)|
|Lost to follow-up||5 (1.2%)||3 (0.7%)|
| Difference (Mycamine - Fluconazole): +7.0% [95% CI=1.5, 12.5]
†Through end-of-study (4 weeks post-therapy)
‡ Through end-of-therapy
Last reviewed on RxList: 7/18/2011
This monograph has been modified to include the generic and brand name in many instances.
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