Description of Micafungin (Mycamine)

Micafungin is an intravenous echinocandin antifungal agent, with antifungal activity against Candida albicans, C. glabrata, C. guilliermondii, C. krusei, C. parapsilosis, and C. tropicalis. Micafungin, a semisynthetic lipopeptide, is derived from a fermentation product of Coleophoma empetri. It is approved for use in adults and pediatric patients 4 months and older to treat esophageal candidiasis, candidemia, acute disseminated candidiasis, Candida peritonitis and abscesses, and for the prophylaxis of Candida infections in patients undergoing hematopoietic stem cell transplantation.

The drug is also approved for use in pediatric patients younger than 4 months of age to treat candidemia, acute disseminated candidiasis, Candida peritonitis and abscesses without meningoencephalitis or ocular dissemination; however, micafungin has been used off-label to treat CNS infections in these patients.

• Micafungin Sodium

• Mycamine

• Antifungal
• Echinocandin
• Glucan Synthesis Inhibitor

Mechanism of Action (Mycamine)

Micafungin prevents the synthesis of an essential fungal cell wall component, beta-1,3-D-glucan, by non-competitively inhibiting beta-1,3-glucan synthase complex. Beta-1,3-D-glucan, which is not present in mammalian cells, interlinks with beta-1,6-D-glucan and chitin to provide fungal cell wall stability. Inhibiting the synthesis of this protein in susceptible yeast (Candida sp.) causes morphological changes to the fungal cell that ultimately result in cell lysis.

Some molds (Aspergillus sp.) are also susceptible to decreases in beta-1,3-D-glucan production; however the resulting morphologic changes do not completely inhibit the growth of these fungi as the effects are limited to active cell growth/division of the fungal hyphae. Echinocandins, such as micafungin, inhibit the growth of Candida sp. for more than 12 hour after exposure; however, this post-antifungal effect is less than 0.5 hours for Aspergillus sp.

Micafungin has demonstrated concentration-dependent fungicidal activity against Candida sp.. Fungistatic activity has been observed for Aspergillus sp. Standardized susceptibility testing methods (broth microdilution technique and disk diffusion technique) are available for Candida sp. Using broth microdilution, the Clinical and Laboratory Standards Institute (CLSI) defines minimum inhibitory concentrations (MICs) for C. albicans, C. krusei, and C. tropicalis as susceptible if 0.25 mcg/mL or less, intermediate if 0.5 mcg/mL, and resistant if 1 mcg/mL or more.

For C. glabrata, the MICs for susceptible, intermediate, and resistant are 0.06 mcg/mL or less, 0.12 mcg/mL, and 0.25 mcg/mL or more, respectively. C. parapsilosis has the highest MIC break-points, susceptible if 2 mcg/mL or less, intermediate if 4 mcg/mL, and resistant if 8 mcg/mL or more. For Aspergillus sp., a minimum effective concentration (MEC) is used to determine echinocandin activity.

The MEC is defined as the lowest concentration that results in morphologic changes, and ranges from 0.015 to 0.25 mcg/mL.
 
Although rare, echinocandin resistance has been observed among strains of Candida glabrata. Other Candida sp., including C. albicans, C. dubliniensis, C. guilliermondii, C. krusei, C. lusitaniae, C. parapsilosis, and C. tropicalis, have displayed reduced susceptibility to echinocandin therapy resulting from mutations in the fks1 gene, a gene that encodes for the catalytic subunit of beta-1,3-D-glucan synthase complex.

The fks1 gene mutation also causes elevations in the MEC of Aspergillus fumigatus; however in Aspergillus sp., reduced susceptibility to echinocandins is thought to result from increased chitin synthesis and mutations in the ecm33 gene. Cross resistance to polyene or the azole antifungals has not been observed.

Pharmacokinetics (Mycamine)

Micafungin is administered by intravenous infusion. Micafungin is highly (more than 99%) protein bound, primarily to albumin. At therapeutically relevant concentrations, micafungin does not competitively displace bilirubin binding to albumin. In general, micafungin is widely distributed throughout the body; however, there is poor penetration into urine (less than 2% of a dose) and vitreous humor (less than 1% based on animal data).

Micafungin’s penetration into the CNS is not fully defined. Data suggest that less than 5% of a dose gets distributed into the cerebrospinal fluid (CSF). Data from an animal model of hematogenous Candida meningoencephalitis which was bridged to neonates using Monte Carlo simulations showed penetration into most CNS compartments, but only at doses more than 2 mg/kg. It was not reliably detected in the CSF.

Micafungin’s volume of distribution (Vd) in adults is 0.39 ± 0.11 L/kg. In pediatric patients, it ranges from 0.28 L/kg to 0.51 L/kg, with extremely-low birth weight neonates having the largest Vd. Micafungin metabolism occurs via arylsulfatase to its catechol form (M-1) with further metabolism via catechol-O-methyltransferase (COMT) to its methoxy form (M-2). Micafungin then undergoes further metabolism via hydroxylation by cytochrome P450 isoenzymes to M-5.

Even though micafungin is a substrate for and weak inhibitor of CYP3A in vitro, hydroxylation by CYP3A is not a major pathway for micafungin in vivo. Micafungin is neither a substrate nor inhibitor of P-glycoprotein (P-gp) in vitro. Single dose administration of radiolabeled micafungin demonstrated a mean urinary and fecal recovery of 82.5%. Fecal excretion was shown to be the major route of elimination with 71% of the administered dose excreted.

The mean elimination half-life of micafungin in adults ranges from 13 to 17.2 hours. In pediatric patients, it ranges from approximately 6.7 to 13.3 hours, with premature neonates typically having the fastest clearance.
 
Affected cytochrome P450 isoenzymes and drug transporters: none
Micafungin is not a substrate or inhibitor of P-gp and is a poor substrate for CYP450 enzymes. It does not have any significant interaction with the CYP450 enzyme system. In clinical studies, micafungin did not induce the CYP3A4 metabolism of other drugs.

Concurrent administration of micafungin and mycophenolate mofetil, cyclosporine, tacrolimus, prednisolone, fluconazole, itraconazole, voriconazole, amphotericin B, sirolimus, nifedipine, ritonavir, or rifampin did not alter the pharmacokinetic parameters of micafungin. Furthermore, there was no effect of a single or multiple doses of micafungin on mycophenolate mofetil, cyclosporine, tacrolimus, prednisolone, voriconazole, or fluconazole pharmacokinetic parameters.

Route-Specific Pharmacokinetics
Oral Route
Micafungin has poor oral bioavailability (less than 5%).

Intravenous Route
Micafungin follows a 2-compartment model of distribution with exposure (AUC) being linear over the daily dosage range of 50 to 150 mg and 3 to 8 mg/kg. In pediatric patients, exposure (AUC) is linear over the dosage range of 0.5 to 4 mg/kg. Peak concentrations are reached approximately 1 hour after administration. A loading dose is not required; typically, 85% of the steady-state concentration is achieved after 3 daily doses.

FDA-Label Indications

• Candidemia: Adult
• Candidemia: Pediatric
• Candidiasis of the esophagus: Adult
• Candidiasis of the esophagus: Pediatric: yes (4 months or older)
• Candidiasis of the esophagus – HIV infection: Adult
• Invasive candidiasis: Adult
• Invasive candidiasis: Pediatric
• Invasive candidiasis, Hematopoietic Stem Cell Transplantation; Prophylaxis: Adult
• Invasive candidiasis, Hematopoietic Stem Cell Transplantation; Prophylaxis: Pediatric: yes (4 months or older)
• Invasive candidiasis, Peritonitis or abscess: Adult
• Invasive candidiasis, Peritonitis or abscess: Pediatric

Common Effects

• Endocrine metabolic: Acidosis (Pediatric, 20% ), Hypokalemia (Pediatric, 25% )
• Gastrointestinal: Diarrhea (Treatment, 7% to less than 15%; prophylaxis, 51% to 77% ), Nausea (Treatment, 7% to 10%; prophylaxis, 70% to 71% ), Vomiting (Treatment, 7% to 18%; prophylaxis, 65% to 66% )
• Hematologic: Thrombocytopenia (Treatment, 9% to 25%; prophylaxis, 72% to 75% )
• Neurologic: Headache (Treatment, 9%; prophylaxis, 44% )
• Respiratory: Oxygen saturation below reference range (Pediatric, 15% )
• Other: Fever (7% to 61% ), Sepsis (Pediatric, 20% )

• Cardiovascular: Atrial fibrillation (Adult, 3% to 5% )
• Hematologic: Anemia (Treatment, 15% to 18%; prophylaxis, 51% ), Hemoglobinuria, Hemolysis, Hemolytic anemia, Intravascular hemolysis
• Hepatic: Hepatitis, Liver failure (Adult, less than 5% )
• Immunologic: Anaphylaxis, Hypersensitivity reaction (Adult, less than 5% ), Non-allergic anaphylaxis
• Renal: Acute renal failure (Pediatric, less than 15% ), Renal impairment, acute

Administration

• Intravenous: Add 5 mL D5W or NS without bacteriostatic agent to each 50-mg or 100-mg vial to yield a concentration of 10 mg/mL or 20 mg/mL, respectively; gently swirl vial, do not vigorously shake vial during reconstitution
• Intravenous: (Adult) Add appropriate volume of reconstituted dose to 100 mL NS or D5W
• Intravenous: (Pediatric) Withdraw appropriate volume of reconstituted solution from vial based on calculation of required dose (ie, pediatric dose [mg/kg] x weight of patient [kg]) divided by concentration of solution in reconstituted vial (ie, either 10 mg/mL or 20 mg/mL); add withdrawn volume to an NS or D5W infusion bag or syringe, ensuring that final concentration of solution is between 0.5 mg/mL to 4 mg/mL; if final concentration of solution is greater than 1.5 mg/mL, label the bag or syringe for administration via central catheter
• Intravenous: Protect diluted solution from light; no need to cover the infusion chamber or the tubing
• Intravenous: Administer within 24 hours of dilution
• Intravenous: (Infusion) Infuse over 1 hour; do not administer as an IV bolus injection
• Intravenous: (Pediatric) Administer doses with concentrations greater than 1.5 mg/mL via central catheter to reduce the risk of infusion reactions
• Intravenous: Do not mix or co-infuse with other medications
• Intravenous: An existing IV line should be flushed with NS prior to infusion

• Mycamine: Intravenous Powder for Solution: 50 MG, 100 MG

• Intravenous Powder for Solution: 50 MG, 100 MG

• Aspergillosis, Invasive: 100 to 150 mg IV once daily for at least 6 to 12 weeks (guideline dosage)
• Aspergillosis, Invasive, high-risk patients; Prophylaxis: 50 to 100 mg IV once daily (guideline dosage)
• Aspergillosis, Invasive, high-risk patients; Prophylaxis: (Less than 50 kg) 1 mg/kg IV once daily (off-label dosage)
• Aspergillosis, Invasive, high-risk patients; Prophylaxis: (50 kg or greater) 50 mg IV once daily (off-label dosage)
• Candidal endocarditis: 150 mg IV daily, followed by step-down therapy with fluconazole 400 to 800 mg (6 to 12 mg/kg) daily (guideline dosage)
• Candidemia: 100 mg once daily as IV infusion over 1 hour; mean duration of therapy in clinical studies was 15 days (range, 10 to 47 days) (FDA dosage)
• Candidemia: 100 mg IV daily ; transition to step-down therapy with fluconazole if patient is clinically stable, have isolates that are susceptible to fluconazole, and have negative repeat blood cultures. Continue treatment for 2 weeks after documented clearance of Candida species from bloodstream and resolution of symptoms (guideline dosage) .
• Candidiasis of the esophagus: 150 mg/day IV infusion over 1 hour; mean duration of therapy (clinical studies), 15 days (range 10 to 30 days; FDA dosage)
• Candidiasis of the esophagus: 150 mg/day IV for 14 to 21 days (guideline dosage)
• Candidiasis of the esophagus – HIV infection: 150 mg/day IV infusion over 1 hour; mean duration of therapy (clinical studies), 15 days (range, 10 to 30 days; FDA dosage) OR 14 to 21 days (guideline dosage)
• Disseminated candidiasis, chronic: 100 mg IV daily for several weeks; oral fluconazole 400 mg (6 mg/kg) should be considered in patients unsuspected to have a fluconazole-resistant isolate (guideline dosage)
• Empirical antifungal therapy, Suspected candidiasis in nonneutropenic patients: 100 mg IV daily for 2 weeks; after 4 to 5 days of therapy, if no clinical response or evidence of candidiasis after starting empiric therapy, or negative non-culture based diagnostic assay with a high negative predictive value is reported, consider discontinuing therapy (guideline dosage)
• Fungal arthritis, Due to Candida species: (Candida osteomyelitis) 100 mg IV daily for at least 2 weeks, followed by fluconazole 400 mg (6 mg/kg) daily for 6 to 12 months (guideline dosage)
• Fungal arthritis, Due to Candida species: (Candida septic arthritis) 100 mg IV daily for at least 2 weeks, followed by fluconazole 400 mg (6 mg/kg) daily for at least 4 weeks (guideline dosage)
• Invasive candidiasis: 100 mg once daily as IV infusion over 1 hour; mean duration of therapy in clinical studies was 15 days (range, 10 to 47 days)
• Invasive candidiasis, Hematopoietic Stem Cell Transplantation; Prophylaxis: (primary therapy) 50 mg/day IV infusion over 1 hour ; mean duration for prophylaxis (clinical studies), 19 days (range, 6 to 51 days)
• Invasive candidiasis, Peritonitis or abscess: 100 mg once daily as IV infusion over 1 hour; mean duration of therapy in clinical studies was 15 days (range, 10 to 47 days) (FDA dosage)
• Invasive fungal infection; Prophylaxis: (Less than 50 kg) 1 mg/kg IV once daily (off-label dosage)
• Invasive fungal infection; Prophylaxis: (50 kg or greater) 50 mg IV once daily (off-label dosage)
• Invasive fungal infection; Prophylaxis: Duration: Prophylaxis continued until one of the following occurred: 5 days after neutrophils exceeded 500/mm(3); development of a fungal infection, unacceptable toxicity or death; or greater than 42 days posttransplantation (off-label dosage)
• Oropharyngeal candidiasis: (Fluconazole-refractory disease) 100 mg/day IV for up to 28 days (guideline dosage)
• Pulmonary aspergillosis, Chronic (cavitary or necrotizing): 100 to 150 mg IV daily (guideline dosage)

• Aspergillosis, Invasive: (4 months or older, 40 kg or less) 2 to 3 mg/kg IV once daily for at least 6 to 12 weeks (guideline dosage)
• Aspergillosis, Invasive: (4 months or older, more than 40 kg) 100 to 150 mg IV once daily for at least 6 to 12 weeks (guideline dosage)
• Aspergillosis, Invasive, high-risk patients; Prophylaxis: (6 months or older and less than 50 kg) 1 mg/kg IV once daily (off-label dosage)
• Aspergillosis, Invasive, high-risk patients; Prophylaxis: (6 months or older and 50 kg or greater) 50 mg IV once daily (off-label dosage)
• Candidemia: (Younger than 4 months, without meningoencephalitis and/or ocular dissemination) 4 mg/kg once daily as IV infusion over 1 hour
• Candidemia: (4 months or older) 2 mg/kg once daily as IV infusion over 1 hour; MAX 100 mg/day
• Candidiasis of the esophagus: (30 kg or less) 3 mg/kg IV infusion over 1 hour once daily
• Candidiasis of the esophagus: (greater than 30 kg) 2.5 mg/kg IV infusion over 1 hour once daily; MAX 150 mg/day
• Invasive candidiasis: (Younger than 4 months, without meningoencephalitis and/or ocular dissemination) 4 mg/kg once daily as IV infusion over 1 hour
• Invasive candidiasis: (4 months or older) 2 mg/kg once daily as IV infusion over 1 hour; MAX 100 mg/day
• Invasive candidiasis, Hematopoietic Stem Cell Transplantation; Prophylaxis: 1 mg/kg IV infused over 1 hour once daily; MAX 50 mg/day
• Invasive candidiasis, Peritonitis or abscess: (Younger than 4 months, without meningoencephalitis and/or ocular dissemination) 4 mg/kg once daily as IV infusion over 1 hour
• Invasive candidiasis, Peritonitis or abscess: (4 months or older) 2 mg/kg once daily as IV infusion over 1 hour; MAX 100 mg/day
• Invasive fungal infection; Prophylaxis: (6 months or older and less than 50 kg) 1 mg/kg IV once daily (off-label dosage)
• Invasive fungal infection; Prophylaxis: (6 months or older and 50 kg or greater) 50 mg IV once daily (off-label dosage)
• Invasive fungal infection; Prophylaxis: Duration: Prophylaxis continued until one of the following occurred: 5 days after neutrophils exceeded 500/mm(3); development of a fungal infection, unacceptable toxicity or death; or greater than 42 days posttransplantation (off-label dosage)