Mycamine

Echinocandins Antifungals

Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit. Discard solution if evidence of precipitation or foreign matter is observed.

Reconstitution
Reconstitute each 50 mg vial or 100 mg vial with 5 mL of either 0.9% Sodium Chloride Injection (without bacteriostatic agent) or 5% Dextrose Injection for a resultant concentration of 10 mg/mL or 20 mg/mL, respectively.
Gently dissolve the powder by swirling the vial. In order to minimize excessive foaming, do not vigorously shake the vial.
Storage: Reconstituted micafungin may be stored in the original vial protected from light for up to 24 hours at room temperature (25 degrees C or 77 degrees F).
 
Dilution
Adults: Transfer the needed amount of reconstituted micafungin to an IV bag containing 100 mL of 0.9% Sodium Chloride Injection or 5% Dextrose Injection.
Pediatric patients:
Withdraw the calculated volume of reconstituted micafungin and add to an IV bag or syringe containing 0.9% Sodium Chloride Injection or 5% Dextrose Injection. Ensure the final concentration of the diluted solution is between 0.5 to 4 mg/mL. Label infusion bags or syringes containing micafungin concentrations more than 1.5 mg/mL for administration through a central catheter only.
Discard partially used vials; micafungin is preservative-free.
Storage: The final diluted solution may be stored protected from light for up to 24 hours at room temperature (25 degrees C or 77 degrees F).[44913]
 
Intermittent IV Infusion
To minimize the risk of infusion-related reactions, infuse solutions with concentrations more than 1.5 mg/mL via a central catheter.
If an existing IV line will be used, flush the line with 0.9% Sodium Chloride Injection before infusing micafungin.
Administer as a slow IV infusion over 1 hour. If administered more rapidly, more frequent histamine-mediated reactions may occur. Do not administer as an IV bolus injection.
Do not mix or co-infuse micafungin with other medications. Micafungin has been shown to precipitate when mixed directly with several commonly used medications.
Protect diluted micafungin from light; however, it is not necessary to cover the infusion drip chamber or the tubing during administration.[44913]

oliguria / Early / 23.0-23.0
GI perforation / Delayed / 0-15.0
ileus / Delayed / 0-15.0
pleural effusion / Delayed / 0-15.0
pancytopenia / Delayed / 0-5.0
coagulopathy / Delayed / 0-5.0
intracranial bleeding / Delayed / 0-5.0
thrombotic thrombocytopenic purpura (TTP) / Delayed / 0-5.0
anaphylactic shock / Rapid / 0-5.0
anaphylactoid reactions / Rapid / 0-5.0
hepatic failure / Delayed / 0-5.0
hyperkalemia / Delayed / 5.0-5.0
seizures / Delayed / 0-5.0
thrombosis / Delayed / 0-5.0
cardiac arrest / Early / 0-5.0
myocardial infarction / Delayed / 0-5.0
pericardial effusion / Delayed / 0-5.0
atrial fibrillation / Early / 3.0-3.0
hemolytic anemia / Delayed / Incidence not known
disseminated intravascular coagulation (DIC) / Delayed / Incidence not known
toxic epidermal necrolysis / Delayed / Incidence not known
Stevens-Johnson syndrome / Delayed / Incidence not known
renal failure (unspecified) / Delayed / Incidence not known
azotemia / Delayed / Incidence not known

thrombocytopenia / Delayed / 9.0-75.0
sinus tachycardia / Rapid / 4.0-26.0
hypokalemia / Delayed / 0-25.0
hematuria / Delayed / 4.0-23.0
phlebitis / Rapid / 19.0-19.0
elevated hepatic enzymes / Delayed / 3.0-16.0
infusion-related reactions / Rapid / 0-16.0
thrombocytosis / Delayed / 0-15.0
hyperbilirubinemia / Delayed / 0-15.0
hypocalcemia / Delayed / 0-15.0
hyperglycemia / Delayed / 0-15.0
hypermagnesemia / Delayed / 0-15.0
dehydration / Delayed / 0-15.0
ascites / Delayed / 0-15.0
peripheral edema / Delayed / 0-15.0
hypotension / Rapid / 0-15.0
edema / Delayed / 0-15.0
hypertension / Early / 15.0-15.0
dyspnea / Early / 0-15.0
hypertonia / Delayed / 0-15.0
hypoglycemia / Early / 6.0-6.0
jaundice / Delayed / 0-5.0
hepatomegaly / Delayed / 0-5.0
hypernatremia / Delayed / 0-5.0
delirium / Early / 0-5.0
encephalopathy / Delayed / 0-5.0
neutropenia / Delayed / 10.0
anemia / Delayed / 10.0
hemolysis / Early / Incidence not known
peripheral vasodilation / Rapid / Incidence not known
hepatitis / Delayed / Incidence not known

diarrhea / Early / 7.0-77.0
nausea / Early / 7.0-71.0
vomiting / Early / 7.0-66.0
fever / Early / 0-61.0
headache / Early / 9.0-44.0
insomnia / Early / 37.0-37.0
abdominal pain / Early / 4.0-35.0
pruritus / Rapid / 33.0-33.0
rash / Early / 2.0-30.0
anxiety / Delayed / 22.0-23.0
urticaria / Rapid / 0-19.0
leukocytosis / Delayed / 0-15.0
epistaxis / Delayed / 9.0-9.0
injection site reaction / Rapid / Incidence not known

Mycamine

Rx

Echinocandin antifungal
Used for Candida infection prophylaxis and treatment
Efficacy for treatment of infections caused by fungi other than Candida has not been established

No dosage adjustment is needed in patients with mild-to-moderate hepatic impairment. There is no clinical experience in those with severe hepatic impairment (Child-Pugh score > 9, class C).

No dosage adjustment is needed in patients with renal impairment.
 
Intermittent hemodialysis
Micafungin is not dialyzable. Supplemental dosing is not required following hemodialysis.
 
Continuous hemodialysis
Micafungin is not dialyzable. Supplemental dosing is not required following hemodialysis.

Corticosteroids: (Moderate) Leukopenia, neutropenia, anemia, and thrombocytopenia have been associated with micafungin. Patients who are taking immunosuppressives such as the corticosteroids with micafungin concomitantly may have additive risks for infection or other side effects. In a pharmacokinetic trial, micafungin had no effect on the pharmacokinetics of prednisolone. Acute intravascular hemolysis and hemoglobinuria was seen in a healthy volunteer during infusion of micafungin (200 mg) and oral prednisolone (20 mg). This reaction was transient, and the subject did not develop significant anemia.
Cyclosporine: (Moderate) Leukopenia, neutropenia, anemia, and thrombocytopenia have been associated with micafungin. In theory, patients who are taking immunosuppressive agents such as cyclosporine concomitantly with micafungin may have additive risks for infection or other side effects. However, the manufacturer has listed no particular precautions for co-use of micafungin with cyclosporine. Concurrent administration of micafungin and cyclosporinel did not alter the pharmacokinetic parameters of micafungin. Furthermore, there was no effect of a single or multiple doses of micafungin on cyclosporine pharmacokinetic parameters.
Dichlorphenamide: (Moderate) Use dichlorphenamide and antifungals together with caution. Dichlorphenamide increases potassium excretion and can cause hypokalemia and should be used cautiously with other drugs that may cause hypokalemia including antifungals. Measure potassium concentrations at baseline and periodically during dichlorphenamide treatment. If hypokalemia occurs or persists, consider reducing the dose or discontinuing dichlorphenamide therapy.
Itraconazole: (Moderate) Micafungin was shown to increase the systemic exposure (AUC) of itraconazole by 22% in a pharmacokinetic study. The mechanism of this interaction has not been identified, as micafungin does not significantly affect CYP450 enzymes or P-glycoprotein (P-gp). Itraconazole is not known to alter the pharmacokinetic parameters of micafungin. Patients should be evaluated for itraconazole-related side effects during concurrent therapy; itraconazole dosage adjustment may be necessary.
Mycophenolate: (Moderate) Leukopenia, neutropenia, anemia, and thrombocytopenia have been associated with micafungin. In theory, patients who are taking immunosuppressive agents such as mycophenolate concomitantly with micafungin may have additive risks for infection or other side effects. However, the manufacturer has listed no particular precautions for co-use of micafungin with these medications. Concurrent administration of micafungin and mycophenolate mofetil did not alter the pharmacokinetic parameters of micafungin. Furthermore, there was no effect of a single or multiple doses of micafungin on mycophenolate mofetil pharmacokinetic parameters.
Nanoparticle Albumin-Bound Sirolimus: (Moderate) Monitor for an increase in sirolimus-related adverse effects and adjust sirolimus dosage as appropriate based on response if concomitant use with micafungin is required. Concomitant use has been observed to increase sirolimus overall exposure by 21% without an effect on sirolimus peak.
Nifedipine: (Moderate) Concomitant nifedipine and micafungin administration may increase the systemic exposure and the maximum serum concentration of nifedipine. Nifedipine AUC and Cmax were increased by 18% and 42%, respectively, in the presence of steady-state micafungin compared with nifedipine alone. Patients should be monitored closely for nifedipine-related side effects; nifedipine dosage reduction may be necessary.
Saccharomyces boulardii: (Major) Because Saccharomyces boulardii is an active yeast, it would be expected to be inactivated by any antifungals. The manufacturer does not recommend taking in conjunction with any antifungal agents. Patients should avoid use of this probiotic yeast until the fungal or yeast infection is completely treated.
Sirolimus: (Moderate) Monitor for an increase in sirolimus-related adverse effects and adjust sirolimus dosage as appropriate based on response if concomitant use with micafungin is required. Concomitant use has been observed to increase sirolimus overall exposure by 21% without an effect on sirolimus peak.
Tacrolimus: (Moderate) Leukopenia, neutropenia, anemia, and thrombocytopenia have been associated with micafungin. In theory, patients who are taking immunosuppressive agents such as tacrolimus concomitantly with micafungin may have additive risks for infection or other side effects. However, the manufacturer has listed no particular precautions for co-use of micafungin with these medications. Concurrent administration of micafungin and tacrolimus did not alter the pharmacokinetic parameters of micafungin. Furthermore, there was no effect of a single or multiple doses of micafungin on tacrolimus pharmacokinetic parameters.

Micafungin Sodium/Mycamine Intravenous Inj Pwd F/Sol: 50mg, 100mg

150 mg/day IV.

150 mg/day IV.

weight more than 30 kg: 2.5 mg/kg/day IV (Max: 150 mg) is the FDA-approved maximum dosage; however, doses up to 4.5 mg/kg/day IV (Max: 225 mg/day) have been used off-label.
weight 30 kg or less: 3 mg/kg/day IV is the FDA-approved maximum dosage; however, doses up to 4.5 mg/kg/day IV have been used off-label.

weight more than 30 kg: 2.5 mg/kg/day IV (Max: 150 mg) is the FDA-approved maximum dosage; however, doses up to 4.5 mg/kg/day IV (Max: 225 mg/day) have been used off-label.
weight 30 kg or less: 3 mg/kg/day IV is the FDA-approved maximum dosage; however, doses up to 4.5 mg/kg/day IV have been used off-label.

4 to 11 months: 3 mg/kg/day IV is the FDA-approved maximum dosage; however, doses up to 4.5 mg/kg/day IV have been used off-label.
1 to 3 months: 4 mg/kg/day IV is the FDA-approved maximum dosage; however, doses up to 4.5 mg/kg/day IV have been used off-label.

4 mg/kg/day IV is the FDA-approved maximum dosage; however, doses up to 15 mg/kg/day IV have been used off-label for CNS infections.

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.

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.

Micafungin has poor oral bioavailability (less than 5%).

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.

There are no adequate and well-controlled studies evaluating the use of micafungin in human pregnancy to inform a drug-associated risk of adverse developmental outcomes. However, based on animal studies, micafungin may cause fetal harm when administered to a pregnant woman. In animal reproduction studies, intravenous administration of micafungin to pregnant rabbits during organogenesis at doses 4 times the maximum recommended human dose resulted in visceral abnormalities and increased abortion. Advise pregnant women of the risk to the fetus if micafungin is used during pregnancy.[44913]

There are no data available on the presence of micafungin in human milk, the effects on the breast-fed infant, or the effects on milk production. Micafungin was present in the milk of lactating rats after IV administration and it is likely to be present in human milk. Fluconazole may be a potential alternative to consider during breast-feeding. However, site of infection, local susceptibility patterns, and specific microbial susceptibility should be assessed before choosing an alternative agent. Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally ingested drug, health care providers are encouraged to report the adverse effect to the FDA.