Treatment of Candidemia, Acute Disseminated Candidiasis, Candida Peritonitis and Abscesses without meningoencephalitis and/or ocular dissemination

The recommended dosage is 4 mg/kg once daily.

The safety and effectiveness of Micafungin for Injection have not been established for the treatment of candidemia with meningoencephalitis and/or ocular dissemination in pediatric patients younger than 4 months of age as a higher dose may be needed [see Use in Specific Populations (8.4), Clinical Pharmacology (12.3) and Microbiology (12.4)].

Reconstitution

Reconstitute Micafungin for Injection vials by aseptically adding 5 mL of one of the following compatible solutions:

• 0.9% Sodium Chloride Injection, USP (without a bacteriostatic agent).
• 5% Dextrose Injection, USP

To minimize excessive foaming, gently dissolve the Micafungin for Injection powder by swirling the vial. Do not vigorously shake the vial. Visually inspect the vial for particulate matter.

Micafungin for Injection 50 mg vial: after reconstitution each mL contains 10 mg of micafungin.

Micafungin for Injection 100 mg vial: after reconstitution each mL contains 20 mg of micafungin.

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Do not use if there is any evidence of precipitation or foreign matter. Aseptic technique must be strictly observed in all handling since no preservative or bacteriostatic agent is present in Micafungin for Injection or in the materials specified for reconstitution and dilution.

The reconstituted product should be protected from light and may be stored in the original vial for up to 24 hours at room temperature, 25°C (77°F).

Dilution and Preparation

The diluted solution should be protected from light. It is not necessary to cover the infusion drip chamber or the tubing.

Adult Patients:

1. Add the appropriate volume of reconstituted Micafungin for Injection into 100 mL of 0.9% Sodium Chloride Injection, USP or 100 mL of 5% Dextrose Injection, USP.
2. Appropriately label the bag.

Pediatric Patients:

1. Calculate the total Micafungin for Injection dose in milligrams (mg) by multiplying the recommended pediatric dose (mg/kg) for a given indication [see Table 2] and the weight of the patient in kilograms (kg).
2. To calculate the volume (mL) of drug needed, divide the calculated dose (mg) from step 1 by the final concentration of the selected reconstituted vial(s) (either 10 mg/mL for the 50 mg vial or 20 mg/mL for the 100 mg vial), see example below:
   Using 50 mg vials:
   Divide the calculated mg dose (from step 1) by 10 mg/mL to determine the volume (mL) needed.
   OR
   Using 100 mg vials:
   Divide the calculated mg dose (from step 1) by 20 mg/mL to determine the volume (mL) needed.
3. Withdraw the calculated volume (mL) of drug needed from the selected concentration and size of reconstituted Micafungin for Injection vial(s) used in Step 2 (ensure the selected concentration and vial size used to calculate the dose is also used to prepare the infusion).
4. Add the withdrawn volume of drug (step 3) to a 0.9% Sodium Chloride Injection, USP or 5% Dextrose Injection, USP intravenous infusion bag or syringe. Ensure that the final concentration of the solution is between 0.5 mg/mL to 4 mg/mL.
   To decrease the risk of infusion reactions, concentrations above 1.5 mg/mL should be administered via central catheter [see Warnings and Precautions (5.5)].
5. Appropriately label the infusion bag or syringe. For concentrations above 1.5 mg/mL, if required, label to specifically warn to administer the solution via central catheter.

The diluted infusion bag should be protected from light and may be stored for up to 24 hours at room temperature, 25°C (77°F).

Micafungin for Injection is preservative-free. Discard partially used vials.

Pediatric Patients

Micafungin for Injection should be infused over one hour. To decrease the risk of infusion reactions, concentrations above 1.5 mg/mL should be administered via central catheter [see Warnings and Precautions (5.5)].

Clinical Trials Experience in Adults

In clinical trials with micafungin, 2,497/2,748 (91%) adult patients experienced at least one adverse reaction.

Candidemia and Other Candida Infections

In a randomized, double-blind trial for the treatment of candidemia and other Candida infections, adverse reactions occurred in 183/200 (92%) and 171/193 (89%) patients in the micafungin 100 mg/day, and caspofungin (70 mg loading dose followed by 50 mg/day dose) treatment groups, respectively. Selected adverse reactions occurring in 5% or more of the patients and more frequently in the micafungin treatment group, are shown in Table 3.

In a second, supportive, randomized, double-blind trial for the treatment of candidemia and other Candida infections, adverse reactions occurred in 245/264 (93%) and 250/265 (94%) adult and pediatric patients in the micafungin (100 mg/day) and amphotericin B liposome (3 mg/kg/day) treatment groups, respectively. In this trial, the following adverse reactions were reported in patients at least 16 years of age in the micafungin and amphotericin B liposome treatment groups, respectively: 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%).

Esophageal Candidiasis

In a randomized, double-blind study for treatment of esophageal candidiasis, a total of 202/260 (78%) patients who received micafungin 150 mg/day and 186/258 (72%) patients who received intravenous fluconazole 200 mg/day experienced an adverse reaction. Adverse reactions resulting in discontinuation were reported in 17 (7%) micafungin-treated patients; and in 12 (5%) fluconazole-treated patients. Selected treatment-emergent adverse reactions occurring in 5% or more of the patients and more frequently in the micafungin group, are shown in Table 4.

Prophylaxis of Candida Infections in Hematopoietic Stem Cell Transplant Recipients

A double-blind trial 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 (382) or fluconazole (409) experienced at least one adverse reaction during the study. Treatment-emergent adverse reactions resulting in micafungin discontinuation were reported in 15 (4%) adult patients; while those resulting in fluconazole discontinuation were reported in 32 (8%). Selected adverse reactions reported in 15% or more of adult patients and more frequently in the micafungin 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
• Metabolism and nutrition disorders: hypernatremia, hypokalemia
• Nervous system disorders: convulsions, encephalopathy, intracranial hemorrhage
• Psychiatric disorders: delirium
• Skin and subcutaneous tissue disorders: urticaria

Clinical Trials Experience in Pediatric Patients

The safety of micafungin was assessed in 593 pediatric patients, 425 of whom were 4 months through 16 years of age and 168 of whom were 3 days to less than 4 months of age who received at least one dose of micafungin across 15 clinical trials.

Of the 425 pediatric patients, 4 months through 16 years of age enrolled in 11 clinical trials, 235 (55%) were male, 290 (68%) were white, with the following age distribution: 62 (15%) 4 months to <2 years, 108 (25%) 2 to 5 years, 140 (33%) 6 to 11 years, and 115 (27%) 12 to 16 years of age. The mean treatment duration was 26.1 days. A total of 246 patients received at least one dose of micafungin ranging from 2 to 10 mg/kg. Overall, 388/425 (91%) patients experienced at least one adverse reaction. Adverse reactions occurring in ≥15% or more of micafungin-treated pediatric patients 4 months of age and older are: vomiting (32%), diarrhea (24%), pyrexia (24%), hypokalemia (22%), nausea (21%), mucosal inflammation (19%), thrombocytopenia (19%), abdominal pain (18%), headache (15%), and hypertension (15%).

Two randomized, double-blind active-controlled trials included pediatric patients. In the invasive candidiasis/candidemia trial, the efficacy and safety of micafungin (2 mg/kg/day for patients weighing 40 kg or less and 100 mg/day for patients weighing greater than 40 kg) was compared to amphotericin B liposome (3 mg/kg/day) in 112 pediatric patients. Treatment-emergent adverse reactions occurred in 51/56 (91%) of patients in the micafungin group and 52/56 (93%) of patients in the amphotericin B liposome group. Treatment-emergent adverse reactions resulting in drug discontinuation were reported in 2 (4%) micafungin-treated pediatric patients and in 9 (16%) amphotericin B liposome-treated pediatric patients.

The prophylaxis study in patients undergoing HSCT investigated the efficacy of micafungin (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 due to adverse reaction, while one (2%) patient discontinued fluconazole.

The selected adverse reactions, occurring in 15% or more of the patients and more frequently in a micafungin group, for the two comparative trials are shown in Table 6.

Other clinically significant adverse reactions reported at less than 15% in pediatric clinical trials are listed below:

• Hepatobiliary disorders: hyperbilirubinemia
• Investigations: liver tests abnormal
• Renal disorders: renal failure

Clinical Trials Experience in Pediatric Patients Younger than 4 Months of Age

The safety of micafungin was assessed in 168 pediatric patients younger than 4 months of age who received varying doses of micafungin in 9 clinical trials. The mean treatment duration was 16.6 days. A total of 59 patients received micafungin at doses ≤4 mg/kg/day and 109 patients received micafungin doses >4 mg/kg/day [5 to 15 mg/kg/day (approximately 1.3 to 3.8 times the recommended dosage in pediatric patients less than 4 months old)].

The adverse reaction profile of micafungin in pediatric patients younger than 4 months of age was generally comparable to that of pediatric patients 4 months of age and older and adults. The most frequent adverse reactions (≥15%) in pediatric patients younger than 4 months old receiving a micafungin dose of approximately 4 mg/kg/day included hypokalemia (25%), thrombocytopenia (25%), acidosis (20%), sepsis (20%), anemia (15%), oxygen saturation decreased (15%), and vomiting (15%). No new safety signals were seen in patients who received 5 to 15 mg/kg/day [see Use in Specific Populations (8.4)].

Additional clinically significant adverse reactions reported in less than 15% of pediatric patients younger than 4 months of age who received approximately 4 mg/kg/day are listed below:

• Blood and Lymphatic System Disorders: leukocytosis, thrombocytosis, coagulation disorder neonatal
• Gastrointestinal Disorders: hematochezia, intestinal perforation, ascites, ileus, intestinal infarction, diarrhea, abdominal distension
• General Disorders and Administration Site Conditions: peripheral swelling, generalized edema, pyrexia, infusion site extravasation, edema neonatal
• Hepatobiliary Disorders: hyperbilirubinemia
• Investigations: blood lactate dehydrogenase increased, blood urea increased, ECG QRS complex prolonged
• Vascular Disorders: neonatal hypotension, thrombophlebitis
• Musculoskeletal and connective tissue disorders: hypertonia neonatal
• Respiratory, thoracic and mediastinal disorders: pleural effusion, respiratory failure, neonatal aspiration, respiratory distress
• Metabolism and nutrition disorders: hyperglycemia, dehydration, hypocalcemia, hypermagnesemia

CYP3A4, CYP2C9 and CYP2C19 Inhibitors

Co-administration of micafungin with cyclosporine, itraconazole, voriconazole and fluconazole did not alter the pharmacokinetics of micafungin.

CYP2C19 and CYP3A4 Inducer

Co-administration of micafungin with rifampin and ritonavir did not alter the pharmacokinetics of micafungin

Co-administration of Micafungin with Other Drugs

Co-administration of micafungin with mycophenolate mofetil (MMF), amphotericin B, tacrolimus, prednisolone, sirolimus and nifedipine did not alter the pharmacokinetics of micafungin.

CYP3A4 Substrates

There was no effect of single or multiple doses of micafungin on cyclosporine, tacrolimus, prednisolone, voriconazole and fluconazole pharmacokinetics.

Sirolimus AUC was increased by 21% with no effect on Cmax in the presence of steady-state micafungin compared with sirolimus alone. Nifedipine AUC and Cmax were increased by 18% and 42%, respectively, in the presence of steady-state micafungin compared with nifedipine alone. Itraconazole AUC and Cmax were increased by 22% and 11%, respectively. Patients receiving sirolimus, nifedipine, and itraconazole in combination with micafungin should be monitored for sirolimus, nifedipine, and itraconazole toxicity and the sirolimus, nifedipine, and itraconazole dosage should be reduced if necessary.

UDP-Glycosyltransferase Substrate

Co-administration of mycophenolate mofetil (MMF) with micafungin did not alter the pharmacokinetics of MMF.

Risk Summary

Based on findings from animal studies, micafungin may cause fetal harm when administered to a pregnant woman (see Data). There is insufficient human data on the use of micafungin in pregnant women to inform a drug-associated risk of adverse developmental outcomes. In animal reproduction studies, intravenous administration of micafungin sodium to pregnant rabbits during organogenesis at doses four times the maximum recommended human dose resulted in visceral abnormalities and increased abortion (see Data). Advise pregnant women of the risk to the fetus.

The estimated background risk of major birth defects and miscarriage for the indicated populations is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively.

Data

Risk Summary

There are no data 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 following intravenous administration. When a drug is present in animal milk, it is likely that the drug will be present in human milk. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for micafungin, and any potential adverse effects on the breast-fed child from micafungin, or from the underlying maternal condition.

Pediatric Patients 4 Months of Age and Older

The safety and effectiveness of micafungin for the treatment of esophageal candidiasis, candidemia, acute disseminated candidiasis, Candida peritonitis and abscesses, esophageal candidiasis, and for prophylaxis of Candida infections in patients undergoing HSCT have been established in pediatric patients 4 months of age and older. Use of micafungin for these indications and in this age group is supported by evidence from adequate and well-controlled studies in adult and pediatric patients with additional pharmacokinetic and safety data in pediatric patients 4 months of age and older [see Indications and Usage (1), Adverse Reactions (6.1), Clinical Pharmacology (12.3), and Clinical Studies (14)].

Pediatric Patients Younger than 4 Months of Age

Treatment of Candidemia, Acute Disseminated Candidiasis, Candida Peritonitis and Abscesses Without Meningoencephalitis and/or Ocular Dissemination in Pediatric Patients Younger Than 4 Months of Age

The safety and effectiveness of micafungin for the treatment of candidemia, acute disseminated candidiasis, Candida peritonitis and abscesses without meningoencephalitis and/or ocular dissemination at a dosage of 4 mg/kg once daily have been established in pediatric patients younger than 4 months of age. This use and dosage of micafungin are supported by evidence from adequate and well-controlled studies in adult and pediatric patients 4 months of age and older with additional pharmacokinetic and safety data in pediatric patients younger than 4 months of age [see Adverse Reactions (6.1) and Clinical Pharmacology (12.3)].

Treatment of Candidemia, Acute Disseminated Candidiasis, Candida Peritonitis and Abscesses With Meningoencephalitis and/or Ocular Dissemination in Pediatric Patients Younger Than 4 Months of Age

The safety and effectiveness of micafungin have not been established for the treatment of candidemia with meningoencephalitis and/or ocular dissemination in pediatric patients younger than 4 months of age.

In a rabbit model of hematogenous Candida meningoencephalitis (HCME) with Candida albicans (minimum inhibitory concentration of 0.125 mcg/mL), a decrease in mean fungal burden in central nervous system (CNS) compartment assessed as the average of combined fungal burden in the cerebrum, cerebellum, and spinal cord relative to untreated controls, was observed with increasing micafungin dosages administered once daily for 7 days. Data from the rabbit model suggest that a micafungin dose regimen of 4 mg/kg once daily is inadequate to treat meningoencephalitis and that a dose regimen of approximately 10 to 25 mg/kg once daily may be necessary to lower fungal burden in the CNS in pediatric patients younger than 4 months of age [see Microbiology (12.4)]. In this rabbit model, micafungin concentrations could not be reliably detected in cerebrospinal fluid (CSF). Due to limitations of the study design, the clinical significance of a decreased CNS fungal burden in the rabbit HCME model is uncertain.

A randomized controlled trial evaluated a micafungin dose regimen of 10 mg/kg once daily in pediatric patients younger than 4 months of age with suspected or proven Candida meningoencephalitis. Fungal-free survival at 1 week after end of therapy was observed in 60% of micafungin-treated vs. 70% of amphotericin B-treated patients, and all- cause mortality was 15% vs. 10%, respectively. However, because this study was terminated early and enrolled only 30 pediatric patients younger than 4 months of age (20 treated with micafungin and 10 treated with amphotericin B) which was 13% of the planned enrollment for the study, no conclusions can be drawn regarding efficacy of micafungin at this dose regimen.

In six uncontrolled, open-label studies, and a neonatal intensive care unit (ICU) medical records database, pediatric patients younger than 4 months of age with suspected Candida meningoencephalitis or disseminated candidemia received micafungin at dose regimens ranging from 5 to 15 mg/kg once daily. Across the entire micafungin development program, only 6 pediatric patients with proven Candida meningoencephalitis were treated with dosages of 2 mg/kg, 8 mg/kg and 10 mg/kg once daily. Micafungin was detected in the CSF of pediatric patients with suspected Candida meningoencephalitis. No conclusions regarding the efficacy of a particular dosage of micafungin or the penetration of micafungin into the CSF can be drawn due to limitations of the data, including but not limited to, multiple confounding factors, variable study designs, and limited numbers of patients. No new safety signals were observed with the use of micafungin at dosages of 5 to 15 mg/kg once daily in pediatric patients younger than 4 months of age, and there was no discernible dose-response for adverse events.

Although the dosage for the treatment of candidemia with meningoencephalitis has not been established, antifungal activity in various CNS compartments in the rabbit HCME model and limited clinical trial data suggest that in patients younger than 4 months of age, dose regimens 10 mg/kg once daily or higher may be necessary for the treatment of candidemia with meningoencephalitis. Safety data from clinical studies for micafungin at dose regimens of 10 to 15 mg/kg once daily in pediatric patients younger than 4 months of age did not reveal new safety signals.

Treatment of Esophageal Candidiasis and Prophylaxis of Candida Infections in Patients Undergoing Hematopoietic Stem Cell Transplantation in Pediatric Patients Younger Than 4 Months of Age

The safety and effectiveness of micafungin in pediatric patients younger than 4 months of age have not been established for the:

• Treatment of esophageal candidiasis
• Prophylaxis of Candida infections in patients undergoing hematopoietic stem cell transplantation

Adults

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. Typically, 85% of the steady-state concentration is achieved after three daily micafungin doses.

Steady-state pharmacokinetic parameters in relevant patient populations after repeated daily administration are presented in Table 7.

Pediatric Patients 4 Months of Age and Older

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.

Pediatric Patients Younger than 4 Months of Age

Micafungin pharmacokinetic data in 103 pediatric patients less than 4 months of age were assessed using population pharmacokinetics. Predicted micafungin AUC estimates were dose proportional across the dose regimens and age ranges studied. The body weight-normalized micafungin clearance in pediatric patients less than 4 months of age is higher than the body weight-normalized micafungin clearance in older pediatric patients greater than 4 months of age and adults.

Administration of 4 mg/kg once daily micafungin to pediatric patients less than 4 months of age produces a mean (SD) steady-state AUC of 131 (50) mcg·h/mL, which is comparable to the steady-state AUC in pediatric patients 4 months of age and older administered micafungin 2 mg/kg/day and adults administered 100 mg once daily.

Specific Populations

Mechanism of Action

Micafungin inhibits the synthesis of 1,3-beta-D-glucan, an essential component of fungal cell walls, which is not present in mammalian cells.

Activity in Animal Models of Candidiasis

Activity of micafungin has been demonstrated in both mucosal and disseminated murine and rabbit models of candidiasis. Micafungin administered to immunocompetent or immunosuppressed mice or rabbits with disseminated candidiasis prolonged survival (mice) and/or decreased the fungal burden in different organs including brain in a dose-dependent manner (mice and rabbits). Overall, antifungal activity of micafungin was demonstrated in the brain and eye tissues of nonneutropenic rabbits with HCME infected with a micafungin-sensitive strain of C. albicans; however, the activity varied in different central nervous system and ocular compartments. In the cerebrum, culture negativity was achieved at a micafungin dose regimen of 32 mg/kg once daily for 7 days; whereas, in spinal cord, vitreous humor, and choroid, culture negativity was achieved at micafungin dose regimens of 24 to 32 mg/kg once daily. Compared to untreated animals, micafungin dose regimens between 8 and 24 mg/kg once daily reduced fungal burden in the cerebrum and cerebellum. When cerebrum, cerebellum and spinal cord data were combined, a decrease in fungal burden relative to untreated controls was evident at micafungin dose regimens between 16 and 32 mg/kg once daily [see Use in Specific Populations (8.4)].

Resistance

There have been reports of clinical failures in patients receiving micafungin 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.

Antimicrobial Activity

Micafungin has been shown to be active against most isolates of the following Candida species, both in vitro and in clinical infections [see Indications and Usage (1)]:

Candida albicans

Candida glabrata

Candida guilliermondii

Candida krusei

Candida parapsilosis

Candida tropicalis

Susceptibility Testing

For specific information regarding susceptibility test interpretive criteria and associated test methods and quality control standards recognized by FDA for this drug, please see: https://www.fda.gov/STIC.