Micafungin Drug Information

Recommended Dosage Administered by Infuse over 1 hour. See Full Prescribing Information for intravenous (IV) preparation and administration instructions. 2.1 Dosage for Adults The recommended dosage for adult patients based on indications are shown in Table 1. Table 1.

Table 2. Micafungin for Injection Dosage in Pediatric Patients (4 Months of Age and Older) 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. 2.4 Directions for Reconstitution, Dilution, and Preparation Do not mix or co-infuse micafungin for injection with other medications.

Micafungin for injection has been shown to precipitate when mixed directly with a number of other commonly used medications. Please read this entire section carefully before beginning reconstitution. 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. Appropriately label the bag. Pediatric Patients Calculate the total micafungin for injection dose in milligrams (mg) by multiplying the recommended pediatric dose (mg/kg) for a given indication and the weight of the patient in kilograms (kg).

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 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). 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. 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. 2.5 Infusion Volume and Duration Administer micafungin for injection by intravenous infusion only.

Infuse over one hour. More rapid infusions may result in more frequent histamine-mediated reactions. Flush an existing intravenous line with 0.9% Sodium Chloride Injection, USP, prior to infusion of micafungin for injection.

Pediatric Patients Micafungin for injection should be infused over one hour.

The following clinically significant adverse reactions are described elsewhere in the labeling: Hypersensitivity Reactions Hematological Effects Hepatic Effects Renal Effects Infusion and Injection Site Reactions Most common adverse reactions across adult and pediatric clinical trials for all indications include diarrhea, nausea, vomiting, abdominal pain, pyrexia, thrombocytopenia, neutropenia, and headache. In pediatric patients younger than 4 months of age, the following additional common adverse reactions were reported at an incidence rate of ≥15%: sepsis, acidosis, anemia, oxygen saturation decreased and hypokalemia. To report SUSPECTED ADVERSE REACTIONS, contact Hisun Pharmaceuticals USA, Inc. at 1-855-554-4786 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in clinical trials of micafungin for injection cannot be directly compared to rates in clinical trials of another drug and may not reflect the rates observed in practice.

The overall safety of micafungin for injection was assessed in 520 healthy volunteers and 3417 adult and pediatric patients who received single or multiple doses of micafungin for injection across 50 clinical trials, including the invasive candidiasis, esophageal candidiasis and prophylaxis trials. The doses of micafungin for injection administered included doses above and below the recommended doses and ranged from 0.75 mg/kg to 15 mg/kg in pediatric patients and 12.5 mg to 150 mg/day or greater in adults. Clinical Trials Experience in Adults In clinical trials with micafungin for injection, 2497/2748 (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 patients in the micafungin for injection 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 for injection treatment group, are shown in Table 3. Table 3.

In a second, supportive, randomized, double-blind trial for the treatment of candidemia and other Candida infections, adverse reactions occurred in adult and pediatric patients in the micafungin for injection (100 mg/day) and amphotericin B liposome (3 mg/kg/day) treatment groups, respectively. Table 4. Selected Adverse Reactions in Adult Patients with Esophageal Candidiasis 14 6 Patient base: all randomized patients who received at least 1 dose of trial drug. During treatment + 3 days. Within a system organ class, patients may experience more than 1 adverse reaction.

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 for injection or fluconazole experienced at least one adverse reaction during the study.

Selected adverse reactions reported in 15% or more of adult patients and more frequently in the micafungin for injection treatment arm, are shown in Table 5. Table 5. Selected Adverse Reactions in Adult Patients During Prophylaxis of Candida Infection in Hematopoietic Stem Cell Transplant Recipients 99 91 Patient base: all randomized adult patients who received at least 1 dose of trial drug.

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 for injection 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 for injection across 15 clinical trials. The mean treatment duration was 26.1 days. A total of 246 patients received at least one dose of micafungin for injection ranging from 2 to 10 mg/kg.

Overall, 388/425 (91%) patients experienced at least one adverse reaction. Two randomized, double-blind active-controlled trials included pediatric patients. All 91 pediatric patients experienced at least one treatment-emergent adverse reaction.

Three (7%) pediatric patients discontinued micafungin for injection due to adverse reaction, while one (2%) patient discontinued fluconazole. Selected adverse reactions, occurring in 15% or more of the patients and more frequently in a micafungin for injection group, for the two comparative trials are shown in Table 6. Table 6.

Selected Adverse Reactions in Pediatric Patients with Candidemia and Other Candida Infections (C/IC), and in Hematopoietic Stem-Cell Recipients During Within a system organ class, patients may experience more than 1 adverse reaction. Study population included 20 pediatric patients younger than 4 months of age (10 in each arm) 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 for injection was assessed in 168 pediatric patients younger than 4 months of age who received varying doses of micafungin for injection in 9 clinical trials. The mean treatment duration was 16.6 days. The adverse reaction profile of micafungin for injection 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.

No new safety signals were seen in patients who received 5 to 15 mg/kg/day. 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 6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of micafungin for injection. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Blood and lymphatic system disorders: disseminated intravascular coagulation Hepatobiliary disorders: hepatic disorder Renal and urinary disorders: renal impairment Skin and subcutaneous tissue disorders: Stevens-Johnson syndrome, toxic epidermal necrolysis Vascular disorders: shock

Monitor for sirolimus, itraconazole or nifedipine toxicity, and dosage of sirolimus, itraconazole or nifedipine should be reduced, if necessary. 7.1 Effect of Other Drugs on Micafungin for Injection CYP3A4, CYP2C9 and CYP2C19 Inhibitors Co-administration of micafungin for injection with cyclosporine, itraconazole, voriconazole and fluconazole did not alter the pharmacokinetics of micafungin for injection. CYP2C19 and CYP3A4 Inducer Co-administration of micafungin for injection with rifampin and ritonavir did not alter the pharmacokinetics of micafungin for injection. Co-administration of Micafungin for Injection with Other Drugs Co-administration of micafungin for injection with mycophenolate mofetil (MMF), amphotericin B, tacrolimus, prednisolone, sirolimus and nifedipine did not alter the pharmacokinetics of micafungin for injection. 7.2 Effect of Micafungin for Injection on Other Drug CYP3A4 Substrates There was no effect of single or multiple doses of micafungin for injection on cyclosporine, tacrolimus, prednisolone, voriconazole and fluconazole pharmacokinetics.

Sirolimus AUC was increased by 21% with no effect on C max in the presence of steady-state micafungin for injection compared with sirolimus alone. Nifedipine AUC and C max were increased by 18% and 42%, respectively, in the presence of steady-state micafungin for injection compared with nifedipine alone. Itraconazole AUC and C max were increased by 22% and 11%, respectively.

Patients receiving sirolimus, nifedipine, and itraconazole in combination with micafungin for injection 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 for injection did not alter the pharmacokinetics of MMF.

Micafungin for injection is contraindicated in persons with known hypersensitivity to micafungin, any component of micafungin for injection, or other echinocandins.

Micafungin for injection is highly protein bound and, therefore, is not dialyzable. No cases of micafungin for injection overdosage have been reported. Repeated daily doses up to 8 mg/kg (maximum total dose of 896 mg) in adult patients, up to 6 mg/kg in pediatric patients 4 months of age and older, and up to 15 mg/kg in pediatric patients younger than 4 months of age have been administered in clinical trials with no reported dose-limiting toxicity.