Micafungin

Micafungin for Injection is indicated for: Treatment of Candidemia, Acute Disseminated Candidiasis, Candida Peritonitis and Abscesses in adult and pediatric patients 4 months of age and older [see Clinical Studies (14.1) and Use in Specific Populations (8.4)] . 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 [see Use in Specific Populations (8.4)] . Treatment of Esophageal Candidiasis in adult and pediatric patients 4 months of age and older [see Clinical Studies (14.2)] . Prophylaxis of Candida Infections in adult and pediatric patients 4 months of age and older undergoing hematopoietic stem cell transplantation [see Clinical Studies (14.3)] . Limitations of Use 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)] . Micafungin for Injection has not been adequately studied in patients with endocarditis, osteomyelitis and meningoencephalitis due to Candida . The efficacy of Micafungin for Injection against infections caused by fungi other than Candida has not been established. Micafungin for Injection is an echinocandin indicated in adult and pediatric patients for (1): Treatment of Candidemia, Acute Disseminated Candidiasis, Candida Peritonitis and Abscesses in adult and pediatric patients 4 months of age and older. 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. Treatment of Esophageal Candidiasis in adult and pediatric patients 4 months of age and older. Prophylaxis of Candida Infections in adult and pediatric patients 4 months of age and older undergoing Hematopoietic Stem Cell Transplantation (HSCT). Limitations of Use 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. (1, 2.3, 8.4) Micafungin for Injection has not been adequately studied in patients with endocarditis, osteomyelitis or meningoencephalitis due to Candida . (1) The efficacy of Micafungin for Injection against infections caused by fungi other than Candida has not been established. (1)

Recommended Dosage Administered by Indication, Weight and Age (2.1, 2.2, 2.3, 8.4) Adult Pediatric Patients 4 Months and Older 30 kg or less Pediatric Patients 4 Months and Older greater than 30 kg Pediatric Patients Younger than 4 Months of Age Treatment of Candidemia, Acute Disseminated Candidiasis, Candida Peritonitis and Abscesses 100 mg daily 2 mg/kg/day (maximum 100 mg daily) See below Treatment of Candidemia, Acute Disseminated Candidiasis, Candida Peritonitis and Abscesses without Meningoencephalitis and/or Ocular Dissemination See above See above 4 mg/kg/day Treatment of Esophageal Candidiasis 150 mg daily 3 mg/kg/day 2.5 mg/kg/day (maximum 150 mg daily) Not approved Prophylaxis of Candida Infections in HSCT Recipients 50 mg daily 1 mg/kg/day (maximum 50 mg daily) Not approved Infuse over 1 hour. (2.5) See Full Prescribing Information for intravenous (IV) preparation and administration instructions. (2) 2.1 Dosage for Adults The recommended dosage for adult patients based on indications are shown in Table 1. Table 1. Micafungin for Injection Dosage in Adult Patients ​​Indication Recommended Reconstituted Dose Once Daily Treatment of Candidemia, Acute Disseminated Candidiasis, Candida Peritonitis and Abscesses * 100 mg Treatment of Esophageal Candidiasis † 150 mg Prophylaxis of Candida Infections in HSCT Recipients ‡ 50 mg *In patients treated successfully for candidemia and other Candida infections, the mean duration of treatment was 15 days (range 10 to 47 days). † In patients treated successfully for esophageal candidiasis, the mean duration of treatment was 15 days (range 10 to 30 days). ‡ In hematopoietic stem cell transplant (HSCT) recipients who experienced success of prophylactic therapy, the mean duration of prophylaxis was 19 days (range 6 to 51 days). 2.2 Dosage for Pediatric Patients 4 Months and Older The recommended dosage for pediatric patients 4 months of age and older based on indication and weight are shown in Table 2. Table 2. Micafungin for Injection Dosage in Pediatric Patients (4 Months of Age and Older) Indication Dosage for Pediatric Patients 4 Months of Age and Older 30 kg or less Greater than 30 kg Treatment of Candidemia, Acute Disseminated Candidiasis, Candida Peritonitis and Abscesses 2 mg/kg once daily (maximum daily dose 100 mg) Treatment of Esophageal Candidiasis 3 mg/kg once daily 2.5 mg/kg once daily (maximum daily dose 150 mg) Prophylaxis of Candida Infections in HSCT Recipients 1 mg/kg once daily (maximum daily dose 50 mg) 2.3 Dosage for Pediatric Patients Younger than 4 Months of Age 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)] . 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: af…

Hypersensitivity Reactions: Anaphylaxis and anaphylactoid reactions (including shock) have been observed. Discontinue micafungin for injection and administer appropriate treatment. (5.1) Hematological Effects: Isolated cases of acute intravascular hemolysis, hemolytic anemia and hemoglobinuria have been reported. Monitor rate of hemolysis. Discontinue if severe. (5.2) Hepatic Effects: Abnormalities in liver tests; isolated cases of hepatic impairment, hepatitis, and hepatic failure have been observed. Monitor hepatic function. Discontinue if severe dysfunction occurs. (5.3) Renal Effects: Elevations in BUN and creatinine; isolated cases of renal impairment or acute renal failure have been reported. Monitor renal function. (5.4) Infusion and Injection Site Reactions can occur including rash, pruritus, facial swelling, and vasodilatation. Monitor infusion closely, slow infusion rate if necessary. (2.5, 5.5) 5.1 Hypersensitivity Reactions Isolated cases of serious hypersensitivity (anaphylaxis and anaphylactoid) reactions (including shock) have been reported in patients receiving micafungin for injection. If these reactions occur, micafungin for injection infusion should be discontinued and appropriate treatment administered. 5.2 Hematological Effects Acute intravascular hemolysis and hemoglobinuria was seen in a healthy volunteer during infusion of micafungin for injection (200 mg) and oral prednisolone (20 mg). Cases of significant hemolysis and hemolytic anemia have also been reported in patients treated with micafungin for injection. Patients who develop clinical or laboratory evidence of hemolysis or hemolytic anemia during micafungin for injection therapy should be monitored closely for evidence of worsening of these conditions and evaluated for the risk/benefit of continuing micafungin for injection therapy. 5.3 Hepatic Effects Laboratory abnormalities in liver function tests have been seen in healthy volunteers and patients treated with micafungin for injection. In some patients with serious underlying conditions who were receiving micafungin for injection along with multiple concomitant medications, clinical hepatic abnormalities have occurred, and isolated cases of significant hepatic impairment, hepatitis, and hepatic failure have been reported. Patients who develop abnormal liver function tests during micafungin for injection therapy should be monitored for evidence of worsening hepatic function and evaluated for the risk/benefit of continuing micafungin for injection therapy. 5.4 Renal Effects Elevations in BUN and creatinine, and isolated cases of significant renal impairment or acute renal failure have been reported in patients who received micafungin for injection. In fluconazole-controlled trials, the incidence of drug-related renal adverse reactions was 0.4% for micafungin for injection-treated patients and 0.5% for fluconazole-treated patients. Patients who develop abnormal renal function tests during micafungin for injection therapy should be monitored for evidence of worsening renal function. 5.5 Infusion and Injection Site Reactions Possible histamine-mediated symptoms have been reported with micafungin for injection, including rash, pruritus, facial swelling, and vasodilatation. Slow the infusion rate if infusion reaction occurs [see Dosage and Administration (2.3)] . Injection site reactions, including phlebitis and thrombophlebitis have been reported, at micafungin for injection doses of 50 to 150 mg/day. These reactions tended to occur more often in patients receiving micafungin for injection via peripheral intravenous administration [see Dosage and Administration (2.3) and Adverse Reactions (6.1)] . 5.1 Hypersensitivity Reactions Isolated cases of serious hypersensitivity (anaphylaxis and anaphylactoid) reactions (including shock) have been reported in patients receiving micafungin for injection. If these reactions occur, micafungin for injection infusion should be discontinued and appropriate treatment…

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 contraindicated in persons with known hypersensitivity to micafungin sodium, any component of micafungin for injection, or other echinocandins. (4)

Monitor for sirolimus, itraconazole or nifedipine toxicity, and dosage of sirolimus, itraconazole or nifedipine should be reduced, if necessary. (7) 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. 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.

The following clinically significant adverse reactions are described elsewhere in the labeling: Hypersensitivity Reactions [see Warnings and Precautions (5.1)] Hematological Effects [see Warnings and Precautions (5.2)] Hepatic Effects [see Warnings and Precautions (5.3)] Renal Effects [see Warnings and Precautions (5.4)] Infusion and Injection Site Reactions [see Warnings and Precautions (5.5)] Most common adverse reactions across adult and pediatric clinical trials for all indications include diarrhea, nausea, vomiting, abdominal pain, pyrexia, thrombocytopenia, neutropenia, and headache. (6.1) 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. (6.1) 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 [see Dosage and Administration (2.1, 2.2)] 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 183/200 (92%) and 171/193 (89%) 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. Selected * Adverse Reactions in Adult Patients with Candidemia and Other Candida Infections Adverse Reactions by System Organ Class † Micafungin for Injection 100 mg n (%) Caspofungin ‡ n (%) Number of Patients 200 193 Gastrointestinal Disorders 81 (41) 76 (39) Diarrhea 15 (8) 14 (7) Vomiting 18 (9) 16 (8) Metabolism and Nutrition Disorders 77 (39) 73 (38) Hypoglycemia 12 (6) 9 (5) Hyperkalemia 10 (5) 5 (3) General Disorders/Administration Site Conditions 59 (30) 51 (26) Investigations 36 (18) 37 (19) Blood Alkaline Phosphatase Increased 11 (6) 8 (4) Cardiac Disorders 35 (18) 36 (19) Atrial Fibrillation 5 (3) 0 Patient base: all randomized patients who received at least 1 dose of trial drug. * During IV treatment + 3 days. † Within a system organ class, patients may experience more than 1 adverse reaction. ‡ 70 mg loading dose on day 1 followed by 50 mg/day thereafter (caspofungin). 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 for injection (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 for injection and amphotericin B liposome treatment groups, respectively: nausea (10% vs. 8%), diarrhea (11% vs. 11%), vomiting (13% vs. 9%), abnorma…