Micafungin Sodium

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 )

Micafungin for injection, USP is a sterile, white lyophilized powder for reconstitution for intravenous infusion available as: 50 mg single-dose vial 100 mg single-dose vial For injection: 50 mg single-dose vial. ( 3 ) For injection: 100 mg single-dose vial. ( 3 )

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 )

Hypersensitivity Reactions: Anaphylaxis and anaphylactoid reactions (including shock) have been observed. Discontinue micafungin 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. If these reactions occur, micafungin 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 (200 mg) and oral prednisolone (20 mg). Cases of significant hemolysis and hemolytic anemia have also been reported in patients treated with micafungin. Patients who develop clinical or laboratory evidence of hemolysis or hemolytic anemia during micafungin therapy should be monitored closely for evidence of worsening of these conditions and evaluated for the risk/benefit of continuing micafungin therapy.

5.3 Hepatic Effects Laboratory abnormalities in liver function tests have been seen in healthy volunteers and patients treated with micafungin. In some patients with serious underlying conditions who were receiving micafungin 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 therapy should be monitored for evidence of worsening hepatic function and evaluated for the risk/benefit of continuing micafungin 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. In fluconazole-controlled trials, the incidence of drug-related renal adverse reactions was 0.4% for micafungin-treated patients and 0.5% for fluconazole-treated patients. Patients who develop abnormal renal function tests during micafungin 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, 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 doses of 50 mg/day to 150 mg/day. These reactions tended to occur more often in patients receiving micafungin via peripheral intravenous administration [see Dosage and Administration ( 2.3 ) and Adverse Reactions ( 6.1 )].

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 Sagent Pharmaceuticals at 1-866-625-1618 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 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 was assessed in 520 healthy volunteers and 3417 adult and pediatric patients who received single or multiple doses of micafungin across 50 clinical trials, including the invasive candidiasis, esophageal candidiasis and prophylaxis trials. The doses of micafungin 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, 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 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 . Table 3. Selected* Adverse Reactions in Adult Patients with Candidemia and Other Candida Infections 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). Adverse Reactions by System Organ Class † Micafungin 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 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 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 . Table 4. Selected* Adverse Reactions in Adult Patients with Esophageal Candidiasis 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. Adverse Reactions by System Organ Class † Micafungin 150 mg/day n (%) Fluconazole 200 mg/day n (%) Number of Patients 260 258 Gastrointestinal Disorders 84 (32) 93 (36) Diarrhea 27 (10) 29 (11) Nausea 20 (8) 23 (9) Vomiting 17 (7) 17 (7) General Disorders/Administration Site Conditions 52 (20) 45 (17) Pyrexia 34 (13) 21 (8) Nervous System Disorders 42 (16) 40 (16) Headache 22 (9) 20 (8) Vascular Disorders 54 (21) 21 (8) Phlebitis 49 (19) 13 (5) Skin and Subcutaneous Tissue Disorders 36 (14) 26 (10) Rash 14 (5) 6 (2) 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 . Table 5. Selected Adverse Reactions in Adult Patients During Prophylaxis of Candida Infection in Hematopoietic Stem Cell Transplant Recipients Patient base: all randomized adult patients who received at least 1 dose of trial drug. […]

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 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.

7.2 Effect of Micafungin on Other Drugs 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 C max in the presence of steady-state micafungin compared with sirolimus alone. Nifedipine AUC and C max were increased by 18% and 42%, respectively, in the presence of steady-state micafungin 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 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.

Pregnancy – Based on animal data, micafungin may cause fetal harm. Advise pregnant women of the risk to the fetus. ( 8.1 )

8.1 Pregnancy 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 Animal Data In an embryo-fetal toxicity study in pregnant rabbits, intravenous administration of micafungin sodium during organogenesis (days 6 to 18 of gestation) resulted in fetal visceral abnormalities and abortion at 32 mg/kg, a dose equivalent to four times the recommended human dose based on body surface area comparisons. Visceral abnormalities included abnormal lobation of the lung, levocardia, retrocaval ureter, anomalous right subclavian artery, and dilatation of the ureter.

8.2 Lactation 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.

8.4 Pediatric Use 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) compartments 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. […]

Micafungin is a member of the echinocandin class of antifungal agents [see Microbiology ( 12.4 )] .