Micafungin

1 INDICATIONS AND USAGE 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 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 has not been adequately studied in patients with endocarditis, osteomyelitis and meningoencephalitis due to Candida. The efficacy of micafungin 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 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 has not been adequately studied in patients with endocarditis, osteomyelitis or meningoencephalitis due to Candida. ( 1 ) The efficacy of micafungin against infections caused by fungi other than Candida has not been established. ( 1 )

2 DOSAGE AND ADMINISTRATION 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 Dosage in Adult Patients * In patients treated successfully for candidemia and other Candida infections, the mean duration of treatment was 15 days (range 10 days to 47 days). ‡ In patients treated successfully for esophageal candidiasis, the mean duration of treatment was 15 days (range 10 days 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 days to 51 days). 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 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 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 MYCAMINE 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 with other medications. Micafungin 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 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 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: Add the appropriate volume of reconstituted micafungin into 100 mL of 0.9% Sodium Chloride Injection, USP or 100 mL of 5% Dextrose Injection, USP. Appropriately label the bag. Pediatric Patients 1. Calculate the total micafungin 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 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. 2.5 Infusion Volume and Duration Administer micafungin by intravenous infusion only. Infuse over one hour. More rapid infusions may result in more frequent histamine-mediated reactions [see Warnings and Precautions ( 5.5 )]. Flush an existing intravenous line with 0.9% Sodium Chloride Injection, USP, prior to infusion of Micafungin. Pediatric Patients Micafungin 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 )].

6 ADVERSE REACTIONS 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 Zydus Pharmaceuticals (USA) Inc. at 1-877-993-8779 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 3,417 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, 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. 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 day 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. System Organ Class Micafungin 50 mg/day n (%) Fluconazole 400 mg/day n (%) Number of Patients 382 409 Gastrointestinal Disorders 377 (99) 404 (99) Diarrhea 294 (77) 327 (80) Nausea 270 (71) 290 (71) Vomiting 252 (66) 274 (67) Abdominal Pain 100 (26) 93 (23) Blood and Lymphatic System Disorders 368 (96) 385 (94) Neutropenia 288 (75) 297 (73) Thrombocytopenia 286 (75) 280 (69) Skin and Subcutaneous Tissue Disorders 257 (67) 275 (67) Rash 95 (25) 91 (22) Nervous System Disorders 250 (65) 254 (62) Headache 169 (44) 154 (38) Psychiatric Disorders 233 (61) 235 (58) Insomnia 142 (37) 140 (34) Anxiety 84 (22) 87 (21) Cardiac Disorders 133 (35) 138 (34) Tachycardia 99 (26) 91 (22) 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. 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. Table 6 Selected Adverse Reactions in Pediatric Patients with Candidemia and Other Candida Infections (C/IC) and in Hematopoietic Stem-Cell Recipients During Prophylaxis of Candida Infections * Study population included 20 pediatric patients younger than 4 months of age (10 in each arm) † Within a system organ class, patients may experience more than 1 adverse reaction. Adverse Reactions † C/IC * Prophylaxis Micafungin n = 56 n (%) Amphotericin B liposome n = 56 n (%) Micafungin n = 43 n (%) Fluconazole n = 48 n (%) Gastrointestinal disorders 22 (40) 18 (32) 43 (100) 45 (94) Vomiting 10 (18) 8 (14) 28 (65) 32 (67) Diarrhea 4 (7) 5 (9) 22 (51) 31 (65) Nausea 4 (7) 4 (7) 30 (70) 25 (52) Abdominal pain 2 (4) 2 (4) 15 (35) 12 (25) Abdominal distension 1 (2) 1 (2) 8 (19) 6 (13) General disorders and administration site conditions 14 (25) 14 (25) 41 (95) 46 (96) Pyrexia 5 (9) 9 (16) 26 (61) 31 (65) Infusion-related reaction 0 3 (5) 7 (16) 4 (8) Skin and subcutaneous tissue disorders 11 (20) 8 (14) 33 (77) 38 (79) Pruritus 0 1 (2) 14 (33) 15 (31) Rash 1 (2) 1 (2) 13 (30) 13 (27) Urticaria 0 1 (2) 8 (19) 4 (8) Respiratory, thoracic and mediastinal disorders 9 (16) 13 (23) 30 (70) 33 (69) Epistaxis 0 0 4 (9) 8 (17) Blood and lymphatic system disorders 17 (30) 13 (23) 40 (93) 44 (92) Thrombocytopenia 5 (9) 3 (5) 31 (72) 37 (77) Neutropenia 3 (5) 4 (7) 33 (77) 34 (71) Anemia 10 (18) 6 (11) 22 (51) 24 (50) Febrile neutropenia 0 0 7 (16) 7 (15) Investigations 12 (21) 8 (14) 24 (56) 25 (52) Alanine aminotransferase increased 0 0 7 (16) 1 (2) Urine output decreased 0 0 10 (23) 8 (17) Cardiac disorders 7 (13) 3 (5) 10 (23) 17 (35) Tachycardia 2 (4) 1 (2) 7 (16) 12 (25) Renal and urinary disorders 4 (7) 4 (7) 16 (37) 15 (31) Hematuria 0 0 10 (23) 7 (15) Psychiatric disorders 3 (5) 1 (2) 20 (47) 9 (19) Anxiety 0 0 10 (23) 3 (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 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

12.3 Pharmacokinetics 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. Table 7 Pharmacokinetic Parameters of Micafungin in Adult Patients * AUC 0-infinity is presented for Day 1; AUC 0-24 is presented for steady-state. † candidemia or other Candida infections. ‡ human immunodeficiency virus. § esophageal candidiasis. ¶ hematopoietic stem cell transplant. Population n Dose (mg) Pharmacokinetic Parameters (Mean ± Standard Deviation) C max (mcg/mL) AUC 0-24 * (mcg·h/mL) t ½ (h) Cl (mL/min/kg) Patients with IC † [Day 1] [Steady-State] 20 20 100 100 5.7 ± 2.2 10.1 ± 4.4 83 ± 51 97 ± 29 14.5 ± 7 13.4 ± 2 0.359 ± 0.179 0.298 ± 0.115 HIV ‡ - Positive Patients with EC § [Day 1] [Day 14 or 21] 20 20 14 20 20 14 50 100 150 50 100 150 4.1 ± 1.4 8 ± 2.4 11.6 ± 3.1 5.1 ± 1 10.1 ± 2.6 16.4 ± 6.5 36 ± 9 108 ± 31 151 ± 45 54 ± 13 115 ± 25 167 ± 40 14.9 ± 4.3 13.8 ± 3 14.1 ± 2.6 15.6 ± 2.8 16.9 ± 4.4 15.2 ± 2.2 0.321 ± 0.098 0.327 ± 0.093 0.340 ± 0.092 0.300 ± 0.063 0.301 ± 0.086 0.297 ± 0.081 HSCT ¶ Recipients [Day 7] 8 10 8 8 per kg 3 4 6 8 21.1 ± 2.84 29.2 ± 6.2 38.4 ± 6.9 60.8 ± 26.9 234 ± 34 339 ± 72 479 ± 157 663 ± 212 14 ± 1.4 14.2 ± 3.2 14.9 ± 2.6 17.2 ± 2.3 0.214 ± 0.031 0.204 ± 0.036 0.224 ± 0.064 0.223 ± 0.081 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. Table 8 Summary (Mean +/- Standard Deviation) of Micafungin Pharmacokinetics in Pediatric Patients 4 Months of Age and Older (Steady-State) * Or the equivalent if receiving the adult dose (50 mg, 100 mg or 150 mg). † Derived from simulations from the population PK model. ‡ Derived from the population PK model. Body weight group N Dose * mg/kg C max.SS † (mcg/mL) AUC. SS † (mcg·h/mL) t ½ ‡ (h) CL ‡ (mL/min/kg) 30 kg or less 149 1 7.1 +/- 4.7 55 +/- 16 12.5 +/- 4.6 0.328 +/- 0.091 2 14.2 +/- 9.3 109 +/- 31 3 21.3 +/- 14 164 +/- 47 Greater than 30 kg 80 1 8.7 +/- 5.6 67 +/- 17 13.6 +/- 8.8 0.241 +/- 0.061 2 17.5 +/- 11.2 134 +/- 33 2.5 23 +/- 14.5 176 +/- 42 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 Adult Patients with Renal Impairment Micafungin does not require dose adjustment in patients with renal impairment. A single 1 hour infusion of 100 mg micafungin was administered to 9 adult subjects with severe renal impairment (creatinine clearance less than 30 mL/min) and to 9 age-, gender- and weight-matched subjects with normal renal function (creatinine clearance greater than 80 mL/min). The maximum concentration (C max ) and AUC were not significantly altered by severe renal impairment. Since micafungin is highly protein bound, it is not dialyzable. Supplementary dosing should not be required following hemodialysis. Adult Patients with Hepatic Impairment A single 1 hour infusion of 100 mg micafungin was administered to 8 adult subjects with moderate hepatic impairment (Child-Pugh score 7 to 9) and 8 age-, gender- and weight-matched subjects with normal hepatic function. The C max and AUC values of micafungin were lower by approximately 22% in subjects with moderate hepatic impairment compared to normal subjects. This difference in micafungin exposure does not require dose adjustment of micafungin in patients with moderate hepatic impairment. A single 1 hour infusion of 100 mg micafungin was administered to 8 adult subjects with severe hepatic impairment (Child-Pugh score 10 to 12) and 8 age-, gender-, ethnic- and weight-matched subjects with normal hepatic function. The mean C max and AUC values of micafungin were lower by approximately 30% in subjects with severe hepatic impairment compared to normal subjects. The mean C max and AUC values of M-5 metabolite were approximately 2.3-fold higher in subjects with severe hepatic impairment compared to normal subjects; however, this exposure (parent and metabolite) was comparable to that in patients with systemic Candida infection. Therefore, no micafungin dose adjustment is necessary in patients with severe hepatic impairment. Distribution The mean ± standard deviation volume of distribution of micafungin at terminal phase was 0.39 L/kg ± 0.11 L/kg body weight when determined in adult patients with esophageal candidiasis at the dose range of 50 mg to 150 mg. Micafungin is highly (greater than 99%) protein bound in vitro , independent of plasma concentrations over the range of 10 mcg/mL to 100 mcg/mL. The primary binding protein is albumin; however, micafungin, at therapeutically relevant concentrations, does not competitively displace bilirubin binding to albumin. Micafungin also binds to a lesser extent to α1-acid- glycoprotein. Micafungin is neither a substrate nor an inhibitor of P-glycoprotein. Metabolism Micafungin is metabolized to M-1 (catechol form) by arylsulfatase, with further metabolism to M-2 (methoxy form) by catechol- O -methyltransferase. M-5 is formed by hydroxylation at the side chain (ω-1 position) of micafungin catalyzed by cytochrome P450 (CYP) isozymes. Even though micafungin is a substrate for and a weak inhibitor of CYP3A in vitro , hydroxylation by CYP3A is not a major pathway for micafungin metabolism in vivo . Micafungin is neither a P-glycoprotein substrate nor inhibitor in vitro . In four healthy volunteer studies, the ratio of metabolite to parent exposure (AUC) at a dose of 150 mg/day was 6% for M-1, 1% for M-2 and 6% for M-5. In patients with esophageal candidiasis, the ratio of metabolite to parent exposure (AUC) at a dose of 150 mg/day was 11% for M-1, 2% for M-2 and 12% for M-5. Excretion The excretion of radioactivity following a single intravenous dose of 14 C-micafungin sodium for injection (25 mg) was evaluated in healthy volunteers. At 28 days after administration, mean urinary and fecal recovery of total radioactivity accounted for 82.5% (76.4% to 87.9%) of the administered dose. Fecal excretion is the major route of elimination (total radioactivity at 28 days was 71% of the administered dose).