Micafungin In Sodium Chloride

1 INDICATIONS AND USAGE Micafungin in Sodium Chloride 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 for whom appropriate dosing with this formulation can be achieved [ 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 for whom appropriate dosing with this formulation can be achieved [ see Use in Specific Populations (8.4) ]. • Treatment of Esophageal Candidiasis in adult and pediatric patients 4 months of age and older for whom appropriate dosing with this formulation can be achieved [ 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 for whom appropriate dosing with this formulation can be achieved [ see Clinical Studies (14.3) ]. Limitations of Use • The safety and effectiveness of Micafungin in Sodium Chloride 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 in Sodium Chloride Injection has not been adequately studied in patients with endocarditis, osteomyelitis and meningoencephalitis due to Candida. • The efficacy of Micafungin in Sodium Chloride Injection against infections caused by fungi other than Candida has not been established. Micafungin in Sodium Chloride 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 for whom appropriate dosing with this formulation can be achieved. • 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 for whom appropriate dosing with this formulation can be achieved. • Treatment of Esophageal Candidiasis in adult and pediatric patients 4 months of age and older for whom appropriate dosing with this formulation can be achieved. • Prophylaxis of Candida Infections in adult and pediatric patients 4 months of age and older undergoing Hematopoietic Stem Cell Transplantation (HSCT) for whom appropriate dosing with this formulation can be achieved. Limitations of Use • The safety and effectiveness of Micafungin in Sodium Chloride 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 , 2.4 , 8.4 ) • Micafungin in Sodium Chloride Injection has not been adequately studied in patients with endocarditis, osteomyelitis or meningoencephalitis due to Candida. ( 1 ) • The efficacy of Micafungin in Sodium Chloride Injection against infections caused by fungi other than Candida has not been established. ( 1 )

2 DOSAGE AND ADMINISTRATION • If a dose of Micafungin in Sodium Chloride Injection is required that does not equal 50 mg, 100 mg, or 150 mg, this product is not recommended for use and an alternative formulation of micafungin should be considered. Recommended Dosage Administered by Indication, Weight and Age ( 2.1 , 2.2 , 2.3 , 2.4 , 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. ( 2.6 ) • See Full Prescribing Information for intravenous (IV) directions for preparation for administration instructions. ( 2.5 , 2.6 ) 2.1 Important Administration Instructions If a dose of Micafungin in Sodium Chloride Injection is required that does not equal 50 mg, 100 mg, or 150 mg, this product is not recommended for use and an alternative formulation of micafungin should be considered. 2.2 Recommended Dosage for Adults The recommended dosage for adult patients based on indications are shown in Table 1 . Table 1. Micafungin in Sodium Chloride Injection Dosage in Adult Patients Indication Recommended Dose Once Daily Treatment of Candidemia, Acute Disseminated Candidiasis, Candida Peritonitis and Abscesses In patients treated successfully for candidemia and other Candida infections, the mean duration of treatment was 15 days (range 10 to 47 days). 100 mg Treatment of Esophageal Candidiasis In patients treated successfully for esophageal candidiasis, the mean duration of treatment was 15 days (range 10 to 30 days). 150 mg Prophylaxis of Candida Infections in HSCT Recipients 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). 50 mg 2.3 Recommended 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 in Sodium Chloride Injection Dosage in Pediatric Patients (4 Months of Age and Older) If a dose of Micafungin in Sodium Chloride Injection is required that does not equal 50 mg, 100 mg, or 150 mg, this product is not recommended for use and an alternative formulation of micafungin should be considered [ see Use in Specific Populations (8.4) ] . 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) 2.4 Recommended 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. If a dose of Micafungin in Sodium Chloride Injection is required that does not equal 50 mg, 100 mg, or 150 mg, this product is not recommended for use and an alternative formulation of micafungin should be considered. The safety and effectiveness of Micafungin in Sodium Chloride 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) ]. 2.5 Directions for Administration Preparation and Storage Conditions for Stability Do not mix or co-infuse Micafungin in Sodium Chloride Injection 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 to prepare for administration. Preparation for Administration • No further dilution is necessary. • Suspend container from support. • Remove protector from outlet port at bottom of container. • Attach Intravenous administration set to outlet port. Refer to the manufacturer’s instructions accompanying the administration set for complete directions. • Check for minute leaks by squeezing container firmly. If leaks are detected, discard solution as sterility may be impaired. • 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. Micafungin in Sodium Chloride Injection is a clear and colorless solution. • Micafungin in Sodium Chloride Injection is preservative-free. Discard partially used bags. Do not freeze. Storage Conditions or Stability • Solution is stable for up to 30 days in the original carton at room temperature up to 25°C (77°F). Once stored at room temperature, do not place back in the refrigerator. Discard Micafungin in Sodium Chloride Injection after 30 days if stored at room temperature [ see How Supplied/Storage and Handling (16) ] . • Do not Freeze. • Micafungin in Sodium Chloride Injection does not require light protection during administration. 2.6 Administration Instructions Adult Patients Administer Micafungin in Sodium Chloride Injection 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 Sodium Chloride Injection prior to infusion of Micafungin in Sodium Chloride Injection. Pediatric Patients Infuse Micafungin in Sodium Chloride Injection over one hour [ see Dosage and Administration (2.3 , 2.4 )] .

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) ] • High Sodium Load [ see Warnings and Precautions (5.6) ] • 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%: hypokalemia, acidosis, sepsis, anemia, and oxygen saturation decreased. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Baxter Healthcare Corporation at 1-866-888-2472 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 , 2.3 )] 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 During IV Treatment + 3 days. Adverse Reactions in Adult Patients with Candidemia and Other Candida Infections Adverse Reactions by System Organ Class Within a system organ class, patients may experience more than 1 adverse reactions Micafungin for Injection 100 mg n (%) Caspofungin 70 mg loading dose on day 1 followed by 50 mg/day thereafter (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. 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%), 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 for injection 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 for injection-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 for injection group, are shown in Table 4 . Table 4. Selected During treatment + 3 days. Adverse Reactions in Adult Patients with Esophageal Candidiasis Adverse Reactions by System Organ Class Within a system organ class, patients may experience more than 1 adverse reaction. Micafungin for Injection 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) Patient base: all randomized patients who received at least 1 dose of trial drug. 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 (382) or fluconazole (409) experienced at least one adverse reaction during the study. Treatment-emergent adverse reactions resulting in micafungin for injection 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 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 System Organ Class Micafungin for Injection 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) 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. 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 for injection 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 for injection (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 for injection 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 for injection-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 for injection (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 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 Prophylaxis of Candida Infections Adverse Reactions Within a system organ class, patients may experience more than 1 adverse reaction. C/IC Study population included 20 pediatric patients younger than 4 months of age (10 in each arm). Prophylaxis Micafungin for Injection n = 56 n (%) Amphotericin B liposome n = 56 n (%) Micafungin for Injection 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 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. A total of 59 patients received micafungin for injection at doses ≤4 mg/kg/day and 109 patients received micafungin for injection 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 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. The most frequent adverse reactions (≥15%) in pediatric patients younger than 4 months old receiving a micafungin for injection 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 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 for injection 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 Population n Dose (mg) Pharmacokinetic Parameters (Mean ± Standard Deviation) C max (mcg/mL) AUC 0-24 AUC 0-infinity is presented for Day 1; AUC 0-24 is presented for steady-state. (mcg h/mL) t 1/2 (h) Cl (mL/min/kg) Patients with IC candidemia or other Candida infections. [Day 1] 20 100 5.7 ± 2.2 83 ± 51 14.5 ± 7.0 0.359 ± 0.179 [Steady-State] 20 100 10.1 ± 4.4 97 ± 29 13.4 ± 2.0 0.298 ± 0.115 HIV human immunodeficiency virus. – Positive Patients with EC esophageal candidiasis. [Day 1] 20 20 14 50 100 150 4.1 ± 1.4 8.0 ± 2.4 11.6 ± 3.1 36 ± 9 108 ± 31 151 ± 45 14.9 ± 4.3 13.8 ± 3.0 14.1 ± 2.6 0.321 ± 0.098 0.327 ± 0.093 0.340 ± 0.092 [Day 14 or 21] 20 20 14 50 100 150 5.1 ± 1.0 10.1 ± 2.6 16.4 ± 6.5 54 ± 13 115 ± 25 167 ± 40 15.6 ± 2.8 16.9 ± 4.4 15.2 ± 2.2 0.300 ± 0.063 0.301 ± 0.086 0.297 ± 0.081 HSCT hematopoietic stem cell transplant. 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 14.0 ± 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 Distribution The mean ± standard deviation volume of distribution of micafungin at terminal phase was 0.39 ± 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 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. Elimination 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). Specific Populations Pediatric Patients 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) Body weight group N Dose Or the equivalent if receiving the adult dose (50, 100, or 150 mg). mg/kg C max.ss Derived from simulations from the population PK model. (mcg/mL) AUC .ss (mcg h/mL) t 1/2 Derived from the population PK model. (h) CL mL/min/kg) 30 kg or less 149 1.0 7.1 +/- 4.7 55 +/- 16 12.5 +/- 4.6 0.328 +/- 0.091 2.0 14.2 +/- 9.3 109 +/- 31 3.0 21.3 +/- 14.0 164 +/- 47 Greater than 30 kg 80 1.0 8.7 +/- 5.6 67 +/- 17 13.6 +/- 8.8 0.241 +/- 0.061 2.0 17.5 +/- 11.2 134 +/- 33 2.5 23.0 +/- 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. Patients with Renal Impairment Micafungin in Sodium Chloride Injection does not require dose adjustment in patients with renal impairment. A single 1-hour infusion of 100 mg micafungin for injection 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. Patients with Hepatic Impairment • A single 1-hour infusion of 100 mg micafungin for injection 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 Sodium Chloride Injection in patients with moderate hepatic impairment. • A single 1-hour infusion of 100 mg micafungin for injection 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 in Sodium Chloride Injection dose adjustment is necessary in patients with severe hepatic impairment.