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 )] .

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 ) 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.

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 Fresenius Kabi USA, LLC at 1-800-551-7176 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, 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 Reaction 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 function 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 Reaction 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.

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.

The 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