Micafungin in Sodium Chloride

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 )

How Supplied Micafungin in Sodium Chloride Injection is supplied as a clear and colorless refrigerated, premixed, iso-osmotic, sterile, nonpyrogenic solution for intravenous infusion, and is available in the following packaging configurations: Code NDC Multiple Cartons NDC Individual Carton Size Number of Containers/Carton 2G3434 NDC 0338-9051-12 NDC 0338-9051-01 50 mL 12 individually packaged 50 mg/50 mL (1 mg/mL) single-dose Galaxy containers 2G3435 NDC 0338-9053-12 NDC 0338-9053-01 100 mL 12 individually packaged 100 mg/100 mL (1 mg/mL) single-dose Galaxy containers 2G3433 NDC 0338-9055-10 NDC 0338-9055-01 150 mL 10 individually packaged 150 mg/150 mL (1 mg/mL) single-dose Galaxy containers Storage and Handling Store Micafungin in Sodium Chloride Injection in the refrigerator at 2°C to 8°C (36°F to 46°F) in the original carton to protect from light. Do not use after the expiration date printed on the carton and container label. If needed, Micafungin in Sodium Chloride Injection may be stored at room temperature 20°C to 25°C (68°F to 77°F) for up to 30 days in the original carton to protect from light. 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. Do not freeze and do not use Micafungin in Sodium Chloride Injection if it has been frozen.

• 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 )] .

Micafungin in Sodium Chloride Injection is contraindicated in persons with known hypersensitivity to micafungin, any component of Micafungin in Sodium Chloride Injection, or other echinocandins. Micafungin in Sodium Chloride Injection is contraindicated in persons with known hypersensitivity to micafungin sodium, any component of Micafungin in Sodium Chloride Injection, or other echinocandins. ( 4 )

• Hypersensitivity Reactions: Anaphylaxis and anaphylactoid reactions (including shock) have been observed. Discontinue Micafungin in Sodium Chloride Injection and administer appropriate treatment. ( 5.1 ) • Hematological Effects: Isolated cases of acute intravascular hemolysis, hemolytic anemia and hemoglobinuria have been reported. Monitor rate of hemolysis. Discontinue if severe. ( 5.2 ) • Hepatic Effects: Abnormalities in liver tests; isolated cases of hepatic impairment, hepatitis, and hepatic failure have been observed. Monitor hepatic function. Discontinue if severe dysfunction occurs. ( 5.3 ) • Renal Effects: Elevations in BUN and creatinine; isolated cases of renal impairment or acute renal failure have been reported. Monitor renal function. ( 5.4 ) • Infusion and Injection Site Reactions can occur including rash, pruritus, facial swelling, and vasodilatation. Monitor infusion closely, slow infusion rate if necessary. ( 2.5 , 5.5 ) • High Sodium Load: Each 50, 100, and 150 mL Galaxy container contains 200, 400, and 600 mg of sodium, respectively. Avoid use in patients with congestive heart failure, elderly patients, and patients requiring restricted sodium intake. ( 5.6 , 8.5 ) 5.1 Hypersensitivity Reactions Isolated cases of serious hypersensitivity (anaphylaxis and anaphylactoid) reactions (including shock) have been reported in patients receiving micafungin for injection. If these reactions occur, Micafungin in Sodium Chloride Injection infusion should be discontinued and appropriate treatment administered. 5.2 Hematological Effects Acute intravascular hemolysis and hemoglobinuria was seen in a healthy volunteer during infusion of micafungin for injection (200 mg) and oral prednisolone (20 mg). Cases of significant hemolysis and hemolytic anemia have also been reported in patients treated with micafungin for injection. Patients who develop clinical or laboratory evidence of hemolysis or hemolytic anemia during Micafungin in Sodium Chloride Injection therapy should be monitored closely for evidence of worsening of these conditions and evaluated for the risk/benefit of continuing Micafungin in Sodium Chloride Injection 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 in Sodium Chloride Injection therapy should be monitored for evidence of worsening hepatic function and evaluated for the risk/benefit of continuing Micafungin in Sodium Chloride Injection therapy. 5.4 Renal Effects Elevations in BUN and creatinine, and isolated cases of significant renal impairment or acute renal failure have been reported in patients who received micafungin for injection. In fluconazole-controlled trials, the incidence of drug-related renal adverse reactions was 0.4% for micafungin for injection-treated patients and 0.5% for fluconazole-treated patients. Patients who develop abnormal renal function tests during Micafungin in Sodium Chloride Injection therapy should be monitored for evidence of worsening renal function. 5.5 Infusion and Injection Site Reactions Possible histamine-mediated symptoms have been reported with micafungin for injection, including rash, pruritus, facial swelling, and vasodilatation. Slow the infusion rate if infusion reaction occurs [see Dosage and Administration (2.6) ]. Injection site reactions, including phlebitis and thrombophlebitis have been reported, at micafungin for injection doses of 50 to 150 mg/day. These reactions tended to occur more often in patients receiving micafungin for injection via peripheral intravenous administration [ see Adverse Reactions (6.1) ]. 5.6 High Sodium Load Each 50 mg/50 mL Galaxy container of Micafungin in Sodium Chloride Injection contains 200 mg of sodium, each 100 mg/100 mL Galaxy container of Micafungin in Sodium Chloride Injection contains 400 mg of sodium, and each 150 mg/150 mL Galaxy container of Micafungin in Sodium Chloride Injection contains 600 mg of sodium. Avoid use of Micafungin in Sodium Chloride Injection in patients with congestive heart failure, elderly patients, and patients requiring restricted sodium intake.

Hypersensitivity Inform patients about the serious adverse effects of Micafungin in Sodium Chloride Injection including hypersensitivity reactions, e.g., anaphylaxis and anaphylactoid reactions including shock. Hepatic Inform patients about the serious adverse effects of Micafungin in Sodium Chloride Injection including hepatic effects, e.g., abnormal liver tests, hepatic impairment, hepatitis or worsening hepatic failure. Hematologic Inform patients about the serious adverse effects of Micafungin in Sodium Chloride Injection including hematological effects, e.g., acute intravascular hemolysis, hemolytic anemia and hemoglobinuria. Renal Inform patients about the serious adverse effects of Micafungin in Sodium Chloride Injection including renal effects, e.g., elevations in BUN and creatinine, renal impairment or acute renal failure. Embryo-Fetal Toxicity Advise pregnant women and females of reproductive potential of the potential risk of Micafungin in Sodium Chloride Injection to a fetus. Advise females to inform their healthcare provider of a known or suspected pregnancy. Concomitant Medications Instruct patients to inform their healthcare provider of any other medications they are currently taking with Micafungin in Sodium Chloride Injection, including over-the-counter medications. High Sodium Load Advise patients to inform their healthcare provider if they are on a salt-restricted diet or have congestive heart failure as increased blood sodium can occur in people who receive Micafungin in Sodium Chloride Injection [ see Warnings and Precautions (5.6) ] . Baxter Logo Manufactured by: Baxter Healthcare Corporation Deerfield, IL 60015 USA Product of USA Baxter and Galaxy are registered trademarks of Baxter International Inc. 07-19-06-083

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 in Sodium Chloride Injection CYP3A4, CYP2C9 and CYP2C19 Inhibitors Co-administration of Micafungin in Sodium Chloride Injection with cyclosporine, itraconazole, voriconazole and fluconazole did not alter the pharmacokinetics of micafungin. CYP2C19 and CYP3A4 Inducer Co-administration of Micafungin in Sodium Chloride Injection with rifampin and ritonavir did not alter the pharmacokinetics of micafungin. Co-administration of Micafungin in Sodium Chloride Injection with Other Drugs Co-administration of Micafungin in Sodium Chloride Injection with mycophenolate mofetil (MMF), amphotericin B, tacrolimus, prednisolone, sirolimus and nifedipine did not alter the pharmacokinetics of micafungin. 7.2 Effect of Micafungin in Sodium Chloride Injection on Other Drugs CYP3A4 Substrates There was no effect of single or multiple doses of micafungin for injection on cyclosporine, tacrolimus, prednisolone, voriconazole and fluconazole pharmacokinetics. Sirolimus AUC was increased by 21% with no effect on C max in the presence of steady-state micafungin for injection compared with sirolimus alone. Nifedipine AUC and C max were increased by 18% and 42%, respectively, in the presence of steady-state micafungin for injection compared with nifedipine alone. Itraconazole AUC and C max were increased by 22% and 11%, respectively. Patients receiving sirolimus, nifedipine, and itraconazole in combination with micafungin for injection should be monitored for sirolimus, nifedipine, and itraconazole toxicity and the sirolimus, nifedipine, and itraconazole dosage should be reduced if necessary. UDP-Glycosyltransferase Substrate Co-administration of mycophenolate mofetil (MMF) with micafungin for injection did not alter the pharmacokinetics of MMF.

Hepatic carcinomas and adenomas were observed in a 6-month intravenous toxicology study with an 18-month recovery period of micafungin sodium in rats designed to assess the reversibility of hepatocellular lesions. Rats administered micafungin sodium for 3 months at 32 mg/kg/day (corresponding to 8 times the highest recommended human dose [150 mg/day], based on AUC comparisons), exhibited colored patches/zones, multinucleated hepatocytes and altered hepatocellular foci after 1 or 3-month recovery periods, and adenomas were observed after a 21-month recovery period. Rats administered micafungin sodium at the same dose for 6 months exhibited adenomas after a 12-month recovery period; after an 18-month recovery period, an increased incidence of adenomas was observed and, additionally, carcinomas were detected. A lower dose of micafungin sodium (equivalent to 5 times the human AUC) in the 6-month rat study resulted in a lower incidence of adenomas and carcinomas following 18 months recovery. The duration of micafungin dosing in these rat studies (3 or 6 months) exceeds the usual duration of Micafungin in Sodium Chloride Injection dosing in patients, which is typically less than 1 month for treatment of esophageal candidiasis, but dosing may exceed 1 month for Candida prophylaxis. Although the increase in carcinomas in the 6-month rat study did not reach statistical significance, the persistence of altered hepatocellular foci subsequent to micafungin for injection dosing, and the presence of adenomas and carcinomas in the recovery periods suggest a causal relationship between micafungin sodium, altered hepatocellular foci, and hepatic neoplasms. Whole-life carcinogenicity studies of micafungin for injection in animals have not been conducted, and it is not known whether the hepatic neoplasms observed in treated rats also occur in other species, or if there is a dose threshold for this effect. Micafungin sodium was not mutagenic or clastogenic when evaluated in a standard battery of in vitro and in vivo tests (i.e., bacterial reversion - S. typhimurium, E. coli ; chromosomal aberration; intravenous mouse micronucleus). Male rats treated intravenously with micafungin sodium for 9 weeks showed vacuolation of the epididymal ductal epithelial cells at or above 10 mg/kg (about 0.6 times the recommended clinical dose for esophageal candidiasis, based on body surface area comparisons). Higher doses (about twice the recommended clinical dose, based on body surface area comparisons) resulted in higher epididymis weights and reduced numbers of sperm cells. In a 39-week intravenous study in dogs, seminiferous tubular atrophy and decreased sperm in the epididymis were observed at 10 and 32 mg/kg, doses equal to about 2 and 7 times the recommended clinical dose, based on body surface area comparisons. There was no impairment of fertility in animal studies with micafungin sodium.

Risk Summary Based on findings from animal studies, Micafungin for Injection may cause fetal harm when administered to a pregnant woman (see Data) . There is insufficient human data on the use of micafungin for injection 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.

Micafungin in Sodium Chloride Injection is indicated in pediatric patients for whom appropriate dosing with this formulation can be achieved. Because of the limitations of the available strengths and administration requirements (i.e., administration of fractional doses is not recommended) of Micafungin in Sodium Chloride Injection, and to avoid unintentional overdose, this product is not recommended for use if a dose of Micafungin in Sodium Chloride Injection that does not equal 50 mg, 100 mg, or 150 mg is required, and an alternative formulation of micafungin should be considered [ see Dosage and Administration (2.3 , 2.4 )]. Pediatric Patients 4 Months of Age and Older The safety and effectiveness of micafungin for injection 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 injection 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 for injection 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 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. 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 for injection 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 for injection-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 for injection 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 for injection 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 for injection at dose regimens ranging from 5 to 15 mg/kg once daily. Across the entire micafungin for injection 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 for injection 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 for injection 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 for injection 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. Treatment of Esophageal Candidiasis and Prophylaxis of Candida Infections in Patients Undergoing Hematopoietic Stem Cell Transplantation in Pediatric Patients Younger Than 4 Months of Age The safety and effectiveness of micafungin for injection in pediatric patients younger than 4 months of age have not been established for the: • Treatment of esophageal candidiasis • Prophylaxis of Candida infections in patients undergoing hematopoietic stem cell transplantation

A total of 418 subjects in clinical studies of micafungin for injection were 65 years of age and older, and 124 subjects were 75 years of age and older. No overall differences in safety and effectiveness were observed between these subjects and younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. The exposure and disposition of a 50 mg micafungin for injection dose administered as a single 1-hour infusion to 10 healthy subjects aged 66 to 78 years were not significantly different from those in 10 healthy subjects aged 20 to 24 years. No dose adjustment is necessary for the elderly. Each 50 mg/50 mL Galaxy container of Micafungin in Sodium Chloride Injection contains 200 mg of sodium, each 100 mg/100 mL Galaxy container of Micafungin in Sodium Chloride Injection contains 400 mg of sodium, and each 150 mg/150 mL Galaxy container of Micafungin in Sodium Chloride Injection contains 600 mg of sodium. The geriatric population may respond with a blunted natriuresis to salt loading. This may be clinically important with regard to such diseases as congestive heart failure and other conditions requiring restricted sodium intake [ see Warnings and Precautions (5.6 )] .

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

Micafungin is highly protein bound and, therefore, is not dialyzable. No cases of micafungin for injection overdosage have been reported. Repeated daily doses up to 8 mg/kg (maximum total dose of 896 mg) in adult patients, up to 6 mg/kg in pediatric patients 4 months of age and older, and up to 15 mg/kg in pediatric patients younger than 4 months of age have been administered in clinical trials with no reported dose-limiting toxicity [ see Adverse Reactions (6.1) and Use in Specific Populations (8.4) ].