Micafungin

(Micafungin Sodium)

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Micafungin Prescribing Information

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
8.4 Pediatric Use
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 injection 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
].
Treatment of Esophageal Candidiasis in adult and pediatric patients 4 months of age and older
[see Clinical Studies (14.2)].
Prophylaxis of
Candida
Infections in adult and pediatric patients 4 months of age and older undergoing hematopoietic stem cell transplantation
[see Clinical Studies (14.3)].

Limitations of Use
The safety and effectiveness of Micafungin for Injection have
not
been established for the treatment of candidemia
with
meningoencephalitis and/or ocular dissemination in pediatric patients younger than 4 months of age as a higher dose may be needed
[see
8.4 Pediatric Use
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 injection 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
]
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.

Administer micafungin for 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 0.9% Sodium Chloride Injection, USP, prior to infusion of micafungin for injection.

Pediatric Patients

Micafungin for injection should be infused over one hour. To decrease the risk of infusion reactions, concentrations above 1.5 mg/mL should be administered via central catheter

[see Warnings and Precautions (5.5)]

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

2.3 Dosage for Pediatric Patients Younger than 4 Months of Age

Treatment of Candidemia, Acute Disseminated Candidiasis,

Candida

Peritonitis and Abscesses

without

meningoencephalitis and/or ocular dissemination

The recommended dosage is 4 mg/kg once daily.

The safety and effectiveness of 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), Clinical Pharmacology (12.3)and Microbiology (12.4)

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

2.3 Dosage for Pediatric Patients Younger than 4 Months of Age

Treatment of Candidemia, Acute Disseminated Candidiasis,

Candida

Peritonitis and Abscesses

without

meningoencephalitis and/or ocular dissemination

The recommended dosage is 4 mg/kg once daily.

The safety and effectiveness of 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), Clinical Pharmacology (12.3)and Microbiology (12.4)

and

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

] 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, 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 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^*Adverse Reactions in Adult Patients with Candidemia and Other

Candida

Infections

Adverse Reactions by System Organ Class ^†	Micafungin for Injection 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

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).

In a second, supportive, randomized, double-blind trial for 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* Adverse Reactions in Adult Patients with Esophageal Candidiasis
Adverse Reactions by System Organ Class ^†	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.

^*During treatment + 3 days.

^†Within a system organ class, patients may experience more than 1 adverse reaction.

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 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 ^†	C/IC*		Prophylaxis
Adverse Reactions ^†	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)

^*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.

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

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

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