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
CYP3A4, CYP2C9 and CYP2C19 Inhibitors
Co-administration of micafungin with cyclosporine, itraconazole, voriconazole and fluconazole did not alter the pharmacokinetics of micafungin.
CYP2C19 and CYP3A4 Inducer
Co-administration of micafungin with rifampin and ritonavir did not alter the pharmacokinetics of micafungin
Co-administration of Micafungin with Other Drugs
Co-administration of micafungin with mycophenolate mofetil (MMF), amphotericin B, tacrolimus, prednisolone, sirolimus and nifedipine did not alter the pharmacokinetics of micafungin.
CYP3A4 Substrates
There was no effect of single or multiple doses of micafungin on cyclosporine, tacrolimus, prednisolone, voriconazole and fluconazole pharmacokinetics.
Sirolimus AUC was increased by 21% with no effect on Cmax in the presence of steady-state micafungin compared with sirolimus alone. Nifedipine AUC and Cmax were increased by 18% and 42%, respectively, in the presence of steady-state micafungin compared with nifedipine alone. Itraconazole AUC and Cmax were increased by 22% and 11%, respectively. Patients receiving sirolimus, nifedipine, and itraconazole in combination with micafungin 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 did not alter the pharmacokinetics of MMF.
Risk Summary
Based on findings from animal studies, micafungin may cause fetal harm when administered to a pregnant woman (see Data). There is insufficient human data on the use of micafungin 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.
Risk Summary
There are no data on the presence of micafungin in human milk, the effects on the breast-fed infant or the effects on milk production. Micafungin was present in the milk of lactating rats following intravenous administration. When a drug is present in animal milk, it is likely that the drug will be present in human milk. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for micafungin, and any potential adverse effects on the breast-fed child from micafungin, or from the underlying maternal condition.
Pediatric Patients 4 Months of Age and Older
The safety and effectiveness of micafungin 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 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 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 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) compartment 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 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-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 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 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 at dose regimens ranging from 5 to 15 mg/kg once daily. Across the entire micafungin 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 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 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 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 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
Adults
The pharmacokinetics of micafungin were determined in healthy subjects, hematopoietic stem cell transplant recipients, and patients with esophageal candidiasis up to a maximum daily dose of 8 mg/kg body weight.
The relationship of area under the concentration-time curve (AUC) to micafungin dose was linear over the daily dose range of 50 mg to 150 mg and 3 mg/kg to 8 mg/kg body weight. Typically, 85% of the steady-state concentration is achieved after three daily micafungin doses.
Steady-state pharmacokinetic parameters in relevant patient populations after repeated daily administration are presented in Table 7.
Table 7. Pharmacokinetic Parameters of Micafungin in Adult Patients
|
|
|
|
|
| Population | n | Dose (mg) | Pharmacokinetic Parameters
(Mean ± Standard Deviation) |
| Cmax
(mcg/mL) | AUC0-24*
(mcg·h/mL) | t½
(h) | Cl
(mL/min/kg) |
Patients with IC†
[Day 1]
|
20
|
100
|
5.7 ± 2.2
|
83 ± 51
|
14.5 ± 7.0
|
0.359 ± 0.179
|
| [Steady State]
| 20
| 100
| 10.1 ± 4.4
| 97 ± 29
| 13.4 ± 2.0
| 0.298 ± 0.115
|
HIV‡-Positive
Patients with EC§
[Day 1]
| 20
20
14
| 50
100
150
| 4.1 ± 1.4
8.0 ± 2.4
11.6 ± 3.1
| 36 ± 9
108 ± 31
151 ± 45
| 14.9 ± 4.3
13.8 ± 3.0
14.1 ± 2.6
| 0.321 ± 0.098
0.327 ± 0.093
0.340 ± 0.092
|
[Day 14 or 21]
| 20
20
14
| 50
100
150
| 5.1 ± 1.0
10.1 ± 2.6
16.4 ± 6.5
| 54 ± 13
115 ± 25
167 ± 40
| 15.6 ± 2.8
16.9 ± 4.4
15.2 ± 2.2
| 0.300 ± 0.063
0.301 ± 0.086
0.297 ± 0.081
|
HSCT¶ Recipients
[Day 7]
|
8
10
8
8
| per kg
3
4
6
8
|
21.1 ± 2.84
29.2 ± 6.2
38.4 ± 6.9
60.8 ± 26.9
|
234 ± 34
339 ± 72
479 ± 157
663 ± 212
|
14 ± 1.4
14.2 ± 3.2
14.9 ± 2.6
17.2 ± 2.3
|
0.214 ± 0.031
0.204 ± 0.036
0.224 ± 0.064
0.223 ± 0.081
|
Pediatric Patients 4 Months of Age and Older
Micafungin pharmacokinetics in 229 pediatric patients 4 months through 16 years of age were characterized using population pharmacokinetics. Micafungin exposure was dose proportional across the dose and age range studied.
Table 8. Summary (Mean +/- Standard Deviation) of Micafungin Pharmacokinetics in Pediatric Patients 4 Months of Age and Older (Steady-State)
|
|
|
| Body weight group | N | Dose*
mg/kg | Cmax.ss†
(mcg/mL) | AUC.ss†
(mcg·h /mL) | t½‡
(h) | CL‡
(mL/min/kg) |
| 30 kg or less
| 149
| 1.0
| 7.1 +/- 4.7
| 55 +/- 16
| 12.5 +/- 4.6
| 0.328 +/- 0.091
|
| 2.0
| 14.2 +/- 9.3
| 109 +/- 31
|
| 3.0
| 21.3 +/- 14
| 164 +/- 47
|
Greater than
30 kg
| 80
| 1.0
| 8.7 +/- 5.6
| 67 +/- 17
| 13.6 +/- 8.8
| 0.241 +/- 0.061
|
| 2.0
| 17.5 +/- 11.2
| 134 +/- 33
|
| 2.5
| 23 +/- 14.5
| 176 +/- 42
|
Pediatric Patients Younger than 4 Months of Age
Micafungin pharmacokinetic data in 103 pediatric patients less than 4 months of age were assessed using population pharmacokinetics. Predicted micafungin AUC estimates were dose proportional across the dose regimens and age ranges studied. The body weight-normalized micafungin clearance in pediatric patients less than 4 months of age is higher than the body weight-normalized micafungin clearance in older pediatric patients greater than 4 months of age and adults.
Administration of 4 mg/kg once daily micafungin to pediatric patients less than 4 months of age produces a mean (SD) steady-state AUC of 131 (50) mcg·h/mL, which is comparable to the steady-state AUC in pediatric patients 4 months of age and older administered micafungin 2 mg/kg/day and adults administered 100 mg once daily.
Specific Populations
Adult Patients with Renal Impairment
Micafungin does not require dose adjustment in patients with renal impairment. A single 1-hour infusion of 100 mg micafungin was administered to 9 adult subjects with severe renal impairment (creatinine clearance less than 30 mL/min) and to 9 age-, gender-, and weight-matched subjects with normal renal function (creatinine clearance greater than 80 mL/min). The maximum concentration (Cmax) and AUC were not significantly altered by severe renal impairment.
Since micafungin is highly protein bound, it is not dialyzable. Supplementary dosing should not be required following hemodialysis.
Adult Patients with Hepatic Impairment
- A single 1-hour infusion of 100 mg micafungin was administered to 8 adult subjects with moderate hepatic impairment (Child-Pugh score 7 to 9) and 8 age-, gender-, and weight-matched subjects with normal hepatic function. The Cmax and AUC values of micafungin were lower by approximately 22% in subjects with moderate hepatic impairment compared to normal subjects. This difference in micafungin exposure does not require dose adjustment of micafungin in patients with moderate hepatic impairment.
- A single 1-hour infusion of 100 mg micafungin was administered to 8 adult subjects with severe hepatic impairment (Child-Pugh score 10 to 12) and 8 age-, gender-, ethnic- and weight-matched subjects with normal hepatic function. The mean Cmax and AUC values of micafungin were lower by approximately 30% in subjects with severe hepatic impairment compared to normal subjects. The mean Cmax and AUC values of M-5 metabolite were approximately 2.3-fold higher in subjects with severe hepatic impairment compared to normal subjects; however, this exposure (parent and metabolite) was comparable to that in patients with systemic Candida infection. Therefore, no micafungin dose adjustment is necessary in patients with severe hepatic impairment.
Distribution
The mean ± standard deviation volume of distribution of micafungin at terminal phase was 0.39 ± 0.11 L/kg body weight when determined in adult patients with esophageal candidiasis at the dose range of 50 mg to 150 mg.
Micafungin is highly (greater than 99%) protein bound in vitro, independent of plasma concentrations over the range of 10 to 100 mcg/mL. The primary binding protein is albumin; however, micafungin, at therapeutically relevant concentrations, does not competitively displace bilirubin binding to albumin. Micafungin also binds to a lesser extent to α1-acid-glycoprotein.
Micafungin is neither a substrate nor an inhibitor of P-glycoprotein.
Metabolism
Micafungin is metabolized to M-1 (catechol form) by arylsulfatase, with further metabolism to M-2 (methoxy form) by catechol-O-methyltransferase. M-5 is formed by hydroxylation at the side chain (ω-1 position) of micafungin catalyzed by cytochrome P450 (CYP) isozymes. Even though micafungin is a substrate for and a weak inhibitor of CYP3A in vitro, hydroxylation by CYP3A is not a major pathway for micafungin metabolism in vivo. Micafungin is neither a P-glycoprotein substrate nor inhibitor in vitro.
In four healthy volunteer studies, the ratio of metabolite to parent exposure (AUC) at a dose of 150 mg/day was 6% for M-1, 1% for M-2, and 6% for M-5. In patients with esophageal candidiasis, the ratio of metabolite to parent exposure (AUC) at a dose of 150 mg/day was 11% for M-1, 2% for M-2, and 12% for M-5.
Excretion
The excretion of radioactivity following a single intravenous dose of 14C-micafungin sodium for injection (25 mg) was evaluated in healthy volunteers. At 28 days after administration, mean urinary and fecal recovery of total radioactivity accounted for 82.5% (76.4% to 87.9%) of the administered dose. Fecal excretion is the major route of elimination (total radioactivity at 28 days was 71% of the administered dose).
Mechanism of Action
Micafungin inhibits the synthesis of 1,3-beta-D-glucan, an essential component of fungal cell walls, which is not present in mammalian cells.
Activity in Animal Models of Candidiasis
Activity of micafungin has been demonstrated in both mucosal and disseminated murine and rabbit models of candidiasis. Micafungin administered to immunocompetent or immunosuppressed mice or rabbits with disseminated candidiasis prolonged survival (mice) and/or decreased the fungal burden in different organs including brain in a dose-dependent manner (mice and rabbits). Overall, antifungal activity of micafungin was demonstrated in the brain and eye tissues of nonneutropenic rabbits with HCME infected with a micafungin-sensitive strain of C. albicans; however, the activity varied in different central nervous system and ocular compartments. In the cerebrum, culture negativity was achieved at a micafungin dose regimen of 32 mg/kg once daily for 7 days; whereas, in spinal cord, vitreous humor, and choroid, culture negativity was achieved at micafungin dose regimens of 24 to 32 mg/kg once daily. Compared to untreated animals, micafungin dose regimens between 8 and 24 mg/kg once daily reduced fungal burden in the cerebrum and cerebellum. When cerebrum, cerebellum and spinal cord data were combined, a decrease in fungal burden relative to untreated controls was evident at micafungin dose regimens between 16 and 32 mg/kg once daily [see Use in Specific Populations (8.4)].
Resistance
There have been reports of clinical failures in patients receiving micafungin therapy due to the development of drug resistance. Some of these reports have identified specific mutations in the FKS protein component of the glucan synthase enzyme that are associated with higher MICs and breakthrough infection.
Antimicrobial Activity
Micafungin has been shown to be active against most isolates of the following Candida species, both in vitro and in clinical infections [see Indications and Usage (1)]:
Candida albicans
Candida glabrata
Candida guilliermondii
Candida krusei
Candida parapsilosis
Candida tropicalis
Susceptibility Testing
For specific information regarding susceptibility test interpretive criteria and associated test methods and quality control standards recognized by FDA for this drug, please see: https://www.fda.gov/STIC.
Hypersensitivity
Inform patients about the serious adverse effects of Micafungin for injection including hypersensitivity reactions e.g., anaphylaxis and anaphylactoid reactions including shock.
Hepatic
Inform patients about the serious adverse effects of Micafungin for 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 for injection including hematological effects e.g., acute intravascular hemolysis, hemolytic anemia and hemoglobinuria.
Renal
Inform patients about the serious adverse effects of Micafungin for 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 for 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 for injection, including over-the-counter medications.
Manufactured for:
Fresenius Kabi (Mic17 0000 02)
Lake Zurich, IL 60047
www.fresenius-kabi.com/us
Made in India
451407
LEA-020291-00
