The safety of micafungin was assessed in 479 pediatric patients through 16 years of age who received at least one dose of micafungin across 11 clinical trials.
Of the 479 pediatric patients, 264 (55%) were male, 319 (67%) were white, with the following age distribution: 116 (24%) to <2 years, 108 (23%) 2 to 5 years, 140 (29%) 6 to 11 years, and 115 (24%) 12 to 16 years of age. The mean treatment duration was 24.8 days. A total of 246 patients received at least one dose of micafungin ranging from 2 to 10 mg/kg. Overall, 439/479 (92%) patients experienced at least one adverse reaction. Adverse reactions occurring in ≥15% or more of micafungin-treated pediatric patients are: vomiting (31%), diarrhea (22%), pyrexia (22%), nausea (19%), abdominal pain (16%), and thrombocytopenia (15%).
Two randomized, double-blind active-controlled trials included pediatric patients. In the invasive candidiasis/candidemia trial, the efficacy and safety of micafungin (2 mg/kg/day for patients weighing 40 kg or less and 100 mg/day for patients weighing greater than 40 kg) was compared to amphotericin B liposome (3 mg/kg/day) in 112 pediatric patients. Treatment-emergent adverse reactions occurred in 51/56 (91%) of patients in the micafungin group and 52/56 (93%) of patients in the amphotericin B liposome group. Treatment-emergent adverse reactions resulting in drug discontinuation were reported in 2 (4%) micafungin-treated pediatric patients and in 9 (16%) amphotericin B liposome-treated pediatric patients.
The prophylaxis study in patients undergoing HSCT investigated the efficacy of micafungin (1 mg/kg/day for patients weighing 50 kg or less and 50 mg/day for patients weighing greater than 50 kg) as compared to fluconazole (8 mg/kg/day for patients weighing 50 kg or less and 400 mg/day for patients weighing greater than 50 kg). All 91 pediatric patients experienced at least one treatment-emergent adverse reaction. Three (7%) pediatric patients discontinued micafungin due to adverse reaction, while one (2%) patient discontinued fluconazole.
Selected adverse reactions, occurring in 15% or more of the patients and more frequently in a micafungin group, for the two comparative trials are shown in Table 6.
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
Additional pediatric use information is approved for Astellas Pharma US, Inc.'s MYCAMINE® (micafungin for injection). However, due to Astellas Pharma US, Inc.'s marketing exclusivity rights, this drug product is not labeled with that information.
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 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) 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. 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.
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
Additional pediatric use information is approved for Astellas Pharma US, Inc.'s MYCAMINE® (micafungin for injection). However, due to Astellas Pharma US, Inc.'s marketing exclusivity rights, this drug product is not labeled with that information.
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 | 20 | 50 | 4.1 ± 1.4 | 36 ± 9 | 14.9 ± 4.3 | 0.321 ± 0.098 |
| Patients with EC§ | 20 | 100 | 8.0 ± 2.4 | 108 ± 31 | 13.8 ± 3.0 | 0.327 ± 0.093 |
[Day 1] | 14 | 150 | 11.6 ± 3.1 | 151 ± 45 | 14.1 ± 2.6 | 0.340 ± 0.092 |
| 20 | 50 | 5.1 ± 1.0 | 54 ± 13 | 15.6 ± 2.8 | 0.300 ± 0.063 |
| [Day 14 or 21] | 20 | 100 | 10.1 ± 2.6 | 115 ± 25 | 16.9 ± 4.4 | 0.301 ± 0.086 |
| 14 | 150 | 16.4 ± 6.5 | 167 ± 40 | 15.2 ± 2.2 | 0.297 ± 0.081 |
| HSCT¶ Recipients [Day 7] | | per kg | | | | |
8
10
8 | 3
4
6 | 21.1 ± 2.84
29.2 ± 6.2
38.4 ± 6.9 | 234 ± 34
339 ± 72
479 ± 157 | 14.0 ± 1.4
14.2 ± 3.2
14.9 ± 2.6 | 0.214 ± 0.031
0.204 ± 0.036
0.224 ± 0.064 |
| 8 | 8 | 60.8 ± 26.9 | 663 ± 212 | 17.2 ± 2.3 | 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 +/- 14.0
| 164 +/- 47
|
Greater than
30 kg
|
80
| 1.0
| 8.7 +/- 5.6
| 67 +/- 17
|
13.6 +/- 8.8
|
0.241 +/- 0.061
|
| 2.0
| 17.5 +/- 11.2
| 134 +/- 33
|
| 2.5
| 23.0 +/- 14.5
| 176 +/- 42
|
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).
Additional pediatric use information is approved for Astellas Pharma US, Inc.'s MYCAMINE® (micafungin for injection). However, due to Astellas Pharma US, Inc.'s marketing exclusivity rights, this drug product is not labeled with that information.
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.
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 including hypersensitivity reactions e.g., anaphylaxis and anaphylactoid reactions including shock.
Hepatic
Inform patients about the serious adverse effects of micafungin 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 including hematological effects e.g., acute intravascular hemolysis, hemolytic anemia and hemoglobinuria.
Renal
Inform patients about the serious adverse effects of micafungin 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 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, including over-the-counter medications.
Brands listed are the trademarks of their respective owners.
meitheal®
Mfd. for Meitheal Pharmaceuticals
Chicago, IL 60631 (USA)
©2022 Meitheal Pharmaceuticals Inc.
Mfd. by Nanjing King-Friend Biochemical Pharmaceutical Co., Ltd.
Nanjing, China 210061
May 2022
810123-00
