Miplyffa
(arimoclomol)Dosage & Administration
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Miplyffa Prescribing Information
MIPLYFFA is indicated for use in combination with miglustat for the treatment of neurological manifestations of Niemann-Pick disease type C (NPC) in adult and pediatric patients 2 years of age and older.
Recommended Dosage
The recommended oral dosage of MIPLYFFA, in combination with miglustat, for patients with an actual body weight of:
- 8 kg to 15 kg, is 47 mg three times a day
- > 15 kg to 30 kg, is 62 mg three times a day
- > 30 kg to 55 kg, is 93 mg three times a day
- > 55 kg, is 124 mg three times a day
Administer MIPLYFFA with or without food.
Missed Dose
If a dose of MIPLYFFA is missed, advise the patient to skip the missed dose and to resume taking the prescribed dose at the next scheduled time.
Recommended Dosage in Patients with Renal Impairment
The recommended dosage of MIPLYFFA, in combination with miglustat, in patients with an eGFR ≥ 50 mL/minute is the same as the recommended dosage in patients with normal renal function [see Dosage and Administration ( 2.1)].
For patients with an eGFR ≥ 15 to < 50 mL/minute, the recommended oral dosage of MIPLYFFA, in combination with miglustat, for patients with an actual body weight of [see Use in Specific Populations ( 8.6) and Clinical Pharmacology ( 12.3)] :
- 8 kg to 15 kg, is 47 mg two times a day
- > 15 kg to 30 kg, is 62 mg two times a day
- > 30 kg to 55 kg, is 93 mg two times a day
- > 55 kg, is 124 mg two times a day
Administer MIPLYFFA with or without food.
Preparation and Administration Instructions
Swallow MIPLYFFA whole. However, for patients who have difficulty swallowing capsules, administer MIPLYFFA in one of two ways:
Oral Administration
- Carefully open the capsule and sprinkle the entire contents into 15 mL of water or apple juice or 15 mL of soft food (e.g., applesauce, pudding, or yogurt).
- Stir the mixture for 15 seconds.
- Consume the entire mixture immediately.
Feeding Tube Administration (nasogastric or gastric tube)
- Carefully open the capsule and sprinkle the entire contents into 20 mL of water. Do not add the capsule contents to other liquids besides water.
- Stir the mixture for 15 seconds.
- Administer the entire mixture immediately via feeding tube.
- Flush the feeding tube with 5 mL of water after administration.
Do not save the mixture for later use.
MIPLYFFA (arimoclomol) capsules are available as follows:
| MIPLYFFA Strength | Description of Capsules |
| 47 mg | White opaque body with black printing “47”, and green opaque cap with black printing “OZ” |
| 62 mg | White opaque body with black printing “62”, and yellow opaque cap with black printing “OZ” |
| 93 mg | White opaque body with black printing “93”, and orange opaque cap with black printing “OZ” |
| 124 mg | White opaque body with black printing “124”, and red opaque cap with black printing “OZ” |
Pregnancy
Risk Summary
Based on findings from animal reproduction studies, MIPLYFFA may cause embryofetal harm when administered during pregnancy. There are no available data on MIPLYFFA use in pregnant females to evaluate a drug-associated risk of major birth defects, miscarriage, or other adverse maternal or fetal outcomes. Advise pregnant females of the potential risk to the fetus.
In animal reproduction studies, oral administration of arimoclomol to pregnant rats and rabbits during organogenesis resulted in post-implantation loss and structural abnormalities in offspring. These occurred at exposures equal to or greater than 10- and 5-fold, in rats and rabbits respectively, the human exposure at the maximum recommended human daily dose of 372 mg ( see Data).
The background risk of major birth defects and miscarriage for the indicated population 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 embryofetal development study in pregnant rats, once daily oral doses of arimoclomol were administered throughout organogenesis from gestation day 6 to 17. Increased post-implantation loss was observed at 10-fold the human exposure, based on AUC at the MRHDD, together with increased ossification in the vertebrae and dilated brain ventricles in litters of dams dosed at equal to or greater than 8-fold the human exposure at the MRHDD.
In another embryofetal development study in pregnant rats in which arimoclomol was administered three times-daily throughout organogenesis from gestation day 6 to 17, there was an increase in postimplantation loss and reduced maternal, placental, and fetal weights at 14-fold the human exposure, based on AUC at the MRHD. In addition, fetuses of dams treated at this exposure level exhibited domed craniums, partially split sternum, hydrocephaly, dilated brain ventricles, dilated interventricular foramen, misaligned and misshapen hemicentres and misaligned ossification sites in the sternebrae, misaligned costal cartilage, increased ossification, cerebral and cerebellar hemorrhages, bipartite supraoccipital, large interparietal bone, marked enlargement of the anterior and posterior fontanelles, hyoid bone, meningocele and fusion of the jugal and maxilla.
In an embryofetal development study in pregnant rabbits, arimoclomol was administered once daily by oral gavage throughout organogenesis from gestation day 7 to 19. Increased incidences of minor skeletal variations (bent hyoid and unossified phalanx) were observed at 5-fold the human AUC at the MRHDD, coinciding with an adverse reduction of maternal body weight.
In a pre- and postnatal development study in pregnant rats, oral arimoclomol was administered from gestation day 6 to lactation day 21. Increased embryofetal lethality and reduced pup weight, with a slight reduction in maternal body weight gain, were observed at 10-fold the human AUC at the MRHDD.
Lactation
Risk Summary
There are no data on the presence of arimoclomol in human or animal milk, the effects on the breastfed infant, or the effects on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for MIPLYFFA and any potential adverse effects on the breastfed infant from MIPLYFFA or from the underlying maternal condition.
Females and Males of Reproductive Potential
MIPLYFFA may cause embryofetal harm when administered to a pregnant female [see Use in Specific Populations ( 8.1)] .
Contraception
Females:Consider pregnancy planning and prevention for females of reproductive potential.
Infertility
Based on findings from animal studies, MIPLYFFA may impair fertility in females and males of reproductive potential. In a rat fertility study, oral administration of arimoclomol resulted in decreased male and female fertility at 9-fold and increased pre-implantation loss at 5-fold the human exposure, based on AUC at MRHD. It is not known if these effects are reversible [see Nonclinical Toxicology ( 13.1)] .
Pediatric Use
The safety and effectiveness of MIPLYFFA in combination with miglustat for the treatment of neurological manifestations of NPC have been established in pediatric patients 2 years of age and older. Use of MIPLYFFA in combination with miglustat for this indication is supported by evidence from a randomized, double-blind, placebo-controlled 12-month trial (Trial 1) [see Clinical Studies ( 14)].
The safety and effectiveness of MIPLYFFA have not been established in pediatric patients younger than 2 years of age.
Juvenile Animal Toxicity Data
In juvenile toxicity studies in rats, increased incidences of renal pelvic dilatation were observed at all dose levels corresponding to 4-, 7- and 17-fold the human exposure based on AUC at MRHDD after both 2 and 8 weeks of dosing when animals were dosed from postnatal day 7.
Geriatric Use
NPC is largely a disease of pediatric and young adult patients. Clinical trials of MIPLYFFA in combination with miglustat in patients with NPC did not include patients aged 65 years or older.
Renal Impairment
The recommended MIPLYFFA dosage in combination with miglustat in patients with an eGFR 15 mL/minute to < 50 mL/minute is lower than the recommended dosage (less frequent dosing) in patients with normal renal function [see Dosage and Administration ( 2.2)]. The recommended dosage of MIPLYFFA in combination with miglustat in patients with an eGFR ≥ 50 mL/minute is the same as the recommended dosage in patients with normal renal function.
Plasma concentrations of arimoclomol increased in patients with eGFR ≥ 15 mL/minute to < 50 mL/minute [see Clinical Pharmacology ( 12.3)].
The pharmacokinetics of arimoclomol have not been evaluated in patients with eGFR < 15 mL/minute.
None.
Hypersensitivity Reactions
Hypersensitivity reactions such as urticaria and angioedema have been reported in patients treated with MIPLYFFA during Trial 1 [see Clinical Studies ( 14)] : two patients reported both urticaria and angioedema (6%) and one patient (3%) experienced urticaria alone. The reactions occurred within the first two months of treatment. Discontinue MIPLYFFA in patients who develop severe hypersensitivity reactions. If a mild or moderate hypersensitivity reaction occurs, stop MIPLYFFA and treat promptly. Monitor the patient until signs and symptoms resolve [see Adverse Reactions ( 6.1)].
Embryofetal Toxicity
Based on findings from animal reproduction studies, MIPLYFFA may cause embryofetal harm when administered during pregnancy. In animal reproduction studies, oral administration of arimoclomol to pregnant rats and rabbits resulted in post-implantation loss and structural abnormalities in offspring. These occurred at exposures equal to or greater than 10- and 5-fold, for rats and rabbits respectively, the human exposure at the maximum recommended human daily dose of 372 mg. Advise pregnant females of the potential risk to the fetus. Consider pregnancy planning and prevention for females of reproductive potential [see Use in Specific Populations ( 8.1, 8.3)] .
Increased Creatinine without Affecting Glomerular Function
Across clinical trials of MIPLYFFA consisting of patients with NPC, healthy subjects, and patients with other diseases, there were mean increases in serum creatinine of 10% to 20% compared to baseline. These increases occurred mostly in the first month of MIPLYFFA treatment and were not associated with changes in glomerular function. The increases in serum creatinine may be due to inhibition of renal tubular secretion transporters [see Drug Interactions ( 7) and Clinical Pharmacology ( 12.2, 12.3)].
During MIPLYFFA treatment, use alternative measures that are not based on creatinine to assess renal function such as BUN, cystatin C, or measured GFR. Increases in creatinine reversed upon MIPLYFFA discontinuation [see Clinical Pharmacology ( 12.2)] .