AHFS Class:

• Enzyme Cofactors/Chaperones 44:08

Brands:

• Miplyffa^®

Generic Name(s):

• Arimoclomol Citrate

Arimoclomol is an oral agent with activity in Niemann-Pick disease type C.1

Arimoclomol citrate has the following uses:

Arimoclomol is indicated for use in combination with miglustat for the treatment of neurological manifestations of Niemann-Pick disease type C (NPC) in adults and pediatric patients 2 years of age and older.1

General

Arimoclomol citrate is available in the following dosage form(s) and strength(s):

• Capsules: 47 mg, 62 mg, 93 mg and 124 mg of arimoclomol.1

Dosage

It is essential that the manufacturer's labeling be consulted for more detailed information on dosage and administration of this drug. Dosage summary:

Adults and Pediatric Patients 2 Years of Age

• Administer orally, in combination with miglustat.1 Administer with or without food.1
• Recommended arimoclomol dosage for patients with actual body weight of 8 kg to 15 kg is 47 mg three times a day.1
• Recommended arimoclomol dosage for patients with actual body weight of >15 kg to 30 kg is 62 mg three times a day.1
• Recommended arimoclomol dosage for patients with actual body weight of >30 kg to 55 kg is 93 mg three times a day.1
• Recommended arimoclomol dosage for patients with actual body weight of >55 kg is 124 mg three times a day.1
• See full prescribing information for recommended dosage in patients with an eGFR ≥ 15 to < 50 mL/minute.1
• See full prescribing information for instructions on preparation and administration.1

Contraindications

None.1

Warnings/Precautions

Hypersensitivity Reactions

Hypersensitivity reactions such as urticaria and angioedema have been reported in patients treated with arimoclomol in the principal efficacy study; two patients reported both urticaria and angioedema (6%) and one patient (3%) experienced urticaria alone.1 The reactions occurred within the first two months of treatment.1 Discontinue arimoclomol in patients who develop severe hypersensitivity reactions.1 If a mild or moderate hypersensitivity reaction occurs, stop arimoclomol and treat promptly.1 Monitor the patient until signs and symptoms resolve. 1

Embryofetal Toxicity

Based on findings from animal reproduction studies, arimoclomol may cause embryofetal harm when administered during pregnancy.1 In animal reproduction studies, oral administration of arimoclomol to pregnant rats and rabbits resulted in post-implantation loss and structural abnormalities in offspring.1 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.1 Advise pregnant females of the potential risk to the fetus.1 Consider pregnancy planning and prevention for females of reproductive potential. 1

Increased Creatinine without Affecting Glomerular Function

Across clinical trials of arimoclomol consisting of patients with Niemann-Pick disease type C (NPC), healthy subjects, and patients with other diseases, there were mean increases in serum creatinine of 10% to 20% compared to baseline.1 These increases occurred mostly in the first month of arimoclomol treatment and were not associated with changes in glomerular function.1 The increases in serum creatinine may be due to inhibition of renal tubular secretion transporters. 1

During arimoclomol treatment, use alternative measures that are not based on creatinine to assess renal function such as BUN, cystatin C, or measured GFR.1 Increases in creatinine reversed upon arimoclomol discontinuation. 1

Specific Populations

Pregnancy

Based on findings from animal reproduction studies, arimoclomol may cause embryofetal harm when administered during pregnancy.1 There are no available data on arimoclomol use in pregnant females to evaluate a drug-associated risk of major birth defects, miscarriage, or other adverse maternal or fetal outcomes.1 Advise pregnant females of the potential risk to the fetus.1

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.1 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). 1

The background risk of major birth defects and miscarriage for the indicated population is unknown.1 All pregnancies have a background risk of birth defect, loss, or other adverse outcomes.1 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.1

Lactation

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.1 The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for arimoclomol and any potential adverse effects on the breastfed infant from the drug or from the underlying maternal condition.1

Females and Males of Reproductive Potential

Arimoclomol may cause embryofetal harm when administered to a pregnant female. 1

Consider pregnancy planning and prevention for females of reproductive potential. 1

Based on findings from animal studies, arimoclomol may impair fertility in females and males of reproductive potential.1 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.1 It is not known if these effects are reversible. 1

Pediatric Use

The safety and effectiveness of arimoclomol in combination with miglustat for the treatment of neurological manifestations of NPC have been established in pediatric patients 2 years of age and older.1 Use of arimoclomol in combination with miglustat for this indication is supported by evidence from a randomized, double-blind, placebo-controlled 12-month trial. 1

The safety and effectiveness of arimoclomol have not been established in pediatric patients younger than 2 years of age.1

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 7.1

Geriatric Use

NPC is largely a disease of pediatric and young adult patients.1 Clinical trials of arimoclomol in combination with miglustat in patients with NPC did not include patients 65 years of age or older.1

Renal Impairment

The recommended arimoclomol 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.1 The recommended dosage of arimoclomol 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. 1

Plasma concentrations of arimoclomol increased in patients with eGFR ≥ 15 mL/minute to <50 mL/minute. 1

The pharmacokinetics of arimoclomol have not been evaluated in patients with eGFR <15 mL/minute.1

Common Adverse Effects

Most common adverse reactions (≥15%) are upper respiratory tract infection, diarrhea, and decreased weight.1

Specific Drugs

It is essential that the manufacturer's labeling be consulted for more detailed information on interactions with this drug, including possible dosage adjustments. Interaction highlights:

• Substrates of the Organic Cationic Transporter 2 (OCT2 substrates): Monitor for adverse reactions and reduce the dosage of the OCT2 substrate.1

Actions

Mechanism of Action

The mechanism(s) by which arimoclomol exerts its clinical effects in patients with Niemann-Pick disease type C (NPC) is unknown.1

Advice to Patients

• Advise patients and/or caregivers to read the FDA-approved patient labeling.1
• Advise patients to inform their healthcare provider if they are taking, or plan to take, any prescription or over-the-counter (OTC) medications and supplements because of the potential for drug interactions. 1
• Advise patients or caregivers to contact their healthcare provider immediately if urticaria (hives), shortness of breath, persistent cough, or facial swelling develop in response to arimoclomol treatment. 1
• Arimoclomol may cause embryo-fetal harm.1 Advise pregnant females of the potential risk to the fetus.1 Advise females of reproductive potential and caregivers to inform their healthcare provider of a known or suspected pregnancy. 1
• Advise females and males of reproductive potential that arimoclomol may impair fertility. 1

Additional Information

AHFS first Release^™. For additional information until a more detailed monograph is developed and published, the manufacturer's labeling should be consulted. It is essential that the manufacturer's labeling be consulted for more detailed information on usual uses, dosage and administration, cautions, precautions, contraindications, potential drug interactions, laboratory test interferences, and acute toxicity.

1. Acer Therapeutics Inc. MIPLYFFA^® (arimoclomol citrate) ORAL prescribing information. 2024 Sept. [Web]