Brand name: Miplyffa (https://miplyffa.com/)
Drug class: Enzyme Cofactors/Chaperones

Introduction

Synthetic pyridine derivative.

Uses for Arimoclomol

Niemann-Pick Disease

Treatment of neurological manifestations of Niemann-Pick disease type C (NPC) in combination with miglustat, in adults and pediatric patients ≥2 years of age.

Designated an orphan drug by FDA for treatment of NPC.

NPC management includes supportive therapy and disease modifying agents when available. A consensus clinical management guideline for NPC recommends that miglustat be considered in all patients with confirmed diagnosis of NPC (not an FDA-labeled use for miglustat in the US). Arimoclomol is not discussed as the guideline predates approval of the drug.

Arimoclomol Dosage and Administration

Administration

Administer orally with or without food.

Oral Administration

Swallow capsules whole.

In patients who have difficulty swallowing capsules, may open capsule and sprinkle into 15 mL of water or apple juice or 15 mL of soft food (e.g., applesauce, pudding, or yogurt). Stir mixture for 15 seconds. Consume mixture immediately; do not save for later use.

Administration via Nasogastric or Gastric Feeding Tube

Open capsule and sprinkle entire contents into 20 mL of water only. Stir mixture for 15 seconds. Administer entire mixture immediately via feeding tube. Flush feeding tube with 5 mL of water after administration.

Administer mixture immediately; do not save for later use.

Dosage

Pediatric Patients

Niemann-Pick Disease

Oral

Pediatric patients ≥2 years of age: recommended dosage based on actual body weight (kg), in combination with miglustat, as follows.

• 8–15 kg: 47 mg 3 times a day.

• >15–30 kg: 62 mg 3 times a day.

• >30–55 kg: 93 mg 3 times a day.

• >55 kg: 124 mg 3 times a day.

If a dose is missed, skip missed dose and resume prescribed dose at next scheduled time.

Adults

Niemann-Pick Disease

Oral

Recommend dosage based on actual body weight (kg), in combination with miglustat, is as follows:

• 8–15 kg: 47 mg 3 times a day.

• >15–30 kg: 62 mg 3 times a day.

• >30–55 kg: 93 mg 3 times a day.

• >55 kg: 124 mg 3 times a day.

If a dose is missed, skip missed dose and resume prescribed dose at next scheduled time.

Special Populations

Hepatic Impairment

No specific population dosage recommendations at this time.

Renal Impairment

In patients with eGFR >15 to <50 mL/minute, dosage of arimoclomol, in combination with miglustat should be adjusted as follows.

• 8–15 kg: 47 mg 2 times a day.

• >15–30 kg: 62 mg 2 times a day.

• >30–55 kg: 93 mg 2 times a day.

• >55 kg: 124 mg 2 times a day.

Geriatric Patients

No specific population dosage recommendations at this time.

Cautions for Arimoclomol

Contraindications

• None.

Warnings/Precautions

Hypersensitivity Reactions

Hypersensitivity reactions such as urticaria and angioedema, reported within first 2 months of treatment.

Discontinue arimoclomol in patients who develop severe hypersensitivity reactions. If mild or moderate hypersensitivity reaction occurs, stop and treat promptly. Monitor until signs and symptoms resolve.

Fetal/Neonatal Morbidity and Mortality

May cause fetal harm.

Consider pregnancy planning and prevention for females of reproductive potential.

Increased Creatinine

Increases in serum creatinine reported; mostly in first month of treatment and not associated with changes in glomerular function.

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 discontinuation.

Specific Populations

Pregnancy

No data available on use during pregnancy. Based on animal studies, may cause embryo-fetal harm.

Decision to continue or discontinue during pregnancy should consider patient’s need for drug, potential drug-related risk to fetus, and potential adverse outcomes from untreated disease.

Lactation

Not known whether arimoclomol is distributed into human milk, or if drug has any effects on the breastfed infant or milk production. Consider developmental and health benefits of breastfeeding along with mother’s clinical need for arimoclomol and any potential adverse effects on breastfed infant from drug or underlying maternal condition.

Females and Males of Reproductive Potential

Consider pregnancy planning and prevention for females of reproductive potential.

Pediatric Use

Safety and efficacy established in pediatric patients ≥2 years of age.

Geriatric Use

No experience in geriatric population because Niemann-Pick type C disease (NPC) is largely a disease of pediatric and young adult patients.

Hepatic Impairment

No clinically significant differences in pharmacokinetics in patients with mild or moderate hepatic impairment. Safety and efficacy not studied in severe hepatic impairment.

Renal Impairment

Patients with moderate to severe renal impairment (eGFR 15-49 mL/minute) had increased total exposure to arimoclomol compared to patients with normal renal function (eGFR ≥90 mL/minute). Safety and efficacy not studied in eGFR <15 mL/minute.

Common Adverse Effects

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

Drug Interactions

Does not inhibit or induce CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 or CYP3A4/5.

Inhibitor of organic cationic transporter 2 (OCT2).

Not an inhibitor of P-glycoprotein (P-gp), breast cancer resistance protein (BCRP), organic anion transporter protein (OATP)1B1, OATP1B3, organic anion transporter (OAT)1, OAT3, multidrug and toxin extrusion protein (MATE)1 and MATE2-K transporters.

Substrate of MATE1 and MATE2-K transporters.

Drugs Affecting or Affected by Transport Systems

OCT substrates: Monitor for adverse reactions and reduce dosage of OCT2 substrate when used concomitantly with arimoclomol.

MATE1 and MATE2-K inhibitors: not expected to have a clinically relevant effect on arimoclomol exposure.

Arimoclomol Pharmacokinetics

Absorption

Bioavailability

Not determined.

Food

No clinically significant differences in pharmacokinetics following high fat meal.

Plasma Concentrations

Median time to maximum plasma concentration approximately 0.5 hours.

Distribution

Plasma Protein Binding

Approximately 10%.

Elimination

Metabolism

Metabolized through glutathionation, O-glucuronidation, and nitric oxide (NO)-oxime cleavage.

Elimination Route

12% feces and 77.5% urine (42% unchanged).

Half-life

Approximately 4 hours.

Stability

Storage

Oral

Capsules

Store at 20-25°C in original container; protect from light.

Actions

• Synthetic pyridine derivative small molecule that crosses the blood brain barrier.

• Exact mechanism of action in treatment of NPC is unknown; however, it is thought that arimoclomol targets several biochemical pathways in NPC.

Advice to Patients

• Advise patients and/or caregivers to read the FDA-approved patient labeling.

• 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.

• Arimoclomol may cause embryo-fetal harm. Advise patients of the potential risk to the fetus. Advise females of reproductive potential and caregivers to inform their healthcare provider of a known or suspected pregnancy.

• Advise females and males of reproductive potential that arimoclomol may impair fertility.

• Advise patients to inform their clinician if they are or plan to breast-feed.

• Advise patients to inform their clinician of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary or herbal supplements, as well as any concomitant illnesses.

• Inform patients of other important precautionary information.

Additional Information

The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer’s labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

Arimoclomol is available through the manufacturer. Contact the manufacturer or consult the arimoclomol website ([Web]) for more information.

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