Amifampridine

Brand name: Firdapse
Drug class: Other Miscellaneous Therapeutic Agents
Chemical name: phosphoric acid;pyridine-3,4-diamine
Molecular formula: C₅H₁₀N₃O₄P
CAS number: 446254-47-3

Introduction

Amifampridine phosphate is a broad spectrum potassium channel blocker.

Uses for Amifampridine

Amifampridine phosphate has the following uses:

Amifampridine phosphate is a potassium channel blocker indicated for the treatment of Lambert-Eaton myasthenic syndrome (LEMS) in adults.

Amifampridine Dosage and Administration

General

Amifampridine phosphate is available in the following dosage form(s) and strength(s):

• Tablets: 10 mg, functionally scored.

Clinicians should be aware that there are 2 different formulations of amifampridine: amifampridine phosphate (Firdapse) and amiframpidine (Ruzurgi). Both are available as scored tablets containing 10 mg of amifampridine and are labeled for use in the treatment of Lambert-Eaton myasthenic syndrome (LEMS). Amifampridine phosphate (Firdapse) is labeled for use in adults, and amiframpidine (Ruzurgi) is labeled for use in pediatric patients 6 to less than 17 years of age.

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

Dosage and Administration

• The usual recommended starting dosage is 15 mg to 30 mg daily taken orally in divided doses (3 to 4 times daily).

• The recommended starting dosage is 15 mg daily taken orally in 3 divided doses for patients with renal impairment (CLcr 15–90 mL/min), hepatic impairment, and in known N-acetyltransferase 2 (NAT2) poor metabolizers.

• Dosage can be increased by 5 mg daily every 3 to 4 days.

• Dosage is not to exceed a maximum of 80 mg daily.

• The maximum single dose is 20 mg.

Cautions for Amifampridine

Contraindications

Amifampridine phosphate is contraindicated in patients with:

• A history of seizures.

• Hypersensitivity to amifampridine or another aminopyridine.

Warnings/Precautions

Seizures

Amifampridine phosphate can cause seizures. Seizures have been observed in patients without a history of seizures taking amifampridine phosphate at the recommended doses, at various times after initiation of treatment, at an incidence of approximately 2%. Many of the patients were taking medications or had comorbid medical conditions that may have lowered the seizure threshold. Seizures may be dose-dependent. Consider discontinuation or dose-reduction of amifampridine phosphate in patients who have a seizure while on treatment. Amifampridine phosphate is contraindicated in patients with a history of seizures.

Hypersensitivity

In clinical trials, hypersensitivity reactions and anaphylaxis associated with amifampridine phosphate administration have not been reported. Anaphylaxis has been reported in patients taking another aminopyridine; therefore, it may occur with amifampridine phosphate. If anaphylaxis occurs, administration of amifampridine phosphate should be discontinued and appropriate therapy initiated.

Specific Populations

Pregnancy

Risk Summary: There are no data on the developmental risk associated with the use of amifampridine phosphate in pregnant women. In animal studies, administration of amifampridine phosphate to rats during pregnancy and lactation resulted in developmental toxicity (increase in stillbirths and pup deaths, reduced pup weight, and delayed sexual development) at doses associated with maternal plasma drug levels lower than therapeutic drug levels. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. The background risk of major birth defects and miscarriage for the indicated population is unknown.

Animal Data: Oral administration of amifampridine phosphate (0, 7.5, 22.5, or 75 mg/kg/day) to female rats prior to and during mating and continuing throughout organogenesis produced no adverse effects on embryofetal development. Plasma amifampridine exposure (AUC) at the highest dose tested is approximately 7 times that in humans at the maximum recommended human dose (MRHD) of 80 mg/day amifampridine. Oral administration of amifampridine phosphate (0, 9, 30, or 57 mg/kg/day) to pregnant rabbits throughout organogenesis produced no adverse effects on embryofetal development. The highest dose tested is approximately 7 times the MRHD (80 mg/day amifampridine) on a body surface area (mg/m²) basis.

Oral administration of amifampridine phosphate (0, 7.5, 22.5, or 75 mg/kg/day) to female rats throughout pregnancy and lactation resulted in an increase in stillbirths and pup deaths, reduced pup weight, and delayed sexual development in female pups at the mid and high doses tested. The no-effect dose (7.5 mg/kg/day amifampridine phosphate) for adverse developmental effects is associated with a plasma amifampridine exposure (AUC) less than that in humans at the MRHD.

Lactation

Risk Summary: There are no data on the presence of amifampridine phosphate in human 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 amifampridine phosphate and any potential adverse effects on the breastfed infant from amifampridine phosphate or from the underlying maternal condition.

In lactating rats, amifampridine was excreted in milk and reached levels similar to those in maternal plasma.

Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

Geriatric Use

Clinical studies of amifampridine phosphate did not include sufficient numbers of subjects aged 65 and over (19 of 63 patients in Studies 1 and 2) to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

Renal Impairment

Renal clearance is an elimination pathway for amifampridine and the inactive metabolite, 3-N-acetyl amifampridine, and exposure of amifampridine is higher in subjects with renal impairment. Therefore, in patients with renal impairment, amifampridine phosphate should be initiated at the lowest recommended starting dosage (15 mg/day), and patients should be closely monitored for adverse reactions. Consider dosage modification or discontinuation of amifampridine phosphate for patients with renal impairment as needed based on clinical effect and tolerability. The safety, efficacy, and pharmacokinetics of amifampridine have not been studied in patients with end-stage renal disease (CLcr <15 mL/min or patients requiring dialysis). No dosage recommendation for amifampridine phosphate can be made for patients with end-stage renal disease.

Hepatic Impairment

The effects of amifampridine phosphate have not been studied in patients with hepatic impairment. Amifampridine phosphate is extensively metabolized by N-acetyltransferase 2 (NAT2) and hepatic impairment may cause an increase in exposure. Therefore, initiate amifampridine phosphate in patients with any degree of hepatic impairment at the lowest recommended starting dosage (15 mg/day) and monitor for adverse reactions. Consider dosage modification or discontinuation of amifampridine phosphate for patients with hepatic impairment as needed based on clinical effect and tolerability.

Pharmacogenomics: NAT2 Poor Metabolizers

Exposure of amifampridine phosphate is increased in patients who are N-acetyltransferase 2 (NAT2) poor metabolizers. Therefore, initiate amifampridine phosphate in patients who are known NAT2 poor metabolizers at the lowest recommended starting dosage (15 mg/day) and monitor for adverse reactions. Consider dosage modification of amifampridine phosphate for patients who are known NAT2 poor metabolizers as needed based on clinical effect and tolerability.

Common Adverse Effects

The most common (> 10%) adverse reactions are: paresthesia, upper respiratory tract infection, abdominal pain, nausea, diarrhea, headache, elevated liver enzymes, back pain, hypertension, and muscle spasms.

Drug Interactions

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:

• Drugs that lower seizure threshold: The concomitant use of amifampridine phosphate and drugs that lower seizure threshold may lead to an increased risk of seizures.

• Drugs with cholinergic effects: The concomitant use of amifampridine phosphate and drugs with cholinergic effects (e.g., direct or indirect cholinesterase inhibitors) may increase the cholinergic effects of amifampridine phosphate and of those drugs, and increase the risk of adverse reactions.

Actions

Mechanism of Action

The mechanism by which amifampridine exerts its therapeutic effect in LEMS patients has not been fully elucidated. Amifampridine is a broad spectrum potassium channel blocker.

Advice to Patients

Advise the patient and/or caregiver to read the FDA-approved patient labeling (Medication Guide).

Risk of Seizures

Inform patients that amifampridine phosphate can cause seizures, and to notify their healthcare provider if they experience a seizure.

Hypersensitivity

Instruct patients to inform their healthcare provider if they have signs or symptoms of hypersensitivity, and to seek emergency help if symptoms of anaphylaxis occur.

Amifampridine Phosphate Dosing

Instruct patients to take amifampridine phosphate exactly as prescribed. Patients should carefully follow the dose escalation schedule provided by their healthcare provider to safely achieve the therapeutic dosage. Inform patients that the tablets may be divided in half at the score, if needed. Instruct patients not to take a double dose to make up for a missed dose.

Drug Interactions

Instruct patients to notify their healthcare provider prior to starting any new medication, including over-the-counter drugs.

Storage

Advise patients to store amifampridine phosphate at 68°F to 77°F (20°C to 25°C).

Additional Information

AHFSfirstRelease^™. 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.

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.

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Frequently asked questions

• What is the difference between Ruzurgi and Firdapse?
• What is Firdapse (amifampridine) used to treat?

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