Amifampridine Phosphate (Monograph)

Brand name: Firdapse
Drug class: Parasympathomimetic (Cholinergic) Agents

Medically reviewed by Drugs.com on Aug 10, 2024. Written by ASHP.

Introduction

Voltage-gated potassium channel blocker.

Uses for Amifampridine Phosphate

Lambert-Eaton Myasthenic Syndrome

Treatment of Lambert-Eaton myasthenic syndrome (LEMS) in adults and pediatric patients ≥6 years of age; designated an orphan drug by FDA for this use.

Amifampridine is one of several symptomatic treatments used in patients with LEMS and has been recommended as a first-line therapy.

Amifampridine Phosphate Dosage and Administration

General

Patient Monitoring

Closely monitor for adverse reactions in patients with renal impairment, hepatic impairment, or N-acetyltransferase gene 2 (NAT2) poor metabolizers.

Administration

Oral Administration

Administer orally in 3 to 5 divided doses per day without regard to meals.

If a dose is missed, it should be skipped; patients should not take double or extra doses.

Tablets can be divided in half at the score. If a dosage in <5 mg increments is required, or for patients with difficulty swallowing tablets or requiring a feeding tube, a 1 mg/mL suspension may be prepared from the tablets.

Preparation of Oral Suspension

Prepare daily one dose at a time or all doses for the day at one time.

Gather the following supplies: empty 50-100 mL bottle with cap, sterile water, and oral syringe with catheter tip (size 10 mL or smaller depending upon the dose).

Prepare suspension using sterile water; do not use any foods or other liquids. Place the appropriate number of amifampridine tablet(s) (or half-tablet) into the empty bottle. Tablets do not need to be crushed. Using the oral syringe, add 10 mL of sterile water for each tablet (5 mL for each half-tablet) to the bottle. Secure the bottle cap; wait 5 minutes for the tablets to disperse. Shake well for 30 seconds.

To administer by mouth, shake bottle well, remove cap, draw dose into an oral syringe, and push syringe plunger to administer dose into the mouth. Depending on size of the oral syringe and dosage, may need to repeat this step.

To administer via feeding tube, gather oral syringe with catheter tip and sterile water; do not use any foods or other liquids. Shake bottle well, remove cap, and draw dose into oral syringe. Immediately inject suspension into feeding tube; depending on size of the oral syringe and dosage, may need to repeat these steps. Once the entire dose has been administered, refill oral syringe with 10 mL sterile water, shake syringe, and inject contents of syringe into feeding tube to flush remaining drug from feeding tube.

Dosage

Dosage of amifampridine phosphate expressed in terms of amifampridine.

Pediatric Patients

Lambert-Eaton Myasthenic Syndrome

Oral

Children ≥6 years of age who weigh <45 kg: Initially, 5 to 15 mg daily in 3 to 5 divided doses. May increase total daily dosage by 2.5 mg every 3 or 4 days based on clinical response and tolerability up to a maximum of 50 mg daily given in divided doses. Maximum single dose: 10 mg.

Children ≥6 years of age who weigh ≥45 kg: Initially, 15 to 30 mg daily in 3 to 5 divided doses. May increase total daily dosage by 5 mg every 3 or 4 days based on clinical response and tolerability up to a maximum of 100 mg given in divided doses. Maximum single dose: 20 mg.

Adults

Lambert-Eaton Myasthenic Syndrome

Oral

Initially, 15 to 30 mg daily in 3 to 5 divided doses. May increase total daily dosage by 5 mg every 3 or 4 days based on clinical response and tolerability up to a maximum of 100 mg given in divided doses. Maximum single dose: 20 mg.

Special Populations

Hepatic Impairment

Any degree of hepatic impairment in adults or pediatric patients weighing ≥45 kg: Recommended initial total daily dosage is 15 mg in 3 to 5 divided doses.

Any degree of hepatic impairment in pediatric patients weighing <45 kg: Recommended initial total daily dosage is 5 mg in 3 to 5 divided doses.

Monitor adverse reactions; consider dosage modification or discontinuance as needed based on clinical effect and tolerability.

Renal Impairment

Adults or pediatric patients weighing ≥45 kg with Cl_cr 15-90 mL/minute: Recommended initial total daily dosage is 15 mg in 3 to 5 divided doses.

Pediatric patients weighing <45 kg with Cl_cr 15-90 mL/minute: Recommended initial total daily dosage is 5 mg in 3 to 5 divided doses.

Closely monitor adverse reactions; consider dosage modification or discontinuance as needed based on clinical effect and tolerability.

End-stage renal disease (Cl_cr <15 mL/minute or dialysis): No dosage recommendation.

Geriatric Use

Select dosage cautiously; start at the low end of the dosing range.

N-acetyltransferase 2 (NAT2) Poor Metabolizers

Adults or pediatric patients weighing ≥45 kg who are known NAT2 poor metabolizers: Recommended initial total daily dosage is 15 mg in 3 to 5 divided doses.

Pediatric patients weighing <45 kg who are known NAT2 poor metabolizers: Recommended initial total daily dosage is 5 mg in 3 to 5 divided doses.

Monitor adverse reactions; consider dosage modification or discontinuance as needed based on clinical effect and tolerability.

Cautions for Amifampridine Phosphate

Contraindications

History of seizures.
Hypersensitivity to amifampridine or another aminopyridine.

Warnings/Precautions

Seizures

May cause seizures; contraindicated in patients with a history of seizures.

Seizures may be dose-dependent.

Consider discontinuance or dose reduction if a seizure occurs.

Hypersensitivity

Hypersensitivity reactions and anaphylaxis not reported in clinical trials; however, anaphylaxis reported with another aminopyridine.

If anaphylaxis occurs, discontinue amifampridine and initiate appropriate therapy.

Specific Populations

Pregnancy

No data in pregnant women.

Developmental toxicity (e.g., increase in stillbirths and pup deaths, reduced pup weight, delayed sexual development) observed in animal studies.

If a patient is exposed to amifampridine during pregnancy, encourage enrollment in pregnancy registry by calling 855-212-5856, emailing firdapsepregnancyregistry@ubc.com, or visiting [Web].

Lactation

No data on presence of amifampridine in human milk, effects on the breastfed infant, or effects on milk production.

Distributes into milk of lactating rats.

Consider developmental and health benefits of breast-feeding along with mother's clinical need for amifampridine and any potential adverse effects on the breast-fed infant from the drug or underlying maternal condition.

Females and Males of Reproductive Potential

No adverse effects on fertility observed in male and female rats.

Pediatric Use

Safety and effectiveness established in pediatric patients ≥6 years of age.

Safety and effectiveness in pediatric patients <6 years of age not established.

Geriatric Use

Insufficient experience in patients ≥65 years of age to determine whether geriatric patients respond differently than younger adults.

Select initial dosage cautiously.

Hepatic Impairment

Extensively metabolized by N-acetyltransferase 2 (NAT2); hepatic impairment may cause increased exposure.

Not studied in patients with hepatic impairment.

Initiate at the lowest recommended initial daily dosage in patients with any degree of hepatic impairment; monitor for adverse reactions. Consider dosage modification or discontinuance as needed based on clinical effect and tolerability.

Renal Impairment

Amifampridine and its inactive metabolite cleared renally.

Mild (Cl_cr 60-89 mL/minute): AUC increased by 36%.

Moderate (Cl_cr 30-59 mL/minute) or severe (Cl_cr 15-29 mL/minute): AUC 2- to 3-fold higher.

End-stage renal disease (Cl_cr <15 mL/minute or patients requiring dialysis): Not studied.

Initiate at the lowest recommended initial daily dosage in patients with renal impairment; closely monitor for adverse reactions.

Pharmacogenomics and Effect of NAT2 Polymorphism

Rate and extent of amifampridine metabolism is affected by NAT2 polymorphism; plasma levels are 3- to 5-times higher in poor metabolizers (slow aceylators) compared to fast acetylators.

Initiate at the lowest recommended initial daily dosage; closely monitor for adverse reactions. Consider dosage modification in such patients as needed based on clinical effect and tolerability.

Common Adverse Effects

Adverse effects (>10%): Paresthesia, upper respiratory tract infection, abdominal pain, nausea, diarrhea, headache, elevated liver enzymes, back pain, hypertension, muscle spasms.

Drug Interactions

Does not inhibit or induce CYP enzymes or transporters.

Not a substrate of CYP enzymes or transporters.

Drugs that Lower Seizure Threshold

Coadministration with drugs that lower seizure threshold may increase risk of seizures.

Due to severity of seizure risk, carefully consider the decision to coadminister such drugs.

Drugs with Cholinergic Effects

Coadministration with drugs having cholinergic effects (e.g., direct or indirect cholinesterase inhibitors) increases cholinergic effects and risk of adverse reactions.

Amifampridine Phosphate Pharmacokinetics

Absorption

Bioavailability

Rapidly absorbed; peak plasma concentration is reached within 20 minutes to 1 hour after oral administration.

Food

Food affects absorption; not clinically significant.

Plasma Protein Binding

Not protein bound.

Elimination

Metabolism

Metabolized by N-acetyltransferase 2 (NAT2) to an inactive metabolite.

Elimination Route

93-100% eliminated in the urine over 24 hours.

Half-life

Fast acetylators: 1.8 hours. Slow acetylators: 2.5 hours.

Special Populations

Pediatric patients ≥6 years of age: Clearance increases as body weight increases.

Renal impairment: Exposure increases.

NAT2 poor metabolizers: Exposure increases 5.6- to 9-fold; peak plasma concentration increases 3.5- to 4.5-fold compared to normal metabolizers.

Stability

Storage

Oral

Tablets

20–25°C (excursions permitted to 15–30°C).

Oral Suspension Prepared from Tablets

2–8°C for up to 24 hours; discard any unused portion.

Actions

Voltage-gated potassium channel blocker.
In patients with LEMS, calcium entry into the nerve is inhibited by P/Q-type voltage-gated calcium channel (VGCC) antibodies and impairs acetylcholine release, resulting in muscle weakness.
Binds to VGCC causing a longer duration of opening allowing for increased calcium influx and subsequent acetylcholine release.
Enhances neuromuscular transmission; improves muscle function.

Advice to Patients

Amifampridine may cause seizures. Advise patients not to take the drug if they have a history of seizures and to immediately contact their clinician if a seizure occurs.
Advise patients and/or caregivers to immediately contact their clinician if signs or symptoms of hypersensitivity occur. Seek emergency help if symptoms of anaphylaxis occur.
Advise women to inform their clinicians if they are or plan to become pregnant or plan to breast-feed.
Advise patients that the effects of the drug on pregnancy and breastfeeding are not known. Advise patients of the existence of a pregnancy registry that monitors pregnancy outcomes in women exposed to amifampridine during pregnancy and encourage them to enroll if they become pregnant while taking the drug. Contact the Pregnancy Coordinating Center by calling 855-212-5856, by emailing firdapsepregnancyregistry@ubc.com, or by visiting the study website [Web].
Advise patients and/or caregivers to administer amifampridine exactly as prescribed, carefully following the dose escalation schedule prescribed by the clinician to safely achieve the therapeutic dose.
Advise patients and/or caregivers that amifampridine tablets are scored and can be split into ½ tablets (5 mg) if needed.
Advise patients and/or caregivers that amifampridine tablets can be administered with or without food.
Advise patients and/or caregivers to not take a double dose to make up for a missed dose. If a dose is missed, skip that dose and take the next dose at the next scheduled dose time.
Provide patients and/or caregivers with detailed instructions (found under ‘Instructions for Use’) to prepare an oral suspension (1 mg/mL) if the patient’s dose is less than 5 mg, the patient has trouble swallowing tablets, or requires administration via a feeding tube.
Advise patients and/or caregivers to store prepared amifampridine oral suspension in the refrigerator for up to 24 hours. Discard unused oral suspension after 24 hours.
Advise patients to inform their clinicians 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.

Amifampridine phosphate is obtained through designated specialty pharmacies. Contact manufacturer or consult the amifampridine website [Web] for specific availability information.