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Amifampridine Tablets

TABLE OF CONTENTS

1. DESCRIPTION 8. USE IN SPECIFIC POPULATIONS
2. INDICATIONS AND USAGE 9. OVERDOSAGE
3. DOSAGE AND ADMINISTRATION 10. MECHANISM OF ACTION
4. CONTRAINDICATIONS 11. PHARMACODYNAMICS
5. WARNINGS AND PRECAUTIONS 12. PHARMACOKINETICS
6. ADVERSE REACTIONS 13. HOW SUPPLIED/STORAGE AND HANDLING
7. DRUG INTERACTIONS

 

1. DESCRIPTION

Amifampridine phosphate is a voltage-gated potassium channel blocker. Amifampridine phosphate is described chemically as 3,4-diaminopyridine phosphate. The structural formula is:

Empirical formula: C5H7N3•H3PO4 - Molecular weight: 207.1 g/mol

Amifampridine phosphate is a white, crystalline powder that is freely soluble in water, and slightly soluble in solvents ethanol, methanol and acetic acid. A 1% aqueous solution of amifampridine phosphate has a pH of 4.4 at ambient conditions.

Each amifampridine tablet contains 10 mg amifampridine (equivalent to 18.98 mg amifampridine phosphate). The tablet formulation includes the following inactive ingredients: calcium stearate, colloidal silicondioxide, and microcrystalline cellulose.

Amifampridine tablets are intended for oral administration only.

2. INDICATIONS AND USAGE

Amifampridine is indicated for the treatment of Lambert-Eaton myasthenic syndrome (LEMS) in adults.

3. DOSAGE AND ADMINISTRATION

3.1 Dosage Information

 The recommended starting dosage of amifampridine is 15 mg to 30 mg daily, taken orally in divided doses (3 to 4 times daily).

 The dosage can be increased by 5 mg daily every 3 or 4 days.

 The maximum recommended total daily dosage is 80 mg.

 The maximum single dose is 20 mg.

 If a dose is missed, patients should not take double or extra doses.

3.2 Patients with Renal Impairment

The recommended starting dosage of amifampridine in patients with renal impairment (creatinine clearance 15 to 90 mL/min) is 15 mg daily, taken orally in 3 divided doses. No dosage recommendation for amifampridine can be made for patients with end-stage renal disease [see Use in Specific Populations (8.6) and Clinical Pharmacology].

3.3 Patients with Hepatic Impairment

The recommended starting dosage of amifampridine in patients with any degree of hepatic impairment is 15 mg daily, taken orally in 3 divided doses [see Use in Specific Populations (8.7) and Clinical Pharmacology].

3.4 Known N-acetyltransferase 2 (NAT2) Poor Metabolizers

The recommended starting dosage of amifampridine in known N-acetyltransferase 2 (NAT2) poor metabolizers is 15 mg daily, taken orally in 3 divided doses [see Use in SpecificPopulations (8.8)and Clinical Pharmacology].

3.5 Administration Instructions

Amifampridine can be taken without regard to food.

4. CONTRAINDICATIONS

Amifampridine is contraindicated in patients with:

 A history of seizures [see Warnings and Precautions (5.1)]

 Hypersensitivity to amifampridine phosphate or another aminopyridine [see Warnings and Precautions (5.2)]

5. WARNINGS AND PRECAUTIONS

5.1 Seizures

Amifampridine can cause seizures. Seizures have been observed in patients without a history of seizures taking amifampridine 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 [see Drug Interactions (7.1)]. Seizures may be dose-dependent. Consider discontinuation or dose-reduction of amifampridine in patients who have a seizure while on treatment. Amifampridine is contraindicated in patients with a history of seizures.

5.2 Hypersensitivity

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

6. ADVERSE REACTIONS

The following serious adverse reactions are described elsewhere inthe labeling:

 Seizures [see Warnings and Precautions (5.1)]

 Hypersensitivity [see Warnings and Precautions (5.2)]

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

In controlled and uncontrolled trials (Study 1 and 2) in patients with LEMS, 63 patients were treated with amifampridine, including 40 patients treated for more than 6 months, and 39 patients treated for more than 12 months. In an expanded access program, 139 patients with LEMS were treated with amifampridine, including 102 patients treated for more than 6 months, 77 patients treated for more than 12 months, and 53 patients treated for more than 18 months.

Study 1 was a double-blind, placebo-controlled, randomized discontinuation study in adults with LEMS. Following an initial open-label run-in phase (up to 90 days), patients were randomized to either continue amifampridine treatment or transition to placebo, for a 14-day double-blind phase. Following final assessments, patients were allowedto resume amifampridine treatment for up to 2 years (openlabel long-term safety phase of the study).

During the open-label run-inphase of Study 1, 53 patients received amifampridine for an average of 81 days at a mean daily dosage of 50.5 mg/day. The mean patient age was 52.1 years and 66% were female. There were 42 patients who had no prior exposure to amifampridine at the initiation of this study.Table 1 shows adverse reactions with an incidence of 5% or greater occurring in the 42 LEMS patients newly initiated on treatment with amifampridine during the run-in phase of the study.

Table 1. Adverse Reactions in ≥ 5% of LEMS Patients Newly Treated with Amifampridine in Study 1

*Includes paresthesia, oral paresthesia, oral hypoesthesia

**Includes elevated alanine aminotransferase (ALT), aspartate aminotransferase (AST), lactate dehydrogenase (LDH), and gamma-glutamyl transferase (GGT)

Other Adverse Reactions

In the overall population treated in Study 1 (n=53), including the double-blind phase and the 2-year open-label long-term safety phase, additional adverse reactions occurring in at least 5% of the patients included: dyspnea, urinary tract infection, gastroesophageal reflex, insomnia, peripheral edema, pyrexia, viral infection, blood creatine phosphokinase increase, depression, erythema, hypercholesterolemia, and influenza. These patients received a mean daily dosage of 66 mg of amifampridine.

7. DRUG INTERACTIONS

7.1 Drugs that Lower Seizure Threshold

The concomitant use of amifampridine and drugs that lower seizure threshold may lead to an increased risk of seizures [see Warnings and Precautions (5.1)]. The decision to administer amifampridine concomitantly with drugs that lower the seizure threshold should be carefully considered in light of the severity of the associated risks.

7.2 Drugs with Cholinergic Effects

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

8. USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Risk Summary

There are no data on the developmental risk associated with the use of amifampridine in pregnant women. In animals 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 (see Animal Data). 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.

Data

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 amifampridine/day. Oral administration of amifampridine phosphate (0, 9, 30, or 57mg/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 still births 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.

8.2 Lactation

Risk Summary

There are no data on the presence of amifampridine 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 and any potential adverse effects on the breastfed infant from amifampridine or from the underlying maternal condition.

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

8.4 Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

8.5 Geriatric Use

Clinical studies of amifampridine 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 [see Dosage and Administration (3.2, 3.3) and Drug Interactions (7.2, 7.3)].

8.6 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 [see Clinical Pharmacology]. Therefore, in patients with renal impairment, amifampridine should be initiated at the lowest recommended starting dosage (15 mg/day), and patients should be closely monitored for adverse reactions [see Dosage and Administration (3.2)]. Consider dosage modification or discontinuation of amifampridine 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 can be made for patients with end-stage renal disease.

8.7 Hepatic Impairment

The effects of amifampridine have not been studied in patients with hepatic impairment. Amifampridine is extensively metabolized by N-acetyltransferase 2 (NAT2) and hepatic impairment may cause an increase in exposure. Therefore, initiate amifampridine in patients with any degree of hepatic impairment at the lowest recommended starting dosage (15 mg/day) and monitor for adverse reactions [see Dosage and Administration (3.3)]. Consider dosage modification or discontinuation of amifampridine for patients with hepatic impairment as needed based on clinical effect and tolerability.

8.8 NAT2 Poor Metabolizers

Exposure of amifampridine is increased in patients who are N-acetyltransferase 2 (NAT2) poor metabolizers [see Clinical Pharmacology]. Therefore, initiate amifampridine in patients who are known NAT2 poor metabolizers at the lowest recommended starting dosage (15 mg/day) and monitor for adverse reactions [see Dosage and Administration (3.4)]. Consider dosage modification of amifampridine for patients who are known NAT2 poor metabolizers as needed based on clinical effect and tolerability.

9. OVERDOSAGE

Overdose with amifampridine was not reported during clinical studies.

In a case report, a 65-year-old patient with LEMS inadvertently received a total daily amifampridine dose of 360 mg/day (more than 4 times the maximum recommended total daily dose) and was hospitalized for general weakness, paresthesia, nausea, vomiting, and palpitations. The patient developed convulsions and paroxysmal supraventricular tachycardia, and four days after admission, experienced cardiac arrest. The patient was resuscitated and ultimately recovered following withdrawal of amifampridine.

Patients with suspected overdose with amifampridine should be monitored for signs or symptoms of exaggerated amifampridine adverse reactions or effects, and appropriate symptomatic treatment instituted immediately.

10. MECHANISM OF ACTION

The mechanism by which amifampridine exerts its therapeutic effect inLEMS patients has not beenfully elucidated. Amifampridine is a broad spectrum potassium channel blocker.

11. PHARMACODYNAMICS

The effect of amifampridine on QTc interval prolongation was studied in a double blind, randomized, placebo and positive controlled study in 52 healthy individuals who are slow acetylators. At an exposure 2-foldthe expectedmaximum therapeutic exposure of amifampridine, amifampridine did not prolong QTc to any clinically relevant extent.

12. PHARMACOKINETICS

The pharmacokinetics o famifampridine are similar between healthy individuals and LEMS patients. Following single andmultiple doses, AUC, Cmax and Cmin were highly variable between individuals. Amifampridine exposure increased proportionally with dose across the range of 20 mg to 80 mg single oral doses.

Absorption

Amifampridine peak plasma concentration is reached 20 minutes to 1 hour after administration. Food does not have a clinically significant effect on the exposure of amifampridine.

Elimination

Amifampridine is eliminated primarily through metabolism to 3-N-acetyl-amifampridine and to a smaller extent through the kidneys. The terminal half-life ranges from 1.8 to 2.5 hours in healthy subjects.

Metabolism

Amifampridine is extensively metabolized by N-acetyltransferase 2 (NAT2) to 3-N-acetyl-amifampridine, which is considered an inactive metabolite.

Excretion

Following administration of amifampridine to healthy subjects, 93% to 100% of the administered dose was eliminated in the urine as amifampridine or 3-N-acetyl amifampridine over 24 hours.

Specific Populations

Patients with Renal Impairment

Pharmacokinetic data are available from a study of 24 otherwise healthy subjects with impaired renal function who received a single 10-mg dose of amifampridine. The exposure of amifampridine (measured as AUC) was 2-to 3-fold higher in subjects with moderate (CLcr 30-59 mL/min) or severe (CLcr 15-29 mL/min) renal impairment than in subjects with normal renal function (CLcr greater than or equal to 90 mL/min). Compared with subjects with normal renal function, subjects with mild renal impairment (CLcr 60-89 mL/min) had a 36% increase in exposure. Therefore, amifampridine should be initiated at the lowest recommended starting dosage (15 mg/day) in patients with renal impairment, and such patients should be closely monitored for adverse reactions [see Dosage and Administration (3.2) and Use in Specific Populations (8.6)]. Cmax was marginally affected by renal impairment.

13. HOW SUPPLIED/STORAGE AND HANDLING

How Supplied:

FIRDAPSE 10 mg tablets are white to off white, round, and functionally scored. Each tablet is debossed on the non-scored side with “CATALYST” and on the scored side with “211” above the score and “10” below the score. Tablets can be divided in half at the score. FIRDAPSE is supplied as follows:

Child Resistant Blister Pack

 blister pack containing 10 tablets NDC 69616-211-04

 carton containing 12 blister packs (120 tablets total) NDC 69616-211-06

Bottles

 60 tablets NDC 69616-211-08

 240 tablets NDC 69616-211-03

Storage and Handling:

Store at 20° to 25°C (68° to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature].

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Rev 11/18