2.1 Dosage Information

The recommended dosage regimen of FIRDAPSE for adults and pediatric patients 6 years of age and older is included in Table 1. For pediatric patients, the recommended dosing regimen is dependent on body weight. Dosage should be increased every 3 to 4 days based on clinical response and tolerability. Titration increments should not exceed those shown in Table 1.

Missed Dose

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

2.2 Patients with Renal Impairment

The recommended starting dosage of FIRDAPSE in patients with renal impairment [creatinine clearance (CLcr) 15 to 90 mL/min] is the lowest recommended initial daily dosage (i.e., 15 mg daily for pediatric patients weighing 45 kg or more and for adults, and 5 mg daily for pediatric patients weighing less than 45 kg) taken orally in divided doses. No dosage recommendation for FIRDAPSE can be made for patients with end-stage renal disease [see Dosage and Administration (2.1), Use in Specific Populations (8.6), and Clinical Pharmacology (12.3)].

2.3 Patients with Hepatic Impairment

The recommended starting dosage of FIRDAPSE in patients with any degree of hepatic impairment is the lowest recommended initial daily dosage (i.e., 15 mg daily for pediatric patients weighing 45 kg or more and for adults, and 5 mg daily for pediatric patients weighting less than 45 kg) taken orally in divided doses [see Dosage and Administration (2.1), Use in Specific Populations (8.7), and Clinical Pharmacology (12.3)].

2.4 Known N-acetyltransferase 2 (NAT2) Poor Metabolizers

The recommended starting dosage of FIRDAPSE in known N-acetyltransferase 2 (NAT2) poor metabolizers is the lowest recommended initial daily dosage (i.e., 15 mg daily for pediatric patients weighing 45 kg or more and for adults, and 5 mg daily for pediatric patients weighing less than 45 kg) taken orally in divided doses [see Dosage and Administration (2.1), Use in Specific Populations (8.8), and Clinical Pharmacology (12.5)].

2.5 Administration Instructions

FIRDAPSE can be taken without regard to food.

Preparation of a 1mg/mL Suspension (see the Instructions for Use for full instructions on how to prepare the 1mg/mL suspension)

When patients require a dosage in less than 5 mg increments, have difficulty swallowing tablets, or require feeding tubes, a 1 mg/mL suspension can be prepared (e.g., by placing the required number of tablets in a 50 to 100 mL container, adding 10 mL of sterile water for each tablet, waiting for 5 minutes, and shaking well for 30 seconds).

Crushing the tablets prior to making the suspension is not necessary. After preparation of the suspension, an oral syringe can be used to draw up and administer the correct dose by mouth or by feeding tube.

Storage of 1mg/mL Prepared Suspension
Refrigerate the suspension between doses and shake well before drawing up each dose. The suspension can be stored under refrigeration
[between 2°C and 8°C (36°F and 46°F)] for up to 24 hours. Discard any unused portion of the suspension after 24 hours.

5.1 Seizures

FIRDAPSE can cause seizures. Seizures have been observed in patients without a history of seizures taking FIRDAPSE 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 FIRDAPSE in patients who have a seizure while on treatment. FIRDAPSE is contraindicated in patients with a history of seizures.

5.2 Hypersensitivity

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

6.1 Clinical Trials Experience

Adults

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 clinical trials (Study 1 and 2) in patients with LEMS [see Clinical Studies (14)], 63 patients were treated with FIRDAPSE, 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 FIRDAPSE, 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 FIRDAPSE treatment or transition to placebo, for a 14- day double-blind phase. Following final assessments, patients were allowed to resume FIRDAPSE treatment for up to 2 years (open- label long-term safety phase of the study).

During the open-label run-in phase of Study 1, 53 patients received FIRDAPSE 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 FIRDAPSE at the initiation of this study. Table 2 shows adverse reactions with an incidence of 5% or greater occurring in the 42 LEMS patients newly initiated on treatment with FIRDAPSE during the run-in phase of the study.

*Includes paresthesia, oral paresthesia, oral hypoesthesia

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

7.1 Drugs that Lower Seizure Threshold

The concomitant use of FIRDAPSE and drugs that lower seizure threshold may lead to an increased risk of seizures [see Warnings and Precautions (5.1)]. The decision to administer FIRDAPSE 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 FIRDAPSE and drugs with cholinergic effects (e.g., direct or indirect cholinesterase inhibitors) may increase the cholinergic effects of FIRDAPSE and of those drugs and increase the risk of adverse reactions.

8.1 Pregnancy

8.2 Lactation

8.4 Pediatric Use

Safety and effectiveness of FIRDAPSE for the treatment of LEMS have been established in pediatric patients 6 years of age and older. Use of FIRDAPSE for this indication is supported by evidence from adequate and well-controlled studies of FIRDAPSE in adults with LEMS, pharmacokinetic data in adult patients, pharmacokinetic modeling and simulation to identify the dosing regimen in pediatric patients, and safety data from pediatric patients aged 6 years and older [see Adverse Reactions (6.1), Clinical Pharmacology (12.3), and Clinical Studies (14)].

Safety and effectiveness in pediatric patients below the age of 6 years have not been established.

8.5 Geriatric Use

Clinical studies of FIRDAPSE did not include a sufficient number 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 (2.2, 2.3) 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 (12.3)]. Therefore, in patients with renal impairment, FIRDAPSE should be initiated at the lowest recommended initial daily dosage, and patients should be closely monitored for adverse reactions [see Dosage and Administration (2.2)]. Consider dosage modification or discontinuation of FIRDAPSE 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 FIRDAPSE can be made for patients with end-stage renal disease.

8.7 Hepatic Impairment

In patients with any degree of hepatic impairment, FIRDAPSE should be initiated at the lowest recommended initial daily dosage, and patients should be monitored for adverse reactions [see Dosage and Administration (2.3)]. Consider dosage modification or discontinuation of FIRDAPSE for patients with hepatic impairment as needed based on clinical effect and tolerability.

8.8 NAT2 Poor Metabolizers

Exposure of FIRDAPSE is increased in patients who are N-acetyltransferase 2 (NAT2) poor metabolizers [see Clinical Pharmacology (12.5)]. Therefore, initiate FIRDAPSE in patients who are known NAT2 poor metabolizers at the lowest recommended initial daily dosage and monitor for adverse reactions [see Dosage and Administration (2.4)]. Consider dosage modification of FIRDAPSE for patients who are known NAT2 poor metabolizers as needed based on clinical effect and tolerability.

12.1 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.

12.2 Pharmacodynamics

The effect of FIRDAPSE 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-fold the expected maximum therapeutic exposure of amifampridine, FIRDAPSE did not prolong QTc to any clinically relevant extent.

12.3 Pharmacokinetics

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

12.5 Pharmacogenomics

Genetic variants in the N-acetyltransferase gene 2 (NAT2) affect the rate and extent of FIRDAPSE metabolism. Poor metabolizers, also referred to as "slow acetylators" (i.e., carriers of two reduced function alleles), have 3.5- to 4.5-fold higher Cmax, and 5.6- to 9- fold higher AUC than normal metabolizers, also referred to as "fast/rapid acetylators" (i.e., carriers of two normal function alleles). Therefore, FIRDAPSE should be initiated at the lowest recommended initial daily dosage in known NAT2 poor metabolizers, and such patients should be closely monitored for adverse reactions [see Dosage and Administration (2.4) and Use in Specific Populations (8.8)]. In the general population, the NAT2 poor metabolizer phenotype prevalence is 40–60% in the White and African American populations, and in 10–30% in Asian ethnic populations (individuals of Japanese, Chinese, or Korean descent).

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Study 1 (NCT01377922)

After an initial open-label run-in phase, 38 patients were randomized in a double-blind fashion to either continue treatment with FIRDAPSE (n=16) or to a downward titration to placebo (n=22) over 7 days. Following the downward titration period, patients remained on blinded FIRDAPSE or placebo for 7 more days. Efficacy was assessed at Day 14 of the double-blind period. Patients were allowed to use stable dosages of peripherally acting cholinesterase inhibitors or oral immunosuppressants. Twenty-six percent of patients randomized to FIRDAPSE were receiving cholinesterase inhibitors, versus 36% in the placebo group, and 28% of patients randomized to FIRDAPSE were receiving oral immunosuppressant therapies, versus 34% in the placebo group.

Patients had a median age of 54 years (range: 21 to 88 years), 61% were female, and 90% were White. Eighty-four percent of patients had a diagnosis of autoimmune LEMS, and 16% of patients had a diagnosis of paraneoplastic LEMS.

During the double-blind period (from Baseline to Day 14), the QMG scores tended to worsen in both treatment groups, but there was significantly greater worsening in the placebo group than in the FIRDAPSE group (p=0.045). Similarly, the SGI score tended to worsen in both treatment groups during the double-blind period, but there was significantly greater worsening in the placebo group than in the FIRDAPSE group (p=0.003), as summarized in Table 3. These results indicate that in Study 1, patients randomized to placebo had a significantly greater worsening of muscle weakness and of global impression of the effects of the study treatment on their physical well-being, compared to patients who continued FIRDAPSE in the double-blind period.

The CGI-I score was significantly greater for patients randomized to placebo than for patients who continued treatment with FIRDAPSE, with a mean difference between FIRDAPSE and placebo of -1.1 (p=0.02), indicating that clinicians perceived a greater worsening of clinical symptoms in patients who were randomized to placebo and discontinued from FIRDAPSE treatment, compared to patients who continued FIRDAPSE in the double-blind period.

Study 2 (NCT02970162)

Patients on stable treatment with FIRDAPSE were randomized 1:1 in a double-blind fashion to either continue treatment with FIRDAPSE (n=13) or change to placebo (n=13) for 4 days. Efficacy was assessed at the end of the 4-day double-blind discontinuation period. Patients were allowed to use stable doses of peripherally acting cholinesterase inhibitors or corticosteroids. Sixty-one percent of patients randomized to FIRDAPSE were receiving cholinesterase inhibitors, versus 54% of patients randomized to placebo.

Corticosteroid use was similar between FIRDAPSE and placebo (8%). Patients with recent use of immunomodulatory therapies (e.g., azathioprine, mycophenolate, cyclosporine), rituximab, intravenous immunoglobulin G, and plasmapheresis were excluded from the study. Patients had a median age of 55.5 years (range: 31 to 75 years), 62% were female, and 88% were white.

From Baseline to Day 4, there was significantly greater worsening in the QMG score in the placebo group than in the FIRDAPSE group (p=0.0004), and also significantly greater worsening in the SGI score in the placebo group than in the FIRDAPSE group(p=0.0003), as summarized in Table 4. These results indicate that in Study 2, patients randomized to placebo had a significantly greater worsening of muscle weakness and of global impression of the effects of the study treatment on their physical well-being, compared to patients who continued FIRDAPSE in the double-blind period.

The clinical global impression improvement (CGI-I) score was significantly greater for patients randomized to placebo than for patients who continued treatment with FIRDAPSE, with a mean difference between FIRDAPSE and placebo of -2.7 (p=0.002), indicating that clinicians perceived a greater worsening of clinical symptoms in patients who were randomized to placebo and discontinued from FIRDAPSE treatment, compared to patients who continued FIRDAPSE in the double-blind period.

16.1 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:

16.2 Storage and Handling

Store FIRDAPSE tablets at 20°C to 25°C (68°F to 77°F) with excursions permitted from 15°C to 30°C (59°F to 86°F) [see USP controlled room temperature]. See Dosage and Administration (2.5) for storage instructions for FIRDAPSE prepared suspension.

Risk of Seizures

Inform patients that FIRDAPSE can cause seizures, and to notify their healthcare provider if they experience a seizure [see Warnings and Precautions (5.1)].

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 [see Warnings and Precautions (5.2)].

FIRDAPSE Dosing

Instruct patients to take FIRDAPSE exactly as prescribed. Patients should carefully follow the dose escalation schedule provided by their healthcare provider to safely achieve the therapeutic dosage [see Dosage and Administration (2)]. 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. If they require a dosage in less than 5 mg increments, have difficulty swallowing tablets, or require feeding tubes, refer patients and/or caregivers to the Instructions for Use on how to prepare a 1 mg/mL suspension [see Dosage and Administration (2.5)]. If the patient requires treatment with the 1 mg/mL FIRDAPSE suspension, advise patients and/or caregivers that supplies required to prepare the suspension may be obtained at their local pharmacy.

Drug Interactions

Instruct patients to notify their healthcare provider prior to starting any new medication, including over-the-counter drugs [see Drug Interactions (7)].

Pregnancy

Instruct patients that if they are pregnant or plan to become pregnant while taking FIRDAPSE they should inform their healthcare provider. Advise patients that there is a pregnancy registry that monitors pregnancy outcomes in women exposed to FIRDAPSE during pregnancy and encourage them to enroll if they become pregnant while taking FIRDAPSE [see Use in Specific Populations (8.1)].

Storage

Advise patients to store FIRDAPSE at 68ºF to 77ºF (20ºC to 25ºC).

Instruct patients and/or caregivers who prepare the 1 mg/mL suspension of FIRDAPSE that it should be prepared daily and refrigerated between doses. The suspension can be stored under refrigeration for up to 24 hours. Instruct the patient and/or caregiver to discard any unused portion of the suspension after 24 hours.