DailyMed Label: Firdapse

DailyMed Label: Firdapse

2024

DailyMed Prescription

Firdapse

amifampridine phosphate

Catalyst Pharmaceuticals, Inc.

NDC: 69616-211

NDC: 69616-211

NDC: 69616-211

NDC: 69616-211

NDC: 69616-211

NDC: 69616-211

NDC: 69616-211

NDC: 69616-211

NDC: 69616-211

NDC: 69616-211

NDC: 69616-211

NDC: 69616-211

NDC: 69616-211

NDC: 69616-211

NDC: 69616-211

NDC: 69616-211

NDC: 69616-211

The active ingredient of FIRDAPSE is amifampridine phosphate, which is a voltage-gated potassium channel blocker. Amifampridine phosphate is described chemically as 3,4-diaminopyridine phosphate with a molecular weight of 207.1 and a molecular formula of C 5 H 7 N 3 • H 3 PO 4 . The structural formula is: 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 FIRDAPSE tablet contains 10 mg amifampridine (equivalent to 18.98 mg amifampridine phosphate). The tablet formulation includes the following inactive ingredients: calcium stearate, colloidal silicon dioxide, and microcrystalline cellulose. FIRDAPSE tablets are intended for oral administration only. Structural Formula

FIRDAPSE ® is indicated for the treatment of Lambert-Eaton myasthenic syndrome (LEMS) in adults and pediatric patients 6 years of age and older. FIRDAPSE is a potassium channel blocker indicated for the treatment of Lambert-Eaton myasthenic syndrome (LEMS) in adults and pediatric patients 6 years of age and older. ( 1 )

Administer orally in divided doses (3 to 5 times daily). ( 2.1 ) The recommended starting dosage for adults (any weight) and pediatric patients weighing 45 kg or more is 15 mg to 30 mg daily, in divided doses. ( 2.1 ) Dosage can be increased by 5 mg daily every 3 to 4 days. ( 2.1 ) The maximum single dose is 20 mg. ( 2.1 ) Dosage is not to exceed a maximum of 100 mg daily. ( 2.1 ) The recommended starting dosage for pediatric patients weighing less than 45 kg is 5 mg to 15 mg daily, in divided doses. ( 2.1 ) Dosage can be increased by 2.5 mg daily every 3 to 4 days. ( 2.1 ) The maximum single dose is 10 mg. ( 2.1 ) Dosage is not to exceed a maximum of 50 mg daily. ( 2.1 ) The recommended starting dosage for adult and pediatric patients with renal impairment, hepatic impairment, and in known N-acetyltransferase 2 (NAT2) poor metabolizers is the lowest recommended initial daily dosage ( 2.1 , 2.2 , 2.3 , 2.4 ) For patients with a dosage adjustment of less than 5 mg increments, or who have difficulty swallowing, or require feeding tube, a l mg/mL suspension can be prepared. ( 2.5 ) The recommended oral dosage 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 . Table 1: Recommended Oral Dosage for the Treatment of LEMS in Adults and Pediatric Patients 6 Years of Age and Older * See Dosage and Administration ( 2.5 ) for a method to achieve these doses Age and Body Weight Initial Daily Dosage * Titration Regimen Maximum Single Dose Maximum Total Daily Maintenance Dosage Adults (any weight) Pediatric patients weighing 45 kg or more 15 mg to 30 mg daily, in 3 to 5 divided doses Increase total daily dosage by 5 mg every 3 or 4 days 20 mg 100 mg Given in divided doses Pediatric patients weighing less than 45 kg 5 mg to 15 mg daily, in 3 to 5 divided doses Increase total daily dosage by 2.5 mg every 3 or 4 days 10 mg 50 mg Given in divided doses Missed Dose If a dose is missed, patients should not take double or extra doses. 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 )]. 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 )]. 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 )]. 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.

FIRDAPSE tablets contain 10 mg amifampridine and 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: 10 mg, functionally scored. ( 3 )

FIRDAPSE 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 )] FIRDAPSE is contraindicated in patients with: A history of seizures ( 4 ) Hypersensitivity to amifampridine or another aminopyridine ( 4 )

Seizures: FIRDAPSE can cause seizures. Consider discontinuation or dose-reduction of FIRDAPSE in patients who have a seizure while on treatment. ( 5.1 ) Hypersensitivity reactions: If a hypersensitivity reaction such as anaphylaxis occurs, FIRDAPSE should be discontinued and appropriate therapy initiated. ( 5.2 ) 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. 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.

The following serious adverse reactions are described elsewhere in the labeling:

Drugs that lower seizure threshold: Concomitant use may lead to an increased risk of seizures. ( 7.1 ) Drugs with cholinergic effects (e.g., direct or indirect cholinesterase inhibitors): Concomitant use may increase the cholinergic effects of FIRDAPSE and of those drugs and increase the risk of adverse reactions. ( 7.2 ) 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. 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.

Pregnancy: Based on animal data, may cause fetal harm. ( 8.1 ) Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to FIRDAPSE during pregnancy. Physicians are encouraged to enroll pregnant patients, or pregnant women may register themselves in the registry by calling 855- 212-5856 (toll-free), using the Fax number 877-867-1874 (toll-free), by contacting the Pregnancy Coordinating Center at firdapsepregnancyregistry@ubc.com, or by visiting the study website www.firdapsepregnancystudy.com. Risk Summary There are no data on the developmental risk associated with the use of FIRDAPSE 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 (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. The highest dose tested is approximately 4 times the maximum recommended human dose (MRHD) of amifampridine (100 mg/day) on a body surface area (mg/m 2 ) basis. 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 6 times the MRHD of amifampridine on a body surface area (mg/m 2 ) 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 of amifampridine. Risk Summary There are no data on the presence of FIRDAPSE 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 FIRDAPSE and any potential adverse effects on the breastfed infant from FIRDAPSE or from the underlying maternal condition. In lactating rat, amifampridine was excreted in milk and reached levels similar to those in maternal plasma. 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. 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 ( 7.1 , 7.2 )] . 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. 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. 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.

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 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.

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. 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. The pharmacokinetics of amifampridine are similar between healthy individuals and LEMS patients. Following single and multiple doses, AUC, C max and C min were highly variable between individuals. FIRDAPSE 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 FIRDAPSE 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 Pediatric Patients (6 Years of Age and Older) A population pharmacokinetic analysis showed that body weight significantly correlates with the clearance of amifampridine; clearance increased with an increase in body weight. A weight-based dosing regimen is necessary to achieve amifampridine exposures in pediatric patients 6 years of age and older, similar to the exposures observed in adults at recommended doses of FIRDAPSE [see Dosage and Administration ( 2.1 ) and Clinical Studies ( 14 )]. 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 FIRDAPSE. 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, FIRDAPSE should be initiated at the lowest recommended initial daily dosage in patients with renal impairment, and such patients should be closely monitored for adverse reactions [see Dosage and Administration ( 2.2 ) and Use in Specific Populations ( 8.6 )] . C max was marginally affected by renal impairment. Patients with Hepatic Impairment A study was conducted to determine the PK, safety, and tolerability of FIRDAPSE (amifampridine phosphate) administered at 10 mg to subjects with moderate hepatic impairment (N = 7) compared to demographically matched healthy subjects with normal hepatic function (N = 9). The subjects with moderate hepatic impairment had a 22% higher C max and a 33% higher AUC inf for amifampridine than subjects with normal hepatic function. FIRDAPSE was not evaluated in subjects with severe hepatic impairment [see Dosage and Administration ( 2.3 ) and Use in Specific Populations ( 8.7 )] . 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 C max , 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).

Carcinogenicity In a 104-week carcinogenicity study in rats, oral administration of amifampridine phosphate (0, 15, 48, or 105 mg/kg/day) resulted in an increase in uterine tumors (endometrial carcinoma and combined endometrial adenoma/endometrial carcinoma/squamous cell carcinoma) at the mid and high doses tested. The low dose, not associated with an increase in tumors, is less than the maximum recommended human dose (MRHD) of amifampridine (100 mg/day) on a body surface area (mg/m 2 basis). In a 26-week carcinogenicity study in transgenic (Tg.rasH2) mice, oral administration of amifampridine phosphate (0, 2, 7, or 21 mg/kg/day in males and 0, 3, 10, or 30 mg/kg/day in females) resulted in no increase in tumors. Mutagenesis Amifampridine phosphate was negative in the in vitro bacterial reverse mutation and in vivo rat micronucleus assays. Amifampridine phosphate was positive for clastogenicity in the in vitro mouse lymphoma tk assay in the absence of metabolic activation. Impairment of Fertility Oral administration of amifampridine phosphate (0, 7.5, 22.5, or 75 mg/kg/day) to male and female rats prior to and during mating, and continuing in females throughout organogenesis, produced no adverse effects on fertility. The highest dose tested is approximately 4 times the MRHD of amifampridine on a body surface area (mg/m 2 ) basis.

The efficacy of FIRDAPSE for the treatment of LEMS was demonstrated in two randomized, double-blind, placebo-controlled discontinuation studies. A total of 64 adults (age 21 to 88 years) with LEMS were enrolled (Study 1 and Study 2). The studies enrolled patients with a confirmed diagnosis of LEMS based on either neurophysiology studies or a positive anti-P/Q type voltage-gated calcium channel antibody test. Patients were required to be on an adequate and stable dosage (30 to 80 mg daily) of amifampridine phosphate prior to entering the randomized discontinuation phases of both studies. The two co-primary measures of efficacy in both studies were the change from baseline to the end of the discontinuation period in the Quantitative Myasthenia Gravis (QMG) score and in the Subject Global Impression (SGI) score. The QMG is a 13-item physician-rated categorical scale assessing muscle weakness. Each item is assessed on a 4-point scale, where a score of 0 represents no weakness, and a score of 3 represents severe weakness (total score 0-39). Higher scores represent greater impairment. The SGI is a 7-point scale on which patients rated their global impression of the effects of the study treatment on their physical well- being. Lower scores on the SGI represent lower perceived benefit with the study treatment. A key secondary efficacy endpoint was the clinical global impression improvement (CGI-I) score, a 7-point scale on which the treating physician rated the global impression of change in clinical symptoms. A higher CGI-I score indicates a perceived worsening of clinical symptoms. 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. Table 3. Change from Baseline to Day 14 in QMG Score and SGI Score in Study 1 a. QMG Score range 0 (no impairment) to 39 (worst impairment) b. SGI Score range 0 (least perceived benefit) to 7 (most perceived benefit) c. Pairwise contrast at Day 14 from mixed-effects model with repeated measures. Assessment FIRDAPSE (n=16) Placebo (n=21) Primary Endpoints QMG Score a Baseline (mean) 6.4 5.6 Change from Baseline (Least Square Mean) 0.4 2.2 FIRDAPSE-placebo Treatment Difference (Least Square Mean (95% CI)) –1.7 (–3.4, –0.0) p -value c 0.045 SGI Score b Baseline (mean) 5.6 5.9 Change from Baseline (Least Square Mean) -0.8 -2.6 FIRDAPSE-placebo Treatment Difference, (Least Square Mean (95% CI)) 1.8 (0.7, 3.0) p -value c 0.003 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. Table 4. Change from Baseline to Day 4 in QMG Scores and SGI Scores in Study 2 Assessment FIRDAPSE (n=13) Placebo (n=13) a. QMG Score range 0 (no impairment) to 39 (worst impairment) b. SGI Score range 0 (least perceived benefit) to 7 (most perceived benefit) c. Change from baseline for QMG total score was modeled as the response, with fixed effects terms for treatment and QMG at Baseline d. p-value based on the Wilcoxon Rank Sum Test for treatment differences. QMG Scores a Baseline, Mean 7.8 8.5 Change from Baseline, Least Square Mean c 0.00 6.54 FIRDAPSE-placebo Treatment Difference, Least Square Mean (95% CI) -6.54 (-9.78, -3.29) p -value d 0.0004 SGI Scores b Baseline, Mean 6.1 5.8 Change from Baseline, Least Square Mean c -0.64 -3.59 FIRDAPSE-placebo Treatment Difference, Least Square Mean (95% CI) 2.95 (1.53, 4.38) p -value d 0.0003 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.

Rx Only NDC 69616-211-06 120 Tablets Total Provided in 12 Child-Resistant Blister Cards Of 10 Tablets Each FIRDAPSE ® (amifampridine) Tablets 10 mg per Tablet Manufactured for: Catalyst Pharmaceuticals, Inc. Coral Gables, FL 33134 image description