ADVERSE REACTIONS SECTION.

6ADVERSE REACTIONS. The following serious adverse reactions are described elsewhere in the labeling:Seizures [see Warnings and Precautions (5.1)] Hypersensitivity [see Warnings and Precautions (5.2)] Seizures [see Warnings and Precautions (5.1)] Hypersensitivity [see Warnings and Precautions (5.2)] 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. (6)To report SUSPECTED ADVERSE REACTIONS, contact Catalyst Pharmaceuticals at 1-844-347-3277 (1-844-FIRDAPSE) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.. 6.1Clinical Trials Experience. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of 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 and 2) in patients with LEMS, 63 patients were treated with FIRDAPSE, including 40 patients treated for more than 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 months, 77 patients treated for more than 12 months, and 53 patients treated for more than 18 months.Study was 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 14- day double-blind phase. Following final assessments, patients were allowed to resume FIRDAPSE treatment for up to 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 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 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.Table 1. Adverse Reactions in >=5% of LEMS Patients Newly Treated with FIRDAPSE in Study 1Adverse ReactionFIRDAPSE N=42%ParesthesiaIncludes paresthesia, oral paresthesia, oral hypoesthesia 62Upper respiratory tract infection33Abdominal pain14Nausea14Diarrhea14Headache14Elevated liver enzymesIncludes elevated alanine aminotransferase (ALT), aspartate aminotransferase (AST), lactate dehydrogenase (LDH), and gamma- glutamyl transferase (GGT) 14Back pain14Hypertension12Muscle spasms12Dizziness10Asthenia10Muscular weakness10Pain in extremity10Cataract10Constipation7Bronchitis7Fall7Lymphadenopathy7. Other Adverse ReactionsIn the overall population treated in Study (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 reflux, insomnia, peripheral edema, pyrexia, viral infection, blood creatine phosphokinase increase, depression, erythema, hypercholesterolemia, and influenza. These patients received mean daily dosage of 66 mg of FIRDAPSE.

CLINICAL PHARMACOLOGY SECTION.

12CLINICAL PHARMACOLOGY. 12.1Mechanism of Action. The mechanism by which amifampridine exerts its therapeutic effect in LEMS patients has not been fully elucidated. Amifampridine is broad spectrum potassium channel blocker.. 12.2Pharmacodynamics. The effect of FIRDAPSE on QTc interval prolongation was studied in 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.. 12.3Pharmacokinetics. 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.. AbsorptionAmifampridine peak plasma concentration is reached 20 minutes to hour after administration. Food does not have clinically significant effect on the exposure of amifampridine.. EliminationAmifampridine is eliminated primarily through metabolism to 3-N-acetyl-amifampridine and to smaller extent through the kidneys. The terminal half-life ranges from 1.8 to 2.5 hours in healthy subjects.. MetabolismAmifampridine is extensively metabolized by N-acetyltransferase (NAT2) to 3-N-acetyl-amifampridine, which is considered an inactive metabolite.. ExcretionFollowing 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. Patients with Renal ImpairmentPharmacokinetic data are available from study of 24 otherwise healthy subjects with impaired renal function who received 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 36% increase in exposure. Therefore, FIRDAPSE 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 (2.2) and Use in Specific Populations (8.6)]. Cmax was marginally affected by renal impairment.. 12.5Pharmacogenomics. Genetic variants in the N-acetyltransferase gene (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 starting dosage (15 mg/day) 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).

CLINICAL STUDIES SECTION.

14CLINICAL STUDIES. The efficacy of FIRDAPSE for the treatment of LEMS was demonstrated in two randomized, double-blind, placebo-controlled discontinuation studies. total of 64 adults (age 21 to 88 years) with LEMS were enrolled (Study and Study 2). The studies enrolled patients with confirmed diagnosis of LEMS based on either neurophysiology studies or 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 13-text physician-rated categorical scale assessing muscle weakness. Each text is assessed on 4 -point scale, where score of represents no weakness, and score of represents severe weakness (total score 0-39). Higher scores represent greater impairment.The SGI is 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, 7-point scale on which the treating physician rated the global impression of change in clinical symptoms. higher CGI-I score indicates perceived worsening of clinical symptoms.. Study (NCT01377922)After an initial open-label run-in phase, 38 patients were randomized in double-blind fashion to either continue treatment with FIRDAPSE (n=16) or to downward titration to placebo (n=22) over days. Following the downward titration period, patients remained on blinded FIRDAPSE or placebo for 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 median age of 54 years (range: 21 to 88 years), 61% were female, and 90% were White. Eighty-four percent of patients had diagnosis of autoimmune LEMS, and 16% of patients had 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 2. These results indicate that in Study 1, patients randomized to placebo had 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 2.Change from Baseline to Day 14 in QMG Score and SGI Score in Study 1AssessmentFIRDAPSE (n=16)Placebo (n=21)Primary EndpointsQMG ScoreQMG Score range (no impairment) to 39 (worst impairment) Baseline (mean)6.45.6Change from Baseline (Least Square Mean)0.42.2FIRDAPSE-placebo Treatment Difference (Least Square Mean (95% CI))-1.7 (-3.4, -0.0)p-valuePairwise contrast at Day 14 from mixed-effects model with repeated measures.0.045SGI ScoreSGI Score range (least perceived benefit) to (most perceived benefit) Baseline (mean)5.65.9Change from Baseline (Least Square Mean)) -0.8 -2.6FIRDAPSE-placebo Treatment Difference, (Least Square Mean (95% CI))1.8 (0.7, 3.0)p-value0.003The CGI-I score was significantly greater for patients randomized to placebo than for patients who continued treatment with FIRDAPSE, with mean difference between FIRDAPSE and placebo of -1.1 (p=0.02), indicating that clinicians perceived 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 (NCT02970162)Patients on stable treatment with FIRDAPSE were randomized 1:1 in double-blind fashion to either continue treatment with FIRDAPSE (n=13) or change to placebo (n=13) for 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 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 3. These results indicate that in Study 2, patients randomized to placebo had 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 in QMG Scores and SGI Scores in Study 2AssessmentFIRDAPSE (n=13)Placebo (n=13)QMG ScoresQMG Score range (no impairment) to 39 (worst impairment) Baseline, Mean7.88.5Change from Baseline, Least Square MeanChange from baseline for QMG total score was modeled as the response, with fixed effects terms for treatment and QMG at Baseline 0.006.54FIRDAPSE-placebo Treatment Difference, Least Square Mean (95% CI)-6.54 (-9.78, -3.29)p-valuep-value based on the Wilcoxon Rank Sum Test for treatment differences.0.0004SGI ScoresSGI Score range (least perceived benefit) to (most perceived benefit) Baseline, Mean6.15.8Change from Baseline, Least Square Mean -0.64-3.59FIRDAPSE-placebo Treatment Difference, Least Square Mean (95% CI)2.95 (1.53, 4.38)p-value0.0003The clinical global impression improvement (CGI-I) score was significantly greater for patients randomized to placebo than for patients who continued treatment with FIRDAPSE, with mean difference between FIRDAPSE and placebo of -2.7 (p=0.002), indicating that clinicians perceived 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.

CLINICAL TRIALS EXPERIENCE SECTION.

6.1Clinical Trials Experience. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of 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 and 2) in patients with LEMS, 63 patients were treated with FIRDAPSE, including 40 patients treated for more than 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 months, 77 patients treated for more than 12 months, and 53 patients treated for more than 18 months.Study was 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 14- day double-blind phase. Following final assessments, patients were allowed to resume FIRDAPSE treatment for up to 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 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 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.Table 1. Adverse Reactions in >=5% of LEMS Patients Newly Treated with FIRDAPSE in Study 1Adverse ReactionFIRDAPSE N=42%ParesthesiaIncludes paresthesia, oral paresthesia, oral hypoesthesia 62Upper respiratory tract infection33Abdominal pain14Nausea14Diarrhea14Headache14Elevated liver enzymesIncludes elevated alanine aminotransferase (ALT), aspartate aminotransferase (AST), lactate dehydrogenase (LDH), and gamma- glutamyl transferase (GGT) 14Back pain14Hypertension12Muscle spasms12Dizziness10Asthenia10Muscular weakness10Pain in extremity10Cataract10Constipation7Bronchitis7Fall7Lymphadenopathy7. Other Adverse ReactionsIn the overall population treated in Study (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 reflux, insomnia, peripheral edema, pyrexia, viral infection, blood creatine phosphokinase increase, depression, erythema, hypercholesterolemia, and influenza. These patients received mean daily dosage of 66 mg of FIRDAPSE.

DOSAGE & ADMINISTRATION SECTION.

2 DOSAGE AND ADMINISTRATION. The recommended starting dosage is 15 mg to 30 mg daily taken orally in divided doses (3 to times daily). (2.1)Starting dosage is 15 mg daily for patients with renal impairment, hepatic impairment, and in known N-acetyltransferase (NAT2) poor metabolizers (2.2, 2.3, 2.4)Dosage can be increased by mg daily every to days. (2.1)Dosage is not to exceed maximum of 80 mg daily. (2.1)The maximum single dose is 20 mg. (2.1). The recommended starting dosage is 15 mg to 30 mg daily taken orally in divided doses (3 to times daily). (2.1). Starting dosage is 15 mg daily for patients with renal impairment, hepatic impairment, and in known N-acetyltransferase (NAT2) poor metabolizers (2.2, 2.3, 2.4). Dosage can be increased by mg daily every to days. (2.1). Dosage is not to exceed maximum of 80 mg daily. (2.1). The maximum single dose is 20 mg. (2.1). 2.1Dosage Information. The recommended starting dosage of FIRDAPSE is 15 mg to 30 mg daily, taken orally in divided doses (3 to times daily).The dosage can be increased by mg daily every or days.The maximum recommended total daily dosage is 80 mg.The maximum single dose is 20 mg.If dose is missed, patients should not take double or extra doses.. The recommended starting dosage of FIRDAPSE is 15 mg to 30 mg daily, taken orally in divided doses (3 to times daily).. The dosage can be increased by mg daily every or days.. The maximum recommended total daily dosage is 80 mg.. The maximum single dose is 20 mg.. If dose is missed, patients should not take double or extra doses.. 2.2Patients with Renal Impairment. The recommended starting dosage of FIRDAPSE in patients with renal impairment (creatinine clearance 15 to 90 mL/min) is 15 mg daily, taken orally in divided doses. No dosage recommendation for FIRDAPSE can be made for patients with end-stage renal disease [see Use in Specific Populations (8.6) and Clinical Pharmacology (12.3, 12.5)]. 2.3Patients with Hepatic Impairment. The recommended starting dosage of FIRDAPSE in patients with any degree of hepatic impairment is 15 mg daily, taken orally in divided doses [see Use in Specific Populations (8.7) and Clinical Pharmacology (12.3, 12.5)]. 2.4Known N-acetyltransferase (NAT2) Poor Metabolizers. The recommended starting dosage of FIRDAPSE in known N-acetyltransferase (NAT2) poor metabolizers is 15 mg daily, taken orally in divided doses [see Use in Specific Populations (8.8) and Clinical Pharmacology (12.3, 12.5)]. 2.5Administration Instructions. FIRDAPSE can be taken without regard to food.

DRUG INTERACTIONS SECTION.

7DRUG INTERACTIONS. Drugs that lower seizure threshold: The concomitant use of FIRDAPSE and drugs that lower seizure threshold may lead to an increased risk of seizures. (7.1)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. (7.2). Drugs that lower seizure threshold: The concomitant use of FIRDAPSE and drugs that lower seizure threshold may lead to an increased risk of seizures. (7.1). 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. (7.2). 7.1Drugs 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.. 7.2Drugs 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.

INFORMATION FOR PATIENTS SECTION.

17PATIENT COUNSELING INFORMATION. Advise the patient and/or caregiver to read the FDA-approved patient labeling (Medication Guide).. Risk of SeizuresInform patients that FIRDAPSE can cause seizures, and to notify their healthcare provider if they experience seizure [see Warnings and Precautions (5.1)].. HypersensitivityInstruct 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 DosingInstruct 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 double dose to make up for missed dose.. Drug InteractionsInstruct patients to notify their healthcare provider prior to starting any new medication, including over-the-counter drugs [see Drug Interactions (7)]. PregnancyInstruct 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 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)].. StorageAdvise patients to store FIRDAPSE at 68oF to 77oF (20oC to 25oC).

PHARMACOKINETICS SECTION.

12.3Pharmacokinetics. 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.. AbsorptionAmifampridine peak plasma concentration is reached 20 minutes to hour after administration. Food does not have clinically significant effect on the exposure of amifampridine.. EliminationAmifampridine is eliminated primarily through metabolism to 3-N-acetyl-amifampridine and to smaller extent through the kidneys. The terminal half-life ranges from 1.8 to 2.5 hours in healthy subjects.. MetabolismAmifampridine is extensively metabolized by N-acetyltransferase (NAT2) to 3-N-acetyl-amifampridine, which is considered an inactive metabolite.. ExcretionFollowing 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. Patients with Renal ImpairmentPharmacokinetic data are available from study of 24 otherwise healthy subjects with impaired renal function who received 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 36% increase in exposure. Therefore, FIRDAPSE 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 (2.2) and Use in Specific Populations (8.6)]. Cmax was marginally affected by renal impairment.

PREGNANCY SECTION.

8.1Pregnancy. Pregnancy Exposure RegistryThere is 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 firdapsepregnancyregistryubc.com, or by visiting the study website www.firdapsepregnancystudy.com.. Risk SummaryThere 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 DataOral 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 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 57 mg/kg/day) to pregnant rabbits throughout organogenesis produced no adverse effects on embryofetal development. The highest dose tested is approximately times the MRHD (80 mg/day amifampridine) on 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 plasma amifampridine exposure (AUC) less than that in humans at the MRHD.

SPL MEDGUIDE SECTION.

MEDICATION GUIDEFIRDAPSE(R) (FIR-dapse)(amifampridine)tablets, for oral useThis Medication Guide has been approved by the U.S. Food and Drug Administration.Revised 02/2021 Read this Medication Guide before you start taking FIRDAPSE and each time you get refill. There may be new information. This information does not take the place of talking with your doctor about your medical condition or your treatment.What is the most important information should know about FIRDAPSEFIRDAPSE can cause seizures.You could have seizure even if you never had seizure before.Do not take FIRDAPSE if you have ever had seizure.Stop taking FIRDAPSE and call your doctor right away if you have seizure while taking FIRDAPSE.What is FIRDAPSEFIRDAPSE is prescription medicine used to treat Lambert-Eaton myasthenic syndrome (LEMS) in adults.It is not known if FIRDAPSE is safe or effective in children.Do not take FIRDAPSE if you:have ever had seizure.are allergic to amifampridine phosphate, or another aminopyridine.Before you take FIRDAPSE, tell your doctor about all of your medical conditions. including if you:are taking another aminopyridine, such as compounded 3,4-diaminopyridine (3,4-DAP)have had seizurehave kidney problemsliver problemsare pregnant or plan to become pregnant. It is not known if FIRDAPSE will harm your unborn baby. You and your doctor will decide if you should take FIRDAPSE while you are pregnant.There is registry for women who become pregnant during treatment with FIRDAPSE. The purpose of this registry is to collect information about your health and your babys health. Contact the registry as soon as you learn that you are pregnant, or ask your healthcare provider to contact for you by calling 855-212-5856 (toll free), contacting the Fax number 877-867-1874 (toll free), emailing the Pregnancy Coordinating Center at firdapsepregnancyregistryubc.com, or visiting the study website www.firdapsepregnancystudy.comare breastfeeding or plan to breastfeed. It is not known if FIRDAPSE passes into your breast milk. Talk to your doctor about the best way to feed your baby while taking FIRDAPSE.Tell your doctor about all the medicines you take, including prescription and over-the-counter medicines, vitamins and herbal supplements.How should take FIRDAPSETake FIRDAPSE exactly as your doctor tells you to take it. Do not change your dose of FIRDAPSE.Do not take more than tablets of FIRDAPSE at one time or more than tablets in 24-hour period.FIRDAPSE can be taken with or without food. If you miss dose of FIRDAPSE, skip that dose and take your next dose at your next scheduled dose time. Do not double your dose to make up the missed dose. Do not take FIRDAPSE together with other medicines known to increase the risk of seizures.If you take too much FIRDAPSE, call your doctor or go to the nearest hospital emergency room right away.What are the possible side effects of FIRDAPSEFIRDAPSE may cause serious side effects, including:Seizures. See What is the most important information should know about FIRDAPSESerious allergic reactions, such as anaphylaxis. FIRDAPSE can cause serious allergic reactions. Stop taking FIRDAPSE and call your doctor right away or get emergency medical help if you have:shortness of breath or trouble breathingswelling of your throat or tonguehives The most common side effects of FIRDAPSE include:tingling around the mouth, tongue, face, fingers, toes, and other body partsupper respiratory infectionstomach painnauseadiarrheaheadacheincreased liver enzymesback painhigh blood pressuremuscle spasmsTell your doctor if you have any side effect that bothers you or that does not go away.These are not all the possible side effects of FIRDAPSE.Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.How should store FIRDAPSEStore FIRDAPSE at 68F to 77F (20C to 25C).Safely throw away FIRDAPSE that is out of date or no longer needed.Keep FIRDAPSE and all medicines out of the reach of children.General Information about the safe and effective use of FIRDAPSEMedicines are sometimes prescribed for purposes other than those listed in Medication Guide. Do not use FIRDAPSE for condition for which it was not prescribed. Do not give FIRDAPSE to other people, even if they have the same symptoms that you have. It may harm them.If you would like more information, talk to your doctor or pharmacist. You can ask your pharmacist or doctor for information about FIRDAPSE that is written for health professionals. What are the ingredients in FIRDAPSEActive ingredient: amifampridine Inactive ingredients: calcium stearate, colloidal silicon dioxide, and microcrystalline cellulose.Distributed by Catalyst Pharmaceuticals, Inc., Coral Gables, FL 33134For more information, go to www.YourCatalyst Pathways .com or call 1-833-422-8259. You could have seizure even if you never had seizure before.. Do not take FIRDAPSE if you have ever had seizure.. have ever had seizure.. are allergic to amifampridine phosphate, or another aminopyridine.. are taking another aminopyridine, such as compounded 3,4-diaminopyridine (3,4-DAP). have had seizure. have kidney problems. liver problems. are pregnant or plan to become pregnant. It is not known if FIRDAPSE will harm your unborn baby. You and your doctor will decide if you should take FIRDAPSE while you are pregnant.. There is registry for women who become pregnant during treatment with FIRDAPSE. The purpose of this registry is to collect information about your health and your babys health. Contact the registry as soon as you learn that you are pregnant, or ask your healthcare provider to contact for you by calling 855-212-5856 (toll free), contacting the Fax number 877-867-1874 (toll free), emailing the Pregnancy Coordinating Center at firdapsepregnancyregistryubc.com, or visiting the study website www.firdapsepregnancystudy.com. are breastfeeding or plan to breastfeed. It is not known if FIRDAPSE passes into your breast milk. Talk to your doctor about the best way to feed your baby while taking FIRDAPSE.. Take FIRDAPSE exactly as your doctor tells you to take it. Do not change your dose of FIRDAPSE.. Do not take more than tablets of FIRDAPSE at one time or more than tablets in 24-hour period.. FIRDAPSE can be taken with or without food. If you miss dose of FIRDAPSE, skip that dose and take your next dose at your next scheduled dose time. Do not double your dose to make up the missed dose. Do not take FIRDAPSE together with other medicines known to increase the risk of seizures.. If you take too much FIRDAPSE, call your doctor or go to the nearest hospital emergency room right away.. Seizures. See What is the most important information should know about FIRDAPSE. Serious allergic reactions, such as anaphylaxis. FIRDAPSE can cause serious allergic reactions. Stop taking FIRDAPSE and call your doctor right away or get emergency medical help if you have:shortness of breath or trouble breathingswelling of your throat or tonguehives shortness of breath or trouble breathing. swelling of your throat or tongue. hives. tingling around the mouth, tongue, face, fingers, toes, and other body parts. upper respiratory infection. stomach pain. nausea. diarrhea. headache. increased liver enzymes. back pain. high blood pressure. muscle spasms. Store FIRDAPSE at 68F to 77F (20C to 25C).. Safely throw away FIRDAPSE that is out of date or no longer needed.

USE IN SPECIFIC POPULATIONS SECTION.

8USE IN SPECIFIC POPULATIONS. Pregnancy: Based on animal data, may cause fetal harm (8.1). Pregnancy: Based on animal data, may cause fetal harm (8.1). 8.1Pregnancy. Pregnancy Exposure RegistryThere is 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 firdapsepregnancyregistryubc.com, or by visiting the study website www.firdapsepregnancystudy.com.. Risk SummaryThere 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 DataOral 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 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 57 mg/kg/day) to pregnant rabbits throughout organogenesis produced no adverse effects on embryofetal development. The highest dose tested is approximately times the MRHD (80 mg/day amifampridine) on 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 plasma amifampridine exposure (AUC) less than that in humans at the MRHD.. 8.2Lactation. Risk SummaryThere 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 mothers 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.. 8.4Pediatric Use. Safety and effectiveness in pediatric patients have not been established.. 8.5Geriatric Use. Clinical studies of FIRDAPSE did not include sufficient numbers of subjects aged 65 and over (19 of 63 patients in Studies 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)].. 8.6Renal 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 starting dosage (15 mg/day), 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.. 8.7Hepatic Impairment. The effects of FIRDAPSE have not been studied in patients with hepatic impairment. FIRDAPSE is extensively metabolized by N- acetyltransferase (NAT2) and hepatic impairment may cause an increase in exposure. Therefore, initiate FIRDAPSE 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 (2.3)]. Consider dosage modification or discontinuation of FIRDAPSE for patients with hepatic impairment as needed based on clinical effect and tolerability.. 8.8NAT2 Poor Metabolizers. Exposure of FIRDAPSE is increased in patients who are N-acetyltransferase (NAT2) poor metabolizers [see Clinical Pharmacology (12.5)]. Therefore, initiate FIRDAPSE 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 (2.4)]. Consider dosage modification of FIRDAPSE for patients who are known NAT2 poor metabolizers as needed based on clinical effect and tolerability.

WARNINGS AND PRECAUTIONS SECTION.

5WARNINGS AND PRECAUTIONS. Seizures: FIRDAPSE can cause seizures. Consider discontinuation or dose-reduction of FIRDAPSE in patients who have seizure while on treatment. (5.1)Hypersensitivity reactions: If hypersensitivity reaction such as anaphylaxis occurs, FIRDAPSE should be discontinued and appropriate therapy initiated. (5.2). Seizures: FIRDAPSE can cause seizures. Consider discontinuation or dose-reduction of FIRDAPSE in patients who have seizure while on treatment. (5.1). Hypersensitivity reactions: If hypersensitivity reaction such as anaphylaxis occurs, FIRDAPSE should be discontinued and appropriate therapy initiated. (5.2). 5.1Seizures. FIRDAPSE can cause seizures. Seizures have been observed in patients without 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 seizure while on treatment. FIRDAPSE is contraindicated in patients with history of seizures.. 5.2Hypersensitivity. 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.

INSTRUCTIONS FOR USE SECTION.

Instructions for Use FIRDAPSE (FIR-dapse) (amifampridine) tablets for oral useThis Instructions for Use contains information on how to mix and use FIRDAPSE prepared suspension. The FIRDAPSE prepared suspension can be used for people who are prescribed dosage that cannot be obtained with whole or half tablets, who have trouble swallowing tablets, or who have feeding tube.Prepare FIRDAPSE oral suspension each day.Supplies you will need:You can get these supplies at your local pharmacy. Instructions to make 1 mg/mL suspension: Important: Do not use any foods or liquids other than sterile water to mix FIRDAPSE.You can prepare each dose separately or all of your doses for the day at one time.Place the number of For each tablet, add 10 mL Secure the cap back on the FIRDAPSE tablets you of water to the bottle, bottle. Wait for minutes. need for your dose or Measure the water with Shake well for 30 seconds. doses in bottle. an oral syringe, and inject the water into the bottle. Note: Depending on the number of tablets and the size of the syringe, you may need to measure and inject the water more than one time. Instructions to administer the prepared suspension:Important: Prepare fresh suspensions daily.If you prepare all of your doses for the day at one time, refrigerate the suspension between doses. Shake well before drawing up each dose.Remove the bottle cap and Push syringe plunger to use an oral syringe with administer by mouth. catheter tip to measure the Note: Depending on the prescribed dose. dose and size of syringe, you may need to repeat steps and until the prescribed dose is given. To administer by feeding tube:Important:Do not use any foods or liquids other than sterile water to mix FIRDAPSE.Use only an oral syringe with catheter tip to give FIRDAPSE through the feeding tube. Talk to your healthcare provider about the size catheter tipped syringe you should use.Remove the bottle cap and Inject the medicine using use an oral syringe with the oral syringe with acatheter tip to measure the catheter tip into the feedingprescribed dose tube right away. Note: Depending on the dose and size of syringe, you may need to repeat steps and until the prescribed dose is given. To flush the feeding tube: Shake the syringe, insert the Refill the syringe with cathether tip into the feeding 10 mL of sterile water. tube to flush any remaining medicine from the feeding tube into the stomach. How should store FIRDAPSEFirdapse tablets:Store FIRDAPSE tablets at room temperature between 68oF to 77oF (20oC to 25oC).Safely throw away FIRDAPSE tablets that are out of date or no longer needed.Firdapse prepared suspension:Store FIRDAPSE prepared oral suspension in the refrigerator between 36F to 46F (2C to 8C) between doses for up to 24 hours.Safely throw away unused FIRDAPSE oral suspension after 24 hours.Distributed by Catalyst Pharmaceuticals, Inc., Coral Gables, FL 33134For more information, go to www.YourCatalystPathways.com or call 1-833-422-8259This Instructions for Use has been approved by the U.S. Food and Drug Administration. Approved: 9/2022 Do not use any foods or liquids other than sterile water to mix FIRDAPSE.. You can prepare each dose separately or all of your doses for the day at one time.. Prepare fresh suspensions daily.. If you prepare all of your doses for the day at one time, refrigerate the suspension between doses. Shake well before drawing up each dose.. Do not use any foods or liquids other than sterile water to mix FIRDAPSE.. Use only an oral syringe with catheter tip to give FIRDAPSE through the feeding tube. Talk to your healthcare provider about the size catheter tipped syringe you should use.. Store FIRDAPSE tablets at room temperature between 68oF to 77oF (20oC to 25oC).. Safely throw away FIRDAPSE tablets that are out of date or no longer needed.. Store FIRDAPSE prepared oral suspension in the refrigerator between 36F to 46F (2C to 8C) between doses for up to 24 hours.. Safely throw away unused FIRDAPSE oral suspension after 24 hours.. image description. image description. image description. image description. image description. image description.