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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 C5H7N3 • H3PO4. 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 silicondioxide, and microcrystalline cellulose.
FIRDAPSE tablets are intended for oral administration only.
FIRDAPSE® is indicated for the treatment of Lambert-Eaton myasthenic syndrome (LEMS) in adults and pediatric patients 6 years of age and older.
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
| Age and Body Weight | Initial Daily Dosage* | Titration Regimen | Maximum Single Dose | Maximum Total Daily Maintenance Dosage |
|
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 |
|
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 |
| *see Administration Instructions for a method to achieve these doses | ||||
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 Information, Use In Specific Populations,and CLINICAL PHARMACOLOGY].
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 Information, Use In Specific Populations ,and CLINICAL PHARMACOLOGY].
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 Information, Use In Specific Populations,and CLINICAL PHARMACOLOGY].
FIRDAPSE can be taken without regard to food.
(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.
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:
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 for storage instructions for FIRDAPSE prepared suspension.
Distributed by Catalyst Pharmaceuticals, Inc., Coral Gables, FL 33134. Revised: May 2024
The following serious adverse reactions are described elsewhere in the labeling:
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], 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. In the expanded access program, patients were treated with FIRDAPSE with up to 100 mg daily in divided doses.
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. Adverse Reactions in ≥5% of LEMS Patients Newly Treated with FIRDAPSE in Study 1
| Adverse Reaction | FIRDAPSE N=42 % |
| Paresthesia* | 62 |
| Upper respiratory tract infection | 33 |
| Abdominal pain | 14 |
| Nausea | 14 |
| Diarrhea | 14 |
| Headache | 14 |
| Elevated liver enzymes** | 14 |
| Back pain | 14 |
| Hypertension | 12 |
| Muscle spasms | 12 |
| Dizziness | 10 |
| Asthenia | 10 |
| Muscular weakness | 10 |
| Pain in extremity | 10 |
| Cataract | 10 |
| Constipation | 7 |
| Bronchitis | 7 |
| Fall | 7 |
| Lymphadenopathy | 7 |
| *Includes paresthesia, oral paresthesia, oral hypoesthesia **Includes elevated alanine aminotransferase (ALT), aspartate aminotransferase (AST), lactate dehydrogenase (LDH), and gamma-glutamyl transferase (GGT) |
|
In the overall population treated in Study 1 (n=53), including the double-blind phase and the 2-year open-label long-term safety phase, additional adverse reactions occurring in at least 5% of the patients included: dyspnea, urinary tract infection, gastroesophageal reflux, insomnia, peripheral edema, pyrexia, viral infection, blood creatine phosphokinase increase, depression, erythema, hypercholesterolemia, and influenza. These patients received a mean daily dosage of 66 mg of FIRDAPSE.
Safety of FIRDAPSE was evaluated in pediatric patients in an expanded access program, where 21 pediatric patients received FIRDAPSE for at least 1 year. Adverse reactions reported in pediatric patients were similar to those seen in adult patients, with the exception of clinically significant weight loss in two pediatric patients at doses of 60 mg per day and higher.
The concomitant use of FIRDAPSE and drugs that lower seizure threshold may lead to an increased risk of seizures [see WARNINGS AND PRECAUTIONS]. 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.
Included as part of the "PRECAUTIONS" Section
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]. 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.
Advise the patient and/or caregiver to read the FDA-approved patient labeling (see PATIENT INFORMATION and INSTRUCTIONS FOR USE).
Inform patients that FIRDAPSE can cause seizures, and to notify their healthcare provider if they experience a seizure [see WARNINGS AND PRECAUTIONS].
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].
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]. 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]. 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.
Instruct patients to notify their healthcare provider prior to starting any new medication, including over-the-counter drugs [see DRUG INTERACTIONS].
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].
Advise patients to store FIRDAPSE at 68°F to 77°F (20°C to 25°C).
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.
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/m2 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.
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.
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/m2) basis.
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 855-2125856 (toll-free), using the Fax number 877-867-1874 (toll-free), by contacting the Pregnancy Coordinating Center at [email protected], or by visiting the study website www.firdapsepregnancystudy.com.
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.
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/m2) 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/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 a plasma amifampridine exposure (AUC) less than that in humans at the MRHD of amifampridine.
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, CLINICAL PHARMACOLOGY, and Clinical Studies].
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 and DRUG INTERACTIONS].
Renal clearance is an elimination pathway for amifampridine and the inactive metabolite, 3-N-acetyl-amifampridine, and exposure of amifampridine is higher in subjects with renal impairment [see CLINICAL PHARMACOLOGY]. Therefore, in patients with renal impairment, FIRDAPSE should be initiated at the lowest recommended initial daily dosage, and patients should be closely monitored for adverse reactions [see DOSAGE AND ADMINISTRATION]. 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]. 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]. 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]. Consider dosage modification of FIRDAPSE for patients who are known NAT2 poor metabolizers as needed based on clinical effect and tolerability.
Overdose with FIRDAPSE was not reported during clinical studies.
In a case report, a 65-year-old patient with LEMS inadvertently received a total daily amifampridine dose of 360 mg/day (approximately 4 times the maximum recommended total daily dose) and was hospitalized for general weakness, paresthesia, nausea, vomiting, and palpitations. The patient developed convulsions and paroxysmal supraventricular tachycardia, and four days after admission, experienced cardiac arrest. The patient was resuscitated and ultimately recovered following withdrawal of amifampridine.
Patients with suspected overdose with FIRDAPSE should be monitored for signs or symptoms of exaggerated FIRDAPSE adverse reactions or effects, and appropriate symptomatic treatment instituted immediately.
FIRDAPSE is contraindicated in patients with:
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, 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.
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.
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.
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 and Clinical Studies].
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 and Use In Specific Populations ]. Cmax was marginally affected by renal 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 Cmax and a 33% higher AUCinf for amifampridine than subjects with normal hepatic function. FIRDAPSE was not evaluated in subjects with severe hepatic impairment [see DOSAGE AND ADMINISTRATION and Use In Specific Populations].
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 9fold 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 and Use In Specific Populations]. 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).
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 wellbeing. 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.
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
| Assessment | FIRDAPSE (n=16) | Placebo (n=21) |
| Primary Endpoints | ||
| QMG Scorea | ||
| 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-valuec | 0.045 | |
| SGI Scoreb | ||
| 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-valuec | 0.003 | |
| 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. |
||
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.
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) |
| QMG Scoresa | ||
| Baseline, Mean | 7.8 | 8.5 |
| Change from Baseline, Least Square Meanc | 0.00 | 6.54 |
| FIRDAPSE-placebo Treatment Difference, Least Square Mean (95% CI) | -6.54 (-9.78, -3.29) | |
| p-valued | 0.0004 | |
| SGI Scoresb | ||
| Baseline, Mean | 6.1 | 5.8 |
| Change from Baseline, Least Square Meanc | -0.64 | -3.59 |
| FIRDAPSE-placebo Treatment Difference, Least Square Mean (95% CI) | 2.95 (1.53, 4.38) | |
| p-valued | 0.0003 | |
| 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 |
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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.
FIRDAPSE®
(FIR-dapse)
(amifampridine) tablets, for oral use
Read this see Patient Information before you start taking FIRDAPSE and each time you get a 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 I should know about FIRDAPSE?
FIRDAPSE can cause seizures.
Stop taking FIRDAPSE and call your doctor right away if you have a seizure while taking FIRDAPSE.
What is FIRDAPSE?
FIRDAPSE is a prescription medicine used to treat Lambert-Eaton myasthenic syndrome (LEMS) in people 6 years of age and older.
It is not known if FIRDAPSE is safe or effective in children less than 6 years of age.
Do not take FIRDAPSE if you:
Before you take FIRDAPSE, tell your doctor about all of your medical conditions, including if you:
Tell your doctor about all the medicines you take, including prescription and over-the-counter medicines, vitamins and herbal supplements.
How should I take FIRDAPSE?
What are the possible side effects of FIRDAPSE?
FIRDAPSE may cause serious side effects, including:
The most common side effects of FIRDAPSE include:
Tell 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 I store FIRDAPSE?
Keep FIRDAPSE and all medicines out of the reach of children.
General Information about the safe and effective use of FIRDAPSE
Medicines are sometimes prescribed for purposes other than those listed in a see PATIENT INFORMATION. Do not use FIRDAPSE for a condition for which it was not prescribed. Do not give FIRDAPSE to other people, even if they have the same symptoms thatyou 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 FIRDAPSE?
Active ingredient: amifampridine
Inactive ingredients: calcium stearate, colloidal silicon dioxide, and microcrystalline cellulose.
This Medication Guide has been approved by the U.S. Food and Drug Administration
INSTRUCTIONS FOR USE
FIRDAPSE
(FIR-dapse)
(amifampridine) tablets, for oral use
This 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 a dosage that cannot be obtained with whole or half tablets, who have trouble swallowing tablets, or who have a feeding tube.
Prepare FIRDAPSE oral suspension each day.
Supplies you will need:
You can get these supplies at your local pharmacy.
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Instructions to make a 1 mg/mL suspension:
Important:
Step 1
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Step 2
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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.
Step 3
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Instructions to administer the prepared suspension:
Important:
OPTION 1 To administer by mouth:
Step 4
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Step 5
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Note: Depending on the dose and size of syringe, you may need to repeat steps 4 and 5 until the prescribed dose is given.
OPTION 2 To administer by feeding tube:
Important:
Step 4
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Step 5
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Note: Depending on the dose and size of syringe, you may need to repeat steps 4 and 5 until the prescribed dose is given.
Step 6
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Step 7
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How should I store FIRDAPSE?
Firdapse tablets:
Firdapse prepared suspension:
For more information, go to www.YourCatalystPathways.com or call 1-833-422-8259
This Instructions for Use has been approved by the U.S. Food and Drug Administration.
