Firdapse Drug Information
Generic name: AMIFAMPRIDINE PHOSPHATE
Uses of 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.
Dosage & Administration of Firdapse
15 mg to 30 mg daily, in 3 to 5 divided doses |
5 mg to 15 mg daily, in 3 to 5 divided doses | | |||||
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Side Effects of Firdapse
Clinical Trials Experience Adults
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. In controlled and uncontrolled clinical trials (Study 1 and 2) in patients with LEMS , 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 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 2. Adverse Reactions in ≥5% of LEMS Patients Newly Treated with FIRDAPSE in Study 1 *Includes paresthesia, oral paresthesia, oral hypoesthesia **Includes elevated alanine aminotransferase (ALT), aspartate aminotransferase (AST), lactate dehydrogenase (LDH), and gamma-glutamyl transferase (GGT) 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 Other Adverse Reactions In the overall population treated in Study 1 (n=53), including the double-blind phase and the 2-year open-label long-term safety phase, additional adverse reactions occurring in at least 5% of the patients included: dyspnea, urinary tract infection, gastroesophageal 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. Pediatrics 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.
Warnings & Cautions for Firdapse
Seizures
FIRDAPSE can cause seizures. Seizures have been observed in patients without a history of seizures taking FIRDAPSE at the recommended doses, at various times after initiation of treatment, at an incidence of approximately 2%. Many of the patients were taking medications or had comorbid medical conditions that may have lowered the seizure threshold. 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.
Hypersensitivity
In clinical trials, hypersensitivity reactions and anaphylaxis associated with FIRDAPSE administration have not been reported. Anaphylaxis has been reported in patients taking another aminopyridine; therefore, it may occur with FIRDAPSE. If anaphylaxis occurs, administration of FIRDAPSE should be discontinued and appropriate therapy initiated.
Drug Interactions with Firdapse
Drugs that Lower Seizure Threshold
The concomitant use of FIRDAPSE and drugs that lower seizure threshold may lead to an increased risk of seizures. 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.
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.
Pregnancy Safety for Firdapse
Pregnancy 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 [email protected], 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.
Pediatric Use of Firdapse
Pediatric Use Safety and effectiveness of FIRDAPSE for the treatment of LEMS have been established in pediatric patients 6 years of age and older. Use of FIRDAPSE for this indication is supported by evidence from adequate and well-controlled studies of FIRDAPSE in adults with LEMS, pharmacokinetic data in adult patients, pharmacokinetic modeling and simulation to identify the dosing regimen in pediatric patients, and safety data from pediatric patients aged 6 years and older . Safety and effectiveness in pediatric patients below the age of 6 years have not been established.
Contraindications for Firdapse
is contraindicated in patients with: A history of seizures Hypersensitivity to amifampridine phosphate or another aminopyridine FIRDAPSE is contraindicated in patients with: A history of seizures Hypersensitivity to amifampridine or another aminopyridine
Overdosage Information for Firdapse
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.
Clinical Studies of Firdapse
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
Change from Baseline (Least Square Mean) -0.8 -2.6
FIRDAPSE-placebo Treatment Difference, (Least Square Mean (95% CI)) 1.8 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
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
Change from Baseline, Least Square Mean c -0.64 -3.59
FIRDAPSE-placebo Treatment Difference, Least Square Mean (95% CI) 2.95 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.
Drug information sourced from the FDA. This content is for informational purposes only and does not constitute medical advice. Consult a healthcare professional before making any medication decisions.
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