Firdapse Drug Information
Generic name: AMIFAMPRIDINE PHOSPHATE
Uses of Firdapse
FIRDAPSE ® is 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
Dosage Information
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.
Patients with Renal Impairment
The recommended starting dosage of FIRDAPSE in patients with renal 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 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.
Administration Instructions FIRDAPSE can be taken without regard to food. Preparation of a 1mg/mL Suspension (see the Instructions for Use for full instructions on how to prepare the 1mg/mL suspension) When patients require a dosage in less than 5 mg increments, have difficulty swallowing tablets, or require feeding tubes, a 1 mg/mL suspension can be prepared (e.g., by placing the required number of tablets in a 50 to 100 mL container, adding 10 mL of sterile water for each tablet, waiting for 5 minutes, and shaking well for 30 seconds). Crushing the tablets prior to making the suspension is not necessary.
After preparation of the suspension, an oral syringe can be used to draw up and administer the correct dose by mouth or by feeding tube. Storage of 1mg/mL Prepared Suspension Refrigerate the suspension between doses and shake well before drawing up each dose. The suspension can be stored under refrigeration for up to 24 hours.
Discard any unused portion of the suspension after 24 hours.
| See Dosage and Administration ( 2.5 ) for a method to achieve these doses | ||||
| Age and Body Weight | Initial Daily Dosage | Titration Regimen | Maximum Single Dose | Maximum Total Daily Maintenance Dosage |
| Adults (any weight) Pediatric patients weighing 45 kg or more | 15 mg to 30 mg daily, in 3 to 5 divided doses | Increase total daily dosage by 5 mg every 3 or 4 days | 20 mg | 100 mg Given in divided doses |
| Pediatric patients weighing less than 45 kg | 5 mg to 15 mg daily, in 3 to 5 divided doses | Increase total daily dosage by 2.5 mg every 3 or 4 days | 10 mg | 50 mg Given in divided doses |
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 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). 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 s 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.
| *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 |
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 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 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
- 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
The efficacy of FIRDAPSE for the treatment of LEMS was demonstrated in two randomized, double-blind, placebo-controlled discontinuation studies. The studies enrolled patients with a confirmed diagnosis of LEMS based on either neurophysiology studies or a positive anti-P/Q type voltage-gated calcium channel antibody test. Patients were required to be on an adequate and stable dosage (30 to 80 mg daily) of amifampridine phosphate prior to entering the randomized discontinuation phases of both studies.
The two co-primary measures of efficacy in both studies were the change from baseline to the end of the discontinuation period in the Quantitative Myasthenia Gravis (QMG) score and in the Subject Global Impression (SGI) score. The QMG is a 13-item physician-rated categorical scale assessing muscle weakness. Each item is assessed on a 4-point scale, where a score of 0 represents no weakness, and a score of 3 represents severe weakness (total score 0-39).
Higher scores represent greater impairment. The SGI is a 7-point scale on which patients rated their global impression of the effects of the study treatment on their physical well- being. Lower scores on the SGI represent lower perceived benefit with the study treatment.
A key secondary efficacy endpoint was the clinical global impression improvement (CGI-I) score, a 7-point scale on which the treating physician rated the global impression of change in clinical symptoms. A higher CGI-I score indicates a perceived worsening of clinical symptoms. Study 1 (NCT01377922) After an initial open-label run-in phase, 38 patients were randomized in a double-blind fashion to either continue treatment with FIRDAPSE (n=16) or to a downward titration to placebo (n=22) over 7 days.
Following the downward titration period, patients remained on blinded FIRDAPSE or placebo for 7 more days. Efficacy was assessed at Day 14 of the double-blind period. Patients were allowed to use stable dosages of peripherally acting cholinesterase inhibitors or oral immunosuppressants.
Twenty-six percent of patients randomized to FIRDAPSE were receiving cholinesterase inhibitors, versus 36% in the placebo group, and 28% of patients randomized to FIRDAPSE were receiving oral immunosuppressant therapies, versus 34% in the placebo group. 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 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. 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.
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. Table 4.
| a. QMG Score range 0 (no impairment) to 39 (worst impairment) | ||
| b. SGI Score range 0 (least perceived benefit) to 7 (most perceived benefit) | ||
| c. Pairwise contrast at Day 14 from mixed-effects model with repeated measures. | ||
| Assessment | FIRDAPSE (n=16) | Placebo (n=21) |
| Primary Endpoints | ||
| QMG Score a | ||
| Baseline (mean) | 6.4 | 5.6 |
| Change from Baseline (Least Square Mean) | 0.4 | 2.2 |
| FIRDAPSE-placebo Treatment Difference (Least Square Mean (95% CI)) | –1.7 (–3.4, –0.0) | |
| p -value c | 0.045 | |
| SGI Score b | ||
| Baseline (mean) | 5.6 | 5.9 |
| Change from Baseline (Least Square Mean) | -0.8 | -2.6 |
| FIRDAPSE-placebo Treatment Difference, (Least Square Mean (95% CI)) | 1.8 (0.7, 3.0) | |
| p -value c | 0.003 | |
| Assessment | FIRDAPSE (n=13) | Placebo (n=13) |
|---|---|---|
| a. QMG Score range 0 (no impairment) to 39 (worst impairment) | ||
| b. SGI Score range 0 (least perceived benefit) to 7 (most perceived benefit) | ||
| c. Change from baseline for QMG total score was modeled as the response, with fixed effects terms for treatment and QMG at Baseline | ||
| d. p-value based on the Wilcoxon Rank Sum Test for treatment differences. | ||
| QMG Scores a | ||
| Baseline, Mean | 7.8 | 8.5 |
| Change from Baseline, Least Square Mean c | 0.00 | 6.54 |
| FIRDAPSE-placebo Treatment Difference, Least Square Mean (95% CI) | -6.54 (-9.78, -3.29) | |
| p -value d | 0.0004 | |
| SGI Scores b | ||
| Baseline, Mean | 6.1 | 5.8 |
| Change from Baseline, Least Square Mean c | -0.64 | -3.59 |
| FIRDAPSE-placebo Treatment Difference, Least Square Mean (95% CI) | 2.95 (1.53, 4.38) | |
| p -value d | 0.0003 | |
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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