Summary Basis of Decision for Firdapse

Review decision

The Summary Basis of Decision explains why the product was approved for sale in Canada. The document includes regulatory, safety, effectiveness and quality (in terms of chemistry and manufacturing) considerations.


Product type:

Drug
Summary Basis of Decision (SBD) documents provide information related to the original authorization of a product. The SBD for Firdapse is located below.
Recent Activity for Firdapse

SBDs written for eligible drugs approved after September 1, 2012 will be updated to include post-authorization information. This information will be compiled in a Post-Authorization Activity Table (PAAT). The PAAT will include brief summaries of activities such as submissions for new uses of the product, and whether Health Canada's decisions were negative or positive. PAATs will be updated regularly with post-authorization activity throughout the product's life cycle.

Post-Authorization Activity Table (PAAT) for Firdapse

Updated:

2023-02-21

The following table describes post-authorization activity for Firdapse, a product which contains the medicinal ingredient amifampridine (supplied as amifampridine phosphate). For more information on the type of information found in PAATs, please refer to the Frequently Asked Questions: Summary Basis of Decision (SBD) Project: Phase II and to the list of abbreviations that are found in PAATs.

For additional information about the drug submission process, refer to the Management of Drug Submissions and Applications Guidance.

Drug Identification Number (DIN):

  • DIN 02502984 - 10 mg amifampridine, tablet, oral administration

Post-Authorization Activity Table (PAAT)

Activity/submission type, control number Date submitted Decision and date Summary of activities
Drug product (DIN 02502984) market notification Not applicable Date of first sale: 2020-10-23 The manufacturer notified Health Canada of the date of first sale pursuant to C.01.014.3 of the Food and Drug Regulations.
NDS # 243044 2020-08-20 Issued NOC
2020-09-24		 Submission filed to transfer ownership of the drug product from Catalyst Pharmaceuticals Inc. to KYE Pharmaceuticals Inc. An NOC was issued.
NDS # 232685 2019-11-06 Issued NOC
2020-07-31		 NOC issued for New Drug Submission.
Summary Basis of Decision (SBD) for Firdapse

Date SBD issued: 2020-10-30

The following information relates to the new drug submission for Firdapse.

Amifampridine (supplied as amifampridine phosphate)

Drug Identification Number (DIN):

  • DIN 02502984 ‑ 10 mg amifampridine, tablet, oral administration

Catalyst Pharmaceuticals Inc.

New Drug Submission Control Number: 232685

 

On July 31, 2020, Health Canada issued a Notice of Compliance to Catalyst Pharmaceuticals Inc. for the drug product Firdapse.

The market authorization was based on quality (chemistry and manufacturing), non‑clinical (pharmacology and toxicology), and clinical (pharmacology, safety, and efficacy) information submitted. Based on Health Canada's review, the benefit‑harm‑uncertainty profile of Firdapse is favourable for the symptomatic treatment of Lambert‑Eaton Myasthenic Syndrome (LEMS) in adults.

1 What was approved?

Firdapse, a potassium channel blocker, was authorized for the symptomatic treatment of Lambert‑Eaton Myasthenic Syndrome (LEMS) in adults.

Firdapse should only be prescribed by health professionals who have experience in the treatment of LEMS, are knowledgeable of the efficacy and safety profile of this drug, and are able to discuss benefits/risks of treatment with patients.

No data are available to Health Canada; therefore, Health Canada has not authorized an indication for pediatric (<18 years of age) use.

In clinical studies of Firdapse (Study 1 and Study 2), 25.4% (16 of 63) of LEMS patients receiving Firdapse were ≥65 years of age. Both studies did not include a sufficient number of patients aged 65 years and over to determine whether its safety and efficacy differs in elderly patients compared to younger patients.

Firdapse is contraindicated in patients:

  • who are hypersensitive to this drug or another aminopyridine.
  • with a history of seizures.
  • who are hypersensitive to any ingredient in the formulation, including any non‑medicinal ingredient, or component of the container.
  • who are taking other forms of amifampridine or other aminopyridines.

Firdapse was approved for use under the conditions stated in its Product Monograph taking into consideration the potential risks associated with the administration of this drug product.

Firdapse (10 mg amifampridine, supplied as amifampridine phosphate) is presented as tablets. In addition to the medicinal ingredient, the tablets also contain the following non‑medicinal ingredients: calcium stearate, colloidal silicon dioxide, and microcrystalline cellulose.

For more information, refer to the Clinical, Non‑clinical, and Quality (Chemistry and Manufacturing) Basis for Decision sections.

Additional information may be found in the Firdapse Product Monograph, approved by Health Canada and available through the Drug Product Database.

2 Why was Firdapse approved?

Health Canada considers that the benefit‑harm‑uncertainty profile of Firdapse is favourable for the symptomatic treatment of Lambert‑Eaton Myasthenic Syndrome in adults.

Lambert-Eaton Myasthenic Syndrome (LEMS) is a rare neuromuscular junction disorder that may present as either a paraneoplastic phenomenon or a primary autoimmune disorder. More than half of the cases of LEMS are associated with an underlying carcinoma, the majority of which are small cell lung cancer. The primary symptom of LEMS is muscle weakness. The cause of LEMS is thought to be due to the generation of autoantibodies against type P/Q voltage‑gated calcium channels (VGCC) located on presynaptic nerve terminals of the neuromuscular junction leading to a diminished release of acetylcholine at the neuromuscular junction. This reduction of acetylcholine at the neuromuscular junction would then lead to a loss of neuromuscular transmission resulting in muscle weakness.

Muscle weakness with LEMS typically spreads proximal to distal and caudal to cranial, finally, in some cases, reaching the oculobulbar region. The late involvement of and the smaller proportion of patients to be affected in the oculobulbar region in LEMS differentiates it from myasthenia gravis, which tends to begin in the oculobulbar region. Proximal leg muscle weakness is usually the first symptom of LEMS, as noted in approximately 80% of cases. Motor weakness in upper and lower extremities affects the ability to walk, climb stairs, and arise from a chair. Some patients may even require a wheelchair. Symptoms related to cranial nerve dysfunction are also common in LEMS and may include slurred speech, weak voice, difficulty chewing and swallowing, drooping eyelids, and difficulty holding the head upright. Autonomic symptoms have also been noted and may include dry mouth, and constipation. Given the cumulative effects of motor weakness, cranial nerve and autonomic dysfunction, LEMS is a severely debilitating condition.

Diagnosis of LEMS is made based on clinical features and is confirmed by serologic testing (detection of specific P/Q subtype VGCC autoantibodies), electromyography, repetitive nerve stimulation, and assessment of compound muscle action potential (CMAP). Although LEMS is associated with a noticeable decrease in CMAP, LEMS has a characteristic feature of a short‑lived increase in CMAP amplitude immediately following exercise (short period of forceful muscle contractions) or high frequency repetitive nerve stimulation. This is thought to be due to high stimulation repetitive nerve frequency, leading to accumulation of calcium in nerve endings and facilitation of impaired acetylcholine release. A minority of patients (approximately 10%) do not have measurable P/Q subtype VGCC autoantibodies (seronegative LEMS). Antibodies to P/Q type VGCC, however, are reported to be highly specific to LEMS.

The mechanism by which amifampridine (the medicinal ingredient in Firdapse) exerts its therapeutic effect in LEMS patients has not been fully elucidated. In vitro, at high concentrations, amifampridine is a voltage‑gated potassium (K+) channel blocker. It is hypothesized that prolonged depolarization results in opening of slow voltage‑gated calcium channels which would allow for the influx of calcium. The increased concentration of intracellular calcium would subsequently induce exocytosis of more synaptic vesicles containing acetylcholine into the synaptic cleft. The influx of acetylcholine into the presynaptic cleft would then enhance neuromuscular transmission and lead to improved muscle function.

Firdapse has been shown to be efficacious for the symptomatic treatment of LEMS in adults. The market authorization was based on two Phase III clinical studies (Studies 1 and 2) which together included 64 patients who received either Firdapse or a placebo. Both studies enrolled patients with a confirmed diagnosis of LEMS based on demonstrated proximal muscle weakness and either neurophysiology studies or a positive anti‑P/Q type VGCC autoantibody test.

The two co‑primary measures of efficacy in both studies were the change from baseline to the end of the double‑blind treatment 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, which assesses muscle weakness. Each item on the QMG scale is assessed on a 4‑point rating. Higher scores represent greater impairment. The SGI is a seven‑point scale on which patients rate their overall 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. In both Studies 1 and 2, based on both QMG and SGI measures, results showed that patients receiving Firdapse experienced a greater benefit compared to those on placebo.

In terms of safety, Firdapse was generally well‑tolerated. The most commonly reported (>10%) adverse reactions in LEMS patients receiving Firdapse included peripheral and perioral paresthesia, dizziness, headache, and oral hypoesthesia. Serious adverse events associated with Firdapse included the occurrences of seizures and QT prolongation. Significant safety uncertainties with Firdapse included risk of schwannomas detected in rat carcinogenicity studies and potential risk of respiratory adverse events such as worsening of asthma symptoms. Adverse events were more frequent and serious in slow acetylators. The adverse events associated with Firdapse have been addressed through appropriate labelling in the Firdapse Product Monograph.

A Risk Management Plan (RMP) for Firdapse was submitted by Catalyst Pharmaceuticals Inc. to Health Canada. Upon review, the RMP is considered acceptable. The RMP is designed to describe known and potential safety issues, to present the monitoring scheme and when needed, to describe measures that will be put in place to minimize risks associated with the product.

The submitted inner and outer labels, package insert and Patient Medication Information section of the Firdapse Product Monograph meet the necessary regulatory labelling, plain language and design element requirements.

A Look‑alike Sound‑alike brand name assessment was performed and the proposed name Firdapse was accepted.

Overall, the therapeutic benefits of Firdapse therapy seen in Studies 1 and 2 are positive and are considered to outweigh the potential risks. Firdapse has been shown to have a favourable benefit‑harm‑uncertainty profile based on non‑clinical and clinical studies.

This New Drug Submission complies with the requirements of sections C.08.002 and C.08.005.1 and therefore Health Canada has granted the Notice of Compliance pursuant to section C.08.004 of the Food and Drug Regulations. For more information, refer to the Clinical, Non‑clinical, and Quality (Chemistry and Manufacturing) Basis for Decision sections.

3 What steps led to the approval of Firdapse?

The drug submission for Firdapse was reviewed under the Priority Review Policy. Sufficient evidence was submitted to demonstrate that Firdapse provides an effective treatment for a serious, life-threatening disease for which currently there is no approved treatment in Canada.

 

Submission Milestones: Firdapse

Submission Milestone Date
Pre-submission meeting: 2019-05-07
Request for priority status  
Filed: 2019-08-16
Approval issued by Director, Bureau of Medical Sciences: 2019-09-13
Submission filed: 2019-11-06
Screening  
Screening Deficiency Notice issued: 2019-11-27
Response filed: 2020-01-10
Screening Acceptance Letter issued: 2020-02-07
Review  
Biopharmaceutics Evaluation complete: 2020-05-05
Review of Risk Management Plan complete: 2020-06-25
Quality Evaluation complete: 2020-07-22
Labelling Review complete, including Look-alike Sound-alike brand name assessment: 2020-07-30
Clinical/Medical Evaluation complete: 2020-07-31
Notice of Compliance issued by Director General, Therapeutic Products Directorate: 2020-07-31

The Canadian regulatory decision on the quality, non-clinical, and clinical review of Firdapse was based on a critical assessment of the data package submitted to Health Canada. The foreign reviews completed by the European Medicines Agency (EMA) and the United States Food and Drug Administration (FDA) were used as added references.

For additional information about the drug submission process, refer to the Management of Drug Submissions Guidance.

4 What follow-up measures will the company take?

Requirements for post‑market commitments are outlined in the Food and Drugs Act and Regulations.

5 What post-authorization activity has taken place for Firdapse?

Summary Basis of Decision documents (SBDs) for eligible drugs authorized after September 1, 2012 will include post-authorization information in a table format. The Post-Authorization Activity Table (PAAT) will include brief summaries of activities such as submissions for new uses of the product, and whether Health Canada's decisions were negative or positive. The PAAT will continue to be updated during the product life cycle.

The PAAT for Firdapse is found above.

For the latest advisories, warnings and recalls for marketed products, see MedEffect Canada.

6 What other information is available about drugs?

Up to date information on drug products can be found at the following links:

7 What was the scientific rationale for Health Canada's decision?
7.1 Clinical basis for decision

 

Clinical Pharmacology

The mechanism by which amifampridine (the medicinal ingredient in Firdapse) exerts its therapeutic effect to treat the symptoms of Lambert‑Eaton Myasthenic Syndrome (LEMS) patients has not been fully elucidated. In vitro, amifampridine at high concentrations is a voltage‑gated potassium (K+) channel blocker. It is hypothesized that prolonged depolarization results in opening of slow voltage‑gated calcium channels which would allow for the influx of calcium. The increased concentration of intracellular calcium would subsequently induce exocytosis of more synaptic vesicles containing acetylcholine into the synaptic cleft. The influx of acetylcholine into the presynaptic cleft would, as a result, enhance neuromuscular transmission and lead to improved muscle function.

Pharmacodynamics

Firdapse can cause QTc interval prolongation in N‑acetyltransferase 2 slow acetylators. In a double‑blind, randomized, placebo‑ and positive‑controlled crossover electrocardiogram assessment study in healthy volunteers of NAT2 slow acetylator genotype (number of patients [n] = 52), amifampridine phosphate was administered at single‑doses of 30 mg and 60 mg (1.5 and 3 times the maximum recommended single dose of 20 mg). The maximum differences from placebo in the mean change from baseline QTcF interval were 4.2 milliseconds (90% confidence interval [CI] 1.7, 6.8) at two hours post‑dosing for the 30 mg dose and 5.5 milliseconds (90% CI 2.8, 8.1) at four hours post‑dosing for the 60 mg dose.

Pharmacokinetics

Amifampridine is absorbed quickly and reaches maximum plasma concentrations in 20 minutes to one hour after administration. In clinical studies, following single‑ and multiple‑doses, the amount of drug exposure over time (area under the curve; AUC) and the minimum and maximum plasma concentrations (Cmin and Cmax) were highly variable between individuals. At any given dose, the systemic exposure (Cmax and AUC) depends on the N‑acetyltransferase phenotype. Individuals who are fast (or rapid) acetylators have an approximately 3.5‑ to 4.5‑fold lower mean Cmax and 5.6‑ to 9‑fold lower AUC of amifampridine when compared to slow acetylators. A high‑fat, high‑calorie meal decreased the rate of amifampridine exposure (Cmax) by 44% and the extent of exposure by 20% when compared to administration under fasting conditions. The highly variable inter‑individual concentration is managed by titrating Firdapse to each patient until an effective and tolerable dose is reached.

For further details, please refer to the Firdapse Product Monograph, approved by Health Canada and available through the Drug Product Database.

Clinical Efficacy

The efficacy of Firdapse to treat the symptoms of Lambert‑Eaton Myasthenic Syndrome (LEMS) in adults was demonstrated in two pivotal Phase III clinical studies (Studies 1 and 2). A total of 64 adults (age 21 to 88 years) with LEMS were enrolled in the double‑blind, placebo‑controlled studies. Enrolled patients had a confirmed diagnosis of LEMS based on demonstrated proximal muscle weakness and either neurophysiology studies or a positive anti‑P/Q type voltage‑gated calcium channel autoantibody test. Patients were also required to be on an adequate and stable dosage (30 to 80 mg daily) of Firdapse prior to entering the randomized double‑blind phases of both studies.

The two co‑primary measures of efficacy in both studies were the change from baseline to the end of the double‑blind 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 to 39). A higher total score on the QMG represents greater impairment. The SGI is a 7‑point scale on which patients rate their global impression of the effects of the study treatment on their physical well‑being. A lower score on the SGI represents lower perceived benefit with the study treatment.

In Study 1, after an initial open‑label run‑in phase, 38 patients were randomized in a double‑blind fashion to either continue treatment with Firdapse (number of patients [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 another 7 days. Efficacy was assessed at Day 14 of the double‑blind period. During the double‑blind period, the QMG scores worsened in both treatment groups, but a significantly greater worsening was observed in the placebo group compared to the Firdapse group. The least square mean increases in QMG scores from baseline to Day 14 were 0.4 (Firdapse) and 2.2 (placebo), with a statistically significant (p = 0.0452) mean difference of ‑1.7 in favor of Firdapse. Similarly, the SGI scores also worsened 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). 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.

In Study 2, patients enrolled from an open‑label expanded access program 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. From baseline to Day 4, there was a significantly greater worsening in the QMG score in the placebo group than in the Firdapse group, with a mean difference of 6.54 (95% confidence interval [CI]: ‑9.78, ‑3.29) in favor of Firdapse (p = 0.0004). As for the SGI scores, there also was a significantly greater worsening in the placebo group when compared to the Firdapse group (p = 0.0003).

The results of both Study 1 and Study 2 indicate that patients randomized to placebo had a 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.

Indication

The New Drug Submission for Firdapse was filed by the sponsor with the following indication:

  • Firdapse (amifampridine) is indicated for the treatment of Lambert‑Eaton Myasthenic Syndrome (LEMS) in adults.

Health Canada approved the following indication:

  • Firdapse (amifampridine) is indicated for the symptomatic treatment of Lambert‑Eaton Myasthenic Syndrome (LEMS) in adults.

For more information, refer to the Firdapse Product Monograph, approved by Health Canada and available through the Drug Product Database.

Clinical Safety

The clinical safety profile of Firdapse was derived from several data sources given Lambert‑Eaton Myasthenic Syndrome (LEMS) is a rare disease and the number of patients available to enroll in clinical studies to characterize the safety of Firdapse is limited. Firdapse has been approved in Europe since December 2009 and in the United States of America since November 2018. Therefore, post‑market safety data contributed greatly to the understanding of the safety profile of Firdapse. Overall, cumulative subject exposure to Firdapse is 302 patients based upon data from completed interventional clinical studies up to the data lock point for this submission. These include 163 healthy volunteers, 80 patients with LEMS, and 59 patients with either Congenital Myasthenic Syndromes, or Muscle Specific Kinase Myasthenia Gravis.

The safety of Firdapse was also characterized through the review of the safety data collected in both pivotal studies (Studies 1 and 2) previously described in the Clinical Efficacy section. The safety data also included a 2‑year follow‑up open‑label extension study, a European registry, and an expanded access study (EAP‑001) including 191 LEMS patients and 720 patients with other conditions in which most patients were enrolled for several months to years.

The most commonly reported (>10%) adverse events associated with Firdapse for healthy individuals and LEMS patients receiving Firdapse in clinical studies include peripheral and perioral paresthesia, dizziness, headache, and oral hypoesthesia.

One main adverse event of interest for Firdapse is the possible occurrence of 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%. It is unclear if the risk of seizures with Firdapse is dose‑dependent. Most cases reported in the literature were of patients receiving a dose higher than the daily recommended dose of 80 mg. However, in post‑market studies and the patient registry, there have been several cases of seizures in patients taking the daily recommended dose or a lower dose. Yet, as there are few cases of seizures, it is difficult to draw solid conclusions on the dose dependency of this risk. In addition, in many cases there were additional confounding factors, such as that of concomitant medications or different health conditions that could lower the threshold for seizure.

In Study 1, elevated liver enzymes (including alanine aminotransferase [ALT], aspartate aminotransferase [AST], lactate dehydrogenase [LDH], and gamma‑glutamyl transferase [GGT]) were observed in 6 individuals (14%). These events were not considered serious by the investigator. During the 2‑year follow‑up open‑label extension study, four serious adverse events of elevated hepatic enzymes were observed and were considered related to amifampridine phosphate. This safety issue has been appropriately captured in the Firdapse Product Monograph.

There were no reported cases of Hy's Law in the safety database of Firdapse. Several subjects had an increase in ALT, AST and GGT above the upper limit of normal (ULN) without an increase in bilirubin above the ULN.

In the Firdapse New Drug Submission submitted to Health Canada, there was no study dedicated to evaluating the impact of hepatic impairment on the metabolism of amifampridine (the medicinal ingredient in Firdapse) and its exposure in the clinical development program. The sponsor does plan to conduct a clinical study to measure the impact of hepatic impairment on the exposure to amifampridine for which results are expected to be available in 2021. However, the lack of such study at this time did not preclude the approval of Firdapse.

There is very limited information on the impact of Firdapse on pregnancy. There are two reported cases of women who continued to take Firdapse during pregnancy (one LEMS patient and one Congenital Myasthenic Syndrome patient); both pregnancies resulted in the births of healthy infants. However, in non‑clinical studies, an increase in stillbirths and pup deaths were observed in rodents when testing Firdapse at mid‑ and high‑dose ranges above the recommended maximum human dose. Given these observations in non‑clinical studies, a statement has been included in the Firdapse Product Monograph that Firdapse should not be used during pregnancy and that women of childbearing potential must use effective contraception.

There is no information available on the impact of Firdapse on human lactation, its presence in human milk, its effects on the breastfed infant, or milk production. No data on lactation are available from case reports or in published literature. Available reproductive data in non‑clinical studies did show the presence of amifampridine (the medicinal ingredient in Firdapse) in the milk of breastfeeding mothers. As a result, the Firdapse Product Monograph includes a statement that it is uncertain if Firdapse is excreted in human milk. Given this, the potential benefits and harms should be carefully evaluated when breastfeeding is considered.

Adverse events of the respiratory system have been reported with Firdapse, some of which were considered serious in people with asthma and a history of asthma. The following adverse events are listed in the Firdapse Product Monograph under the section Post-Market Adverse Events: asthma attack in patients with a history of asthma, bronchial hypersecretion, cough, and dyspnea. There is no mention elsewhere in the Firdapse Product Monograph of the risks of respiratory adverse events given only a few post‑market reports were identified, and these cases were confounded by indication (as LEMS patients can present with respiratory difficulties).

Isolated reports of bronchospasm have been reported, as well as asthma attacks in asthmatic patients or patients with a history of asthma, some of which were serious. The Firdapse Product Monograph has a warning to describe the respiratory adverse events that occurred in post‑market settings and to warn that Firdapse could exacerbate asthma symptoms.

There is limited information on potential drug‑drug interactions (including QTc‑prolonging drugs, seizure threshold reducing drugs, atropinic and cholinergic drugs, and depolarizing and non‑depolarizing muscle relaxants) from the drug development program and post‑market safety information collected. No specific drug interaction studies have been conducted.

For more information, refer to the Firdapse Product Monograph, approved by Health Canada and available through the Drug Product Database.

7.2 Non-Clinical Basis for Decision

As part of the New Drug Submission (NDS) for Firdapse, several general toxicology, reproductive and development toxicology studies were included in the submission in addition to a carcinogenicity study.

General Toxicology

The principal findings in toxicology studies conducted with amifampridine in rats and dogs were clinical signs presumably related to known pharmacological actions that were reversible, apart from the resulting mortality and moribund sacrifice at high‑dose levels. Evidence for other target organ effects in the salivary glands, muscle, liver, and kidneys were inconsistent.

In acute and chronic studies, central and autonomic nervous system toxicities were observed related to the exaggerated pharmacology of amifampridine. Central nervous system and respiratory clinical signs in both rats and dogs included tremors, convulsion, non‑responsiveness to stimuli, stiffness of limbs, outstretched limbs, hyperesthesia, and/or labored breathing. Mortality was observed at high‑doses (53 mg/kg in mice, 40 mg/kg in rats, and 4 mg/kg in dogs).

Carcinogenicity

In a 104‑week rat carcinogenicity study, oral administration of amifampridine in the diet (8, 25, or 55 mg free base/kg/day) resulted in an increase in uterine tumours (endometrial carcinoma and combined endometrial adenoma/endometrial carcinoma/squamous cell carcinoma) at the mid‑ and high‑dose levels and a low incidence of mainly malignant schwannomas in males and/or females at all dose levels, which were not observed in controls. The significance of these tumours to humans is unknown, although human schwannomas are largely benign. The low‑dose, not associated with an increase in uterine tumours, is similar to the maximum recommended human dose (80 mg/day amifampridine) on a body surface area (mg/m2) basis. The relevance of these increased tumour incidences in rats for patients is unknown.

Mutagenesis

Amifampridine was not mutagenic in the in vitro bacterial reverse mutation assay (with and without metabolic activation) or in the in vivo rat micronucleus and unscheduled deoxyribonucleic synthesis assays. Amifampridine was positive for clastogenicity in the in vitro mouse lymphoma tk assay in the absence of metabolic activation. Amifampridine was not genotoxic in vivo.

Reproductive and Development Toxicity

A combination fertility and embryo fetal development study was conducted in rats. Oral administration of amifampridine (0, 3.9, 12.0, or 39.6 mg free base/kg/day) to male and female rats prior to and during mating, and continuing in females throughout organogenesis to gestation day (GD) 17 had no adverse effects on fertility in either males or females. In this study, amifampridine was not teratogenic and had no effect on fetal growth. The no‑observed‑adverse‑effect level (NOAEL) was approximately five times the maximum recommended human dose (80 mg amifampridine) based on a body surface area (mg/m2).

In the rabbit embryo fetal toxicity study, amifampridine at 4.74, 15.9 or 30 mg free base/kg/day was administrated orally from GD 7 to 20. Amifampridine at 4.74 mg/kg/day did not cause any maternal toxicity whereas 30 mg/kg/day resulted in severe central nervous system toxicities and decreased body weight gain and food consumption with moribundity/mortality of five animals. Amifampridine had no effect on embryo fetal development that included evaluations for external, visceral and skeletal anomalies. The NOAEL for maternal toxicity is at 4.74 mg/kg/day and the no‑observed‑effect level (NOEL) for embryo fetal developmental toxicity is 30 mg/kg/day. The 30 mg/kg/day dose is approximately seven times the maximum recommended human dose based on body surface area (mg/m2).

Peri‑ and post‑natal toxicity was evaluated after oral administration of amifampridine (0, 3.95, 12.0, or 39.6 mg free base/kg/day) to female rats from GD 6 of pregnancy and throughout lactation. An increase in stillbirths and pup deaths, reduced pup weight, and delayed sexual development in female pups were observed at the mid‑ and high‑doses tested. The no‑effect dose (3.95 mg free base/kg/day) for adverse developmental effects is less than that in humans at the maximum recommended human dose (MRHD) based on body surface area.

Abuse Risk

Amifampridine's potential for risk of abuse was assessed in rats. There were no indications of drug abuse in rats where cocaine was used as the reference for dependence and benzodiazepine for withdrawal. There are no class specific standards for reference.

Conclusion

The results of the non‑clinical studies, as well as the potential risks to humans, have been included in the Firdapse Product Monograph. In view of the intended use of Firdapse, there are no pharmacological/toxicological issues within the Firdapse submission which preclude authorization of the product. Appropriate warnings and precaution measures are in place in the Firdapse Product Monograph to address the identified safety concerns.

For more information, refer to the Firdapse Product Monograph, approved by Health Canada and available through the Drug Product Database.

7.3 Quality Basis for Decision

The Chemistry and Manufacturing information submitted for Firdapse has demonstrated that the drug substance and drug product can be consistently manufactured to meet the approved specifications. Proper development and validation studies were conducted, and adequate controls are in place for the commercial processes. Changes to the manufacturing process and formulation made throughout the pharmaceutical development are considered acceptable upon review. Based on the stability data submitted, the proposed shelf life of 36 months is acceptable when the drug product is stored at room temperature (15ºC to 30ºC).

Proposed limits of drug‑related impurities are considered adequately qualified (i.e. within International Council for Harmonisation [ICH] limits and/or qualified from toxicological studies).

All sites involved in production are compliant with Good Manufacturing Practices.

All non-medicinal ingredients (described earlier) found in the drug product are acceptable for use in drugs according to the Food and Drug Regulations.

None of the excipients used in the formulation of Firdapse is of human or animal origin.

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