Summary Basis of Decision for Vimpat ™
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:
VimpatTM
Lacosamide
50 mg, 100 mg, 150 mg, and 200 mg, Tablets, Oral
10 mg/mL, Solution for injection, Intravenous
UCB Canada Inc.
Submission control no: 116632
Date issued: 2011-09-08
Foreword
Health Canada's Summary Basis of Decision (SBD) documents outline the scientific and regulatory considerations that factor into Health Canada regulatory decisions related to drugs and medical devices. SBDs are written in technical language for stakeholders interested in product-specific Health Canada decisions, and are a direct reflection of observations detailed within the evaluation reports. As such, SBDs are intended to complement and not duplicate information provided within the Product Monograph.
Readers are encouraged to consult the 'Reader's Guide to the Summary Basis of Decision - Drugs' to assist with interpretation of terms and acronyms referred to herein. In addition, a brief overview of the drug submission review process is provided in the Fact Sheet entitled 'How Drugs are Reviewed in Canada'. This Fact Sheet describes the factors considered by Health Canada during the review and authorization process of a drug submission. Readers should also consult the 'Summary Basis of Decision Initiative - Frequently Asked Questions' document.
The SBD reflects the information available to Health Canada regulators at the time a decision has been rendered. Subsequent submissions reviewed for additional uses will not be captured under Phase I of the SBD implementation strategy. For up-to-date information on a particular product, readers should refer to the most recent Product Monograph for a product. Health Canada provides information related to post-market warnings or advisories as a result of adverse events (AE).
For further information on a particular product, readers may also access websites of other regulatory jurisdictions. The information received in support of a Canadian drug submission may not be identical to that received by other jurisdictions.
Other Policies and Guidance
Readers should consult the Health Canada website for other drug policies and guidance documents. In particular, readers may wish to refer to the 'Management of Drug Submissions Guidance'.
1 Product and submission information
Brand name:
Manufacturer/sponsor:
Medicinal ingredient:
International non-proprietary Name:
Strength:
10 mg/mL
Dosage form:
Route of administration:
Drug identification number(DIN):
- 02357615 - 50 mg/tablet
- 02357623 - 100 mg/tablet
- 02357631 - 150 mg/tablet
- 02357658 - 200 mg/tablet
- 02357666 - 10 mg/mL solution for injection
Therapeutic Classification:
Non-medicinal ingredients:
Colloidal silicon dioxide, crospovidone, hydroxypropylcellulose, hypromellose, lecithin, magnesium stearate, microcrystalline cellulose, polyethylene glycol, polyvinyl alcohol, talc, titanium dioxide, and dye pigments:
50 mg tablets: red iron oxide, black iron oxide, and FD&C Blue #2/indigo carmine aluminum lake
100 mg tablets: yellow iron oxide
150 mg tablets: yellow iron oxide, red iron oxide, and black iron oxide
200 mg tablets: FD&C Blue #2/indigo carmine aluminum lake
Solution for injection:
Hydrochloric acid, sodium chloride, and water for injection.
Submission type and control no:
Date of Submission:
Date of authorization:
2 Notice of decision
On September 30, 2010, Health Canada issued a Notice of Compliance to UCB Canada Inc. for the drug product Vimpat.
Vimpat contains the medicinal ingredient lacosamide which is an antiepileptic agent.
Vimpat is indicated as adjunctive therapy in the management of partial-onset seizures in adult patients with epilepsy who are not satisfactorily controlled with conventional therapy. Vimpat solution for injection for intravenous (IV) use is an alternative when oral administration is temporarily not feasible.
The precise mechanism by which lacosamide exerts its antiepileptic effect in humans is unknown; however, in vitro electrophysiological studies have shown that lacosamide selectively enhances slow inactivation of voltage-gated sodium channels.
The market authorization was based on quality, non-clinical, and clinical information submitted. The efficacy and safety of Vimpat were primarily based on three randomized, double-blind, placebo-controlled, multicentre studies involving 944 adult patients randomized to receive Vimpat and 364 adult patients randomized to receive placebo. Patients had partial-onset seizures with or without secondary generalization and were not adequately controlled with 1 to 3 concomitant antiepileptic drugs. The primary efficacy endpoint in all three studies was the change in 28-day seizure frequency from baseline to maintenance phase in the Vimpat arms versus placebo. All three studies were positive with respect to the primary endpoint as a statistically significant effect in the reduction of seizure frequency from baseline to the maintenance phase was observed with Vimpat doses of 200 mg/day (Study 3), 400 mg/day (Studies 1, 2, and 3), and 600 mg/day (Studies 1 and 2). The percent of patients with at least 50% reduction in seizure frequency from baseline to the maintenance phase was also statistically significant for Vimpat doses of 400 mg and 600 mg/day, compared to placebo. The efficacy of the IV solution was supported by bioequivalence to the oral formulation. Based on the safety data presented, treatment with Vimpat was generally well-tolerated.
Vimpat (lacosamide) is presented as 50 mg, 100 mg, 150 mg, and 200 mg film-coated tablets, as well as a 10 mg/mL solution for injection. The recommended starting dose for Vimpat is 50 mg twice a day, with or without food, which should be increased to an initial therapeutic dose of 100 mg twice a day after one week. Depending on patient response and tolerability, the maintenance dose can be further increased by 50 mg twice a day every week, to a maximum recommended daily dose of 400 mg (200 mg twice a day). Doses above 400 mg/day do not confer additional benefit, are associated with more severe and substantially higher frequency of adverse reactions and are not recommended. Conversion to or from oral and IV administration can be done directly without titration. Vimpat solution for IV use, is an alternative when oral administration is temporarily not feasible. The solution for injection is infused over a period of 30 to 60 minutes twice daily. Dosing guidelines are available in the Product Monograph.
Vimpat is contraindicated for patients who are hypersensitive to the active substance or to any of the excipients; and for patients with a history of, or presence of, second-or third-degree atrioventricular block. Patients with a hypersensitivity to peanuts or soya should not take Vimpat film-coated tablets. Vimpat should be administered under the conditions stated in the Product Monograph taking into consideration the potential risks associated with the administration of this drug product. Detailed conditions for the use of Vimpat are described in the Product Monograph.
Based on the Health Canada review of data on quality, safety, and efficacy, Health Canada considers that the benefit/risk profile of Vimpat is favourable as adjunctive therapy in the management of partial-onset seizures in adult patients with epilepsy who are not satisfactorily controlled with conventional therapy.
3 Scientific and Regulatory Basis for Decision
3.1 Quality Basis for Decision
3.1.1 Drug Substance (Medicinal Ingredient)
General Information
Epilepsy is a neurological disorder characterized by recurrent seizures. Manifestations of epilepsy include impaired consciousness, involuntary movement, autonomic disturbance, or psychotic or sensory experiences.
Lacosamide, the medicinal ingredient of Vimpat, is an antiepileptic agent. Vimpat belongs to a novel class of functional amino acids. Although its mechanism of action in humans is unknown, lacosamide is thought to exert its anticonvulsant effects by selectively enhancing slow inactivation of voltage-gated sodium channels.
Manufacturing Process and Process Controls
The drug substance is synthetically derived. Lacosamide is manufactured via a multi-step synthesis. Each step of the manufacturing process is considered to be controlled within acceptable limits:
- The sponsor has provided information on the quality and controls for all materials used in the manufacture of the drug substance.
- The drug substance specifications are found to be satisfactory. Impurity limits meet International Conference on Harmonisation (ICH) requirements.
- The processing steps have been evaluated and the appropriate ranges for process parameters have been established.
Characterization
The structure of lacosamide has been adequately elucidated and the representative spectra have been provided. Physical and chemical properties have been described and are found to be satisfactory. The route of synthesis of lacosamide supports the chemical structure assigned.
Impurities and degradation products arising from manufacturing and/or storage were reported and characterized. These products were found to be within ICH-established limits and/or were qualified from batch analysis and therefore, are considered to be acceptable. Appropriate tests are adequately controlling the levels of product- and process-related impurities.
Control of Drug Substance
The drug substance specifications and analytical methods used for quality control of lacosamide are considered acceptable. Batch analysis results were reviewed and all results comply with the specifications and demonstrate consistent quality of the batches produced.
The drug substance packaging is considered acceptable.
Stability
Based on the long-term, real-time, accelerated, and stress stability data submitted, the proposed retest period and storage conditions for the drug substance were supported and are considered to be satisfactory.
3.1.2 Drug Product
Description and Composition
Vimpat 50 mg, 100 mg, 150 mg, and 200 mg film-coated tablets are coloured, oval, biconvex tablets of different sizes and are compositionally proportional formulations. The tablets are debossed with "SP" on one side and the tablet strength ("50", "100", "150", or "200") on the other side. Vimpat tablets are packaged in high density polyethylene bottles sealed with a polypropylene cap and polyvinyl chloride/polyvinylidene chloride aluminium blisters.
In addition to lacosamide, each Vimpat tablet contains the following excipients: colloidal silicon dioxide; crospovidone; hydroxypropylcellulose; hypromellose; lecithin; magnesium stearate; microcrystalline cellulose; polyethylene glycol; polyvinyl alcohol; talc; titanium dioxide; and the following dye pigments:
- 50 mg tablets: red iron oxide, black iron oxide, and FD&C Blue #2/indigo carmine aluminum lake;
- 100 mg tablets: yellow iron oxide;
- 150 mg tablets: yellow iron oxide, red iron oxide, and black iron oxide; and
- 200 mg tablets: FD&C Blue #2/indigo carmine aluminum lake.
Vimpat 10 mg/mL solution for injection is a clear, colourless, odourless liquid. The container closure system is a 20-mL clear vial of colourless Type I glass with a grey chlorobutyl rubber stopper coated with a fluoropolymer on the lower side and a flanged aluminum cap with tear-off seal. The vial contains 20 mL of solution for injection.
In addition to lacosamide, Vimpat solution for injection contains the following excipients: hydrochloric acid, sodium chloride, and water for injection.
All non-medicinal ingredients (excipients) found in the tablet and solution for injection are acceptable for use in drugs according to the Food and Drug Regulations. The compatibility of lacosamide with the excipients is demonstrated by the stability data presented on the proposed commercial formulation.
Pharmaceutical Development
Changes to the manufacturing process and formulation for Vimpat tablets and Vimpat solution for injection made throughout the pharmaceutical development are considered acceptable upon review. Parameters relevant to the performance of the drug product were not affected by the changes described.
Manufacturing Process and Process Controls
Vimpat tablets are manufactured by a wet granulation process, fluid bed drying, compression, and film-coating. One common granulate is used for all strengths. Vimpat solution for injection is formulated, sterilized by filtration, and filled. Both manufacturing processes use conventional pharmaceutical equipment and facilities.
The validated process is capable of consistently generating product that meets release specifications.
All manufacturing equipment, in-process manufacturing steps, and detailed operating parameters were adequately described in the submitted documentation and are considered acceptable. The manufacturing process is considered to be adequately controlled within justified limits.
Control of Drug Product
Vimpat tablets are tested to verify that their identity, appearance, content uniformity, assay, dissolution, moisture content, levels of degradation products, and microbiological impurities are within acceptance criteria.
Vimpat solution for injection is tested to verify that its identity, appearance, assay, pH, fill volume, particulates, sterility, osmolality, levels of degradation products and bacterial endotoxins are within acceptance criteria.
The test specifications and analytical methods for the control of both drug products are considered acceptable; the shelf-life and the release limits, for individual and total degradation products, are within acceptable limits.
Data from final batch analyses for both Vimpat tablets and Vimpat solution for injection were reviewed and are considered to be acceptable according to the specifications of the drug products.
Stability
Based on the real-time, long-term, accelerated, and stress stability data submitted, the proposed 36-month shelf-life at 15 to 30°C for Vimpat tablets is considered acceptable. Similarly, the results of the real-time, long-term, and accelerated stability data submitted for Vimpat solution for injection support the proposed 36-month shelf-life at 15 to 30°C.
The compatibility of the drug products with their respective container closure systems was demonstrated through compendial testing and stability studies. The container closure systems met all validation test acceptance criteria.
3.1.3 Facilities and Equipment
The design, operations, and controls of the facilities and equipment that are involved in the production of Vimpat are considered suitable for the activities and products manufactured.
The manufacturing sites are compliant with Good Manufacturing Practices.
3.1.4 Adventitious Agents Safety Evaluation
Not applicable. The excipients used in the drug product formulation are not from animal or human origin.
3.1.5 Conclusion
The Chemistry and Manufacturing information submitted for Vimpat 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.
3.2 Non-Clinical Basis for Decision
3.2.1 Pharmacodynamics
Primary Pharmacodynamics
The precise mechanism by which lacosamide exerts its antiepileptic effect in humans is unknown. In vitro electrophysiological studies have shown that lacosamide selectively enhances slow inactivation of voltage-gated sodium channels.
Lacosamide protected against seizures in a broad range of rodent models (mice and rats) of partial and primary generalized seizures and delayed kindling development. In non-clinical experiments, lacosamide in combination with levetiracetam, carbamazepine, phenytoin, valproate, lamotrigine, topiramate or gabapentin showed synergistic or additive anticonvulsant effects.
Lacosamide was not effective in a rat WAG/rij model of absence epilepsy and caused mild dose-dependent increases in the number of characteristic electroencephalogram (EEG) spike wave discharges for one hour after single intraperitoneal (IP) doses of 3 to 30 mg/kg). A similar phenomenon also occurs in WAG/rij rats given the other antiepileptic drugs phenytoin and carbamazepine.
Safety Pharmacology
Lacosamide caused convulsions in mice, rats, rabbits and dogs in repeat dose oral toxicity studies (see section 3.2.3 Toxicology, Long-Term Toxicity). A pro-convulsant potential was also apparent in the anticonvulsant rat models (see section 3.2.1 Pharmacodynamics, Primary Pharmacodynamics). After repeated administration in a rat amygdala kindling development model a lacosamide dose of 30 mg/kg IP triggered seizures 5-25 minutes after dosing. In the cobalt/homocysteine model for generalized tonic-clonic seizures in rats, a lacosamide dose of 100 mg/kg IP abolished seizures. However, a slightly higher dose of 120 mg/kg IP resulted in all animals dying within 25 minutes of injection after showing severe tonic and generalized tonic-clonic seizures.
Lacosamide has also demonstrated cardiodepressant effects in anaesthetized dogs and monkeys, consisting mainly of reduced blood pressure, contractility, and cardiac output. These effects were detected at plasma concentrations that overlapped those observed at the maximum recommended human dose (MRHD) of 200 mg twice daily. Decreased cardiac conductivity, atrioventricular (AV) block, and AV dissociation occurred at higher doses and exposures. In vitro correlates were reduced sodium currents, action potential duration, and maximum rate of depolarization in cardiac cells.
Both pro-convulsant and cardiovascular effects are likely related, at least in part, to the action of lacosamide at sodium channels. Effects on sodium current were dependent on membrane potential with greater inhibition at more depolarized potentials, suggesting the possibility of greater effects under conditions such as myocardial ischaemia. In human clinical trials, the cause of syncope was not determined in most cases. However, several cases were associated with either changes in orthostatic blood pressure, atrial flutter/fibrillation (and associated tachycardia) or bradycardia. The pro-convulsant effect of lacosamide, particularly if it triggers an increase in absence-like spike waves in the EEG, might also be a contributing factor, particularly if used for indications other than as an anticonvulsant. Additional human data in the form of electroencephalogram (EEG), blood pressure and electrocardiogram (ECG) measurements at high or even supra-therapeutic doses that have been explored previously in clinical trials might help resolve this issue.
As lacosamide was associated with dose-dependent PR interval prolongation in non-clinical and clinical studies, a contraindication for the use of Vimpat in patients with a history of, or presence of, second or third degree AV block has been included in the Product Monograph. In addition, warning statements regarding cardiovascular-related adverse events [for example (e.g.) atrial fibrillation, atrial flutter, syncope] were included.
3.2.2 Pharmacokinetics
Absorption, distribution, metabolism and excretion of lacosamide were studied in several animal species. Further pharmacokinetic information was obtained from safety pharmacology and toxicity studies. Lacosamide was rapidly absorbed and eliminated. After oral administration in dogs, the time to maximum concentration (Tmax) was usually slightly over an hour, and the half-life was 2 to 2.5 hours. Exposure increments were linear with dose. Values for Cmax and area under the concentration time curve (AUC) ranged throughout the studies depending on dose. In a 30-day toxicity study in dogs, after first oral dosing at the no-observed-effect-level (NOEL) (12 mg/kg), Cmax and AUC were approximately 12 μg/mL and 45 μg.h/mL, respectively. Throughout the studies, the variability of the AUC values among species was large.
Plasma lacosamide levels in dogs 2 minutes after intravenous bolus administration of 4, 8, and 12 mg/kg ranged from 11.3 to 22.6, 29.2 to 46, and 59.2 to 85.6 µg/mL, respectively, for males and from 5.8 to 8.5, 15.8 to 19.5, 29 to 44.7, and 56.5 to 80.2 μg/mL, respectively, for females.
3.2.3 Toxicology
Acute Toxicity
Results from acute oral dose toxicity studies with lacosamide indicate a NOEL of 31.6 mg/kg in both mice and rats. The estimated LD50 (dose that is lethal to 50% of the treated animals) values were 383 and 253 mg/kg for mice and rats, respectively. After intravenous (IV) administration, the NOELs were 10 and 25 mg/kg and the estimated LD50 values were 178 and >100 mg/kg for mice and rats, respectively. In acute toxicity studies, clinical signs at high doses included exaggerated pharmacodynamic effects of lacosamide on the central nervous system (CNS) such as reduced motility, ataxia, abdominal/lateral position, loss of righting reflex, reduced muscle tone, hind limb weakness, tremor, dyspnea and convulsions.
Long-Term Toxicity
In repeat-dose oral toxicity studies, lacosamide caused convulsions in mice, rats, rabbits, and dogs after oral dosing at Cmax exposures generally only slightly higher than the Cmax at steady state of 10.9 µg/mL obtained after the MRHD of 200 mg twice daily (BID). The convulsions usually occurred in the context of other significant clinical signs including one or more of tremors, ataxia, hypoactivity, and recumbency, which also all occurred at dose levels not associated with convulsions.
Consistent with the safety pharmacology studies, lacosamide caused 13 to 37% decreases in systolic blood pressure in females in the 12-month chronic dog toxicity study at dose levels of 10 to 25 mg/kg/day with the Cmax at 10 mg/kg similar to that of humans given the MRHD of 200 mg BID.
In the repeat-dose toxicity studies, mild reversible liver changes were observed in rats starting at about three-times the clinical exposure. These changes included an increased organ weight, hypertrophy of hepatocytes, increases in serum concentrations of liver enzymes, and increases in total cholesterol and triglycerides. Apart from the hypertrophy of hepatocytes, no other histopathologic changes were observed.
Mutagenicity
Lacosamide was negative in an in vitro Ames test, an in vivo mouse micronucleus assay, and an in vivo unscheduled deoxyribonucleic acid (DNA) synthesis test. In the in vivo tests, plasma exposures (AUC) were up to approximately three-times the plasma AUC in humans at the MRHD of 200 mg BID. Lacosamide induced a positive response in the in vitro mouse lymphoma assay at excessively high concentrations [that is to say (i.e.) at concentrations above the maximum recommended concentration of 10 mM.
Carcinogenicity
There was no evidence of drug-related carcinogenicity in mice or rats. Mice and rats received lacosamide once daily by oral administration for 104 weeks at doses producing plasma exposures (AUC) up to approximately one- and three-times, respectively, the plasma AUC in humans at the MRHD of 200 mg BID.
Reproductive and Developmental Toxicity
In reproductive and developmental toxicity studies in rodents and rabbits, no teratogenic effects were noted; however, an increase in the number of stillborn pups and pup deaths in the peripartum period, and slightly reduced live litter sizes and pup bodyweights were observed at maternal toxic doses in rats corresponding to clinically relevant plasma exposure levels. Since higher exposure levels could not be tested in animals due to maternal toxicity, data are insufficient to fully characterize the embryofoetotoxic and teratogenic potential of lacosamide. Studies in pregnant rats revealed that lacosamide and/or its metabolites readily crossed the placental barrier.
Oral administration of lacosamide (30, 90, or 180 mg/kg/day) to rats during the neonatal and juvenile periods of postnatal development resulted in decreased brain weights and long-term neurobehavioral changes (altered open field performance, deficits in learning and memory). The relevance of these observations remains equivocal; however, potential adverse effects on CNS development cannot be ruled out. The early postnatal period in rats is generally thought to correspond to late pregnancy in humans in terms of brain development. The NOEL for developmental neurotoxicity in rats was associated with a plasma lacosamide AUC approximately 0.5-times that in humans at the MRHD of 200 mg BID.
3.2.4 Summary and Conclusion
Safety concerns from non-clinical studies included cardiovascular-related events [for example (e.g.): PR-interval prolongation/AV-block] and convulsions. Full disclosure of these findings has been made by the inclusion of appropriate statements in the Vimpat Product Monograph.
3.3 Clinical basis for decision
3.3.1 Pharmacodynamics
A pharmacokinetic-pharmacodynamic (efficacy) analysis was performed based on the pooled data from the three efficacy trials for partial-onset seizures. Lacosamide exposure is correlated with the reduction in seizure frequency. However, in group analyses, doses above 400 mg/day did not confer additional benefit and were associated with more severe and substantially higher frequency of adverse reactions.
The pharmacodynamics of Vimpat were assessed in section 3.2.1 Pharmacodynamics.
3.3.2 Pharmacokinetics
In humans, lacosamide is completely absorbed after oral administration with absolute bioavailability of approximately 100% and is not affected by food. The maximum lacosamide plasma concentrations occur approximately 0.25 to 4 hours post-dose after oral dosing, and the elimination half-life is approximately 13 hours. Steady-state plasma concentrations of the drug are achieved after 3 days of repeated twice-daily dosing. The pharmacokinetics of lacosamide are dose proportional between 100 to 800 mg. Lacosamide's major metabolite, O-desmethyl metabolite, has a Tmax of 0.5 to 12 hours and an elimination half-life of 15 to 23 hours. This metabolite has no known pharmacologic activity.
Lacosamide is primarily eliminated from systemic circulation by renal excretion and biotransformation by cytochrome P450 (CYP) 2C19. The major compounds excreted into urine after both oral and IV administration were lacosamide (~40% of the administered dose), its O-desmethyl metabolite (~30% of the dose; no known activity), and a polar fraction, proposed to be serine derivatives (~20% of the dose). Small amounts of further metabolites (p-hydroxy-, O-desmethyl-p-hydroxy-, O-desmethyl-m-hydroxy-, and desacetyl-derivatives of lacosamide) representing 0.5% to 2% of the dose were also found in urine.
Special Populations
Cytochrome P450 (CYP) 2C19 Polymorphism
A study was conducted to examine the issue of CYP2C19 polymorphism and the metabolism of lacosamide. The results indicated no clinically relevant differences in the pharmacokinetics of lacosamide between CYP2C19 poor metabolizers and extensive metabolizers; however, the amount of O-desmethyl metabolite excreted in the urine was reduced by approximately 70% in poor metabolizers.
Hepatic Impairment
Lacosamide undergoes hepatic metabolism. In patients withmild to moderate hepatic impairment, dose titration should be performed with caution to a maximum dose of 300 mg/day. Vimpat is not recommended for patients with severe hepatic impairment.
Renal Impairment
Lacosamide and its major metabolite are eliminated from the systemic circulation primarily by renal excretion. No dose adjustment is considered necessary in patients with mild to moderate renal impairment. A maximum dose of 300 mg/day is recommended for patients with severe renal impairment [creatinine clearance (CLCR) ≤30 mL/min] and in patients with end-stage renal disease.
3.3.3 Clinical Efficacy
Oral Formulation
The efficacy of Vimpat tablets was assessed in three randomized, double-blind, placebo-controlled, multicentre trials (Studies 1, 2, and 3) conducted in the United States, Europe, and Australia. In these studies, adult patients with partial-onset seizures were administered Vimpat at doses of 200 to 600 mg/day as an adjunct therapy to one to three concomitant antiepileptic drugs (AEDs). In the three studies combined, 944 patients were randomized to receive Vimpat and 364 were randomized to receive placebo. The enrolled patients had a mean duration of epilepsy of 24 years and a median baseline seizure frequency ranging from 10 to 17 seizures per 28 days, with no seizure-free period exceeding 21 days. Patient age ranged from 16 to 71 years (mean: 38.6 years of age), and ~50% of patients were female. In total, these studies included very few paediatric [<18 years; total number (n) = 10] and elderly (≥65 years; n = 18) patients.
Following an 8-week Baseline Phase, patients were randomized and up-titrated by initiating treatment at 100 mg/day (50 mg BID) followed by increases in weekly increments of 100 mg/day to the target dose. A one-step down titration of 100 mg was permitted in the case of intolerable adverse events (AEs) at the end of the Titration Phase. The Titration Phase lasted 4 weeks in Study 3 and 6 weeks in Studies 1 and 2. Patients then received a stable dose of Vimpat for 12 weeks (Maintenance Phase). Study 1 tested Vimpat doses of 200, 400, and 600 mg/day versus (vs.) placebo. Study 2 compared Vimpat doses of 400 and 600 mg/day vs. placebo and Study 3 compared Vimpat doses of 200 and 400 mg/day vs. placebo.
The primary efficacy endpoint for all three studies was change in 28-day seizure frequency from Baseline to Maintenance Phase in the Vimpat arms vs. the placebo arms (p <0.05). Secondary endpoints included 50% responder rates (the percentage of patients with at least 50% reduction in seizure frequency from Baseline to Maintenance Phase).
All three studies were positive with respect to the primary efficacy endpoint and responder rates. The best results were achieved in patients taking the Vimpat 400 mg/day dose which is the maximum recommended daily dose. The 200 mg/day dose was also efficacious and is the recommended initial therapeutic dose. The Vimpat 600 mg/day dose was no more efficacious than the 400 mg/day dose, but it had a higher incidence of AEs and discontinuations.
Solution for Injection
In a study, Vimpat solution for injection was shown to be bioequivalent to the oral formulation. Furthermore, two trials were conducted in patients with partial-onset seizures using Vimpat solution for injection. These studies were designed to identify the appropriate infusion duration(s) for Vimpat solution for injection as a short-term replacement for Vimpat tablets and to provide data to support the safety of infusion rates including 30 and 60 minutes. A total of 199 patients with partial-onset seizures were exposed to Vimpat solution for injection (see section 3.3.4 Clinical Safety).
3.3.4 Clinical Safety
The clinical safety of Vimpat was evaluated in the three double-blind placebo-controlled studies described in section 3.3.3 Clinical Efficacy as well as in three open-label extension studies. A total of 924 patients with partial-onset seizures were exposed to Vimpat in the controlled studies and 1,048 patients in the extension studies.
Across the three controlled studies, the most common treatment-emergent AEs included dizziness, nausea, and diplopia. Other AEs of interest were ataxia, peripheral oedema, vertigo, blurred vision and skin rash. The frequency of occurrence of most AEs increased in a dose-proportional manner. Reported serious AEs (SAEs) included dizziness, diplopia, and ataxia.
Approximately 75% of patients randomized to Vimpat completed the controlled studies as compared to 87% of the patients randomized to placebo. Discontinuation due to lack of efficacy was 0.8% across the Vimpat arms as compared to 1.4% in the placebo arm. Events experienced by patients randomized to Vimpat that lead to discontinuation included dizziness (5.9% vs. placebo: 0.5%), ataxia (1.9% vs. placebo: 0%), diplopia (1.9% vs. placebo: 0.3%), vertigo (1.3% vs. placebo: 0%), and blurred vision (1.1% vs. placebo: 0%) all of which were dose-dependent. The Vimpat 600 mg/day dose did not provide additional efficacy and was associated with a higher frequency of AEs and discontinuations.
Three open-label studies were extensions of the controlled studies discussed above. A total of 1,048 patients received Vimpat at various doses. Overall, 702 patients received Vimpat ≥400 mg/day.
In the three open-label, extension studies, the most commonly reported AEs in Vimpat-treated patients were dizziness (31.0%), headache (14.0%), diplopia (12.6%), and nasopharyngitis (10.2%). About 37% of the patients discontinued the trials prematurely. The most common reasons for discontinuation were lack of efficacy (18%) and AEs (7%).
In Vimpat-treated patients across all epilepsy trials, 98 rash and rash-related events were reported (7.4%). Of these, 5 led to discontinuation (0.4%), 4 were considered "serious" (0.3%), and 25 were considered "related" to Vimpat use (1.9%).
Consistent with observations in the controlled studies, the number of AEs reported, the frequency of occurrence of AEs, and the discontinuation rates were dose-dependent.
Solution for Injection
Two trials were conducted in patients with partial-onset seizures using Vimpat solution for injection. These trials were designed to identify the appropriate infusion duration(s) for Vimpat solution for injection as a short-term replacement for Vimpat tablets and to provide data to support the safety of 30 and 60-minute infusion rates.
The first trial was a double-blind, double-dummy study which also provided pharmacokinetic data for the IV solution of Vimpat. Thirty-nine patients received Vimpat solution for injection and 21 patients received placebo for a maximum of 2 days at 30 to 60 minute infusion rates. In comparing those patients who received Vimpat (IV or orally in a previous treatment) vs. placebo, there was no difference in the number of seizures experienced, the severity or type of AEs experienced, nor in the number of cardiac-related events.
The second study included 160 patients who received IV Vimpat at 10-minute (20 patients), 15-minute (100 patients), and 30-minute (40 patients) infusion rates. The results of the study indicated that the pharmacokinetic data of the IV Vimpat were similar to those of the oral formulation. The IV solution of Vimpat appeared to be an efficacious short-term replacement for oral Vimpat as the pattern of seizure frequency for individual patients did not appear to be different than that obtained 8 weeks prior to entry into this study. The AE profile of this study was similar to that of the oral formulation(s) study with two exceptions. There was a serious event of bradycardia that occurred during a 15-minute infusion on Day 2. As well, in all infusion groups, there was an increase in mean PR-interval. Although transient, 2 patients had a PR-interval of >250 ms but remained asymptomatic.
These data support the use of the IV formulation as a temporary replacement for the oral formulation. An injection of Vimpat should be infused over 30 to 60 minutes.
Safety Issues of Interest
PR Interval
Cases of PR-interval prolongation leading to AV block were observed in both non-clinical and clinical studies. In humans, PR-interval increases at steady-state levels of Vimpat were dose-dependent and were observed at Tmax for Vimpat 400 mg/day (13.6 ms) and Tmax for Vimpat 800 mg/day (18.2 ms) vs. 6.3 ms for placebo.
In controlled epilepsy and neuropathic pain studies of Vimpat, the frequency of first-degree AV block as an adverse reaction in Vimpat arms was 0.4% and 0.6%, respectively, vs. 0% for each in the placebo arm.
Caution should be exercised when Vimpat is given with other drugs that prolong the PR interval (e.g., carbamazepine, pregabalin, lamotrigine or beta-blockers), as further PR prolongation is possible.
Syncope
In phase I epilepsy clinical trials, two Vimpat-treated patients experienced syncope (none in the placebo group). In controlled phase II/III epilepsy studies, two Vimpat-treated patients (0.2%) and one placebo-treated patient (0.3%) experienced syncope or loss of consciousness. In open-label epilepsy studies, 12 Vimpat-treated patients had syncope (2 at 400 mg/day, 2 at 500 mg/day and 8 at ≥600 mg/day).
In neuropathic pain placebo-controlled studies, a total of 15 Vimpat-treated patients or 1.0% (9 patients on a 600 mg/day regimen) experienced syncope or loss of consciousness vs. 0% in the placebo group. An additional 15 patients experienced syncope or loss of consciousness in the open-label studies with 4 of these patients withdrawing due to these AEs.
The cause of syncope was not determined in most cases; however, several cases were associated with changes in orthostatic blood pressure, atrial flutter/fibrillation (and associated tachycardia), or bradycardia.
Ophthalmological Effects
In controlled trials in patients with partial-onset seizures, Vimpat treatment was associated with vision-related AEs such as blurred vision (Vimpat, 8%; placebo, 3%) and diplopia (Vimpat, 11%; placebo, 2%). These events were mainly dose-dependent. Three percent of the patients randomized to Vimpat discontinued treatment due to these AEs (primarily diplopia).
Safety Conclusions
The cardiovascular-related findings of dose-dependent PR interval prolongation, atrial fibrillation, atrial flutter and syncope, have been addressed in the Product Monograph. The Product Monograph includes a contraindication for use in patients with second or third-degree AV-block or a previous history of this condition. Warning statements have been added to address disease states which might be adversely affected by PR interval prolongation. In addition, warning statements regarding cardiovascular-related events (e.g., atrial fibrillation, atrial flutter, syncope) were included.
Warning statements have also been added to the Vimpat Product Monograph to address other safety issues including ophthalmological events.
3.4 Benefit/Risk Assessment and Recommendation
3.4.1 Benefit/Risk Assessment
The benefit/risk profile for Vimpat for use as adjunctive therapy for the management of partial-onset seizures in adult patients with epilepsy who are not satisfactorily controlled with conventional therapy is favourable when used according to the conditions of use described in the Product Monograph. The 200 mg/day dose was efficacious and is the recommended initial therapeutic dose with Vimpat 400 mg/day as the target dose, which is also the recommended maximum daily dose. The Vimpat 600 mg/day dose was no more efficacious than the 400 mg/day dose, but had a higher incidence of AEs and discontinuations.
Vimpat is not indicated in paediatrics (<18 years of age) as there were only 10 paediatric patients in all studies combined.
Based on the long-term findings in animals, lacosamide demonstrated the potential to cause convulsions in human patients, particularly if plasma concentrations are much higher than the mean Cmax of 10.9 μg/mL after the MRHD of 200 mg BID, or possibly in particularly susceptible individuals. Adverse events termed "convulsions and related events" have been reported, albeit at low incidence, in patients with diabetic neuropathy taking lacosamide. Presumably, if lacosamide triggers convulsions in some patients with epilepsy, that would be reflected in reduced or loss of efficacy prompting discontinuation of lacosamide treatment.
In order to mitigate the risks associated with Vimpat, a contraindication for the use of Vimpat in patients with a history of, or presence of, second or third-degree AV block has been included in the Product Monograph. Warning statements have been added to address disease states which might be adversely affected by PR interval prolongation. In addition, warning statements regarding cardiovascular-related events (e.g., atrial fibrillation, atrial flutter and syncope) reported in both the clinical trials and the post-marketing database for this product, were included. Up to the end of August, 2010, worldwide post-market exposure to Vimpat stands at approximately 49,720 patients. Post-marketing data support the inclusion of contraindication and warning statements currently present in the Product Monograph.
3.4.2 Recommendation
Based on the Health Canada review of data on quality, safety and efficacy, Health Canada considers that the benefit/risk profile of Vimpat is favourable as adjunctive therapy in the management of partial-onset seizures in adult patients with epilepsy who are not satisfactorily controlled with conventional therapy. The 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.
4 Submission Milestones
Submission Milestones: VimpatTM
| Submission Milestone | Date |
|---|---|
| Pre-submission meeting: | 2007-11-20 |
| Submission filed: | 2009-03-17 |
| Screening | |
| Screening Acceptance Letter issued: | 2009-05-08 |
| Review | |
| Biopharmaceutics Evaluation complete: | 2010-07-08 |
| Quality Evaluation complete: | 2010-09-17 |
| Clinical Evaluation complete: | 2010-09-29 |
| Labelling Review complete: | 2010-09-24 |
| Notice of Compliance issued by Director General: | 2010-09-30 |
Related Drug Products
| Product name | DIN | Company name | Active ingredient(s) & strength |
|---|---|---|---|
| VIMPAT | 02357623 | UCB CANADA INC | LACOSAMIDE 100 MG |
| VIMPAT | 02357615 | UCB CANADA INC | LACOSAMIDE 50 MG |
| VIMPAT | 02357631 | UCB CANADA INC | LACOSAMIDE 150 MG |
| VIMPAT | 02357658 | UCB CANADA INC | LACOSAMIDE 200 MG |
| VIMPAT | 02357666 | UCB CANADA INC | LACOSAMIDE 10 MG / ML |