Drug Class Description
Other antiepileptics

Generic Name
Lacosamide

Drug Description
Solution for infusion. Clear, colourless solution.

Presentation
Each ml of solution for infusion contains 10 mg lacosamide. 1 vial of 20 ml solution for infusion contains 200 mg lacosamide. Excipient: Each ml of solution for infusion contains includes 2.99 mg sodium.

Indications
Vimpat is indicated as adjunctive therapy in the treatment of partial-onset seizures with or without secondary generalisation in patients with epilepsy aged 16 years and older. Vimpat solution for infusion is an alternative for patients when oral administration is temporarily not feasible.

Adult Dosage
Vimpat must be administered twice a day. The recommended starting dose is 50 mg twice a day which should be increased to an initial therapeutic dose of 100 mg twice a day after one week.Depending on 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). In accordance with current clinical practice, if Vimpat has to be discontinued, it is recommended this be done gradually (e.g. taper the daily dose by 200 mg/week).Vimpat therapy can be initiated with either oral or i.v. administration. The solution for infusion is infused over a period of 15 to 60 minutes twice daily. Vimpat solution for infusion can be administered i.v. without further dilution. Conversion to or from oral and i.v. administration can be done directly without titration. The total daily dose and twice daily administration should be maintained.There is experience with twice daily infusions of Vimpat up to 5 days. Use in patients with renal impairment No dose adjustment is necessary in mildly and moderately renally impaired patients (CLCR >30 ml/min). A maximum dose of 250 mg/day is recommended for patients with severe renal impairment (CLCR =30 ml/min) and in patients with endstage renal disease. For patients requiring haemodialysis a supplement of up to 50% of the divided daily dose directly after the end of haemodialysis is recommended.Treatment of patients with end-stage renal disease should be made with caution as there is little clinical experience and accumulation of a metabolite (with no known pharmacological activity). In all patients with renal impairment, the dose titration should be performed with caution. Use in patients with hepatic impairment No dose adjustment is needed for patients with mild to moderate hepatic impairment. The dose titration in these patients should be performed with caution considering co-existing renal impairment. The pharmacokinetics of lacosamide has not been eva luated in severely hepatic impaired patients.

Child Dosage
Paediatric patients Vimpat is not recommended for use in children and adolescents below the age of 16 as there is no data on safety and efficacy in these age groups.

Elderly Dosage
Use in elderly (over 65 years of age) No dose reduction is necessary in elderly patients. The experience with lacosamide in elderly patients with epilepsy is limited. Age associated decreased renal clearance with an increase in AUC levels should be considered in elderly patients.

Contra Indications
Hypersensitivity to the active substance or to any of the excipients. Known second- or third-degree atrioventricular (AV) block.

Special Precautions
DizzinessTreatment with lacosamide has been associated with dizziness which could increase the occurrence of accidental injury or falls. Therefore, patients should be advised to exercise caution until they are familiar with the potential effects of the medicine.Cardiac Rhythm and ConductionProlongations in PR interval with lacosamide have been observed in clinical studies. Lacosamide should be used with caution in patients with known conduction problems or severe cardiac disease such as a history of myocardial infarction or heart failure. Caution should especially be exerted when treating elderly patients as they may be at an increased risk of cardiac disorders or when lacosamide is used in combination with products known to be associated with PR prolongation.Second degree or higher AV block has been reported in post-marketing experience. In the placebo-controlled trials of lacosamide in epilepsy patients, atrial fibrillation or flutter were not reported; however both have been reported in open-label epilepsy trials and in post-marketing experience.Patients should be made aware of the symptoms of second-degree or higher AV block (e.g. slow or irregular pulse, feeling of lightheaded and fainting) and of the symptoms of atrial fibrillation and flutter (e.g. palpitations, rapid or irregular pulse, shortness of breath). Patients should be counseled to seek medical advice should any of these symptoms occur.Suicidal ideation and behaviourSuicidal ideation and behaviour have been reported in patients treated with anti-epileptic agents in several indications. A meta-analysis of randomised placebo controlled trials of anti-epileptic drugs has also shown a small increased risk of suicidal ideation and behaviour. The mechanism of this risk is not known and the available data do not exclude the possibility of an increased risk for lacosamide.Therefore patients should be monitored for signs of suicidal ideation and behaviours and appropriate treatment should be considered. Patients (and caregivers of patients) should be advised to seek medical advice should signs of suicidal ideation or behaviour emerge.Syrup:Vimpat syrup contains sodium methylhydroxybenzoate (E219), which may cause allergic reactions (possibly delayed). It contains 3.7 g sorbitol (E420) per dose (200 mg lacosamide), corresponding to a calorific value of 9.7 kcal. Patients with rare hereditary problems of fructose intolerance should not take this medicine. The syrup contains aspartame (E951), a source of phenylalanine, which may be harmful for people with phenylketonuria. It contains 1.13 mmol (or 26.01 mg) sodium per dose (200 mg lacosamide). To be taken into consideration for patients on a controlled sodium diet.Solution for infusion:This medicinal product contains 2.6 mmol (or 59.8 mg) sodium per vial. To be taken into consideration for patients on a controlled sodium diet.

Interactions
Lacosamide should be used with caution in patients treated with medicinal products known to be associated with PR prolongation (e.g. carbamazepine, lamotrigine, pregabalin) and in patients treated with class I antiarrhythmic drugs. However, subgroup analysis did not identify an increased magnitude of PR prolongation in patients with concomitant administration of carbamazepine or lamotrigine in clinical trials.Data generally suggest that lacosamide has a low interaction potential. In vitro studies indicate that the enzymes CYP1A2, 2B6, and 2C9 are not induced and that CYP1A1, 1A2, 2A6, 2B6, 2C8, 2C9, 2D6, and 2E1 are not inhibited by lacosamide at plasma concentrations observed in clinical trials. An in vitro study indicated that lacosamide is not transported by P-glycoprotein in the intestine. Lacosamide does not inhibit or induce the enzyme CYP2C19 in vivo. In vitro studies indicate that lacosamide may be a weak inhibitor and inducer of CYP3A4. The clinical relevance of this is presently unknown. An interaction study with carbamazepine does not indicate a marked inhibitory effect of lacosamide on CYP3A4 catalysed metabolism at therapeutic doses. Strong enzyme inducers such as rifampicin or St John´s wort (Hypericum perforatum) may moderately reduce the systemic exposure of lacosamide. Therefore, starting or ending treatment with these enzyme inducers should be done with caution.Antiepileptic drugs In interaction trials lacosamide did not significantly affect the plasma concentrations of carbamazepine and valproic acid. Lacosamide plasma concentrations were not affected by carbamazepine and by valproic acid. A population PK analysis estimated that concomitant treatment with other anti-epileptic drugs known to be enzyme inducers (carbamazepine, phenytoin, phenobarbital, in various doses) decreased the overall systemic exposure of lacosamide by 25%. Oral contraceptives In an interaction trial there was no clinically relevant interaction between lacosamide and the oral contraceptives ethinylestradiol and levonorgestrel. Progesterone concentrations were not affected when the medicinal products were co-administered. Others Interaction trials showed that lacosamide had no effect on the pharmacokinetics of digoxin. There was no clinically relevant interaction between lacosamide and metformin. Omeprazole 40 mg q.d. increased the AUC of lacosamide by 19%. The effect probably lacks clinical relevance.Lacosamide did not affect the single-dose pharmacokinetics of omeprazole. No data on the interaction of lacosamide with alcohol are available. Lacosamide has a low protein binding of less than 15%. Therefore, clinically relevant interactions with other drugs through competition for protein binding sites are considered unlikely. Pregnancy: Risk related to epilepsy and antiepileptic medicinal products in general For all anti-epileptic drugs, it has been shown that in the offspring of women treated with epilepsy, the preva lence of malformations is two to three times greater than the rate of approximately 3% in the general population. In the treated population, an increase in malformations has been noted with polytherapy, however, the extent to which the treatment and/or the illness is responsible has not been elucidated. Moreover, effective anti-epileptic therapy must not be interrupted, since the aggravation of the illness is detrimental to both the mother and the foetus.Risk related to lacosamide There are no adequate data from the use of lacosamide in pregnant women. Studies in animals did not indicate any teratogenic effects in rats or rabbits, but embryotoxicity was observed in rats and rabbits at maternal toxic doses. The potential risk for humans is unknown. Lacosamide should not be used during pregnancy unless clearly necessary (if the benefit to the mother clearly outweighs the potential risk to the foetus). If women decide to become pregnant, the use of this product should be carefully re-eva luated. Lactation: It is unknown whether lacosamide is excreted in human breast milk. Animal studies have shown excretion of lacosamide in breast milk. For precautionary measures, breast-feeding should be discontinued during treatment with lacosamide.

Adverse Reactions
Summary of safety profileBased on the analysis of pooled placebo-controlled clinical trials in 1,308 patients with partial-onset seizures, a total of 61.9% of patients randomized to lacosamide and 35.2% of patients randomized to placebo reported at least 1 adverse reaction. The most frequently reported adverse reactions with lacosamide treatment were dizziness, headache, nausea and diplopia. They were usually mild to moderate in intensity. Some were dose-related and could be alleviated by reducing the dose. Incidence and severity of CNS and gastrointestinal (GI) adverse reactions usually decreased over time.Over all controlled studies, the discontinuation rate due to adverse reactions was 12.2% for patients randomized to lacosamide and 1.6% for patients randomized to placebo. The most common adverse reaction resulting in discontinuation of lacosamide therapy was dizziness.Tabulated list of adverse reactionsThe table below shows the frequencies of adverse reactions which have been reported in pooled placebo-controlled clinical trials (with an incidence rate1% in the lacosamide group and which are >1% more than placebo) and post-marketing experience. The frequencies are defined as follows: very common (1/10), common (1/100 to <1/10), uncommon (1/1,000 to <1/100). Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.System organ classVery commonCommonUncommonImmune system disordersDrug hypersensitivity(2)Psychiatric disordersDepressionConfusional state(1)Insomnia(2)Aggression(2)Agitation(2)Euphoric mood(2)Psychotic disorder(2)Suicide attempt(2)Suicidal ideation(2)Nervous system disordersDizzinessHeadacheBalance disorderCoordination abnormalMemory impairmentCognitive disorderSomnolenceTremorNystagmusHypoesthesia(1)Dysarthria(1)Disturbance in attention(1)Eye disordersDiplopiaVision blurredEar and labyrinth disordersVertigoTinnitus(1)Cardiac disordersAtrioventricular block(2)Bradycardia(2)Atrial Fibrillation(2)Atrial Flutter(2)Gastrointestinal disordersNauseaVomitingConstipationFlatulenceDyspepsia(1)Dry mouth(1)Hepatobiliary disordersLiver function test abnormal(2)Skin and subcutaneous tissue disordersPruritusRash(2)Angioedema(2)Urticaria(2)Musculoskeletal and connective tissue disordersMuscle spasms(1)General disorders and administration site conditionsGait disturbanceAstheniaFatigueIrritability(1)injection site pain or discomfort(3)irritation(3)Erythema(3)Injury, poisoning and procedural complicationsFallSkin laceration(1)potentially important adverse drug reactions identified as being reported in pooled clinical trials with an incidence rate not meeting the criteria used above.(2)adverse reactions reported in post marketing experience.(3)local adverse events associated with intravenous administrationDescription of selected adverse reactionsThe use of lacosamide is associated with dose-related increase in the PR interval. Adverse reactions associated with PR interval prolongation (e.g. atrioventricular block, syncope, bradycardia) may occur.In clinical trials in epilepsy patients the incidence rate of reported first degree AV Block is uncommon, 0.7%, 0%, 0.5% and 0% for lacosamide 200 mg, 400 mg, 600 mg or placebo, respectively. No second or higher degree AV Block was seen in these studies. However, cases with second and third degree AV Block associated with lacosamide treatment have been reported in post-marketing experience.In clinical trials, the incidence rate for syncope is uncommon and did not differ between lacosamide treated epilepsy patients (0.1%) and placebo treated epilepsy patients (0.3%).Atrial fibrillation or flutter were not reported in short term clinical trials; however both have been reported in open-label epilepsy trials and in post-marketing experience.Laboratory abnormalitiesAbnormalities in liver function tests have been observed in controlled trials with lacosamide in adult patients with partial-onset seizures who were taking 1 to 3 concomitant anti-epileptic drugs. Elevations of ALT to3XULN occurred in 0.7% (7/935) of Vimpat patients and 0% (0/356) of placebo patients.MultiorganHypersensitivity ReactionsMultiorgan hypersensitivity reactions have been reported in patients treated with some antiepileptic agents. These reactions are variable in expression but typically present with fever and rash and can be associated with involvement of different organ systems. Potential cases have been reported rarely with lacosamide and if multiorgan hypersensitivity reaction is suspected, lacosamide should be discontinued.

Manufacturer
UCB Pharma

Drug Availability
(POM)

Updated
23 November 2011