Lacosamide

Caution is recommended in concomitant treatment with strong inhibitors of CYP2C9 (e.g. fluconazole) and CYP3A4 (e.g. itraconazole, ketoconazole, ritonavir, clarithromycin), which may lead to increased systemic exposure of lacosamide. Such interactions have not been established in vivo, but are possible based on in vitro data.

Lacosamide should be used with caution in patients treated with medicinal products known to be associated with PR prolongation (including sodium channel blocking antiepileptic medicinal products) and in patients treated with antiarrhythmics. However, subgroup analysis in clinical trials did not identify an increased magnitude of PR prolongation in patients with concomitant administration of carbamazepine or lamotrigine.

No dose adjustment is necessary in mildly and moderately renally impaired adult and paediatric patients (CL_CR >30 ml/min). In paediatric patients weighing 50 kg or more and in adult patients with mild or moderate renal impairment a loading dose of 200 mg may be considered, but further dose titration (>200 mg daily) should be performed with caution.

In paediatric patients weighing 50 kg or more and in adult patients with severe renal impairment (CL_CR ≤30 ml/min) or with end-stage renal disease, a maximum dose of 250 mg/day is recommended and the dose titration should be performed with caution. If a loading dose is indicated, an initial dose of 100 mg followed by a 50 mg twice daily regimen for the first week should be used. In paediatric patients weighing less than 50 kg with severe renal impairment (CL_CR ≤30 ml/min) and in those with end-stage renal disease, a reduction of 25% of the maximum dose is recommended. For all 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).

A maximum dose of 300 mg/day is recommended for paediatric patients weighing 50 kg or more and for adult patients with mild to moderate hepatic impairment. The dose titration in these patients should be performed with caution considering co-existing renal impairment. In adolescents and adults weighing 50 kg or more, a loading dose of 200 mg may be considered, but further dose titration (>200 mg daily) should be performed with caution. Based on data in adults, in paediatric patients weighing less than 50 kg with mild to moderate hepatic impairment, a reduction of 25% of the maximum dose should be applied.

The pharmacokinetics of lacosamide has not been evaluated in severely hepatic impaired patients. Lacosamide should be administered to adult and paediatric patients with severe hepatic impairment only when the expected therapeutic benefits are anticipated to outweigh the possible risks. The dose may need to be adjusted while carefully observing disease activity and potential side effects in the patient.

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. Population pharmacokinetic analyses in different age groups estimated that concomitant treatment with other antiepileptic medicinal products known to be enzyme inducers (carbamazepine, phenytoin, phenobarbital, in various doses) decreased the overall systemic exposure of lacosamide by 25% in adults and 17% in paediatric patients.

Dose-related prolongations in PR interval with lacosamide have been observed in clinical studies. Lacosamide should be used with caution in patients with underlying proarrhythmic conditions such as patients with known cardiac conduction problems or severe cardiac disease (e.g. myocardial ischaemia/infarction, heart failure, structural heart disease or cardiac sodium channelopathies). In these patients it should be considered to perform an ECG before a lacosamide dose increase above 400 mg/day and after lacosamide is titrated to steady-state.

Risk related to epilepsy and antiepileptic medicinal products in general

For all antiepileptic medicinal products, it has been shown that in the offspring of treated women with epilepsy, the prevalence 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 antiepileptic 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-evaluated.

Lacosamide is excreted in human breast milk. A risk to the newborns/infants cannot be excluded. It is recommended that breast-feeding should be discontinued during treatment with lacosamide.

Women of childbearing potential

Physicians should discuss family planning and contraception with women of childbearing potential taking lacosamide (see Pregnancy).

If a woman decides to become pregnant, the use of lacosamide should be carefully re-evaluated.

Fertility

No adverse reactions on male or female fertility or reproduction were observed in rats at doses producing plasma exposures (AUC) up to approximately 2 times the plasma AUC in humans at the maximum recommended human dose (MRHD).

Lacosamide has minor to moderate influence on the ability to drive and use machines. Lacosamide treatment has been associated with dizziness or blurred vision. Accordingly, patients should be advised not to drive or to operate other potentially hazardous machinery until they are familiar with the effects of lacosamide on their ability to perform such activities.

Summary of safety profile

Based on the analysis of pooled placebo-controlled clinical studies in adjunctive therapy in 1,308 patients with partial-onset seizures, a total of 61.9% of patients randomised to lacosamide and 35.2% of patients randomised to placebo reported at least 1 adverse reaction. The most frequently reported adverse reactions (≥10%) 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 central nervous system (CNS) and gastrointestinal (GI) adverse reactions usually decreased over time.

In all of these controlled clinical studies, the discontinuation rate due to adverse reactions was 12.2% for patients randomised to lacosamide and 1.6% for patients randomised to placebo. The most common adverse reaction resulting in discontinuation of lacosamide therapy was dizziness. Incidence of CNS adverse reactions such as dizziness may be higher after a loading dose.

Based on the analysis of data from a non-inferiority monotherapy clinical study comparing lacosamide to carbamazepine controlled release (CR), the most frequently reported adverse reactions (≥10%) for lacosamide were headache and dizziness. The discontinuation rate due to adverse reactions was 10.6% for patients treated with lacosamide and 15.6% for patients treated with carbamazepine CR.

The safety profile of lacosamide reported in a study conducted in patients aged 4 years and older with idiopathic generalised epilepsy with primary generalised tonic-clonic seizures (PGTCS) was consistent with the safety profile reported from the pooled placebo-controlled clinical studies in partial-onset seizures. Additional adverse reactions reported in PGTCS patients were myoclonic epilepsy (2.5% in he lacosamide-group and 0% in the placebo-group) and ataxia (3.3% in the lacosamide-group and 0% in the placebo-group). The most frequently reported adverse reactions were dizziness and somnolence. The most common adverse reactions resulting in discontinuation of lacosamide therapy were dizziness and suicidal ideation. The discontinuation rate due to adverse reactions was 9.1% in the lacosamide group and 4.1% in the placebo group.

Tabulated list of adverse reactions

The table below shows the frequencies of adverse reactions which have been reported in clinical trials 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) and not known (frequency cannot be estimated from available data). Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

¹ Adverse reactions reported in post marketing experience.
² See Description of selected adverse reactions.
³ Reported in open-label studies.

Description of selected adverse reactions

The 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 adjunctive 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 the monotherapy clinical trial comparing lacosamide to carbamazepine CR, the extent of increase in PR interval was comparable between lacosamide and carbamazepine. The incidence rate for syncope reported in pooled adjunctive therapy clinical trials is uncommon and did not differ between lacosamide (n=944) treated epilepsy patients (0.1%) and placebo (n=364) treated epilepsy patients (0.3%). In the monotherapy clinical trial comparing lacosamide to carbamazepine CR, syncope was reported in 7/444 (1.6%) lacosamide patients and in 1/442 (0.2%) carbamazepine CR patients.

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 abnormalities

Abnormalities in liver function tests have been observed in placebo-controlled trials with lacosamide in adult patients with partial-onset seizures who were taking 1 to 3 concomitant antiepileptic medicinal products. Elevations of ALT to ≥3x ULN occurred in 0.7% (7/935) of lacosamide patients and 0% (0/356) of placebo patients.

Multiorgan hypersensitivity reactions

Multiorgan hypersensitivity reactions (also known as Drug Reaction with Eosinophilia and Systemic Symptoms, DRESS) have been reported in patients treated with some antiepileptic medicinal products. These reactions are variable in expression, but typically present with fever and rash and can be associated with involvement of different organ systems. If multiorgan hypersensitivity reaction is suspected, lacosamide should be discontinued.

Paediatric population

The safety profile of lacosamide in placebo-controlled (255 patients from 1 month to less than 4 years of age and 343 patients from 4 years to less than 17 years of age) and in open-label clinical studies (847 patients from 1 month to less than or equal to 18 years of age) in adjunctive therapy in paediatric patients with partial-onset seizures was consistent with the safety profile observed in adults. As data available in paediatric patients younger than 2 years of age is limited, lacosamide is not indicated in this age range.

The additional adverse reactions observed in the paediatric population were pyrexia, nasopharyngitis, pharyngitis, decreased appetite, abnormal behaviour and lethargy. Somnolence was reported more frequently in the paediatric population (≥1/10) compared to the adult population (≥1/100 to <1/10).

Elderly population

In the monotherapy study comparing lacosamide to carbamazepine CR, the types of adverse reactions related to lacosamide in elderly patients (≥65 years of age) appear to be similar to that observed in patients less than 65 years of age. However, a higher incidence (≥5% difference) of fall, diarrhoea and tremor has been reported in elderly patients compared to younger adult patients. The most frequent cardiac-related adverse reaction reported in elderly compared to the younger adult population was first-degree AV block. This was reported with lacosamide in 4.8% (3/62) in elderly patients versus 1.6% (6/382) in younger adult patients. The discontinuation rate due to adverse events observed with lacosamide was 21.0% (13/62) in elderly patients versus 9.2% (35/382) in younger adult patients. These differences between elderly and younger adult patients were similar to those observed in the active comparator group.