VIMPAT Solution for infusion Ref.[8019] Active ingredients: Lacosamide

Source: European Medicines Agency (EU)  Revision Year: 2022  Publisher: UCB Pharma S.A., Allée de la Recherche 60, B-1070, Bruxelles, Belgium

Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

Known second- or third-degree atrioventricular (AV) block.

Special warnings and precautions for use

Suicidal ideation and behaviour

Suicidal ideation and behaviour have been reported in patients treated with antiepileptic medicinal products in several indications. A meta-analysis of randomised placebo-controlled trials of antiepileptic medicinal products 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 (see section 4.8).

Cardiac rhythm and conduction

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) or patients treated with medicinal products affecting cardiac conduction, including antiarrhythmics and sodium channel blocking antiepileptic medicinal products (see section 4.5), as well as in elderly patients.

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.

In the placebo-controlled clinical studies of lacosamide in epilepsy patients, atrial fibrillation or flutter were not reported; however, both have been reported in open-label epilepsy studies and in postmarketing experience.

In post-marketing experience, AV block (including second degree or higher AV block) has been reported. In patients with proarrhythmic conditions, ventricular tachyarrhythmia has been reported. In rare cases, these events have led to asystole, cardiac arrest and death in patients with underlying proarrhythmic conditions.

Patients should be made aware of the symptoms of cardiac arrhythmia (e.g. slow, rapid or irregular pulse, palpitations, shortness of breath, feeling lightheaded, fainting). Patients should be counselled to seek immediate medical advice if these symptoms occur.

Dizziness

Treatment 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 (see section 4.8).

Potential for new onset or worsening of myoclonic seizures

New onset or worsening of myoclonic seizures has been reported in both adult and paediatric patients with PGTCS, in particular during titration. In patients with more than one seizure type, the observed benefit of control for one seizure type should be weighed against any observed worsening in another seizure type.

Potential for electro-clinical worsening in specific paediatric epilepsy syndromes

The safety and efficacy of lacosamide in paediatric patients with epilepsy syndromes in which focal and generalised seizures may coexist have not been determined.

Interaction with other medicinal products and other forms of interaction

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.

In vitro data

Data generally suggest that lacosamide has a low interaction potential. In vitro studies indicate that the enzymes CYP1A2, CYP2B6, and CYP2C9 are not induced and that CYP1A1, CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2D6, and CYP2E1 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. In vitro data show that CYP2C9, CYP2C19 and CYP3A4 are capable of catalysing the formation of the O-desmethyl metabolite.

In vivo data

Lacosamide does not inhibit or induce CYP2C19 and CYP3A4 to a clinically relevant extent. Lacosamide did not affect the AUC of midazolam (metabolised by CYP3A4, lacosamide given 200 mg twice a day), but Cmax of midazolam was slightly increased (30%). Lacosamide did not affect the pharmacokinetics of omeprazole (metabolised by CYP2C19 and CYP3A4, lacosamide given 300 mg twice a day).

The CYP2C19 inhibitor omeprazole (40 mg once daily) did not give rise to a clinically significant change in lacosamide exposure. Thus, moderate inhibitors of CYP2C19 are unlikely to affect systemic lacosamide exposure to a clinically relevant extent.

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.

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 medicinal products

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.

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 studies showed that lacosamide had no effect on the pharmacokinetics of digoxin. There was no clinically relevant interaction between lacosamide and metformin.

Co-administration of warfarin with lacosamide does not result in a clinically relevant change in the pharmacokinetics and pharmacodynamics of warfarin.

Although no pharmacokinetic data on the interaction of lacosamide with alcohol are available, a pharmacodynamic effect cannot be excluded.

Lacosamide has a low protein binding of less than 15%. Therefore, clinically relevant interactions with other medicinal products through competition for protein binding sites are considered unlikely.

Fertility, pregnancy and lactation

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.

Pregnancy

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 (see section 5.3). 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.

Breastfeeding

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.

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).

Effects on ability to drive and use machines

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.

Undesirable effects

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.

System organ class Very commonCommon Uncommon Not known
Blood and
lymphatic
disorders
   Agranulocytosis1
Immune system
disorders
  Drug
hypersensitivity1
Drug reaction with
eosinophilia and
systemic symptoms
(DRESS)1,2
Psychiatric
disorders
 Depression
Confusional state
Insomnia1
Aggression
Agitation1
Euphoric mood1
Psychotic
disorder1
Suicide attempt1
Suicidal ideation
Hallucination1
 
Nervous system
disorders
Dizziness
Headache
Myoclonic
seizures3
Ataxia
Balance disorder
Memory
impairment
Cognitive disorder
Somnolence
Tremor
Nystagmus
Hypoesthesia
Dysarthria
Disturbance in
attention
Paraesthesia
Syncope2
Coordination
abnormal
Dyskinesia
Convulsion
Eye disorders Diplopia Vision blurred  
Ear and labyrinth
disorders
 Vertigo
Tinnitus
  
Cardiac disorders   Atrioventricular
block1,2
Bradycardia1,2
Atrial Fibrillation1,2
Atrial Flutter1,2
Ventricular
tachyarrhythmia1
Gastrointestinal
disorders
Nausea Vomiting
Constipation
Flatulence
Dyspepsia
Dry mouth
Diarrhoea
  
Hepatobiliary
disorders
  Liver function test
abnormal2
Hepatic enzyme
increased
(>2x ULN)1
 
Skin and
subcutaneous
tissue disorders
 Pruritus
Rash1
Angioedema1
Urticaria1
Stevens-Johnson
syndrome1
Toxic epidermal
necrolysis1
Musculoskeletal
and connective
tissue disorders
 Muscle spasms  
General disorders
and administration
site conditions
 Gait disturbance
Asthenia
Fatigue
Irritability
Feeling drunk
Injection site pain
or discomfort4
Irritation4
Erythema4  
Injury, poisoning
and procedural
complications
 Fall
Skin laceration
Contusion
  

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 Vimpat 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.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V.

Incompatibilities

This medicinal product must not be mixed with other medicinal products except those mentioned in section 6.6.

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