4.1. Therapeutic indications

Vimpat is indicated as monotherapy in the treatment of partial-onset seizures with or without secondary generalisation in adults, adolescents and children from 2 years of age with epilepsy.

Vimpat is indicated as adjunctive therapy

• in the treatment of partial-onset seizures with or without secondary generalisation in adults, adolescents and children from 2 years of age with epilepsy.

• in the treatment of primary generalised tonic-clonic seizures in adults, adolescents and children from 4 years of age with idiopathic generalised epilepsy.

4.2. Posology and method of administration

Posology

The physician should prescribe the most appropriate formulation and strength according to weight and dose.

The recommended posology for adults, adolescents and children from 2 years of age is summarised in the following table.

Lacosamide must be taken twice a day, approximately 12 hours apart.

If a dose is missed, the patient should be instructed to take the missed dose immediately, and then to take the next dose of lacosamide at the regularly scheduled time. If the patient notices the missed dose within 6 hours of the next one, he/she should be instructed to wait to take the next dose of lacosamide at the regularly scheduled time. Patients should not take a double dose.

Adolescents and children weighing 50 kg or more, and adults

Starting dose

Titration (incremental steps)

Maximum recommended dose

Monotherapy: 50 mg twice a day (100 mg/day) or 100 mg twice a day (200 mg/day)

Adjunctive therapy: 50 mg twice a day (100 mg/day)

50 mg twice a day (100 mg/day) at weekly intervals

Monotherapy: up to 300 mg twice a day (600 mg/day)

Adjunctive therapy: up to 200 mg twice a day (400 mg/day)

Alternate initial dosage* (If applicable):

200 mg single loading dose followed by 100 mg twice a day (200 mg/day)

* A loading dose may be initiated in patients in situations when the physician determines that rapid attainment of lacosamide steady state plasma concentration and therapeutic effect is warranted. It should be administered under medical supervision with consideration of the potential for increased incidence of serious cardiac arrhythmia and central nervous system adverse reactions (see section 4.8). Administration of a loading dose has not been studied in acute conditions such as status epilepticus.

Children from 2 years of age and adolescents weighing less than 50 kg

Starting dose

Titration (incremental steps)

Maximum recommended dose

Monotherapy and Adjunctive therapy: 1 mg/kg twice a day (2 mg/kg/day)

1 mg/kg twice a day (2 mg/kg/day) at weekly intervals

Monotherapy:

- up to 6 mg/kg twice a day (12 mg/kg/day) in patients ≥ 10 kg to < 40 kg

- up to 5 mg/kg twice a day (10 mg/kg/day) in patients ≥ 40 kg to < 50 kg

Adjunctive therapy:

- up to 6 mg/kg twice a day (12 mg/kg/day) in patients ≥ 10 kg to < 20 kg

- up to 5 mg/kg twice a day (10 mg/kg/day) in patients ≥ 20 kg to < 30 kg

- up to 4 mg/kg twice a day (8 mg/kg/day) in patients ≥ 30 kg to < 50 kg

Adolescents and children weighing 50 kg or more, and adults

Monotherapy (in the treatment of partial-onset seizures)

The recommended starting dose is 50 mg twice a day (100 mg/day) which should be increased to an initial therapeutic dose of 100 mg twice a day (200 mg/day) after one week.

Lacosamide can also be initiated at the dose of 100 mg twice a day (200 mg/day) based on the physician's assessment of required seizure reduction versus potential side effects. Depending on response and tolerability, the maintenance dose can be further increased at weekly intervals by 50 mg twice a day (100 mg/day), up to a maximum recommended daily dose of 300 mg twice a day (600 mg/day).

In patients having reached a dose greater than 200 mg twice a day (400 mg/day) and who need an additional antiepileptic medicinal product, the posology that is recommended for adjunctive therapy below should be followed.

Adjunctive therapy (in the treatment of partial-onset seizures or in the treatment of primary generalised tonic-clonic seizures)

The recommended starting dose is 50 mg twice a day (100 mg/day) which should be increased to an initial therapeutic dose of 100 mg twice a day (200 mg/day) after one week. Depending on response and tolerability, the maintenance dose can be further increased at weekly intervals by 50 mg twice a day (100 mg/day), up to a maximum recommended daily dose of 200 mg twice a day (400 mg/day).

Children from 2 years of age and adolescents weighing less than 50 kg

The dose is determined based on body weight. It is therefore recommended to initiate treatment with the syrup and switch to tablets, if desired. When prescribing the syrup, the dose should be expressed in volume (ml) rather than weight (mg).

Monotherapy (in the treatment of partial-onset seizures)

The recommended starting dose is 1 mg/kg twice a day (2 mg/kg/day) which should be increased to an initial therapeutic dose of 2 mg/kg twice a day (4 mg/kg/day) after one week.

Depending on response and tolerability, the maintenance dose can be further increased by 1 mg/kg twice a day (2 mg/kg/day) every week. The dose should be gradually increased until the optimum response is obtained. The lowest effective dose should be used. In children weighing from 10 kg to less than 40 kg, a maximum dose of up to 6 mg/kg twice a day (12 mg/kg/day) is recommended. In children weighing from 40 to under 50 kg, a maximum dose of 5 mg/kg twice a day (10 mg/kg/day) is recommended.

The tables below provide examples of volumes of syrup per intake depending on prescribed dose and body weight. The precise volume of syrup is to be calculated according to the exact body weight of the child. The calculated volume should be rounded to the nearest measuring device graduated increment. If the calculated volume is equidistant between two graduated increments, the larger graduated increment should be used (see Method of administration).

Monotherapy doses in the treatment of partial-onset seizures to be taken twice a day for children from 2 years of age weighing from 10 kg to less than 40 kg

Week

Week 1

Week 2

Week 3

Week 4

Week 5

Week 6

Prescribed dose

0.1 ml/kg

(1 mg/kg)

Starting dose

0.2 ml/kg

(2 mg/kg)

0.3 ml/kg

(3 mg/kg)

0.4 ml/kg

(4 mg/kg)

0.5 ml/kg

(5 mg/kg)

0.6 ml/kg

(6 mg/kg)

Maximum recommended dose

Recommended device: 10 ml syringe for volume between 1 ml and 20 ml

*30 ml measuring cup for volume more than 20 ml

Weight

Volume administered

10 kg

1 ml

(10 mg)

2 ml

(20 mg)

3 ml

(30 mg)

4 ml

(40 mg)

5 ml

(50 mg)

6 ml

(60 mg)

15 kg

1.5 ml

(15 mg)

3 ml

(30 mg)

4.5 ml

(45 mg)

6 ml

(60 mg)

7.5 ml

(75 mg)

9 ml

(90 mg)

20 kg

2 ml

(20 mg)

4 ml

(40 mg)

6 ml

(60 mg)

8 ml

(80 mg)

10 ml

(100 mg)

12 ml

(120 mg)

25 kg

2.5 ml

(25 mg)

5 ml

(50 mg)

7.5 ml

(75 mg)

10 ml

(100 mg)

12.5 ml

(125 mg)

15 ml

(150 mg)

30 kg

3 ml

(30 mg)

6 ml

(60 mg)

9 ml

(90 mg)

12 ml

(120 mg)

15 ml

(150 mg)

18 ml

(180 mg)

35 kg

3.5 ml

(35 mg)

7 ml

(70 mg)

10.5 ml

(105 mg)

14 ml

(140 mg)

17.5 ml

(175 mg)

21 ml*

(210 mg)

For volume between 1 ml and 20 ml, the patient should be instructed to use the 10 ml oral syringe.

* For volume above 20 ml, the patient should be instructed to use the 30 ml measuring cup.

Monotherapy doses in the treatment of partial-onset seizures to be taken twice a day for children and adolescents weighing from 40 kg to less than 50 kg(1)

Week

Week 1

Week 2

Week 3

Week 4

Week 5

Prescribed dose

0.1 ml/kg

(1 mg/kg)

Starting dose

0.2 ml/kg

(2 mg/kg)

0.3 ml/kg

(3 mg/kg)

0.4 ml/kg

(4 mg/kg)

0.5 ml/kg

(5 mg/kg)

Maximum recommended dose

Recommended device: 10 ml syringe for volume between 1 ml and 20 ml

*30 ml measuring cup for volume more than 20 ml

Weight

Volume administered

40 kg

4 ml

(40 mg)

8 ml

(80 mg)

12 ml

(120 mg)

16 ml

(160 mg)

20 ml

(200 mg)

45 kg

4.5 ml

(45 mg)

9 ml

(90 mg)

13.5 ml

(135 mg)

18 ml

(180 mg)

22.5 ml*

(225 mg)

(1) Dosage in adolescents 50 kg or more is the same as in adults.

For volume between 1 ml and 20 ml, the patient should be instructed to use the 10 ml oral syringe.

* For volume above 20 ml, the patient should be instructed to use the 30 ml measuring cup.

Adjunctive therapy (in the treatment of primary generalised tonic-clonic seizures from 4 years of age or in the treatment of partial-onset seizures from 2 years of age)

The recommended starting dose is 1 mg/kg twice a day (2 mg/kg/day) which should be increased to an initial therapeutic dose of 2 mg/kg twice a day (4 mg/kg/day) after one week.

Depending on response and tolerability, the maintenance dose can be further increased by 1 mg/kg twice a day (2 mg/kg/day) every week. The dose should be gradually adjusted until the optimum response is obtained. The lowest effective dose should be used. Due to an increased clearance compared to adults, in children weighing from 10 kg to less than 20 kg, a maximum dose of up to 6 mg/kg twice a day (12 mg/kg/day) is recommended. In children weighing from 20 to under 30 kg, a maximum dose of 5 mg/kg twice a day (10 mg/kg/day) is recommended and in children weighing from 30 to under 50 kg, a maximum dose of 4 mg/kg twice a day (8 mg/kg/day) is recommended, although in open-label studies (see sections 4.8 and 5.2), a dose up to 6 mg/kg twice a day (12 mg/kg/day) has been used by a small number of children from this latter group.

The tables below provide examples of volumes of syrup per intake depending on prescribed dose and body weight. The precise volume of syrup is to be calculated according to the exact body weight of the child. The calculated volume should be rounded to the nearest measuring device graduated increment. If the calculated volume is equidistant between two graduated increments, the larger graduated increment should be used.

Adjunctive therapy doses to be taken twice a day for children from 2 years weighing from 10 kg to less than 20 kg

Week

Week 1

Week 2

Week 3

Week 4

Week 5

Week 6

Prescribed dose

0.1 ml/kg

(1 mg/kg)

Starting dose

0.2 ml/kg

(2 mg/kg)

0.3 ml/kg

(3 mg/kg)

0.4 ml/kg

(4 mg/kg)

0.5 ml/kg

(5 mg/kg)

0.6 ml/kg

(6 mg/kg)

Maximum recommended dose

Recommended device: 10 ml syringe for volume between 1 ml and 20 ml

Weight

Volume administered

10 kg

1 ml

(10 mg)

2 ml

(20 mg)

3 ml

(30 mg)

4 ml

(40 mg)

5 ml

(50 mg)

6 ml*

(60 mg)

12 kg

1.2 ml

(12 mg)

2.4 ml

(24 mg)

3.6 ml

(36 mg)

4.8 ml

(48 mg)

6 ml

(60 mg)

7.2 ml

(72 mg)

14 kg

1.4 ml

(14 mg)

2.8 ml

(28 mg)

4.2 ml

(42 mg)

5.6 ml

(56 mg)

7 ml

(70 mg)

8.4 ml

(84 mg)

15 kg

1.5 ml

(15 mg)

3 ml

(30 mg)

4.5 ml

(45 mg)

6 ml

(60 mg)

7.5 ml

(75 mg)

9 ml

(90 mg)

16 kg

1.6 ml

(16 mg)

3.2 ml

(32 mg)

4.8 ml

(48 mg)

6.4 ml

(64 mg)

8 ml

(80 mg)

9.6 ml

(96 mg)

18 kg

1.8 ml

(18 mg)

3.6 ml

(36 mg)

5.4 ml

(54 mg)

7.2 ml

(72 mg)

9 ml

(90 mg)

10.8 ml

(108 mg)

Adjunctive therapy doses to be taken twice a day for children and adolescents weighing from 20 kg to less than 30 kg

Week

Week 1

Week 2

Week 3

Week 4

Week 5

Prescribed dose

0.1 ml/kg

(1 mg/kg)

Starting dose

0.2 ml/kg

(2 mg/kg)

0.3 ml/kg

(3 mg/kg)

0.4 ml/kg

(4 mg/kg)

0.5 ml/kg

(5 mg/kg)

Maximum recommended dose

Recommended device: 10 ml syringe for volume between 1 ml and 20 ml

Weight

Volume administered

20 kg

2 ml

(20 mg)

4 ml

(40 mg)

6 ml

(60 mg)

8 ml

(80 mg)

10 ml

(100 mg)

22 kg

2.2 ml

(22 mg)

4.4 ml

(44mg)

6.6 ml

(66 mg)

8.8 ml

(88 mg)

11 ml

(110 mg)

24 kg

2.4 ml

(24 mg)

4.8 ml

(48 mg)

7.2 ml

(72 mg)

9.6 ml

(96 mg)

12 ml

(120 mg)

25 kg

2.5 ml

(25 mg)

5 ml

(50 mg)

7.5 ml

(75 mg)

10 ml

(100 mg)

12.5 ml

(125 mg)

26 kg

2.6 ml

(26 mg)

5.2 ml

(52 mg)

7.8 ml

(78 mg)

10.4 ml

(104 mg)

13 ml

(130 mg)

28 kg

2.8 ml

(28 mg)

5.6 ml

(56 mg)

8.4 ml

(84 mg)

11.2 ml

(112 mg)

14 ml

(140 mg)

Adjunctive therapy doses to be taken twice a day for children and adolescents weighing from 30 kg to less than 50 kg

Week

Week 1

Week 2

Week 3

Week 4

Prescribed dose

0.1 ml/kg

(1 mg/kg)

Starting dose

0.2 ml/kg

(2 mg/kg)

0.3 ml/kg

(3 mg/kg)

0.4 ml/kg

(4 mg/kg)

Maximum recommended dose

Recommended device: 10 ml syringe for volume between 1 ml and 20 ml

Weight

Volume administered

30 kg

3 ml (30 mg)

6 ml (60 mg)

9 ml (90 mg)

12 ml (120 mg)

35 kg

3.5 ml (35 mg)

7 ml (70 mg)

10.5 ml (105 mg)

14 ml (140 mg)

40 kg

4 ml (40 mg)

8 ml (80 mg)

12 ml (120 mg)

16 ml (160 mg)

45 kg

4.5 ml (45 mg)

9 ml (90 mg)

13.5 ml (135 mg)

18 ml (180 mg)

Initiation of lacosamide treatment with a loading dose (initial monotherapy or conversion to monotherapy in the treatment of partial-onset seizures or adjunctive therapy in the treatment of partial-onset seizures or adjunctive therapy in the treatment of primary generalised tonic-clonic seizures)

In adolescents and children weighing 50 kg or more, and adults, lacosamide treatment may also be initiated with a single loading dose of 200 mg, followed approximately 12 hours later by a 100 mg twice a day (200 mg/day) maintenance dose regimen. Subsequent dose adjustments should be performed according to individual response and tolerability as described above. A loading dose may be initiated in patients in situations when the physician determines that rapid attainment of lacosamide steady state plasma concentration and therapeutic effect is warranted. It should be administered under medical supervision with consideration of the potential for increased incidence of serious cardiac arrhythmia and central nervous system adverse reactions (see section 4.8). Administration of a loading dose has not been studied in acute conditions such as status epilepticus.

Discontinuation

If lacosamide has to be discontinued, it is recommended that the dose is reduced gradually in weekly decrements of 4 mg/kg/day (for patients with a body weight less than 50 kg) or 200 mg/day (for patients with a body weight of 50 kg or more) for patients who have achieved a dose of lacosamide ≥ 6 mg/kg/day or ≥ 300 mg/day, respectively. A slower taper in weekly decrements of 2 mg/kg/day or 100 mg/day can be considered, if medically necessary.

In patients who develop serious cardiac arrhythmia, clinical benefit/risk assessment should be performed and if needed lacosamide should be discontinued.

Special populations

Elderly (over 65 years of age)

No dose reduction is necessary in elderly patients. Age associated decreased renal clearance with an increase in AUC levels should be considered in elderly patients (see following paragraph 'renal impairment' and section 5.2). There is limited clinical data in the elderly patients with epilepsy, particularly at doses greater than 400 mg/day (see sections 4.4, 4.8, and 5.1).

Renal impairment

No dose adjustment is necessary in mildly and moderately renally impaired adult and paediatric patients (CLCR > 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 (CLCR ≤ 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 (CLCR ≤ 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).

Hepatic impairment

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 (see section 5.2). 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.

Paediatric population

Lacosamide is not recommended for use in children below the age of 4 years in the treatment of primary generalized tonic-clonic seizures and below the age of 2 years in the treatment of partial-onset seizures as there is limited data on safety and efficacy in these age groups.

Loading dose

Administration of a loading dose has not been studied in children. Use of a loading dose is not recommended in adolescents and children weighing less than 50 kg.

Method of administration

Lacosamide syrup must be taken orally.

The bottle containing Vimpat syrup should be shaken well before use. Lacosamide may be taken with or without food.

Lacosamide syrup is provided with:

- a 30 ml measuring cup. One full measuring cup (30 ml) corresponds to 300 mg of lacosamide. The minimum volume is 5 ml which corresponds to 50 mg of lacosamide. As from the 5 ml graduation mark, each increment corresponds to 5 ml which is 50 mg of lacosamide;

- a 10 ml oral syringe (black graduation marks) with an adaptor. One full oral syringe (10 ml) corresponds to 100 mg of lacosamide. The minimum extractable volume is 1 ml which is 10 mg of lacosamide. As from the 1 ml graduation mark, each increment corresponds to 0.25 ml which is 2.5 mg of Lacosamide.

The physician should instruct the patient on the appropriate measuring device to use.

If the required dose is between 10 mg (1 ml) and 100 mg (10 ml), the 10 ml oral syringe should be used.

If the required dose is between 100 mg (10 ml) and 200 mg (20 ml), the 10 ml oral syringe should be used two times.

If the required dose is more than 200 mg (20 ml), the 30 ml measuring cup should be used.

The dose should be rounded to the nearest graduated increment.

Instructions for use are provided in the package leaflet.

4.3. 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.

4.4. 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 clinical studies 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 post-marketing 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.

Excipients

Excipients which may cause intolerance

Vimpat syrup contains sodium methyl parahydroxybenzoate (E219), which may cause allergic reactions (possibly delayed).

Vimpat syrup contains sorbitol (E420). Patients with rare hereditary problems of fructose intolerance should not take this medicine. Sorbitol may cause gastrointestinal discomfort and mild laxative effect.

Vimpat syrup contains aspartame (E951), a source of phenylalanine, which may be harmful for people with phenylketonuria. Neither non-clinical nor clinical data are available to assess aspartame use in infants below 12 weeks of age.

Vimpat syrup contains propylene glycol (E1520).

Sodium content

Vimpat syrup contains 1.42 mg sodium per ml, equivalent to 0.07 % of the WHO recommended maximum daily intake of 2 g sodium for an adult.

Potassium content

This medicine contains potassium, less than 1 mmol (39 mg) per 60 ml, i.e. essentially 'potassium-free'.

4.5. 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 studies 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 studies. 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 studies 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 study 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.

4.6. 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).

4.7. 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.

4.8. 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 the 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 studies 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 common

Common

Uncommon

Not known

Blood and lymphatic disorders

Agranulocytosis(1)

Immune system disorders

Drug hypersensitivity(1)

Drug reaction with eosinophilia and systemic symptoms (DRESS) (1,2)

Psychiatric disorders

Depression

Confusional state

Insomnia(1)

Aggression Agitation(1)

Euphoric mood(1)

Psychotic disorder(1)

Suicide attempt (1)

Suicidal ideation

Hallucination (1)

Nervous system disorders

Dizziness

Headache

Myoclonic seizures(3)

Ataxia

Balance disorder

Memory impairment

Cognitive disorder

Somnolence

Tremor

Nystagmus

Hypoesthesia

Dysarthria

Disturbance in attention

Paraesthesia

Syncope(2)

Coordination abnormal

Dyskinesia

Convulsion

Eye disorders

Diplopia

Vision blurred

Ear and labyrinth disorders

Vertigo

Tinnitus

Cardiac disorders

Atrioventricular block(1,2)

Bradycardia(1,2)

Atrial Fibrillation (1,2)

Atrial Flutter (1,2)

Ventricular tachyarrhythmia (1)

Gastrointestinal disorders

Nausea

Vomiting

Constipation

Flatulence

Dyspepsia

Dry mouth

Diarrhoea

Hepatobiliary disorders

Liver function test abnormal(2)

Hepatic enzyme increased (> 2x ULN) (1)

Skin and subcutaneous tissue disorders

Pruritus

Rash(1)

Angioedema(1)

Urticaria(1)

Stevens-Johnson syndrome(1)

Toxic epidermal necrolysis(1)

Musculoskeletal and connective tissue disorders

Muscle spasms

General disorders and administration site conditions

Gait disturbance

Asthenia

Fatigue

Irritability

Feeling drunk

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 PGTCS 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 studies 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 study 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 studies 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 study 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 studies; however, both have been reported in open-label epilepsy studies and in post-marketing experience.

Laboratory abnormalities

Abnormalities in liver function tests have been observed in placebo-controlled clinical studies 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:

Yellow Card Scheme

Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9. Overdose

Symptoms

Symptoms observed after an accidental or intentional overdose of lacosamide are primarily associated with CNS and gastrointestinal system.

• The types of adverse reactions experienced by patients exposed to doses above 400 mg up to 800 mg were not clinically different from those of patients administered recommended doses of lacosamide.

• Reactions reported after an intake of more than 800 mg are dizziness, nausea, vomiting, seizures (generalised tonic-clonic seizures, status epilepticus). Cardiac conduction disorders, shock and coma have also been observed. Fatalities have been reported in patients following an intake of acute single overdose of several grams of lacosamide.

Management

There is no specific antidote for overdose with lacosamide. Treatment of lacosamide overdose should include general supportive measures and may include haemodialysis if necessary (see section 5.2).