Vimpat 50 mg film-coated tablets

Vimpat 100 mg film-coated tablets

Vimpat 150 mg film-coated tablets

Vimpat 200 mg film-coated tablets

Vimpat 15 mg/ml syrup

Vimpat 10 mg/ml solution for infusion

Tablets:

Each film-coated tablet contains 50 mg lacosamide, 100 mg lacosamide, 150 mg lacosamide or 200 mg lacosamide and 0.17 mg, 0.34 mg, 0.50 mg or 0.67 mg, respectively, of the excipient soya-lecithin.

Syrup:

Each ml of syrup contains 15 mg lacosamide.

1 bottle of 200 ml contains 3000 mg lacosamide.

Excipients: each ml of Vimpat syrup contains 280 mg sorbitol (E420), 0.2 mg sodium propylparahydroxybenzoate (E217), 2.0 mg sodium methylparahydroxybenzoate (E219), 0.05 mg aspartame (E951) and 1.89 mg sodium.

Solution for infusion:

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 2.99 mg sodium.

For a full list of excipients, see section 6.1.

Tablets:

Film-coated tablet

50 mg: Pinkish, oval film-coated tablet debossed with 'SP' on one side and '50' on the other side.

100 mg: Dark yellow, oval film-coated tablet debossed with 'SP' on one side and '100' on the other side.

150 mg: Salmon, oval film-coated tablet debossed with 'SP' on one side and '150' on the other side.

200 mg: Blue, oval film-coated tablet debossed with 'SP' on one side and '200' on the other side.

Syrup:

Clear solution, slightly yellow to yellow-brown in colour.

Solution for infusion:

Clear, colourless solution.

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.

Solution for infusion:

Vimpat solution for infusion is an alternative for patients when oral administration is temporarily not feasible.

Vimpat must be taken 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). Vimpat may be taken with or without food.

Vimpat therapy can be initiated with either oral or i.v. administration.

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).

Syrup:

Vimpat syrup is provided with a measuring cup with graduation marks and instructions for use in the package leaflet.

Solution for infusion:

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 (CL_CR >30 ml/min). A maximum dose of 250 mg/day is recommended for patients with severe renal impairment (CL_CR30 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 (see section 5.2).

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 evaluated in severely hepatic impaired patients (see section 5.2).

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 (see 'Use in patients with renal impairment' above and section 5.2).

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.

Tablets:

Hypersensitivity to the active substance or to peanuts or soya or to any of the excipients.

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

Syrup and Solution for infusion:

Hypersensitivity to the active substance or to any of the excipients.

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

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).

Prolongations 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.

Suicidal 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 propylhydroxybenzoate (E217) and 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 1.06 mmol (or 25.2 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.

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 Pglycoprotein 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 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 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 embyrotoxicity 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.

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.

Vimpat may have minor to moderate influence on the ability to drive and use machines. Vimpat treatment has been associated with dizziness or blurred vision.

Accordingly, patients should be advised not to drive a car or to operate other potentially hazardous machinery until they are familiar with the effects of Vimpat on their ability to perform such activities.

Based 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.

The table below shows the frequencies of adverse reactions which have been reported in pooled placebo-controlled clinical trials. 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.

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 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 lacosamide treated patients.

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%).

There is limited clinical experience with lacosamide overdose in humans. Clinical symptoms (dizziness and nausea) following doses of 1200 mg/day were mainly related to the central nervous system and the gastrointestinal system and resolved with dose adjustments.

The highest reported overdose in the clinical development program for lacosamide was 12 g taken in conjunction with toxic doses of multiple other antiepileptic drugs. The subject was initially comatose and then fully recovered without permanent sequelae.

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).

Pharmacotherapeutic group: other antiepileptics, ATC code: N03AX18

The active substance, lacosamide (R2acetamidoNbenzyl3methoxypropionamide) is a functionalised amino acid.

Mechanism of action

The precise mechanism by which lacosamide exerts its antiepileptic effect in humans remains to be fully elucidated. Two observations that may be of relevance for the observed therapeutic effects are:

In vitro electrophysiological studies have shown that lacosamide selectively enhances slow inactivation of voltage-gated sodium channels, resulting in stabilization of hyperexcitable neuronal membranes. Further, lacosamide binds to collapsin response mediator protein2 (CRMP2), a phosphoprotein which is mainly expressed in the nervous system and is involved in neuronal differentiation and control of axonal outgrowth.

Pharmacodynamic effects

Lacosamide protected against seizures in a broad range of animal models 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.

Clinical experience

The efficacy of Vimpat as adjunctive therapy at recommended doses (200 mg/day, 400 mg/day) was established in 3 multicenter, randomized, placebo-controlled clinical trials with a 12-week maintenance period. Vimpat 600 mg/day was also shown to be effective in controlled adjunctive therapy trials, although the efficacy was similar to 400 mg/day and patients were less likely to tolerate this dose because of CNS- and gastrointestinal-related adverse reactions. Thus, the 600 mg/day dose is not recommended. The maximum recommended dose is 400 mg/day. These trials, involving 1308 patients with a history of an average of 23 years of partial-onset seizures, were designed to evaluate the efficacy and safety of lacosamide when administered concomitantly with 13 antiepileptic drugs in patients with uncontrolled partial-onset seizures with or without secondary generalisation. Overall the proportion of subjects with a 50% reduction in seizure frequency was 23%, 34%, and 40% for placebo, lacosamide 200 mg/day and lacosamide 400 mg/day.

There are insufficient data regarding the withdrawal of concomitant antiepileptic medicinal products to achieve monotherapy with lacosamide.

Absorption

Tablets and Syrup:

Lacosamide is rapidly and completely absorbed after oral administration. The oral bioavailability of lacosamide tablets is approximately 100%. Following oral administration, the plasma concentration of unchanged lacosamide increases rapidly and reaches C_max about 0.5 to 4 hours post-dose. Vimpat tablets and oral syrup are bioequivalent. Food does not affect the rate and extent of absorption.

Solution for infusion:

After i.v. administration, C_max is reached at the end of infusion. The plasma concentration increases proportionally with dose after oral (100800 mg) and i.v. (50300 mg) administration.

Distribution

The volume of distribution is approximately 0.6 L/kg. Lacosamide is less than 15% bound to plasma proteins.

Metabolism

95% of the dose is excreted in the urine as drug and metabolites. The metabolism of lacosamide has not been completely characterised.

The major compounds excreted in urine are unchanged lacosamide (approximately 40% of the dose) and its Odesmethyl metabolite less than 30%.

A polar fraction proposed to be serine derivatives accounted for approximately 20% in urine, but was detected only in small amounts (02%) in human plasma of some subjects. Small amounts (0.52%) of additional metabolites were found in the urine.

CYP2C19 is mainly responsible for the formation of the Odesmethyl metabolite. However, no clinically relevant difference in lacosamide exposure was observed comparing its pharmacokinetics in extensive metabolisers (EMs, with a functional CYP2C19) and poor metabolisers (PMs, lacking a functional CYP2C19). Furthermore an interaction trial with omeprazole (CYP2C19inhibitor) demonstrated no clinically relevant changes in lacosamide plasma concentrations indicating that the importance of this pathway is minor. No other enzymes have been identified to be involved in the metabolism of lacosamide.

The plasma concentration of Odesmethyllacosamide is approximately 15% of the concentration of lacosamide in plasma. This major metabolite has no known pharmacological activity.

Elimination

Lacosamide is primarily eliminated from the systemic circulation by renal excretion and biotransformation. After oral and intravenous administration of radiolabeled lacosamide, approximately 95% of radioactivity administered was recovered in the urine and less than 0.5% in the faeces. The elimination half-life of the unchanged drug is approximately 13 hours. The pharmacokinetics is dose-proportional and constant over time, with low intra- and inter-subject variability. Following twice daily dosing, steady state plasma concentrations are achieved after a 3 day period. The plasma concentration increases with an accumulation factor of approximately 2.

Pharmacokinetics in special patient groups

Gender

Clinical trials indicate that gender does not have a clinically significant influence on the plasma concentrations of lacosamide.

Renal impairment

The AUC of lacosamide was increased by approximately 30% in mildly and moderately and 60% in severely renal impaired patients and patients with endstage renal disease requiring hemodialysis compared to healthy subjects, whereas c_max was unaffected.

Lacosamide is effectively removed from plasma by haemodialysis. Following a 4hour haemodialysis treatment, AUC of lacosamide is reduced by approximately 50%. Therefore dosage supplementation following haemodialysis is recommended (see section 4.2). The exposure of the Odesmethyl metabolite was several-fold increased in patients with moderate and severe renal impairment. In absence of haemodialysis in patients with endstage renal disease, the levels were increased and continuously rising during the 24hour sampling. It is unknown whether the increased metabolite exposure in endstage renal disease subjects could give rise to adverse effects but no pharmacological activity of the metabolite has been identified.

Hepatic impairment

Subjects with moderate hepatic impairment (Child-Pugh B) showed higher plasma concentrations of lacosamide (approximately 50% higher AUC_norm). The higher exposure was partly due to a reduced renal function in the studied subjects. The decrease in non-renal clearance in the patients of the study was estimated to give a 20% increase in the AUC of lacosamide. The pharmacokinetics of lacosamide has not been evaluated in severe hepatic impairment (see section 4.2).

Elderly (over 65 years of age)

In a study in elderly men and women including 4 patients >75 years of age, AUC was about 30 and 50% increased compared to young men, respectively. This is partly related to lower body weight. The body weight normalized difference is 26 and 23%, respectively. An increased variability in exposure was also observed. The renal clearance of lacosamide was only slightly reduced in elderly subjects in this study.

A general dose reduction is not considered to be necessary unless indicated due to reduced renal function (see section 4.2).

In the toxicity studies, the plasma concentrations of lacosamide obtained were similar or only marginally higher than those observed in patients, which leaves low or non-existing margins to human exposure.

A safety pharmacology study with intravenous administration of lacosamide in anesthetized dogs showed transient increases in PR interval and QRS complex duration and decreases in blood pressure most likely due to a cardiodepressant action. These transient changes started in the same concentration range as after maximum recommended clinical dosing. In anesthetized dogs and Cynomolgus monkeys, at intravenous doses of 15-60 mg/kg, slowing of atrial and ventricular conductivity, atrioventricular block and atrioventricular dissociation were seen.

In the repeated dose toxicity studies, mild reversible liver changes were observed in rats starting at about 3 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.

In reproductive and developmental toxicity studies in rodents and rabbits, no teratogenic effects but an increase in numbers of stillborn pups and pup deaths in the peripartum period, and slightly reduced live litter sizes and pup body weights were observed at maternal toxic doses in rats corresponding to systemic exposure levels similar to the expected clinical exposure. Since higher exposure levels could not be tested in animals due to maternal toxicity, data are insufficient to fully characterise the embryofetotoxic and teratogenic potential of lacosamide.

Studies in rats revealed that lacosamide and/or its metabolites readily crossed the placental barrier.

Tablets:

Tablet core:

microcrystalline cellulose

hydroxypropylcellulose

hydroxypropylcellulose (low substituted)

silica, colloidal, anhydrous

crospovidone

magnesium stearate

Tablet coat:

polyvinyl alcohol

polyethylene glycol 400, 3350 and 8000

talc

soya-lecithin

hypromellose

titanium dioxide (E171)

50 mg tablet: red iron oxide (E172), black iron oxide (E172), indigo carmine aluminium lake (E132)

100 mg tablet: yellow iron oxide (E172)

150 mg tablet: yellow iron oxide (E172), red iron oxide (E172), black iron oxide (E172)

200 mg tablet: indigo carmine aluminium lake (E132)

Syrup:

glycerol (E422)

carmellose sodium

sorbitol liquid (crystallizing) (E420)

polyethylene glycol 4000

sodium chloride

citric acid, anhydrous

acesulfame potassium (E950)

sodium propylparahydroxybenzoate (E217)

sodium methylparahydroxybenzoate (E219)

strawberry flavour (contains propylene glycol, maltol)

masking flavour (contains propylene glycol, aspartame (E951), acesulfame potassium (E950), maltol, deionised water)

purified water

Solution for infusion:

water for injection

sodium chloride

hydrochloric acid (for pH adjustment)

Tablets and Syrup:

Not applicable.

Solution for infusion:

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

Tablets:

3 years.

Syrup:

2 years

After first opening: 4 weeks.

Solution for infusion:

3 years.

Chemical and physical in-use stability has been demonstrated for 24 hours at temperatures up to 25° C for product mixed with the diluents mentioned in 6.6.

From a microbiological point of view, the product should be used immediately. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user and would not be longer than 24 hours at 2 to 8°C, unless dilution has taken place in controlled and validated aseptic conditions.

Tablets:

This medicinal product does not require any special storage conditions.

Syrup:

Do not store above 30°C.

Solution for infusion:

Do not store above 25°C.

Tablets:

PVC/PVDC blister sealed with an aluminium foil.

50 mg & 100 mg: Packs of 14, 56 and 168 film-coated tablets.

150 mg & 200 mg: Packs of 14, 56 and 168 film-coated tablets (multipacks containing 3 packs of 56 tablets).

The treatment initiation pack contains 4 cartons, each carton with 14 tablets of 50 mg, 100 mg, 150 mg and 200 mg

Not all pack sizes may be marketed.

Syrup:

200 ml and 465 ml amber type III glass or polyethylene terephthalate (PET) bottles with a polypropylene screw cap and a measuring cup.

Not all pack sizes may be marketed.

Solution for infusion:

Colourless type I glass vial with a chlorobutyl rubber closure coated with a fluoropolymer.

Packs of 1x20 ml and 5x20 ml.

Not all pack sizes may be marketed.

Tablets and Syrup:

No special requirements.

Solution for infusion:

This medicinal product is for single use only, any unused solution should be discarded.

Product with particulate matter or discolouration should not be used. Vimpat solution for infusion was found to be physically compatible and chemically stable when mixed with the following diluents for at least 24 hours and stored in glass or PVC bags at temperatures up to 25°C.

Diluents:

sodium chloride 9 mg/ml (0.9%) solution for injection

glucose 50 mg/ml (5%) solution for injection

lactated Ringer's solution for injection.

UCB Pharma SA

Allée de la Recherche 60

B1070 Bruxelles

Belgium

50 mg x 14 tabs: EU/1/08/470/001

100 mg x 14 tabs: EU/1/08/470/004

100 mg x 56 tabs: EU/1/08/470/005

150 mg x 14 tabs: EU/1/08/470/007

150 mg x 56 tabs: EU/1/08/470/008

200 mg x 56 tabs: EU/1/08/470/011

Syrup (15 mg/ml) x 200 ml: EU/1/08/470/014

Solution for Infusion (10 mg/ml) x 20 ml: EU/1/08/470/016

Date of first authorisation: 29 August 2008

07/2009

Detailed information on this medicine is available on the European Medicines Agency (EMEA) web site: http://www.emea.europa.eu/.