FC tab: Each film-coated tablet contains 50 mg lacosamide, or 100 mg lacosamide.
Soln for infusion: Each ml of solution for infusion contains 10 mg lacosamide.
1 vial of 20 ml solution for infusion contains 200 mg lacosamide.
Excipients with known effect: Each ml of solution for infusion contains includes 2.99 mg sodium.
Excipients/Inactive Ingredients: FC tab: Tablet core: Microcrystalline cellulose, hydroxypropylcellulose, hydroxypropylcellulose (low substituted), colloidal anhydrous silica, crospovidone (polyplasdone XL-10 Pharmaceutical Grade), magnesium stearate.
Tablet coat: Polyvinyl alcohol, polyethylene glycol 3350, talc, titanium dioxide (E171).
50 mg tablets: Red iron oxide (E172), black iron oxide (E172), indigo carmine aluminium lake (E132).
100 mg tablets: Yellow iron oxide (E172).
Soln for infusion: Water for injection, sodium chloride, hydrochloric acid (for pH adjustment).
Pharmacotherapeutic Group: Antiepileptics, other antiepileptics. ATC Code: N03AX18.
Pharmacology: Pharmacodynamics: Mechanism of action: The active substance, lacosamide (R-2-acetamido-N-benzyl-3-methoxypropionamide) is a functionalised amino acid. The precise mechanism by which lacosamide exerts its antiepileptic effect in humans remains to be fully elucidated. In vitro electrophysiological studies have shown that lacosamide selectively enhances slow inactivation of voltage-gated sodium channels, resulting in stabilization of hyperexcitable neuronal membranes.
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 efficacy and safety: Conversion to monotherapy: The efficacy of VIMPAT in conversion to monotherapy was established in a historical-controlled, multicenter, double-blind, randomized trial with a 16-week maintenance period (i.e. a 6-week withdrawal period for background antiepileptic drugs, followed by a 10-week monotherapy period) involving 425 patients aged 16 to 70 years with partial-onset seizures. In this study, patients were taking stable doses of 1 or 2 marketed antiepileptic drugs during the 8 weeks baseline period. Patients taking 2 antiepileptic drugs must have been taking ≤50% of the minimum recommended maintenance dose for 1 of the 2 antiepileptic drugs. Patients were randomized 3 to 1 to ultimately receive either lacosamide 400 mg/day (200 mg twice a day) or 300 mg/day (150 mg twice a day), and their responses were compared to those of a historical control group. The historical control consisted of a pooled analysis of the control groups from 8 studies of similar design, which utilized a sub-therapeutic dose of an antiepileptic drug as a control. Statistical superiority to the historical control was considered to be demonstrated if the upper limit from a 2 sided 95% confidence interval for the percentage of patients meeting exit criteria in patients receiving lacosamide remained below the lower 95% prediction limit of 65.3% derived from the historical control data.
The exit criteria were one or more of the following: (1) doubling of average monthly seizure frequency during any 28 consecutive days, (2) doubling of highest consecutive 2-day seizure frequency, (3) occurrence of a single generalized tonic-clonic seizure, (4) clinically significant prolongation or worsening of overall seizure duration, frequency, type or pattern considered by the investigator to require trial discontinuation, (5) status epilepticus or new onset of serial/cluster seizures.
The study population was comparable to the historical controlled population.
For the lacosamide 400 mg/day group, the estimate of the percentage of patients meeting at least 1 exit criterion was 30.0% (95% CI: 24.6%, 35.5%). The upper limit of the 2-sided 95% CI (35.5%) was below the threshold of 65.3% derived from the historical control data and superiority of lacosamide 400 mg/day over historical control was demonstrated. The primary efficacy result was supported by sensitivity analyses.
For the lacosamide 300 mg/day group, the estimate of the percentage of patients meeting at least 1 exit criterion was 27.3% (95% CI: 18.4%, 36.3%). The upper limit of the 2-sided 95% CI (36.3%) was below the threshold of 65.3% derived from the historical control data although the study was not powered for the evaluation of lacosamide 300 mg/day versus the historical control group.
In both the Clinical (CGIC) and Patient (PGIC) Global Impression of Change assessments, the majority of patients in both lacosamide treatment groups were reported to have an improved status (CGIC: 75.4% and 72.7% of subjects in the 400 mg/day and 300 mg/day groups, respectively. PGIC: 74.3% and 72.7% of subjects in the 400 mg/day and 300 mg/day groups, respectively).
Adjunctive therapy: 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 1-3 antiepileptics 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.
The pharmacokinetics and safety of a single loading dose of iv lacosamide were determined in a multicenter, open-label study designed to assess the safety and tolerability of rapid initiation of lacosamide using a single iv loading dose (including 200 mg) followed by twice daily oral dosing (equivalent to the iv dose) as adjunctive therapy in adult subjects 16 to 60 years of age with partial-onset seizures.
Pharmacokinetics: Absorption: FC tab: 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 Cmax about 0.5 to 4 hours post-dose. Food does not affect the rate and extent of absorption.
Soln for infusion: After intravenous administration, Cmax is reached at the end of infusion. The plasma concentration increases proportionally with dose after oral (100-800 mg) and intravenous (50-300 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 O-desmethyl 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 (0-2%) in human plasma of some subjects. Small amounts (0.5-2%) of additional metabolites were found in the urine.
In vitro data show that CYP2C9, CYP2C19 and CYP3A4 are capable of catalysing the formation of the O-desmethyl metabolite but the main contributing isoenzyme has not been confirmed in vivo. 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 (CYP2C19-inhibitor) demonstrated no clinically relevant changes in lacosamide plasma concentrations indicating that the importance of this pathway is minor. The plasma concentration of O-desmethyl-lacosamide 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 feces. 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.
A single loading dose of 200 mg approximates steady-state concentrations comparable to 100 mg twice daily oral administration.
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 Cmax was unaffected.
Lacosamide is effectively removed from plasma by haemodialysis. Following a 4-hour haemodialysis treatment, AUC of lacosamide is reduced by approximately 50%. Therefore dosage supplementation following haemodialysis is recommended (see Dosage & Administration). The exposure of the O-desmethyl 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 24-hour 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 AUCnorm). 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 Dosage & Administration).
Older people (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 Dosage & Administration).
Toxicology: Preclinical safety data: 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.
VIMPAT is indicated as: Monotherapy in the treatment of partial-onset seizures in patients with epilepsy aged 16 years and older.
Adjunctive therapy in the treatment of partial-onset seizures with or without secondary generalisation in patients with epilepsy aged 16 years and older.
Monotherapy: Initial monotherapy: Patients not currently being treated with antiepileptic drugs may have monotherapy initiated with lacosamide.
The recommended starting dose is 100 mg twice a day (200 mg/day) which should be increased to a therapeutic dose of 150 mg twice a day (300 mg/day) after one week.
Depending on response and tolerability, the dose can be further increased at weekly interval by 50 mg twice a day (100 mg/day), to a maximum recommended maintenance daily dose of 200 mg twice a day (400 mg/day).
Conversion to monotherapy: For patients who will convert to lacosamide monotherapy, the recommended starting dose is 100 mg twice a day (200 mg/day) which should be increased to a therapeutic dose of 150 mg twice a day (300 mg/day) after one week.
Depending on response and tolerability, the dose can be further increased at weekly interval by 50 mg twice a day (100 mg/day), to a maximum recommended maintenance daily dose of 200 mg twice a day (400 mg/day).
The recommended maintenance daily dose should be maintained for at least 3 days before initiating conversion to lacosamide monotherapy. A gradual withdrawal of the concomitant antiepileptic drug over at least 6-weeks is recommended. If the patient is on more than one antiepileptic drug, the antiepileptic drugs should be withdrawn sequentially.
Safety and efficacy of lacosamide have not been established for simultaneous conversion to monotherapy from two or more concomitant antiepileptic drugs.
Adjunctive therapy: 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).
Initiation of lacosamide treatment with a loading dose: Lacosamide treatment (initial monotherapy, conversion to monotherapy and adjunctive therapy) may also be initiated with a single loading dose of 200 mg, followed approximately 12 hours later by a 100 mg twice daily (200 mg/day) maintenance dose regimen. 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 central nervous system adverse reactions (see Adverse Reactions). Administration of a loading dose has not been studied in acute conditions such as status epilepticus.
Discontinuation: 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).
Method of administration: FC tab: For oral use.
VIMPAT must be taken twice a day (usually once in the morning and once in the evening).
VIMPAT may be taken with or without food.
Soln for infusion: Vimpat must be administered twice a day.
Vimpat therapy can be initiated with either oral or i.v. administration.
Vimpat solution for infusion is also an alternative for patients when oral administration is temporarily not feasible.
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.
Special populations: Renal impairment: No dose adjustment is necessary in mildly and moderately renally impaired patients (CLCR >30 ml/min). In 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 patients with severe renal impairment (CLCR ≤30 ml/min) and in patients with endstage renal disease, a maximum maintenance dose of 250 mg/day is recommended. In these patients, 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. 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 endstage 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: FC tab: A maximum dose of 300 mg/day is recommended for patients with mild to moderate hepatic impairment.
Soln for infusion: No dose adjustment is needed for patients with mild to moderate hepatic impairment.
FC tab and Soln for infusion: The dose titration in these patients should be performed with caution considering co-existing renal impairment. A loading dose of 200 mg may be considered, but further dose titration (>200 mg daily) should be performed with caution.
The pharmacokinetics of lacosamide has not been evaluated in severely hepatic impaired patients (see Pharmacology: Pharmacokinetics under Actions).
FC tab: Lacosamide should be administered to 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.
Elderly population (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 Renal impairment in the previous text and Pharmacology: Pharmacokinetics under Actions).
Paediatric population: The safety and efficacy of lacosamide in children aged below 16 years have not yet been established. No data are available.
Symptoms: FC tab: Symptoms observed after an accidental or intentional overdose of lacosamide are primarily associated with CNS and gastrointestinal system.
The types of adverse events 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.
Events reported after an intake of more than 800 mg are dizziness, nausea, vomiting, seizures (generalized 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.
Soln for infusion: There is limited clinical experience with lacosamide overdose in humans.
In clinical trials: The types of adverse events experienced by patients exposed to supratherapeutic doses were not clinically different from those of patients administered recommended doses of lacosamide.
Following doses of 1200 mg/day, symptoms related to the central nervous system (dizziness) and the gastrointestinal system (nausea) were observed and resolved with dose adjustments. The highest reported overdose for lacosamide was 12000 mg taken in conjunction with toxic doses of multiple other antiepileptic drugs. The subject was initially comatose with AV block and then fully recovered without permanent sequelae.
In post-marketing experience: Following acute single overdoses ranging between 1000 mg and 12000 mg, seizures (generalized tonic-clonic seizures, status epilepticus) and cardiac conduction disorders were observed. Fatal cardiac arrest was reported after an acute overdose of 7000 mg of lacosamide in a patient with cardiovascular risk factors.
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 Pharmacology: Pharmacokinetics under Actions).
Hypersensitivity to the active substance or to any of the excipients listed in Description.
Known second- or third-degree atrioventricular (AV) block.
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 Adverse Reactions).
Cardiac rhythm and conduction: 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.
Second degree or higher AV block has been reported in post-marketing experience. In the placebo-controlled trials of lacosamide in epilepsy patients, atrial fibrillation or flutter were not reported; however both have been reported in open-label epilepsy trials and in post-marketing experience (see Adverse Reactions).
Patients should be made aware of the symptoms of second-degree or higher AV block (e.g. slow or irregular pulse, feeling of lightheaded and fainting) and of the symptoms of atrial fibrillation and flutter (e.g. palpitations, rapid or irregular pulse, shortness of breath). Patients should be counselled to seek medical advice should any of these symptoms occur.
Suicidal ideation and behaviour: 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-epileptics 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 Adverse Reactions).
Soln 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.
Effects on ability to drive and use machines: Vimpat has 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.
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).
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 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 embryotoxicity was observed in rats and rabbits at maternal toxic doses (see Pharmacology: Toxicology: Preclinical safety data under Actions). 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.
Summary of safety profile:
Based on the analysis of pooled placebo-controlled clinical trials in adjunctive therapy 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 Central nervous system (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. Incidence of CNS adverse reactions such as dizziness may be higher after a loading dose.
The safety profile of lacosamide reported in the conversion to monotherapy clinical trial was similar to the safety profile reported from the pooled placebo-controlled clinical trials in adjunctive therapy. The discontinuation rate due to adverse reactions was 16.2% for patients randomized to lacosamide at the recommended doses of 300 and 400 mg/day. The most common adverse reaction resulting in discontinuation of lacosamide therapy was dizziness. Dizziness, headache, nausea, somnolence, and fatigue were all reported at lower incidences during the antiepileptic drug withdrawal phase and monotherapy phase compared with the titration phase. (See Pharmacology: Pharmacodynamics: Clinical efficacy and safety under Actions).
Tabulated list of adverse reactions:
The table as follows 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. (See table.)
Click on icon to see table/diagram/image
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 clinical trials in epilepsy patients the incidence rate of reported first degree AV Block is uncommon, 0.7%, 0%, 0.5% and 0% for lacosamide 200 mg, 400 mg, 600 mg or placebo, respectively. No second or higher degree AV Block was seen in these studies. However, cases with second and third degree AV Block associated with lacosamide treatment have been reported in post-marketing experience.
In clinical trials, the incidence rate for syncope is uncommon and did not differ between lacosamide treated epilepsy patients (0.1%) and placebo treated epilepsy patients (0.3%).
Atrial fibrillation or flutter were not reported in short term clinical trials; however both have been reported in open-label epilepsy trials and in post-marketing experience.
Abnormalities in liver function tests have been observed in controlled trials with lacosamide in adult patients with partial-onset seizures who were taking 1 to 3 concomitant anti-epileptic drugs. Elevations of ALT 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 agents. 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.
Frequency, type and severity of adverse reactions in adolescents aged 16-18 years are expected to be the same as in adults. The safety of lacosamide in children aged below 16 years has not yet been established. No data are available.
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.
In vitro data: Data generally suggest that lacosamide has a low interaction potential. In vitro studies indicate that the enzymes CYP1A2, 2B6, and 2C9 are not induced and that CYP1A1, 1A2, 2A6, 2B6, 2C8, 2C9, 2D6, and 2E1 are not inhibited by lacosamide at plasma concentrations observed in clinical trials. An in vitro study indicated that lacosamide is not transported by P-glycoprotein in the intestine. 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 the enzyme CYP2C19 and CYP3A4 to a clinically relevant extent.
Lacosamide did not affect the AUC of midazolam (metabolised by CYP3A4, lacosamide given 200 mg b.i.d.) but Cmax of midazolam was slightly increased (30%). Lacosamide did not affect the pharmacokinetics of omeprazole (metabolised by CYP2C19 and 3A4, lacosamide given 300 mg b.i.d.).
The CYP2C19 inhibitor omeprazole (40 mg q.d.) 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 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-epileptics 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.
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.
Protein Binding: 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.
Incompatibilities: FC tab: Not applicable.
Soln for infusion: This medicinal product must not be mixed with other medicinal products except those mentioned as follows.
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.
FC tab: Store below 30°C.
Soln for infusion: Do not store above 30°C.
Shelf-Life: FC tab: 5 years.
Soln 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 Cautions for Usage.
From a microbiological point of view, the product should be used immediately.
N03AX18 - lacosamide ; Belongs to the class of other antiepileptics.
FC tab 50 mg (pinkish, oval debossed with 'SP' on one side and '50' on the other side) x 56's. 100 mg (dark yellow, oval debossed with 'SP' on one side and '100' on the other side) x 56's. Soln for infusion (vial) 10 mg/mL (clear and colorless) x 20 mL x 5's.