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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 generalised 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 (partial-onset seizures): Adult population: Monotherapy: Efficacy of lacosamide as monotherapy was established in a double-blind, parallel group, non-inferiority comparison to carbamazepine CR in 886 patients 16 years of age or older with newly or recently diagnosed epilepsy. The patients had to present with unprovoked partial-onset seizures with or without secondary generalisation. The patients were randomised to carbamazepine CR or lacosamide, provided as tablets, in a 1:1 ratio. The dose was based on dose-response and ranged from 400 to 1,200 mg/day for carbamazepine CR and from 200 to 600 mg/day for lacosamide. The duration of the treatment was up to 121 weeks depending on the response.
The estimated 6-month seizure freedom rates were 89.8% for lacosamide-treated patients and 91.1% for carbamazepine CR treated patients using the Kaplan-Meier survival analysis method. The adjusted absolute difference between treatments was -1.3% (95% CI: -5.5, 2.8). The Kaplan-Meier estimates of 12-month seizure freedom rates were 77.8% for lacosamide-treated patients and 82.7% for carbamazepine CR treated patients.
The 6-month seizure freedom rates in elderly patients of 65 and above (62 patients in lacosamide, 57 patients in carbamazepine CR) were similar between both treatment groups. The rates were also similar to those observed in the overall population. In the elderly population, the maintenance lacosamide dose was 200 mg/day in 55 patients (88.7%), 400 mg/day in 6 patients (9.7%) and the dose was escalated to over 400 mg/day in 1 patient (1.6%).
Conversion to monotherapy: The efficacy and safety of lacosamide in conversion to monotherapy has been assessed in a historical-controlled, multicentre, double-blind, randomised study. In this study, 425 patients aged 16 to 70 years with uncontrolled partial-onset seizures taking stable doses of 1 or 2 marketed antiepileptic medicinal products were randomised to be converted to lacosamide monotherapy (either 400 mg/day or 300 mg/day in a 3:1 ratio). In treated patients who completed titration and started withdrawing antiepileptic medicinal products (284 and 99 respectively), monotherapy was maintained in 71.5% and 70.7% of patients respectively for 57-105 days (median 71 days), over the targeted observation period of 70 days.
Adjunctive therapy: The efficacy of lacosamide as adjunctive therapy at recommended doses (200 mg/day, 400 mg/day) was established in 3 multicenter, randomised, placebo-controlled clinical studies with a 12-week maintenance period. Lacosamide 600 mg/day was also shown to be effective in controlled adjunctive therapy studies, 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 studies, involving 1,308 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 antiepileptic medicinal products 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.
The pharmacokinetics and safety of a single loading dose of intravenous lacosamide were determined in a multicenter, open-label study designed to assess the safety and tolerability of rapid initiation of lacosamide using a single intravenous loading dose (including 200 mg) followed by twice daily oral dosing (equivalent to the intravenous dose) as adjunctive therapy in adult subjects 16 to 60 years of age with partial-onset seizures.
Paediatric population: Partial-onset seizures have a similar clinical expression in children from 4 years of age and in adults. The efficacy of lacosamide in children aged 4 years and older has been extrapolated from data of adolescents and adults with partial-onset seizures, for whom a similar response was expected provided the paediatric dose adaptations are established (see Dosage & Administration) and safety has been demonstrated (see Adverse Reactions).
The efficacy supported by the extrapolation principle stated previously was confirmed by a double-blind, randomised, placebo-controlled clinical study. The study consisted of an 8-week baseline period followed by a 6-week titration period. Eligible patients on a stable dose regimen of 1 to ≤3 antiepileptic medicinal products, who still experienced at least 2 partial-onset seizures during the 4 weeks prior to screening with seizure-free phase no longer than 21 days in the 8-week period prior to entry into the baseline period, were randomised to receive either placebo (n=172) or lacosamide (n=171).
Dosing was initiated at a dose of 2 mg/kg/day in subjects weighing less than 50 kg or 100 mg/day in subjects weighing 50 kg or more in 2 divided doses. During the titration period, lacosamide doses were adjusted in 1 or 2 mg/kg/day increments in subjects weighing less than 50 kg or 50 or 100 mg/day in subjects weighing 50 kg or more at weekly intervals to achieve the target maintenance period dose range.
Subjects must have achieved the minimum target dose for their body weight category for the final 3 days of the titration period to be eligible for entry into the 10-week maintenance period. Subjects were to remain on stable lacosamide dose throughout the maintenance period or were withdrawn and entered in the blinded taper period.
Statistically significant (p=0.0003) and clinically relevant reduction in partial-onset seizure frequency per 28 days from baseline to the maintenance period was observed between the lacosamide and the placebo group. The percent reduction over placebo based on analysis of covariance was 31.72% (95% CI: 16.342, 44.277).
Overall, the proportion of subjects with at least a 50% reduction in partial-onset seizure frequency per 28 days from baseline to the maintenance period was 52.9% in the lacosamide group compared with 33.3% in the placebo group.
The quality of life assessed by the Pediatric Quality of Life Inventory indicated that subjects in both lacosamide and placebo groups had a similar and stable health-related quality of life during the entire treatment period.
Clinical efficacy and safety (primary generalized tonic-clonic seizures): The efficacy of lacosamide as adjunctive therapy in patients 4 years of age and older with idiopathic generalized epilepsy experiencing primary generalized tonic-clonic seizures (PGTCS) was established in a 24-week double-blind, randomized, placebo-controlled, parallel-group, multi-center clinical study. The study consisted of a 12-week historical baseline period, a 4-week prospective baseline period and a 24-week treatment period (which included a 6-week titration period and an 18-week maintenance period). Eligible patients on a stable dose of 1 to 3 antiepileptic drugs experiencing at least 3 documented PGTCS during the 16-week combined baseline period were randomized 1 to 1 to receive lacosamide or placebo (patients in the full analysis set: lacosamide n=118, placebo n=121; of them 8 patients in the ≥4 to <12 years age group and 16 patients in the ≥12 to <18 years range were treated with lacosamide and 9 and 16 patients, respectively with placebo). (See Table 1.)
Patients were titrated up to the target maintenance period dose of 12 mg/kg/day in patients weighing less than 30 kg, 8 mg/kg/day in patients weighing from 30 to less than 50 kg or 400 mg/day in patients weighing 50 kg or more.
Click on icon to see table/diagram/imageThe findings in the paediatric subgroup were consistent with the results of the overall population for the primary, secondary and other efficacy endpoints.
Pharmacokinetics: Absorption: 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. Vimpat tablets and syrup are bioequivalent. Food does not affect the rate and extent of absorption.
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.
Biotransformation: 95% of the dose is excreted in the urine as lacosamide 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 study 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 faeces. The elimination half-life of lacosamide 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 studies 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 end-stage renal disease requiring haemodialysis 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 end-stage renal disease, the levels were increased and continuously rising during the 24-hour sampling. It is unknown whether the increased metabolite exposure in end-stage 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).
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 Dosage & Administration).
Paediatric population: The paediatric pharmacokinetic profile of lacosamide was determined in a population pharmacokinetic analysis using sparse plasma concentration data obtained in one placebo-controlled randomised clinical study and three open-label studies in 414 children with epilepsy aged 6 months to 17 years. The administered lacosamide doses ranged from 2 to 17.8 mg/kg/day in twice daily intake, with a maximum of 600 mg/day for children weighing 50 kg or more.
The typical plasma clearance was estimated to be 1.04 L/h, 1.32 L/h and 1.86 L/h for children weighing 20 kg, 30 kg and 50 kg, respectively. In comparison, plasma clearance was estimated at 1.92 L/h in adults (70 kg body weight).
Population pharmacokinetic analysis using sparse pharmacokinetic samples from PGTCS study showed a similar exposure in patients with PGTCS and in patients with partial-onset seizures.
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 anesthetised 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 anesthetised 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.
In juvenile rats and dogs, the types of toxicity do not differ qualitatively from those observed in adult animals. In juvenile rats, a reduced body weight was observed at systemic exposure levels similar to the expected clinical exposure. In juvenile dogs, transient and dose-related CNS clinical signs started to be observed at systemic exposure levels below the expected clinical exposure.
