Lacosamide is a functionalized amino acid (R)-2-acetamido-N-benzyl-3-methoxypropionamide. It is one of the latest AEDs to be licensed (at the end of 2008), under the brand name Vimpat.
SmPC: adjunctive therapy in the treatment of focal seizures with or without secondary generalisation in patients with epilepsy aged 16 years and older. Solution for infusion is an alternative for patients for whom oral administration is temporarily not feasible.
FDA: (1) tablets are indicated as adjunctive therapy in the treatment of focal seizures in patients with epilepsy aged 17 years and older and (2) injection for intravenous use is indicated as adjunctive therapy in the treatment of focal seizures in patients with epilepsy aged 17 years and older when oral administration is temporarily not feasible.
Based on RCTs, lacosamide is a useful addition to our armamentarium in the treatment of epilepsy. This is also supported by experience since its introduction in clinical practice.
Lacosamide has proven efficacy and a high retention rate (77% in a year) in difficult to treat patients. It is particularly important in adjunctive AED therapy because of its excellent pharmacokinetic profile, minimal drug to drug interactions, good safety and novel mechanism/s of action, which is different than any other AED co-medication. It is considered as having less sedative effects than most other AEDs. Intravenous solution is important when oral drug administration is impossible.
Dosage and titration
“Start low and go slow”
Adults: Start with 50 mg twice daily (100 mg/day). Increase at weekly intervals by 100 mg/day to 200–400 mg/day.
The maximum recommended dose of lacosamide is 400 mg/day because higher doses may be associated with CNS and gastrointestinal ADRs.
A maximum dose of 300 mg/day is recommended by the FDA for patients with mild or moderate hepatic impairment; no such upper limits are recommended by the EMEA.
Lacosamide injection (without further dilution or mixed in compatible diluents) should be administered intravenously over 15–60 minutes. When switching from oral lacosamide, the initial total daily intravenous dosage should be equivalent to the total daily dosage and frequency of oral lacosamide. When used as shortterm replacement for oral lacosamide, intravenous lacosamide was well tolerated when administered as a 15-, 30- or 60-minute infusion.
Dosing: twice daily
Reference range: unknown.
Frequent and/or important: Dizziness, headache, diplopia, nausea, vomiting and blurred vision.
Serious: A small, asymptomatic, dose-related increase in the PR interval measured on ECG has been observed in clinical studies (see also eslicarbazepine ). However, atrioventricular block is uncommon, with an occurrrence of 0.7%, 0%, 0.5% and 0% for lacosamide 200 mg, 400 mg, 600 mg or placebo, respectively. No second or higher degree atrioventricular block was seen in lacosamide patients. Also, the incidence rate for syncope did not differ between lacosamide (0.1%) and placebo treated epilepsy patients (0.3%). However, caution is needed in patients with known conduction problems or severe cardiac disease, in the elderly and in comedication with drugs known to be associated with PR prolongation (e.g. carbamazepine, lamotrigine, pregabalin, eslicarbazepine or class I antiarrhythmic drugs), though an increased magnitude of PR prolongation has not been found so far in comedication with carbamazepine or lamotrigine.
Considerations in women
Pregnancy: category C. Breastfeeding: unknown but possibly excreted in breast milk (animal data). Interactions with hormonal contraception: none.
Main mechanisms of action
Not fully elucidated but two mechanisms are possible: (a) lacosamide selectively enhances slow inactivation of voltage-gated sodium channels, resulting in stabilization of hyperexcitable neuronal membranes and inhibition of repetitive neuronal firing (Figure 1) and (b) lacosamide may bind to collapsin response mediator protein–2 (CRMP–2), a phosphoprotein which is mainly expressed in the nervous system and is involved in neuronal differentiation and control of axonal outgrowth. The role of CRMP-2 binding in seizure control is unknown.
Lacosamide has near-ideal pharmacokinetics (score 96 out of maximal best 100).
Oral bioavailability: 100%.
Protein binding: <15%
Metabolism: Primarily eliminated by renal excretion and biotransformation. Its metabolism has not been fully elucidated but CYP-2C19 is involved in the demethylation of lacosamide. Lacosamide showed no potential to induce or inhibit the activity of CYP isoforms 1A1, 1A2, 2A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1 and 3A4 in human hepatocytes at therapeutic concentrations, although inhibition of the CYP2C19 iso-enzyme was noted at concentrations 15-times higher than therapeutic concentrations.
Elimination half-life: ours.
These are minimal and probably of no clinical significance. From available evidence, lacosamide does not affect plasma levels of carbamazepine or its epoxide metabolite, gabapentin, lamotrigine, levetiracetam, oxcarbazepine, phenytoin, topiramate, valproate and zonisamide or the oral contraceptive levonorgestrel/ethinylestradiol, metformin and digoxin.1 Carbamazepine, phenytoin and phenobarbital may decrease plasma levels of lacosamide by 15–20%. Omeprazole (a CYP2C19 inhibitor) did not produce any clinically significant changes in lacosamide plasma concentrations.
Not yet exposed to lengthy clinical practice but its use so far has met with favourable results.
- Beydoun A, D’Souza J, Hebert D, Doty P. Lacosamide: pharmacology, mechanisms of action and pooled efficacy and safety data in partialonset seizures. Expert Rev Neurother 2009;9:33-42.