Epilepsy & Seizures
Generalized onset tonic seizures
Nov. 08, 2022
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Lacosamide, with the chemical name of (R)N-acetyl-D,L-alanine benzyl-3-methoxypropionamide, is a functionalized amino acid with novel mechanisms of action. It has been specifically developed as an antiepileptic drug for the adjunctive treatment of partial-onset seizures. It was approved in the United States by the FDA in 2008 and was also approved in the European Union in the same year. It is marketed under the trade name of Vimpat (UCB Pharmaceuticals). The DEA has placed lacosamide into schedule V of the Controlled Substances Act. It is also being developed for the treatment of diabetic neuropathic pain.
Pharmacodynamics. Lacosamide is the only antiepileptic/analgesic drug that selectively enhances slow inactivation of voltage-gated sodium channels but without apparent interaction with fast inactivation gating. Slow inactivation is a process like fast inactivation except that it does not produce complete blockade of voltage gated sodium channels, and it occurs over the course of hundreds of milliseconds or more, and recovery from this state takes equally as long.
Lacosamide is sometimes described as having a dual mechanism of action, as it interferes in vitro with the activity of collapsin response mediator protein-2 (CRMP-2), which is involved in neuronal differentiation and control of axonal outgrowth (17). The role of CRMP-2 binding in seizure control, however, has not been established. Electrophysiological characterization of lacosamide binding sites on CRMP-2 has identified a pocket that is important in modulating sodium channel slow inactivation (30).
Pharmacokinetics. Lacosamide is completely absorbed after oral administration with negligible first-pass effect with a bioavailability of approximately 100%. The maximum lacosamide plasma concentrations occur approximately 1 to 4 hours post-dose after oral dosing, and elimination half-life is approximately 13 hours. Steady state plasma concentrations are achieved after 3 days of twice-daily repeated administration. Pharmacokinetics of lacosamide is proportional to dose within a range of 100 to 800 mg with low inter- and intra-subject variability. Compared to lacosamide, the major metabolite, O-desmethyl metabolite, has a longer Tmax (0.5 to 12 hours) and elimination half-life (15 to 23 hours).
Favorable pharmacokinetic characteristics of lacosamide include rapid absorption and high oral bioavailability that is not affected by food and dose-proportional pharmacokinetics with low inter- and intraindividual variability. Lacosamide does not induce or inhibit cytochrome P450 enzymes or known drug transporter systems, and it has low protein binding of less than 15%. Also, because it has multiple elimination pathways, lacosamide has no clinically relevant interactions with commonly prescribed medications (04).
Therapeutic drug monitoring. A simple method based on high-performance liquid chromatography with ultraviolet detection for the quantification of lacosamide in human plasma is available for determination of serum levels of the drug. A small volume of the extracted specimen is injected into a reversed-phase chromatography column, and lacosamide is identified by positive electrospray ionization mass spectrometry in the multiple reaction monitoring, which provides selectivity for quantitative analysis of lacosamide (33). The practical significance of therapeutic drug monitoring is that patients on concomitant strong inducer antiepileptic drugs such as oxcarbazepine, levetiracetam, lamotrigine, and valproic acid, may require a 30% higher dose of lacosamide compared with patients not receiving strongly inducing antiepileptic drug cotherapy to achieve the same plasma drug concentration (07).
Formulations. Lacosamide is available in oral or intravenous formulations, which have been used successfully for the control of status epilepticus. Bioequivalence between the oral tablet and the oral syrup of lacosamide has been established. The bioavailability of the oral lacosamide tablet is like that of a 30- or 60-minute intravenous infusion of lacosamide administered at the same dosage. Intravenous lacosamide is well tolerated when administered as a 15-, 30-, or 60-minute infusion.
Pharmacogenetics. There is no significant effect of CYP2C19 polymorphism on the pharmacokinetics of lacosamide. There are no clinically relevant differences in the pharmacokinetics between CYP2C19 poor metabolizers and extensive metabolizers, but concentrations and the amount excreted into urine of the O-desmethyl metabolite were about 70% reduced in the former as compared to the latter.
A review of the findings of earlier clinical trials suggests that lacosamide is an effective agent for adjunctive treatment of refractory partial-onset seizures (14). Subsequent clinical trials, including those for investigating efficacy of lacosamide in the relief of pain, are shown in Table 1.
A multicenter, double-blind, placebo-controlled trial randomized patients with partial-onset seizures with or without secondary generalization to placebo, lacosamide 200 mg/day, or lacosamide 400 mg/day. The trial consisted of an 8-week baseline, a 4-week titration, and a 12-week maintenance period.
Results demonstrated the efficacy and tolerability of adjunctive lacosamide (13). The 50% responder rate for lacosamide 400 mg/day (40.5%) was significant over placebo (25.8%) but that of 200 mg/day (35.0%) was not.
A multicenter, randomized, placebo-controlled, double-blind trial was conducted to confirm the efficacy of lacosamide 400 mg/day and to explore the efficacy, safety, and tolerability of 200 mg/day and 600 mg/day doses for treatment of painful diabetic neuropathy.
Lacosamide 400 mg/day provided an optimal balance between efficacy and side effects in patients with painful diabetic neuropathy (32).
In a multicenter, randomized, double-blind, placebo-controlled trial as adjunct therapy in partial epilepsy patients taking up to 3 antiepileptic drugs, patients placed on lacosamide were titrated by 100 mg/day increments to the target dose of 400 mg/day or 600 mg/day and entered a 12-week maintenance period.
Lacosamide 400 mg/day was effective in controlling seizures and was well tolerated; lacosamide 600 mg/day provided additional benefit for some patients as suggested by secondary efficacy analyses, including response in patients with secondarily generalized tonic-clonic seizures (06).
A multicenter, double-blind, randomized trial was conducted to determine if lacosamide is safe and effective, when taken alone, to decrease the number and severity of seizures in adult patients who are withdrawn from 1 to 2 marketed antiepileptic drugs
Lacosamide 400 mg/day monotherapy was effective, with a favorable safety profile in patients with focal epilepsy (31).
Phase III open-label extension trial to determine long-term safety and efficacy of lacosamide in patients with uncontrolled partial-onset seizures
Safety and efficacy profile of lacosamide up to 5 years was consistent with that established in double-blind, placebo- controlled trials (16).
Analysis of data pooled from 3 randomized, double-blind, placebo-controlled clinical trials showed that safety and tolerability profile of adjunctive lacosamide was like that observed in the individual double-blind trials (02). Treatment-emergent adverse events related to the nervous system and gastrointestinal tract occurred mostly during titration. The VITOBA study (NCT01098162) showed effectiveness and tolerability of adjunctive lacosamide added to 1 baseline antiepileptic drug in real-world clinical practice (25). Posthoc analyses of clinical trials suggested that lacosamide is generally well tolerated and effective in patients with epilepsy due to cerebrovascular causes, with data from the initial monotherapy trial suggesting better efficacy than carbamazepine-controlled release (24).
Lacosamide tablets and oral solutions are indicated as adjunctive therapy in the treatment of partial-onset seizures in adult patients with epilepsy. Lacosamide injection is indicated as short-term replacement when oral administration is not feasible in these patients.
Although lacosamide has been reported to be effective for refractory status epilepticus, the currently available evidence does not support routine use; however, it may be a reasonable option in complex partial status epilepticus after more established drug therapies fail (08). A prospective add-on study of lacosamide in refractory mixed epilepsy in children showed that it was effective in treating 62.5% of localization-related epilepsies and only 25% of generalized epilepsies, but none of the very refractory patients remained seizure-free (22). Lacosamide was reported to be effective in a patient with epilepsia partialis continua who had failed to respond to other antiepileptic drugs (28). Intravenous lacosamide is effective as a second or third option after benzodiazepines for the management of nonconvulsive or focal motor status epilepticus (26).
Lacosamide, which was used as a fourth or later option, was effective in stopping resistant status epilepticus in 45% of patients, with seizures terminating within 12 hours in some children (12). No serious adverse events attributable to lacosamide were reported. A systematic literature review of lacosamide reports a success rate of 57% in status epilepticus and discusses the advantages of the lack of interaction potential as well as the option for intravenous use in emergency situations requiring rapid uptitration (29).
An open observational trial has shown effectiveness of lacosamide in the treatment of refractory neuropathic pain, including diabetic polyneuropathy, post-herpes neuralgia, trigeminal neuralgia, and suboccipital and lumbar-radicular neuralgia (10).
Based on studies in rats, lacosamide may be a promising candidate for preventive treatment of chemotherapy-induced painful neuropathy in patients receiving vinca alkaloids or platinum drugs (09).
A retrospective study shows that lacosamide is well tolerated as well as effective as an add-on antiepileptic drug in patients with brain tumors (27).
According to the results of a retrospective study, lacosamide is an effective and a well-tolerated antiepileptic drug for focal seizures in infants and young children (11).
Therapy-resistant small fiber neuropathy has been treated successfully by preassessment of in vitro response to lacosamide on patient-derived sensory neurons using induced pluripotential stem cell technology and personalizing therapy (19).
Lacosamide is contraindicated in patients who have a demonstrated hypersensitivity to lacosamide or any of its ingredients.
Lacosamide use as an adjunct antiepileptic drug is correlated with reduction in seizure frequency. However, doses above 400 mg/day do not appear to confer additional benefit in group analyses of clinical trials. Long-term (up to 8 years of exposure) safety and efficacy of lacosamide were evaluated in an open-label extension trial following participation in a double-blind trial or 1 of 2 open-label trials of adjunctive lacosamide for partial-onset seizures (23). Long-term exposure to lacosamide was generally well tolerated, with a safety profile like that of previous double-blind trials, and efficacy was maintained.
Therapeutic drug monitoring of lacosamide is proving to be advantageous by allowing for the control of inter- and intraindividual variability and promoting successful personalized therapy, particularly in special populations (03).
The starting dose is 50 mg twice daily (100 mg/day). The dose may be increased at weekly intervals by 100 mg/day according to clinical response and tolerability, given as 2 divided doses to a daily dose of 200 to 400 mg/day. The injectable preparation may be administered intravenously over a period of 30 to 60 minutes. At the end of the intravenous treatment period, the patient may be switched to oral lacosamide at the equivalent daily dosage and frequency of the intravenous administration.
Patients should be warned about possible occurrence of suicidal behavior and ideation. Lacosamide may cause syncope. Caution is advised for patients with known cardiac conduction problems or those with myocardial ischemia or heart failure. In patients with seizure disorders, lacosamide should be withdrawn gradually to minimize the risk of increased seizure frequency.
Anesthesia. No relevant information.
Pregnancy. Lacosamide produces increased developmental neurotoxicity in rats following administration during pregnancy. A woman with status epilepticus due to cerebral venous thrombosis in early pregnancy was treated with levetiracetam, lacosamide, and enoxaparin throughout the pregnancy (34). At full-term delivery, levetiracetam and lacosamide were present in cord blood of the infant in levels like those in maternal blood, resulting in sleepiness, which resolved after 2 weeks. The infant was breastfed, and lacosamide level in milk was low. There are no adequate and well-controlled studies in pregnant women. Lacosamide should be used during pregnancy only if the potential benefits justify the potential risks to the fetus. For details, please consult the Physicians Desk Reference.
Lacosamide is excreted in human milk, and the decision whether to discontinue nursing or to discontinue lacosamide should consider the importance of the drug to the mother. A study from a large epilepsy center suggests a good level of efficacy and safety for lacosamide throughout pregnancy and breastfeeding without teratogenicity or toxicity (18).
Pediatric. A systematic review of the literature shows that lacosamide is safe and effective for pediatric patients with focal drug-resistant epilepsy and refractory status epilepticus as an add-on therapy (20).
Geriatric. Results of a retrospective, single-center study show that lacosamide is well tolerated even at relatively high doses and in combination therapy in patients over the age of 60 years (21). No adjustment of dose of lacosamide based on age is considered necessary if renal and hepatic functions are normal. Caution should be exercised in dose titration, as pharmacokinetic parameters are approximately 20% higher in elderly subjects compared to those of young subjects.
Hepatic and renal disease. Dosage adjustments are recommended for patients with mild or moderate hepatic impairment or severe renal impairment. Use in patients with severe hepatic impairment is not recommended.
There was no evidence for any relevant drug-to-drug interaction of lacosamide with common antiepileptic drugs in the placebo-controlled clinical trials in patients with partial-onset seizures. No pharmacokinetic interactions have been reported between lacosamide and digoxin, metformin, omeprazole, or an oral contraceptive containing ethinylestradiol and levonorgestrel. Therefore, coadministration of lacosamide and an oral contraceptive is unlikely to result in contraceptive failure or loss of seizure control (05).
In clinical trials, the most common adverse reactions occurring in 10% or more of lacosamide-treated patients were dizziness, headache, nausea, and diplopia. These do not require special treatment. A retrospective study showed that dizziness as the leading adverse event occurred significantly more often if lacosamide was combined with classic sodium channel blockers (15).
Absence status induced by lacosamide adjunctive therapy has been reported, which was successfully managed by discontinuation of lacosamide and replacement with lorazepam (01).
K K Jain MD†
Dr. Jain was a consultant in neurology and had no relevant financial relationships to disclose.See Profile
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