Lacosamide …

K K Jain MD†

Neuropharmacology & Neurotherapeutics

Updated 09.12.2021
Released 11.02.2010
Expires For CME 09.12.2024

Lacosamide

Author: K K Jain MD†

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Lacosamide

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Introduction

Historical note and terminology

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.

Pharmacology

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.

Clinical trials

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.

Table 1. Clinical Trials of Lacosamide

Method	Results/reference
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).

Indications

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.

Off-label uses

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).

Special considerations

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.

References

01: Ákos Szabó C, Morgan LC, Sonnenberg S, Karkar KM. Absence status induced by lacosamide adjunctive therapy. Epileptic Disord 2019;21(1):97-101. PMID 30782579
02: Biton V, Gil-Nagel A, Isojarvi J, Doty P, Hebert D, Fountain NB. Safety and tolerability of lacosamide as adjunctive therapy for adults with partial-onset seizures: Analysis of data pooled from three randomized, double-blind, placebo-controlled clinical trials. Epilepsy Behav 2015;52(Pt A):119-27. PMID 26414341
03: Carona A, Bicker J, Silva R, Fonseca C, Falcão A, Fortuna A. Pharmacology of lacosamide: from its molecular mechanisms and pharmacokinetics to future therapeutic applications. Life Sci 2021;275:119342. PMID 33713668
04: Cawello W. Clinical pharmacokinetic and pharmacodynamic profile of lacosamide. Clin Pharmacokinet 2015;54(9):901-14.** PMID 25957198
05: Cawello W, Rosenkranz B, Schmid B, Wierich W. Pharmacodynamic and pharmacokinetic evaluation of coadministration of lacosamide and an oral contraceptive (levonorgestrel plus ethinylestradiol) in healthy female volunteers. Epilepsia 2013;54(3):530-6. PMID 23360419
06: Chung S, Sperling MR, Biton V, et al; SP754 Study Group. Lacosamide as adjunctive therapy for partial-onset seizures: a randomized controlled trial. Epilepsia 2010;51(6):958-67. PMID 20132285
07: Contin M, Albani F, Riva R, Candela C, Mohamed S, Baruzzi A. Lacosamide therapeutic monitoring in patients with epilepsy: effect of concomitant antiepileptic drugs. Ther Drug Monit 2013;35(6):849-52. PMID 23942540
08: Fernandez EM, Franck AJ. Lacosamide for the treatment of refractory status epilepticus. Ann Pharmacother 2011;45(11):1445-9. PMID 22010001
09: Geis C, Beyreuther BK, Stöhr T, Sommer C. Lacosamide has protective disease modifying properties in experimental vincristine neuropathy. Neuropharmacology 2011;61(4):600-7. PMID 21586299
10: Gómez-Argüelles JM, Bermejo PE, Lara M, et al. Effectiveness of lacosamide in the treatment of refractory neuropathic pain: an open observational trial [Article in Spanish]. Rev Neurol 2014;59(7):289-93. PMID 25245872
11: Grosso S, Parisi P, Spalice A, Verrotti A, Balestri P. Efficacy and safety of lacosamide in infants and young children with refractory focal epilepsy. Eur J Paediatr Neurol 2014a;18(1):55-9. PMID 24129195
12: Grosso S, Zamponi N, Bartocci A, et al. Lacosamide in children with refractory status epilepticus. A multicenter Italian experience. Eur J Paediatr Neurol 2014b;18(5):604-8. PMID 24836405
13: Halász P, Kälviäinen R, Mazurkiewicz-Beldzińska M, et al; SP755 Study Group. Adjunctive lacosamide for partial-onset seizures: Efficacy and safety results from a randomized controlled trial. Epilepsia 2009;50(3):443-53. PMID 19183227
14: Harris JA, Murphy JA. Lacosamide and epilepsy. CNS Neurosci Ther 2011;17(6):678-82. PMID 20950330
15: Hillenbrand B, Wisniewski I, Jürges U, Steinhoff BJ. Add-on lacosamide: A retrospective study on the relationship between serum concentration, dosage, and adverse events. Epilepsy Behav 2011;22(3):548-51. PMID 21962950
16: Husain A, Chung S, Faught E, Isojarvi J, McShea C, Doty P. Long-term safety and efficacy in patients with uncontrolled partial-onset seizures treated with adjunctive lacosamide: results from a Phase III open-label extension trial. Epilepsia 2012;53(3):521-8. PMID 22372628
17: Kelemen A, Halász P. Lacosamide for the prevention of partial onset seizures in epileptic adults. Neuropsychiatr Dis Treat 2010;6:465-71. PMID 20856610
18: Lattanzi S, Cagnetti C, Foschi N, Provinciali L, Silvestrini M. Lacosamide during pregnancy and breastfeeding. Neurol Neurochir Pol 2017;51(3):266-9. PMID 28385340
19: Namer B, Schmidt D, Eberhardt E, et al. Pain relief in a neuropathy patient by lacosamide: proof of principle of clinical translation from patient-specific iPS cell-derived nociceptors. EBioMedicine 2019;39:401-8.** PMID 30503201
20: Ortiz de la Rosa JS, Ladino LD, Rodríguez PJ, Rueda MC, Polanía JP, Castañeda AC. Efficacy of lacosamide in children and adolescents with drug-resistant epilepsy and refractory status epilepticus: A systematic review. Seizure 2018;56:34-40.** PMID 29428899
21: Rainesalo S, Mäkinen J, Raitanen J, Peltola J. Clinical management of elderly patients with epilepsy; the use of lacosamide in a single center setting. Epilepsy Behav 2017;75:86-9. PMID 28834781
22: Rastogi RG, Ng YT. Lacosamide in refractory mixed pediatric epilepsy: a prospective add-on study. J Child Neurol 2012;27(4):492-5. PMID 22467791
23: Rosenfeld W, Fountain NB, Kaubrys G, et al. Safety and efficacy of adjunctive lacosamide among patients with partial-onset seizures in a long-term open-label extension trial of up to 8 years. Epilepsy Behav 2014;41:164-70. PMID 25262499
24: Rosenow F, Brandt C, Bozorg A, et al. Lacosamide in patients with epilepsy of cerebrovascular etiology. Acta Neurol Scand 2020;141(6):473-82. PMID 32068241
25: Runge U, Arnold S, Brandt C, et al. A noninterventional study evaluating the effectiveness and safety of lacosamide added to monotherapy in patients with epilepsy with partial-onset seizures in daily clinical practice: The VITOBA study. Epilepsia 2015;56(12):1921-30. PMID 26526971
26: Santamarina E, Toledo M, Sueiras M, et al. Usefulness of intravenous lacosamide in status epilepticus. J Neurol 2013;260(12):3122-8. PMID 24122063
27: Saria MG, Corle C, Hu J, et al. Retrospective analysis of the tolerability and activity of lacosamide in patients with brain tumors: clinical article. J Neurosurg 2013;118(6):1183-7. PMID 23451905
28: Spalletti M, Comanducci A, Vagaggini A, Bucciardini L, Grippo A, Amantini A. Efficacy of lacosamide on seizures and myoclonus in a patient with epilepsia partialis continua. Epileptic Disord 2013;15(2):193-6. PMID 23761109
29: Strzelczyk A, Zöllner JP, Willems LM, et al. Lacosamide in status epilepticus: Systematic review of current evidence. Epilepsia 2017;58(6):933-50. PMID 28295226
30: Wang Y, Brittain JM, Jarecki BW, et al. In silico docking and electrophysiological characterization of lacosamide binding sites on collapsin response mediator protein-2 identifies a pocket important in modulating sodium channel slow inactivation. J Biol Chem 2010;285(33):25296-307. PMID 20538611
31: Wechsler RT, Li G, French J, et al. Conversion to lacosamide monotherapy in the treatment of focal epilepsy: results from a historical-controlled, multicenter, double-blind study. Epilepsia 2014;55(7):1088-98. PMID 24915838
32: Wymer JP, Simpson J, Sen D, Bongardt S; Lacosamide SP742 Study Group. Efficacy and safety of lacosamide in diabetic neuropathic pain: an 18-week double-blind placebo-controlled trial of fixed-dose regimens. Clin J Pain 2009;25(5):376-85. PMID 19454870
33: Yang HS, Edinboro L. Therapeutic Drug monitoring of lacosamide by LC-MS/MS. Methods Mol Biol 2019;1872:67-73. PMID 30350280
34: Ylikotila P, Ketola RA, Timonen S, Malm H, Ruuskanen JO. Early pregnancy cerebral venous thrombosis and status epilepticus treated with levetiracetam and lacosamide throughout pregnancy. Reprod Toxicol 2015;57:204-6. PMID 26187779

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Lacosamide

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Lacosamide …

Lacosamide

Introduction

Historical note and terminology

Pharmacology

Clinical trials

Table 1. Clinical Trials of Lacosamide

Indications

Off-label uses

Contraindications

Goals and duration of treatment

Dosing

Special considerations

Interactions

Adverse effects

References

Contributors

Author

This is an article preview.
Start a Free Account
to access the full version.

Questions or Comment?

Also in This Category

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Self-limited (familial) neonatal epilepsy

Drug-induced myasthenic syndromes

Lacosamide

Introduction

Historical note and terminology

Pharmacology

Clinical trials

Table 1. Clinical Trials of Lacosamide

Indications

Off-label uses

Contraindications

Goals and duration of treatment

Dosing

Special considerations

Interactions

Adverse effects

References

Contributors

Author

This is an article preview. Start a Free Account to access the full version.

Questions or Comment?

Also in This Category

Photosensitive occipital lobe epilepsy

Intermittent explosive disorder

Serotonin syndrome

Pyridoxine/P5P-dependent developmental epileptic encephalopathy

Reflex seizures

Anti-LGI1 encephalitis

Self-limited (familial) neonatal epilepsy

Drug-induced myasthenic syndromes

This is an article preview.
Start a Free Account
to access the full version.