Lacosamide - Drug Monograph

Introduction

Lacosamide is an antiepileptic drug (AED) approved for the treatment of partial-onset seizures in patients with epilepsy. First approved by the FDA in 2008, lacosamide represents a novel therapeutic approach with a unique dual mechanism of action. It is available in oral tablet, oral solution, and intravenous formulations, providing flexibility in administration across various clinical scenarios.

Mechanism of Action

Lacosamide exhibits a unique dual mechanism of action: 1. Selective enhancement of slow inactivation of voltage-gated sodium channels, stabilizing hyperexcitable neuronal membranes and inhibiting repetitive neuronal firing 2. Binding to collapsin response mediator protein 2 (CRMP-2), which may modulate neuronal differentiation and axon outgrowth

Unlike traditional sodium channel blockers (e.g., carbamazepine, phenytoin) that primarily affect fast inactivation, lacosamide's selective action on slow inactivation provides a distinct pharmacological profile with potentially different efficacy and side effect characteristics.

Indications

FDA-approved indications:

• Monotherapy or adjunctive therapy for partial-onset seizures in patients 4 years of age and older
• Adjunctive therapy for primary generalized tonic-clonic seizures in patients 4 years and older

Off-label uses (based on clinical evidence):

• Neuropathic pain management
• Migraine prophylaxis
• Fibromyalgia treatment (investigational)

Dosage and Administration

• Adults: 50 mg twice daily (100 mg/day)
• May increase weekly by 100 mg/day to recommended maintenance dose

• 200-400 mg/day in two divided doses
• Maximum recommended dose: 400 mg/day

• Renal impairment: Maximum dose 300 mg/day for severe impairment (CrCl ≤30 mL/min)
• Hepatic impairment: Maximum dose 300 mg/day for severe impairment (Child-Pugh Class C)
• Geriatric patients: Consider lower starting doses due to potential decreased clearance
• Pediatrics (4-17 years): Starting dose 1 mg/kg twice daily, titrated based on weight

• Oral tablets: May be taken with or without food
• Oral solution: Use provided measuring device
• IV formulation: For when oral administration is temporarily not feasible; administer over 30-60 minutes

Pharmacokinetics

• Rapid and complete oral bioavailability (~100%)
• Food does not affect absorption
• Tmax: 1-4 hours post-dose

• Volume of distribution: ~0.6 L/kg
• Low protein binding (<15%)

• Primarily via CYP2C19 to O-desmethyl metabolite (inactive)
• Minor pathways: CYP3A4 and CYP2C9

• Renal excretion: ~40% as unchanged drug, ~30% as inactive metabolite
• Half-life: ~13 hours
• Clearance: Reduced in renal and hepatic impairment

Contraindications

• Known hypersensitivity to lacosamide or any component of the formulation
• Second- or third-degree AV block (unless patient has functioning pacemaker)

Warnings and Precautions

• Dose-dependent PR interval prolongation
• Risk of atrial fibrillation and flutter
• Syncope and bradycardia reported
• Monitor ECG in patients with known cardiac conduction problems or structural heart disease

• Suicidal ideation and behavior (AED class warning)
• Monitor for emergence or worsening of depression, suicidal thoughts, or unusual changes in mood or behavior

• Dizziness and ataxia may impair physical or mental abilities
• Risk of multidrug hypersensitivity syndrome

• Withdrawal seizures: Taper gradually when discontinuing
• Drug reaction with eosinophilia and systemic symptoms (DRESS) reported

Drug Interactions

• Strong CYP2C19 inhibitors (e.g., fluconazole): May increase lacosamide levels
• Strong CYP3A4 inducers (e.g., carbamazepine, rifampin): May decrease lacosamide levels
• Other sodium channel blockers: Potential additive effects on cardiac conduction

• Metformin: Lacosamide may increase metformin exposure
• Omeprazole: Weak interaction, unlikely clinically significant

Adverse Effects

• Dizziness (30%)
• Headache (14%)
• Nausea (11%)
• Diplopia (11%)
• Fatigue (9%)

• Prolonged PR interval
• Atrioventricular block
• Syncope
• Suicidal ideation
• Stevens-Johnson syndrome
• Drug reaction with eosinophilia and systemic symptoms (DRESS)

Monitoring Parameters

• Complete medical history with focus on cardiac conditions
• ECG (if cardiac risk factors present)
• Renal and hepatic function tests
• Pregnancy test if applicable

• Seizure frequency and characteristics
• Neurological examination for ataxia, dizziness
• Mental status assessment for mood changes
• ECG monitoring if symptoms suggest arrhythmia or conduction abnormalities
• Renal and hepatic function (periodically)

• Not routinely required
• Consider in special populations: target range 5-20 μg/mL

Patient Education

• Take medication exactly as prescribed; do not stop abruptly
• Potential side effects: dizziness, drowsiness, blurred vision
• Avoid alcohol and other CNS depressants
• Use caution when driving or operating machinery
• Report any cardiac symptoms (palpitations, dizziness, fainting)
• Notify provider of mood changes or suicidal thoughts
• Use effective contraception; discuss pregnancy planning
• Inform all healthcare providers about lacosamide use

• Tablets may be taken with or without food
• Use provided measuring device for oral solution
• Report missed doses; do not double dose

References

1. FDA Prescribing Information: Vimpat (lacosamide). Revised 2022. 2. Beyreuther BK, et al. Lacosamide: a review of preclinical properties. CNS Drug Reviews. 2007;13(1):21-42. 3. Chung S, et al. Lacosamide: pharmacology, mechanisms of action and pooled efficacy and safety data in partial-onset seizures. Expert Review of Neurotherapeutics. 2010;10(6):929-941. 4. Cawello W, et al. Clinical pharmacokinetic and pharmacodynamic profile of lacosamide. Clinical Pharmacokinetics. 2015;54(9):901-914. 5. Wechsler RT, et al. Lacosamide: 10 years of clinical experience in epilepsy. Epilepsy Research. 2019;151:24-32. 6. Krause LU, et al. Lacosamide in the treatment of epilepsy: a review of the literature. Therapeutic Advances in Neurological Disorders. 2021;14:17562864211031150.