What is lacosamide?

What is Lacosamide?

Lacosamide is a functionalized amino acid antiepileptic medication that works through a novel mechanism—selectively enhancing slow inactivation of voltage-gated sodium channels—and is FDA-approved as adjunctive therapy for partial-onset seizures in patients 1 month and older, and for primary generalized tonic-clonic seizures in patients 4 years and older. 1

Mechanism of Action

• Lacosamide selectively enhances slow inactivation of voltage-gated sodium channels, which stabilizes hyperexcitable neuronal membranes and inhibits repetitive neuronal firing 1
• This mechanism differs fundamentally from traditional sodium channel blockers (carbamazepine, phenytoin, lamotrigine) that primarily affect fast inactivation 2
• In vitro studies suggest lacosamide may also interact with collapsin-response mediator protein-2, potentially mediating neuronal plasticity 3, 4

Chemical Structure and Formulation

• The chemical name is (R)-2-acetamido-N-benzyl-3-methoxypropionamide, with molecular formula C₁₃H₁₈N₂O₃ and molecular weight 250.30 1
• Lacosamide is a white to light yellow powder, sparingly soluble in water 1
• Available formulations include oral tablets, oral solution (10 mg/mL), and intravenous solution 1

FDA-Approved Indications

• Partial-onset seizures: Approved for patients 1 month of age and older 1
• Primary generalized tonic-clonic seizures: Approved for patients 4 years of age and older 1
• Used as adjunctive (add-on) therapy with other antiepileptic medications 1

Pharmacokinetic Profile

• Bioavailability: Approximately 100% with negligible first-pass effect; oral and IV formulations are bioequivalent 1, 5
• Time to peak concentration: 1-4 hours after oral administration 1
• Elimination half-life: Approximately 13 hours 1, 3
• Steady state: Achieved after 3 days of twice-daily dosing 1
• Protein binding: Minimal (less than 15%), reducing potential for displacement interactions 1, 3
• Metabolism: Primarily renal excretion; does not induce or inhibit cytochrome P450 enzymes 1, 3
• Drug interactions: Low potential for clinically significant drug-drug interactions 3, 2

Dosing Strategy

• Starting dose: The Mayo Clinic recommends 50 mg twice daily (100 mg/day total) 6
• Titration: Increase by 50 mg twice daily (100 mg/day total) at weekly intervals based on response and tolerability 6
• Target maintenance dose: Typically 200-400 mg daily in divided doses 6
• Maximum recommended dose: 400 mg/day; doses above this do not appear to confer additional benefit 1

Efficacy Data

• Pooled analysis of three Phase II/III trials (n=1,308) showed 34% of patients on 200 mg/day and 40% on 400 mg/day achieved ≥50% reduction in seizure frequency versus 23% on placebo 5
• Demonstrates rapid onset of anticonvulsant effects even in severely refractory populations 7
• Efficacy maintained over long-term use (up to 7 years in extension studies) 7

Safety Profile and Common Adverse Effects

• Most common adverse events: Dizziness, nausea, headache, and double vision 1, 3
• CNS effects: Somnolence, ataxia, vertigo, and coordination problems 8, 1
• Most adverse events are mild to moderate in severity 5, 3
• Cardiac effects: Small dose-related increases in PR interval (7.3 ms at 400 mg/day, 11.9 ms at 800 mg/day) 8, 1

Critical Safety Considerations

Cardiac Monitoring

• Baseline ECG required before starting lacosamide due to documented PR interval prolongation 6
• Monitor for cardiac conduction abnormalities, particularly in patients with pre-existing cardiac disease 6
• Rare cases of cardiac arrest have been reported with overdose 1
• Patients may experience irregular heartbeat, palpitations, or syncope 1

Psychiatric Effects

• Like other antiepileptic drugs, lacosamide may cause suicidal thoughts or actions in approximately 1 in 500 patients 1
• Monitor for new or worsening depression, anxiety, agitation, or behavioral changes 1

Abuse Potential

• Lacosamide is a Schedule V controlled substance due to potential for abuse 1
• Single doses of 800 mg produced euphoria-type responses similar to alprazolam in abuse potential studies 1
• At therapeutic doses (≤400 mg/day), euphoria rates are less than 1% 1

Withdrawal Risks

• Never discontinue abruptly except in cases of serious medical toxicity 9
• Abrupt discontinuation can precipitate status epilepticus (continuous seizures) in patients with epilepsy 1
• The American Academy of Neurology recommends tapering by 100 mg/day at weekly intervals 9

Special Populations

Pregnancy

• Pregnant women with well-controlled epilepsy should continue lacosamide, as risks of seizure recurrence outweigh potential medication risks 10
• Seizure control is critical for reducing maternal and fetal morbidity and mortality 10
• Patients should be enrolled in the North American Antiepileptic Drug Pregnancy Registry (1-888-233-2334) 1

Renal Impairment

• Lacosamide requires dose adjustment in severe renal disease 6
• Hemodialysis removes approximately 50% of lacosamide in 4 hours and may be indicated in overdose 1

Hepatic Impairment

• Use with caution; specific dosing adjustments may be necessary 6

Driving and Operating Machinery

• Lacosamide may cause dizziness, double vision, somnolence, and coordination problems 8, 1
• Patients should not drive or operate heavy machinery until they know how lacosamide affects them 1
• Pharmacodynamic studies show effects on neuropsychological tests relevant to driving performance 8

Clinical Context Beyond Epilepsy

• Lacosamide was extensively studied for painful diabetic peripheral neuropathy (DPN) in multiple Phase 2 and 3 trials 8
• Despite some positive results, lacosamide was not approved by the FDA or European Medicines Agency for neuropathic pain treatment 8
• The Mayo Clinic notes that one Phase 3 trial showed only marginal statistical significance (P=0.0507), and another Phase 3 trial failed to show benefit over placebo 8

Key Clinical Pitfalls to Avoid

• Do not load lacosamide rapidly: Unlike phenytoin or levetiracetam, loading dosages have not been adequately studied 8
• Do not ignore cardiac history: Always obtain baseline ECG and monitor patients with pre-existing cardiac conduction abnormalities 6
• Do not taper too quickly: Withdrawal seizures can occur despite the 13-hour half-life 6
• Do not assume all sodium channel blockers are equivalent: Lacosamide's unique mechanism (slow vs. fast inactivation) may provide benefit in patients who failed traditional agents 2