Lacosamide
Lacosamide Indications
| Indication | Approved Population | Therapy Type | Status |
|---|---|---|---|
| Partial-onset (focal) seizures | Adults & pediatric ≥1 month | Monotherapy or adjunctive | FDA Approved |
| Primary generalized tonic-clonic seizures (PGTCS) | ≥4 years (with idiopathic generalized epilepsy) | Adjunctive | FDA Approved |
Lacosamide received FDA approval on October 29, 2008, initially for adjunctive therapy of partial-onset seizures in adults aged 17 and older. The monotherapy indication and pediatric expansion for partial-onset seizures (down to 1 month of age) were added subsequently. The PGTCS indication for patients 4 years and older with idiopathic generalized epilepsy was approved based on a pivotal 24-week RCT demonstrating significant reduction in seizure frequency. Lacosamide is distinguished from other sodium channel blockers by its unique mechanism of selectively enhancing slow inactivation of voltage-gated sodium channels.
Diabetic neuropathic pain: Phase III trials completed but FDA approval not granted; pain reduction demonstrated at 400 mg/day. Evidence quality: Moderate.
Status epilepticus (IV loading): Used in practice as an alternative IV AED when benzodiazepines and phenytoin/fosphenytoin fail. Evidence quality: Low–Moderate (retrospective and observational data).
Lacosamide Dosing
Partial-Onset & PGTC Seizures — Adults and Pediatric ≥50 kg
| Clinical Scenario | Starting Dose | Maintenance Dose | Maximum Dose | Notes |
|---|---|---|---|---|
| Focal seizures — adjunctive or monotherapy (standard titration) | 50 mg BID (100 mg/day) | 100–200 mg BID (200–400 mg/day) | 400 mg/day | Increase by 50 mg BID (100 mg/day) at weekly intervals; 600 mg/day was not more effective than 400 mg/day but less well tolerated (FDA PI) |
| Focal seizures — rapid initiation with loading dose (≥17 y, monotherapy) | 200 mg single loading dose, then 100 mg BID starting 12 h later | 100–200 mg BID (200–400 mg/day) | 400 mg/day | Loading dose under medical supervision due to increased incidence of CNS and cardiovascular adverse reactions Titrate after week 1 if needed, no more frequently than weekly |
| PGTCS — adjunctive | 50 mg BID (100 mg/day) | 100–200 mg BID (200–400 mg/day) | 400 mg/day | Same titration schedule as partial-onset seizures |
| IV substitution (when oral not feasible) | Same dose as oral, 1:1 substitution; infuse over 30–60 min | Short-term replacement only (up to 5 consecutive days); transition back to oral as soon as feasible | ||
Monotherapy Conversion
For patients on a single AED converting to lacosamide monotherapy: do not withdraw the concomitant AED until the therapeutic dosage of lacosamide has been achieved and maintained for at least 3 days. Gradual withdrawal of the prior AED over at least 6 weeks is recommended to minimize the risk of breakthrough seizures.
Renal and Hepatic Dosing Adjustments
| Population | Adjustment | Maximum Dose | Notes |
|---|---|---|---|
| Mild-moderate renal impairment (CrCl >30) | No adjustment necessary | 400 mg/day | Titrate with caution |
| Severe renal impairment (CrCl ≤30) or ESRD | Reduce maximum dose | 300 mg/day | Titrate with caution |
| Hemodialysis | Supplemental dose after each 4-hour session | Up to 50% of the daily dose as supplement; lacosamide is effectively removed (~50% in 4 h) | |
| Mild-moderate hepatic impairment | Reduce maximum dose by 25% | 300 mg/day | Observe closely for adverse reactions during titration |
| Severe hepatic impairment | Use NOT recommended (PK not evaluated in severe hepatic impairment) | ||
Lacosamide has ~100% oral bioavailability, meaning IV and oral doses are interchangeable at a 1:1 ratio. This makes IV lacosamide particularly useful in hospital settings where patients cannot take oral medications (e.g., postoperatively, status epilepticus). The IV formulation should be infused over 30–60 minutes, and can be used for up to 5 consecutive days before transitioning back to oral therapy.
Lacosamide Pharmacology
Mechanism of Action
Lacosamide has a unique mechanism of action among antiepileptic drugs. It selectively enhances slow inactivation of voltage-gated sodium channels, a mechanism distinct from the fast inactivation enhancement used by traditional sodium channel blockers such as carbamazepine, phenytoin, and lamotrigine. Slow inactivation is a conformational state that develops over seconds of sustained depolarization, characteristic of hyperexcitable neurons in seizure foci. By stabilizing sodium channels in this slowly inactivated state, lacosamide reduces the availability of channels for repetitive firing without affecting normal neuronal activity. This selective targeting of pathologically active neurons may contribute to its favorable tolerability profile. Additionally, lacosamide has been shown to bind to collapsin response mediator protein-2 (CRMP-2), though the clinical significance of this interaction remains uncertain.
ADME Profile
| Parameter | Value | Clinical Implication |
|---|---|---|
| Absorption | Bioavailability ~100% (negligible first-pass); Tmax 1–4 h; dose-proportional (100–800 mg); food does not affect rate or extent | Oral and IV doses are interchangeable 1:1; can be taken with or without food; predictable dose-response |
| Distribution | Vd ~0.6 L/kg; protein binding <15% | Low protein binding minimizes displacement interactions; distributes into CNS adequately for antiepileptic effect |
| Metabolism | CYP3A4, CYP2C9, and CYP2C19 produce inactive O-desmethyl metabolite (~30% of dose); additional polar fraction (~20%); ~40% excreted unchanged; does not inhibit or induce CYP enzymes at therapeutic doses | Strong CYP3A4 or CYP2C9 inhibitors may increase lacosamide levels; dose reduction may be needed in renal/hepatic impairment with concurrent strong inhibitors |
| Elimination | t½ ~13 h; ~95% recovered in urine (~40% unchanged, ~30% O-desmethyl, ~20% polar fraction); <0.5% feces; removed by hemodialysis (~50% in 4 h); steady state in 3 days | BID dosing adequate; dose cap at 300 mg/day in severe renal or hepatic impairment; supplement after dialysis |
Lacosamide Side Effects
| Adverse Effect | Incidence | Clinical Note |
|---|---|---|
| Dizziness | 16–53% | 25% at recommended doses (200–400 mg/day) vs 8% placebo; most common AE and most frequent cause of discontinuation (3%); dose-dependent; onset usually during titration |
| Headache | 11–14% | Similar to placebo in some trials; more common in PGTCS trial (14% vs 10% placebo) |
| Diplopia | 11–16% | 11% at 400 mg/day vs 2% placebo; dose-dependent; unique among AEDs for high diplopia rate |
| Nausea | 7–17% | 11% at 400 mg/day vs 4% placebo; PGTCS trial: 10% vs 6% placebo |
| Adverse Effect | Incidence | Clinical Note |
|---|---|---|
| Ataxia / gait disturbance | 4–15% | 6% at 200–400 mg/day vs 2% placebo; dose-dependent; increases fall risk |
| Somnolence | 5–9% | PGTCS trial: 17% vs 14% placebo |
| Tremor | 4–7% | Dose-related |
| Nystagmus | 5–10% | Dose-dependent; more common at higher doses |
| Vomiting | 3–9% | May lead to discontinuation at higher doses |
| Fatigue | 7–9% | Usually during titration; improves over time |
| Blurred vision | 2–9% | Dose-related; reversible |
| Vertigo | 3–5% | Distinct from dizziness; dose-related |
| Memory impairment | 2–4% | Generally mild |
| Adverse Effect | Estimated Frequency | Typical Onset | Required Action |
|---|---|---|---|
| PR interval prolongation / AV block | Dose-dependent; first-degree AV block 0.4% at 200–400 mg/day | Dose-related; correlates with Tmax | ECG before starting and after reaching steady state; caution with concurrent PR-prolonging drugs, sodium channel blockers, or pre-existing conduction disease. Mean PR increase: 3.1 ms at 400 mg/day in epilepsy, 7.3–11.9 ms in pharmacology studies. |
| Atrial fibrillation / flutter | 0.5% in diabetic neuropathy population | Variable | Monitor for palpitations, irregular pulse; particular caution in patients with diabetic neuropathy and cardiac risk factors. |
| DRESS syndrome | Rare (postmarketing) | Typically 2–8 weeks | Discontinue immediately if no alternate etiology; evaluate organ involvement (fever, rash, lymphadenopathy, hepatitis, eosinophilia). |
| Suicidal ideation (AED class effect) | 0.43% (AED class pooled) | As early as 1 week after starting | Monitor mood and behavior; AED class-wide FDA warning. |
| Cardiac conduction abnormalities (overdose) | Rare (overdose setting) | Acute overdose | Conduction disorders, cardiogenic shock, and cardiac arrest reported with overdoses >800 mg. Hemodialysis can remove ~50% in 4 hours. |
Lacosamide produces dose-dependent PR interval prolongation. In clinical pharmacology studies in healthy subjects, the placebo-subtracted maximum PR increase was 7.3 ms at 400 mg/day and 11.9 ms at 800 mg/day. In epilepsy trials, the mean maximum PR increase was 3.1 ms at 400 mg/day. First-degree AV block was observed in 0.4% (4/944) of patients at recommended doses. Obtain an ECG before initiating lacosamide and after titration to steady state, particularly in patients with known conduction abnormalities, those taking concurrent PR-prolonging drugs (beta-blockers, calcium channel blockers, digoxin), or other sodium channel blocking AEDs.
Lacosamide Drug Interactions
Lacosamide is partially metabolized by CYP3A4, CYP2C9, and CYP2C19 (~60% of dose undergoes metabolism), but does not inhibit or induce any major CYP enzyme at therapeutic concentrations. It has no clinically significant pharmacokinetic interactions with common AEDs. The primary interaction concerns are pharmacodynamic: additive PR prolongation with other cardiac conduction-modifying drugs and additive CNS depression. However, patients with renal or hepatic impairment taking strong CYP3A4 or CYP2C9 inhibitors may have significantly increased lacosamide exposure.
Lacosamide Monitoring
- ECG / PR IntervalBaseline and at steady state
RoutineLacosamide causes dose-dependent PR prolongation. Obtain ECG before starting, after titration to maintenance dose, and when adding other PR-prolonging medications. Monitor for symptoms of AV block (syncope, bradycardia, palpitations). - Renal FunctionBaseline, then periodically
Routine~40% of lacosamide is excreted renally unchanged. Max 300 mg/day in severe renal impairment (CrCl ≤30 mL/min). Supplement after hemodialysis. - Hepatic FunctionBaseline
Routine~60% undergoes metabolism (CYP3A4/2C9/2C19). Reduce max dose by 25% in mild-moderate hepatic impairment; not recommended in severe hepatic impairment. - Mood / SuicidalityEach visit
RoutineAED class-wide suicidality risk; monitor for emergence of depression, suicidal ideation, or unusual behavioral changes. - Seizure ControlEach visit
RoutineTrack seizure frequency and type. Lacosamide exposure correlates with seizure reduction; doses above 400 mg/day do not provide additional benefit. - DRESS SyndromeIf symptoms arise
Trigger-basedMonitor for fever, rash, lymphadenopathy, hepatitis, eosinophilia, particularly in the first 2–8 weeks. Discontinue immediately if suspected.
Contraindications & Cautions
Absolute Contraindications
- Known hypersensitivity to lacosamide or any of its ingredients (FDA PI)
Relative Contraindications (Specialist Input Recommended)
- Second- or third-degree AV block — lacosamide causes dose-dependent PR prolongation; may worsen conduction disease
- Severe hepatic impairment — pharmacokinetics not evaluated; use not recommended
- Concurrent use with multiple sodium channel blocking AEDs and/or PR-prolonging drugs — additive cardiac conduction risk
Use with Caution
- Known cardiac conduction problems — obtain ECG before starting and at steady state
- Patients with diabetic neuropathy — increased incidence of atrial fibrillation/flutter (0.5% vs 0% placebo)
- Severe renal impairment (CrCl ≤30) — max 300 mg/day; supplement after hemodialysis
- Pregnancy — developmental toxicity in animal studies; limited human data; enroll in NAAED Pregnancy Registry
- Abrupt discontinuation — taper gradually over at least 1 week to minimize risk of increased seizure frequency
All AEDs, including lacosamide, carry an increased risk of suicidal thoughts and behavior. The pooled analysis of 199 placebo-controlled AED trials showed approximately twice the risk (adjusted RR 1.8, 95% CI: 1.2–2.7) compared to placebo. Monitor all patients for emergence of depression, suicidal ideation, or unusual behavioral changes.
Patient Counselling
Purpose of Therapy
Lacosamide is a medication used to control seizures. It works by stabilizing overactive nerve cells in the brain. It is taken twice daily and should be taken at consistent times to maintain steady levels in the body.
How to Take
Take lacosamide exactly as prescribed, with or without food. Swallow tablets whole. If using the oral solution, measure with a calibrated measuring device (not a household spoon). Do not stop taking lacosamide suddenly, as this may increase the risk of seizures. Your prescriber will taper the dose gradually if you need to stop.
Sources
- UCB, Inc. VIMPAT (lacosamide) Tablets, Oral Solution, and Injection — Full Prescribing Information. Revised 2023. FDA LabelPrimary source for all FDA-approved indications, dosing, contraindications, warnings, adverse reaction incidence data, and renal/hepatic dosing.
- UCB, Inc. VIMPAT Prescribing Information — Updated 2025. UCB LabelMost current manufacturer PI with expanded pediatric data and PGTCS indication.
- Ben-Menachem E, Biton V, Jatuzis D, Abou-Khalil B, Doty P, Rudd GD. Efficacy and safety of oral lacosamide as adjunctive therapy in adults with partial-onset seizures. Epilepsia. 2007;48(7):1308-1317. doi:10.1111/j.1528-1167.2007.01188.xPivotal Phase III adjunctive epilepsy trial (Study 2) demonstrating dose-dependent seizure reduction at 200, 400, and 600 mg/day.
- Halász P, Kälviäinen R, Mazurkiewicz-Bełdzińska M, et al. Adjunctive lacosamide for partial-onset seizures: efficacy and safety results from a randomized controlled trial. Epilepsia. 2009;50(3):443-453. doi:10.1111/j.1528-1167.2008.01951.xConfirmatory adjunctive trial (Study 3) supporting 400 mg/day efficacy with 200–400 mg/day as the recommended dose range.
- Chung S, Sperling MR, Biton V, et al. Lacosamide as adjunctive therapy for partial-onset seizures: a randomized controlled trial. Epilepsia. 2010;51(6):958-967. doi:10.1111/j.1528-1167.2009.02502.xThird pivotal trial (Study 4) confirming efficacy at 200 and 400 mg/day with dose-dependent adverse events.
- Wechsler RT, Li G, French J, et al. Adjunctive lacosamide for primary generalized tonic-clonic seizures: a randomized controlled trial. Neurology. 2022;99(10):e1040-e1052. doi:10.1212/WNL.0000000000200800Pivotal PGTCS trial (Study 5) demonstrating significant reduction in PGTCS frequency vs placebo in patients with idiopathic generalized epilepsy.
- Kanner AM, Ashman E, Gloss D, et al. Practice guideline update: efficacy and tolerability of the new antiepileptic drugs II. Neurology. 2018;91(2):74-81. doi:10.1212/WNL.0000000000005756AAN guideline update including lacosamide as having Level C evidence for adjunctive treatment of drug-resistant partial-onset epilepsy.
- Errington AC, Stöhr T, Heers C, Lees G. The investigational anticonvulsant lacosamide selectively enhances slow inactivation of voltage-gated sodium channels. Mol Pharmacol. 2008;73(1):157-169. doi:10.1124/mol.107.039867Definitive electrophysiology study establishing lacosamide’s unique mechanism: selective enhancement of slow (not fast) inactivation of voltage-gated sodium channels.
- Beyreuther BK, Freitag J, Heers C, Krebsfänger N, Scharfenecker U, Stöhr T. Lacosamide: a review of preclinical properties. CNS Drug Rev. 2007;13(1):21-42. doi:10.1111/j.1527-3458.2007.00001.xComprehensive preclinical review covering mechanism of action, CRMP-2 binding, and pharmacological profile.
- Cawello W, Nickel B, Eggert-Formella A. No pharmacokinetic interaction between lacosamide and carbamazepine in healthy volunteers. J Clin Pharmacol. 2010;50(4):459-471. doi:10.1177/0091270009347675PK interaction study confirming no clinically significant interaction between lacosamide and carbamazepine.
- Cawello W, Fuhr U, Hering U, Maatouk H, Halabi A. Impact of impaired renal function on the pharmacokinetics of the antiepileptic drug lacosamide. Clin Pharmacokinet. 2013;52(10):897-906. doi:10.1007/s40262-013-0080-7Renal PK study establishing dose adjustment recommendations for CrCl-based dosing and hemodialysis.
- Thomas D, Scharfenecker U, Schiltmeyer B, Koch M, Cawello W. Low potential for drug-drug interaction of lacosamide. Epilepsia. 2006;47(Suppl 4):200. Epilepsia AbstractDrug interaction analysis confirming lacosamide does not inhibit or induce major CYP enzymes at therapeutic concentrations.
- Biton V, Rosenfeld WE, Whitesides J, et al. Intravenous lacosamide as replacement for oral lacosamide in patients with partial-onset seizures. Epilepsia. 2008;49(3):418-424. doi:10.1111/j.1528-1167.2007.01317.xStudy establishing IV-to-oral 1:1 bioequivalence and safety of short-term IV substitution.