Introduction
Lamictal (lamotrigine) is an antiepileptic drug (AED) belonging to the phenyltriazine class, approved by the FDA in 1994. It is a broad-spectrum anticonvulsant with additional FDA-approved indications for bipolar disorder maintenance treatment. Lamotrigine represents a significant advancement in epilepsy and mood disorder management due to its favorable pharmacokinetic profile and generally good tolerability compared to older antiepileptic medications.
Mechanism of Action
Lamotrigine's primary mechanism involves voltage-sensitive sodium channel blockade, which stabilizes neuronal membranes and inhibits the release of excitatory neurotransmitters, particularly glutamate. The drug preferentially inhibits the release of glutamate from depolarized neurons while having minimal effect on normal neuronal activity. Additionally, lamotrigine demonstrates weak inhibition of serotonin 5-HT3 receptors and may affect calcium channels. Unlike many other antiepileptics, it does not significantly enhance GABAergic transmission.
Indications
FDA-approved indications:- Epilepsy: Adjunctive therapy for partial seizures, generalized seizures of Lennox-Gastaut syndrome, and primary generalized tonic-clonic seizures in patients ≥2 years
- Epilepsy: Monotherapy for conversion to monotherapy in adults (≥16 years) with partial seizures who are receiving treatment with a single enzyme-inducing AED
- Bipolar disorder: Maintenance treatment of bipolar I disorder to delay the time to occurrence of mood episodes in adults (≥18 years)
- Bipolar depression
- Neuropathic pain
- Migraine prophylaxis
- Borderline personality disorder
Dosage and Administration
Epilepsy (adjunctive therapy):- Adults and children >12 years: Initial 25-50 mg daily; increase gradually to maintenance dose of 100-400 mg/day in divided doses
- Children 2-12 years: Weight-based dosing with slower titration
- Target dose: 200 mg daily (without enzyme-inducing or inhibiting drugs)
- Titration must be gradual to minimize risk of serious rash
- Hepatic impairment: Reduce dose by approximately 25% in moderate impairment and 50% in severe impairment
- Renal impairment: Caution advised; consider reduced maintenance doses
- Elderly: May require lower doses due to decreased clearance
- Pregnancy: Category C; requires careful risk-benefit assessment
- Must be titrated slowly (over weeks) to reduce rash risk
- Available as tablets, chewable dispersible tablets, and orally disintegrating tablets
- Not recommended for rapid titration or loading doses
Pharmacokinetics
Absorption: Rapid and complete (98% bioavailability) with negligible first-pass metabolism Distribution: Volume of distribution: 0.9-1.3 L/kg; 55% protein-bound Metabolism: Primarily hepatic via glucuronidation (UGT1A4) Elimination: Half-life: 25-35 hours (monotherapy); significantly reduced with enzyme-inducing drugs Excretion: Primarily renal (94%, mostly as glucuronide metabolites)Contraindications
- Hypersensitivity to lamotrigine or any component of the formulation
- History of rash associated with prior lamotrigine treatment
Warnings and Precautions
Boxed Warning: Serious skin rashes requiring hospitalization have occurred, including Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN). Risk factors include: concomitant valproate use, exceeding recommended initial dose, exceeding recommended dose escalation, pediatric patients, and history of rash or hypersensitivity to other AEDs. Additional warnings:- Aseptic meningitis: Rare cases reported
- Blood dyscrasias: Including neutropenia, agranulocytosis, anemia, thrombocytopenia
- Suicidal behavior and ideation: AEDs increase risk
- Withdrawal seizures: Abrupt discontinuation may increase seizure frequency
- Multiorgan hypersensitivity reactions: May be fatal if not recognized
- Medication errors: Potential confusion with other medications (Lamisil, Lomotil, etc.)
Drug Interactions
Clinically significant interactions:- Valproate: Increases lamotrigine levels approximately 2-fold; requires dose reduction
- Enzyme-inducing AEDs (carbamazepine, phenytoin, phenobarbital, primidone): Decrease lamotrigine levels approximately 40-50%
- Oral contraceptives: Estrogen-containing contraceptives decrease lamotrigine levels by approximately 50%; may require dose adjustment during pill-free week
- Rifampin: Significantly decreases lamotrigine levels
- Other UGT inducers/inhibitors: May affect lamotrigine concentrations
Adverse Effects
Common (≥5%):- Dizziness
- Headache
- Diplopia
- Ataxia
- Nausea
- Somnolence
- Rash (benign; approximately 10%)
- Fatigue
- Stevens-Johnson syndrome/Toxic epidermal necrolysis (<0.1%)
- Drug reaction with eosinophilia and systemic symptoms (DRESS)
- Hemophagocytic lymphohistiocytosis
- Aseptic meningitis
- Blood dyscrasias
- Suicidal behavior and ideation
- Worsening of seizures
Monitoring Parameters
Baseline:- Comprehensive dermatologic history
- Pregnancy test if appropriate
- CBC with differential
- Liver function tests
- Renal function
- Skin examination for rash (especially first 2-8 weeks)
- Seizure frequency and characteristics
- Mood assessment in bipolar patients
- Signs of hematologic dysfunction
- Signs of hypersensitivity reactions
- Therapeutic drug monitoring (target range: 2-20 mcg/mL, though clinical correlation essential)
Patient Education
Critical counseling points:- Report any skin rash immediately (stop medication and contact provider)
- Never abruptly discontinue medication
- Understand titration schedule importance
- Recognize signs of serious reactions: fever, swollen glands, mouth sores, blistering, peeling skin
- Use caution when driving or operating machinery until effects known
- Inform all healthcare providers about lamotrigine use
- Use reliable contraception and discuss pregnancy planning
- Be aware of potential mood changes or suicidal thoughts
- Do not change brands without medical supervision
- Take exactly as prescribed; do not double doses if missed
- Lamotrigine may cause false-positive urine immunoassay screening tests for PCP
- Photosensitivity may occur; use sun protection
- Alcohol may enhance CNS depression
References
1. FDA Prescribing Information: Lamictal (lamotrigine) tablets. Revised 2023. 2. Goldsmith DR, Wagstaff AJ, Ibbotson T, et al. Lamotrigine: a review of its use in bipolar disorder. Drugs. 2003;63(19):2029-2050. 3. Patsalos PN, Berry DJ, Bourgeois BF, et al. Antiepileptic drugs—best practice guidelines for therapeutic drug monitoring: a position paper by the subcommission on therapeutic drug monitoring, ILAE Commission on Therapeutic Strategies. Epilepsia. 2008;49(7):1239-1276. 4. Calabrese JR, Bowden CL, Sachs G, et al. A placebo-controlled 18-month trial of lamotrigine and lithium maintenance treatment in recently depressed patients with bipolar I disorder. J Clin Psychiatry. 2003;64(9):1013-1024. 5. Mockenhaupt M, Messenheimer J, Tennis P, et al. Risk of Stevens-Johnson syndrome and toxic epidermal necrolysis in new users of antiepileptics. Neurology. 2005;64(7):1134-1138. 6. Johannessen Landmark C, Patsalos PN. Drug interactions involving the new second- and third-generation antiepileptic drugs. Expert Rev Neurother. 2010;10(1):119-140.