Lamotrigine - Drug Monograph

Introduction

Lamotrigine is an anticonvulsant medication belonging to the phenyltriazine class. Initially approved by the FDA in 1994, it has become a widely used antiepileptic drug and mood stabilizer. Lamotrigine represents an important therapeutic option for various neurological and psychiatric conditions due to its unique mechanism of action and generally favorable side effect profile compared to older antiepileptic drugs.

Mechanism of Action

Lamotrigine exerts its therapeutic effects primarily through voltage-sensitive sodium channel blockade. The drug inhibits voltage-gated sodium channels, stabilizing neuronal membranes and modulating presynaptic transmitter release of excitatory amino acids, particularly glutamate. Additionally, lamotrigine weakly inhibits certain calcium channels (N-type and P/Q-type). Unlike many other antiepileptic drugs, it does not significantly enhance GABAergic neurotransmission. This mechanism results in decreased neuronal excitability and reduced seizure activity.

Indications

• Epilepsy: Adjunctive therapy for partial seizures, generalized seizures of Lennox-Gastaut syndrome, and primary generalized tonic-clonic seizures
• Epilepsy: Conversion to monotherapy in adults with partial seizures
• Bipolar disorder: Maintenance treatment of bipolar I disorder to prevent or delay mood episodes

• Bipolar depression
• Neuropathic pain
• Borderline personality disorder
• Migraine prophylaxis

Dosage and Administration

• Adults and children >12 years: Initial dose 25 mg daily for 2 weeks, then 50 mg daily for 2 weeks, then increase by 50-100 mg every 1-2 weeks to maintenance dose of 300-500 mg daily in divided doses
• Children 2-12 years: Weight-based dosing with slower titration

• Adults: Initial dose 25 mg daily for 2 weeks, then 50 mg daily for 2 weeks, then 100 mg daily for 1 week, then 200 mg daily
• Target maintenance dose: 200-400 mg daily

• Hepatic impairment: Reduce dose by approximately 50% in moderate impairment and 75% in severe impairment
• Renal impairment: Caution advised; may need dose reduction
• Elderly: Initiate at lower doses due to possible reduced clearance
• Pregnancy: Requires careful risk-benefit assessment (Pregnancy Category C)

Pharmacokinetics

• Absorption: Rapid and complete (98% bioavailability), not affected by food
• Distribution: Volume of distribution 0.9-1.3 L/kg, 55% protein bound
• Metabolism: Primarily hepatic via glucuronidation (UGT1A4)
• Elimination: Half-life approximately 24-35 hours; primarily renal excretion (94% as metabolites, 10% unchanged)
• Steady-state: Reached in 5-7 days with once-daily dosing

Contraindications

• Hypersensitivity to lamotrigine or any component of the formulation
• History of serious rash or hypersensitivity reaction to lamotrigine

Warnings and Precautions

• Risk of Stevens-Johnson syndrome, toxic epidermal necrolysis, and Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)
• Higher incidence with rapid dose escalation, concomitant valproate therapy, and pediatric patients
• Discontinue immediately at first sign of rash unless clearly not drug-related

• Antiepileptic drugs increase risk of suicidal thoughts or behavior
• Monitor for emergence or worsening of depression, suicidal thoughts, or unusual changes in mood or behavior

• Reports of neutropenia, leukopenia, anemia, thrombocytopenia, pancytopenia, and aplastic anemia

• May present with fever, lymphadenopathy, facial edema, hepatic, renal, or hematologic abnormalities

• Rare cases reported with symptoms including headache, fever, nausea, vomiting, and nuchal rigidity

• Abrupt discontinuation may increase seizure frequency; taper gradually over at least 2 weeks

Drug Interactions

• Valproate: Increases lamotrigine levels approximately 2-fold; requires dose reduction of lamotrigine by approximately 50%
• Carbamazepine: Decreases lamotrigine levels by approximately 40%; may require higher lamotrigine doses
• Phenytoin, phenobarbital, primidone: Decrease lamotrigine levels
• Oral contraceptives: Estrogen-containing contraceptives decrease lamotrigine levels by approximately 50%; may require dose adjustment
• Rifampin: Significantly decreases lamotrigine levels

Adverse Effects

• Dizziness
• Headache
• Diplopia
• Ataxia
• Nausea
• Somnolence
• Rash (benign, up to 10%)

• Stevens-Johnson syndrome
• Toxic epidermal necrolysis
• DRESS
• Aseptic meningitis
• Blood dyscrasias
• Suicidal ideation
• Hepatotoxicity
• Multiorgan hypersensitivity reactions

Monitoring Parameters

• Baseline: CBC with differential, liver function tests, renal function, pregnancy test if applicable
• During titration: Monitor for rash weekly during first 2 months, then monthly
• Routine monitoring: CBC, LFTs every 6-12 months
• Therapeutic drug monitoring: Not routinely required; target range 1-15 mcg/mL (varies by indication)
• Psychiatric monitoring: Regular assessment for mood changes, depression, suicidal ideation
• Clinical response: Seizure frequency, mood stability, adverse effects

Patient Education

• Take exactly as prescribed; do not discontinue abruptly
• Importance of slow dose titration to minimize rash risk
• Immediately report any skin rash, fever, sore throat, mouth ulcers, or swollen glands
• Be aware of potential for dizziness, drowsiness, or blurred vision; use caution when driving or operating machinery
• Inform all healthcare providers about lamotrigine use, especially before starting new medications
• Use effective contraception; discuss pregnancy planning with healthcare provider
• Regular follow-up appointments are essential
• Do not crush, chew, or break extended-release tablets
• Chewable tablets may be swallowed whole, chewed, or dispersed in liquid

References

1. FDA Prescribing Information: Lamotrigine (Lamictal). Revised 2023. 2. Patsalos PN, et al. Therapeutic drug monitoring of antiepileptic drugs in epilepsy: a 2018 update. Ther Drug Monit. 2018;40(5):526-548. 3. Hirsch LJ, et al. Expert opinion: lamotrigine and valproate efficacy and safety in epilepsy. Epilepsy Behav. 2019;90:128-138. 4. Calabrese JR, et al. Lamotrigine in the treatment of bipolar disorder. Expert Opin Pharmacother. 2022;23(1):89-99. 5. Mockenhaupt M. Stevens-Johnson syndrome and toxic epidermal necrolysis: clinical patterns, diagnostic considerations, etiology, and therapeutic management. Semin Cutan Med Surg. 2014;33(1):10-16. 6. GlaxoSmithKline. Lamictal clinical study reports and data on file. 7. Micromedex Solutions. Lamotrigine Drug Information. Truven Health Analytics. 2023. 8. Lexicomp Online. Lamotrigine: Drug Information. UpToDate. 2023.