Generic Name

Lamotrigine

Mechanism

• Voltage‑gated sodium channel blockade: stabilises the inactive state of Na⁺ channels, reducing high‑frequency firing.
• Inhibition of glutamate release: via suppression of presynaptic Ca²⁺ influx, dampening excitatory neurotransmission.
• Minimal effect on GABAergic transmission, T‑type calcium channels, or AMPA receptors.
• The combined sodium‑channel and glutamate‑modulating actions account for efficacy in both seizure control and bipolar prophylaxis.

Pharmacokinetics

• Absorption: Oral bioavailability ~98%; peak plasma concentration 2–4 h post‑dose; food delays peak by ~1 h.
• Distribution: Vd 0.9‑1.5 L/kg; protein binding 5‑10 %.
• Metabolism: Predominantly hepatic glucuronidation via UGT1A4; minor CYP2C9/2A6 involvement; *rate of elimination* ~12–13 h.
• Excretion: 80 % glucuronide conjugate, 20 % unchanged in urine.
• Population variability: Higher levels in pregnancy (↓clearance), in renal insufficiency (↑AUC), and when combined with valproate (↑Serum concentration).

Indications

• Epilepsy:
• Refractory partial‑onset seizures
• Lennox–Gastaut syndrome
• Absence and myoclonic seizures (adjunct)
• Psychiatry: Maintenance treatment of bipolar disorder (prevention of both manic and depressive episodes).
• Adjunct for refractory generalized tonic‑clonic seizures (in children).

Contraindications

• Contraindications:
• Known hypersensitivity to lamotrigine or any component
• Severe hepatic impairment
• Active pregnancy (category B; avoid when combined with valproate)
• Warnings & Precautions:
• Serious rash: Stevens‑Johnson syndrome (SJS), toxic epidermal necrolysis (TEN) – monitor skin closely during dose escalation.
• Hepatotoxicity: Rare at therapeutic doses; monitor LFTs initially.
• Drug interactions:
• Valproate ↑lamotrigine AUC → slow titration.
• Carbamazepine/down‑regulates UGT1A4 → higher lamotrigine levels.
• Pregnancy: Not associated with major teratogenicity, but avoid valproate co‑therapies.

Dosing

| Children (≥2 yr) | 5 mg QD for 50 mg/week** → rash risk ↑.

Adverse Effects

• Common: rash, dizziness, headache, nausea, insomnia, vertigo, mild photophobia.
• Serious:
• Dermatologic: Stevens‑Johnson syndrome, TEN, hypersensitivity.
• Hepatotoxicity: ALT/AST elevations (rare).
• Blood dyscrasias (especially with valproate): neutropenia, thrombocytopenia.
• Neuropsychiatric: suicidal ideation (rare), mania emergence.

Monitoring

• Baseline: CBC, LFTs, serum electrolytes; pregnancy test if indicated.
• During ramp‑up:
• Daily skin checks for rash until dose is stable.
• CBC every 2–3 wks if on valproate.
• Therapeutic: Periodic serum lamotrigine level (if therapeutic failure or toxicity suspected).
• Long‑term: BP, weight, renal function every 6 mo.

Clinical Pearls

• Dual‑mode DRY: Sodium‑channel block *and* glutamate inhibition give lamotrigine superior efficacy in both seizure and mood disorders.
• Slow and steady: Rapid titration > 50 mg/week raises rash risk > 20 %—the safest regimen is 25 mg QD for 2–3 wk, then 50 mg QD.
• Valproate caution: Co‑therapy increases lamotrigine AUC 4–6×; start at 25 mg QD and titrate by 25 mg every 2 wk.
• Pregnancy & Pediatric Use: Despite Category B, avoid when combined with valproate; in infants, titrate ≤ 5 mg QD, monitor weight-based dosing.
• Bipolar spec: Lamotrigine is effective for maintenance only; it is not suitable for acute mania or as a single‑agent in bipolar mania.

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• Key references:

1. Brunton, L., et al. *Katzung & Trevor’s Pharmacology: Examination & Board Review*, 14th ed.

2. Loring, J. P., et al. “Lamotrigine: pharmacology and approved indications.” *Neurol Clin* 2004.

3. American Psychiatric Association. *Practice Guidelines for the Treatment of Patients with Bipolar Disorder*, 2024.