Lamotrigine

• Approved Indications:

  • Epilepsy:
  • Adjunctive therapy in adults and pediatric patients (≥2 years) for partial-onset seizures, primary generalized tonic-clonic seizures, and seizures associated with Lennox-Gastaut syndrome.
  • Monotherapy for partial seizures in patients ≥16 years transitioning from other antiepileptic drugs.
  • Bipolar I Disorder:
  • Maintenance treatment in adults to delay the recurrence of mood episodes (depression, mania, hypomania, or mixed episodes).

  Clinically Accepted Off-label Uses:

  • Acute bipolar depression
  • Borderline personality disorder
  • Neuropathic pain and migraine prevention (under specialist supervision)

General Considerations:

• Lamotrigine requires gradual dose titration to minimize the risk of serious skin reactions.
• Dosing depends on concomitant antiepileptic medications.

Epilepsy (Adults):

• Without enzyme inducers/inhibitors:
  Start: 25 mg once daily (Week 1–2) → 50 mg once daily (Week 3–4) → Increase by 50 mg every 1–2 weeks to a maintenance dose of 225–375 mg/day (divided BID).
• With valproate (inhibitor):
  Start: 25 mg every other day (Week 1–2) → 25 mg once daily (Week 3–4) → Increase by 25–50 mg every 1–2 weeks. Maintenance: 100–200 mg/day (once or divided).
• With enzyme inducers (without valproate):
  Start: 50 mg once daily (Week 1–2) → 100 mg/day in 2 divided doses (Week 3–4) → Increase by 100 mg every 1–2 weeks. Maintenance: 300–500 mg/day (divided BID).

Bipolar I Disorder (Adults):

• With valproate:
  Start: 25 mg every other day → Target: 100–200 mg once daily
• Without interacting drugs:
  Start: 25 mg once daily → Target: 200 mg once daily
• With enzyme inducers:
  Start: 50 mg once daily → Target: 300–400 mg once daily or divided

Pediatric and Special Populations:

• Pediatric dosing must be calculated based on weight and co-medications.
• In renal or hepatic impairment, dose reductions and slow titration are necessary.

Lamotrigine inhibits voltage-sensitive sodium channels, thereby stabilizing neuronal membranes and reducing the presynaptic release of excitatory neurotransmitters like glutamate and aspartate. These effects contribute to its antiepileptic activity. In bipolar disorder, lamotrigine modulates glutamatergic and serotonergic systems, aiding mood stabilization and reducing depressive episode frequency.

• Absorption: Rapid and complete oral absorption; bioavailability ~98%
• Time to Peak: 1.4 to 4.8 hours post-dose
• Distribution: Volume of distribution ~0.9–1.3 L/kg; crosses the placenta and is present in breast milk
• Protein Binding: ~55%
• Metabolism: Primarily hepatic glucuronidation
• Half-life:
• ~25–33 hours (monotherapy)
• ~14 hours with enzyme inducers
• ~60 hours with valproate
• Excretion: Renal (~94% as glucuronide conjugates); minimal fecal excretion

Pregnancy:

• Former FDA Category C.
• Use only if clearly needed. Possible risk of oral clefts with first-trimester exposure; however, uncontrolled seizures pose greater risks.

Lactation:

• Lamotrigine is excreted into breast milk (~40–60% of maternal levels).
• Monitor infants for rash, sedation, or feeding issues. Breastfeeding may be continued with caution.

• Primary: Anticonvulsant
• Subclassification: Phenyltriazine derivative; also a Mood Stabilizer

• Hypersensitivity to lamotrigine or formulation components
• History of lamotrigine-induced rash or serious allergic reaction
• Severe hepatic impairment (without dose adjustment and monitoring)
• Concomitant use with valproate without appropriate dose modification

• Severe Rash (SJS/TEN/DRESS): Risk is highest in pediatric patients, rapid dose escalation, and with valproate co-administration. Discontinue at first sign of rash.
• Suicidality: Monitor for suicidal thoughts and behaviors.
• Aseptic Meningitis: Rare cases reported.
• Blood Dyscrasias: Includes neutropenia, thrombocytopenia, and aplastic anemia.
• Multiorgan Hypersensitivity Reaction: Discontinue if suspected.
• Withdrawal: Taper gradually to avoid rebound seizures.

Common:

• CNS: Dizziness, somnolence, headache, tremor, insomnia
• GI: Nausea, vomiting
• Skin: Rash (mild or severe)
• Psychiatric: Anxiety, irritability

Serious:

• Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN)
• DRESS (Drug Reaction with Eosinophilia and Systemic Symptoms)
• Hepatotoxicity
• Blood disorders (e.g., aplastic anemia)
• Suicidal ideation or behavior

• Valproate: Increases lamotrigine levels → higher risk of toxicity/rash
• Carbamazepine/Phenytoin/Phenobarbital: Lower lamotrigine levels → adjust dose upward
• Oral Contraceptives: Reduce lamotrigine levels by up to 50%; risk of seizure breakthrough
• Sertraline/Lithium: Minimal interactions

Metabolism Pathway:

• Not significantly affected by CYP450 enzymes; primarily metabolized via UGT1A4 (glucuronidation).

• FDA & EMA Warnings:
  Reinforced boxed warnings for serious skin reactions and highlighted the importance of proper titration schedules.
• NICE Guidelines (2024):
  Recommend lamotrigine as a first-line maintenance treatment for bipolar I disorder due to its favorable metabolic profile and low risk of sedation.

• Temperature: Store between 20°C to 25°C (68°F to 77°F); excursions permitted between 15°C and 30°C
• Humidity: Protect from moisture
• Light: Store in original light-resistant packaging
• Handling:
• Do not crush or chew extended-release tablets
• Chewable tablets may be chewed or dispersed in water
• Keep away from children