Lamotrigine

Generic Name: Lamotrigine
Pharmacological Class: Anticonvulsant
Therapeutic Class: Antiepileptic drug (AED) and mood stabilizer
ATC Code: N03AX09
Common Brand Names: Lamictal, Lamictal XR, Lamotrigine Teva, Lamictal CD (chewable dispersible)
Legal Status: Prescription-only medicine (Rx)
Available Formulations:
– Oral tablets (25 mg, 50 mg, 100 mg, 200 mg)
– Chewable/dispersible tablets
– Orally disintegrating tablets
– Extended-release tablets
– Oral suspension (limited availability)

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Chemical and Pharmacological Characteristics

• Molecular Formula: C9H7Cl2N5

• Molecular Weight: 256.1 g/mol

• Mechanism of Action:
  Lamotrigine stabilizes neuronal membranes by inhibiting voltage-sensitive sodium channels, thereby suppressing excessive glutamate release. This reduces excitatory neurotransmission and limits seizure propagation and mood cycling.

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Therapeutic Indications

Approved Indications (by FDA, EMA, MHRA):

1. Epilepsy:

   • Focal (partial-onset) seizures

   • Primary generalized tonic-clonic seizures

   • Generalized seizures of Lennox-Gastaut syndrome

   • Adjunct or monotherapy in adults and children ≥2 years

2. Bipolar Disorder:

   • Maintenance treatment of bipolar I disorder to delay the time to occurrence of mood episodes (especially depression)

   • Not effective for acute mania

3. Off-label uses (region-dependent):

   • Treatment-resistant depression (adjunct)

   • Cyclothymia

   • Neuropathic pain

   • Borderline personality disorder

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Dosage and Administration

Important Note: Dose titration is essential to minimize the risk of serious skin reactions.

Initial Dosage (Adults – Without Interacting Drugs):

• Week 1–2: 25 mg once daily

• Week 3–4: 50 mg once daily

• Week 5: 100 mg once daily

• Maintenance: 100–200 mg once daily (or in two divided doses)

When Used with Valproate (inhibits lamotrigine metabolism):

• Week 1–2: 25 mg every other day

• Week 3–4: 25 mg once daily

• Maintenance: 100 mg/day maximum

When Used with Enzyme Inducers (e.g., carbamazepine, phenytoin):

• Week 1–2: 50 mg once daily

• Week 3–4: 50 mg twice daily

• Maintenance: 300–500 mg/day (divided doses)

Pediatric Dosing:

• Based on weight and concomitant medications

• Always start with lower doses and titrate gradually

Extended-Release Formulations:

• Suitable for once-daily dosing

• Do not chew or crush

Discontinuation:

• Taper gradually over 2 weeks to minimize risk of seizures or withdrawal

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Pharmacokinetics

• Absorption: ~98% bioavailable orally

• Peak Plasma Levels: 1.4–4.8 hours post-dose (immediate-release)

• Half-Life:

  • Monotherapy: ~25–30 hours

  • With valproate: ~48–70 hours

  • With enzyme inducers: ~13–15 hours

• Metabolism: Primarily hepatic (via glucuronidation)

• Excretion: Urine (~94%) as inactive metabolites

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Contraindications

• Known hypersensitivity to lamotrigine or any tablet excipients

• History of lamotrigine-induced skin rash or Stevens-Johnson syndrome

• Concurrent use with valproate without dose adjustment

• Abrupt withdrawal in epilepsy patients (risk of rebound seizures)

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Warnings and Precautions

1. Serious Skin Reactions:

   • Stevens-Johnson Syndrome (SJS), Toxic Epidermal Necrolysis (TEN)

   • Risk factors: rapid dose escalation, valproate co-administration, age <16

   • Requires immediate discontinuation if rash appears

2. Multiorgan Hypersensitivity Reaction (DRESS):

   • May include fever, lymphadenopathy, hepatitis, nephritis

   • Can be fatal if untreated

3. Suicidal Thoughts and Behavior:

   • Like other AEDs, lamotrigine increases the risk

   • Monitor for mood or behavior changes

4. Aseptic Meningitis:

   • Headache, fever, neck stiffness, photophobia

   • Onset typically within days to weeks

5. Blood Dyscrasias:

   • Rare but serious: neutropenia, pancytopenia, aplastic anemia

6. Hormonal Contraceptives:

   • Estrogen-containing contraceptives increase clearance of lamotrigine

   • May require dose increase; monitor levels during pill-free intervals

7. Cardiac Conduction Disorders (High Dose):

   • Caution in patients with pre-existing conduction abnormalities

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Adverse Effects

Very Common (>10%):

• Headache

• Dizziness

• Drowsiness

• Blurred vision

• Ataxia

• Nausea

• Insomnia

Common (1–10%):

• Rash (including non-serious)

• Diplopia

• Fatigue

• Vomiting

• Tremor

• Irritability

• Abdominal pain

• Anxiety

• Somnolence

Uncommon (0.1–1%):

• Serious rash (SJS, DRESS)

• Aggression, hallucinations

• Pruritus

• Photosensitivity

Rare (<0.1%):

• Stevens-Johnson syndrome

• Toxic epidermal necrolysis

• Aseptic meningitis

• Liver failure

• Hematologic abnormalities (e.g., leukopenia)

• Anaphylaxis

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Drug Interactions

Interacting Drug	Mechanism/Outcome
Valproate	Inhibits metabolism → ↑ lamotrigine levels (requires lower dose)
Carbamazepine, phenytoin, phenobarbital	Induce metabolism → ↓ lamotrigine levels
Oral contraceptives	Estrogens ↑ clearance of lamotrigine
Rifampin	Induces metabolism → ↓ efficacy
Sertraline, lithium	No major interactions; monitor CNS effects
Clozapine	May increase risk of hematologic toxicity

No significant interaction with alcohol; however, both can cause CNS depression.

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Pregnancy and Lactation

Pregnancy:

• Category C (FDA); Category 2 (UK BNF)

• Crosses the placenta

• Increased clearance during pregnancy → need for dose adjustment

• Associated with a small increased risk of oral clefts in early pregnancy

• Not considered highly teratogenic compared to valproate

Lactation:

• Excreted in breast milk

• Monitor infants for sedation, rash, feeding problems

• Use cautiously during breastfeeding

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Therapeutic Drug Monitoring (TDM)

• Target plasma concentration: 3–15 mcg/mL (for epilepsy)

• Routine TDM not required except in:
  – Pregnancy
  – Suspected toxicity or noncompliance
  – Valproate co-administration
  – Oral contraceptive adjustments

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Comparison with Other AEDs

Feature	Lamotrigine	Valproate	Carbamazepine	Levetiracetam
Rash Risk	Moderate	Low	Low	Low
Teratogenicity	Low	High	Moderate	Low
Cognitive Effects	Minimal	Moderate	Moderate	Low
Mood Stabilization	Yes	Yes	No	Unclear
TDM Recommended	Optional	Yes	Yes	No

Lamotrigine is often preferred for bipolar depression and epilepsy in pregnancy or adolescents due to a better safety profile than other AEDs.

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Patient Counseling Points

• Start low and go slow – dose must be increased gradually

• Report any rash, especially with fever or facial swelling

• Avoid abrupt discontinuation – may trigger seizures

• Oral contraceptives may affect dosing – inform your doctor if starting/stopping

• May cause drowsiness, dizziness, blurred vision – avoid driving initially

• Do not double dose if a dose is missed

• Inform all healthcare providers of lamotrigine use (e.g., for drug interactions)

• Monitor mood changes, suicidal ideation, or signs of hypersensitivity

• Tablets should be swallowed whole; some forms may be chewed or dispersed in water