Lamotrigine
Lamotrigine is an oral antiepileptic and mood stabiliser used in adults and children for partial-onset seizures, primary generalised seizures, Lennox-Gastaut syndrome and bipolar disorder maintenance. Slow titration is essential to minimise serious skin reactions.
- Chemical formula
- C9H7Cl2N5
- CAS number
- 84057-84-1
- ATC code
- N03AX09
- Molecular weight
- 256.09 g/mol
- Drug class
- Antiepileptic (sodium channel blocker)
- Also known as
- BW-430C, Lamotrigina
What is it?
Lamotrigine was approved as an antiepileptic in 1994 and for bipolar disorder maintenance in 2003. It is supplied as oral tablets, chewable tablets, orally disintegrating tablets and extended-release tablets. Lamotrigine is dispensed only on prescription and is part of the World Health Organization List of Essential Medicines. Multiple authorised generics are now widely available worldwide.
Mechanism of action
Lamotrigine is a phenyltriazine that selectively blocks voltage-gated sodium channels, stabilising neuronal membranes and reducing the release of excitatory neurotransmitters, particularly glutamate. The result is anticonvulsant activity in partial and generalised seizures, and mood-stabilising effects in bipolar disorder, particularly the prevention of depressive episodes. Unlike many other antiepileptics, lamotrigine does not cause significant cognitive impairment or sedation.
Pharmacokinetics
Oral lamotrigine is well absorbed, with bioavailability of approximately 98%. Plasma protein binding is approximately 55%. The drug is metabolised primarily by glucuronidation via UGT1A4 to inactive metabolites. The plasma half-life ranges widely depending on co-administered drugs: approximately 25-33 hours in monotherapy, 13-15 hours when co-administered with enzyme inducers (e.g. carbamazepine), and up to 70 hours when co-administered with valproate (which inhibits glucuronidation).
Indications
Lamotrigine is approved in adults and children aged 2 years and older as adjunctive or monotherapy for partial-onset seizures, primary generalised tonic-clonic seizures and seizures associated with Lennox-Gastaut syndrome. It is also approved in adults for the maintenance treatment of bipolar I disorder, particularly to delay depressive episodes. According to international guidelines, lamotrigine is one of the recommended agents in pregnancy because of its relatively favourable teratogenicity profile compared with valproate.
Safety profile
Common adverse effects include dizziness, headache, ataxia, double vision and rash. The most serious adverse effect is severe skin reaction including Stevens-Johnson syndrome, toxic epidermal necrolysis and drug reaction with eosinophilia and systemic symptoms (DRESS), with a higher risk if titration is too rapid or if co-administered with valproate. Haemophagocytic lymphohistiocytosis has also been reported. According to the prescribing information, slow titration is essential and any rash requires immediate medical review.
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Frequently asked questions
Why must lamotrigine be titrated slowly? ▾
Lamotrigine has been associated with serious skin reactions including Stevens-Johnson syndrome and toxic epidermal necrolysis, with a higher risk if the dose is escalated too quickly or if it is co-administered with valproate (which inhibits its metabolism). According to the prescribing information, lamotrigine must be titrated slowly over weeks, with even slower titration when combined with valproate. Any rash during initiation requires immediate medical review.
Why does the dose of lamotrigine differ when combined with valproate? ▾
Valproate strongly inhibits the glucuronidation of lamotrigine, doubling or more its plasma half-life and concentrations. According to the prescribing information, when combined with valproate, lamotrigine should be initiated at lower doses, titrated more slowly and maintained at lower target doses than in monotherapy. Conversely, enzyme inducers (carbamazepine, phenytoin) decrease lamotrigine concentrations and require higher target doses.
Is lamotrigine an effective mood stabiliser? ▾
Yes, particularly for the prevention of depressive episodes in bipolar I disorder. Several randomised trials and meta-analyses support its efficacy as maintenance therapy, with relatively limited efficacy for the treatment of acute manic episodes compared with lithium or quetiapine. According to international guidelines, lamotrigine is recommended for bipolar maintenance, particularly in patients with predominant depressive episodes or who cannot tolerate lithium.
Is lamotrigine safe in pregnancy? ▾
Lamotrigine has a relatively favourable teratogenicity profile compared with valproate or topiramate, with most studies showing no consistent increase in major congenital malformations at typical therapeutic doses. According to international guidelines, lamotrigine is one of the recommended antiepileptics for women of childbearing potential when an antiepileptic is required, with monitoring of plasma concentrations during pregnancy because clearance increases substantially. The prescriber must individualise.
What are the main contraindications for lamotrigine? ▾
Lamotrigine is contraindicated in known hypersensitivity to lamotrigine or its excipients. Caution is required in hepatic and severe renal impairment, in concurrent use with valproate (with mandatory dose modification), in patients with a history of rash on lamotrigine, and during pregnancy and breastfeeding (with the prescriber individualising). According to the prescribing information, the medical history must be reviewed by a clinician before any prescription.
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