Lamotrigine (Lamictal)

Pharmacokinetics of Lamotrigine

Absorption Rapidly absorbed, Tmax = 1.4 to 4.8 hours
Distribution High volume of distribution (77L), 55% bound to proteins
Metabolism Liver, primarily glucoroindation
Elimination Renal, approximately 70%
Half-life 33 hours

Lamotrigine: Cytochrome P450 Metabolism

Substrate of (Metabolized by) Although lamotrigine is primary metabolized by glucoronidation, strong/moderate inducers of CYP 3A4 can enhance the metabolism of lamotrigine.
Induces Not applicable
Inhibits Not applicable
  • Lamotrigine blocks the α subunit of voltage-sensitive sodium channels (VSNaC), which inhibits the release of glutamate
  • For psychiatric disorders, this may modulate reuptake of serotonin (5-HT) and may block reuptake of dopamine (DA)
  • It is also thought to stabilize neuronal membranes and inhibit the release of excitatory amino acid neurotransmitters (e.g. - glutamate, aspartate) that are thought to play a role in the generation and spread of epileptic seizures.
  • In overdose, symptoms including nystagmus, ataxia, seizures, coma and intraventricular conduction delay (QRS widening).

Dosing for Lamotrigine

Starting 25mg PO daily for 2 weeks
Titration Increase by 25 mg every 2 weeks
Maximum 200 mg PO daily (doses >200mg are actually better for clinical response in bipolar disorder)
Taper Unless there are safety concerns (i.e. - rash) that require immediate withdrawal, taper over at least 2 weeks
  • It is recommended to do a slow titration to reduce risk of Stevens-Johnson syndrome (SJS)
  • Unlike other mood stabilizers, lamotrigine takes a long time to work! The minimum effective dose is at least 200 mg per day, and this dose can take many weeks to achieve if you do a slow titration. Always make sure the dose is optimized before making a determination that lamotrigine does not work.[1]
  • Lamotrigine comes in oral formulation.
  • The FDA has issued a black box warning on the 0.8 in 1000 risk of developing Stevens Johnson Syndrome (there is a higher risk if someone is on concurrent valproic acid or age <16 years, increases by 10 times to 8 in 1000)
    • Always your patients to monitor for any skin rashes or mucosal ulcers when starting lamotrigine or making dose increases
  • Interaction with hormonal contraceptives
    • Estrogen in contraceptives increases the clearance of lamotrigine
    • Conversely, lamotrigine decreases the progestin (levonorgestrel) levels by ~20%.[2]
  • Hypersensitivity to lamotrigine
  • See drug-drug interactions below
  • Breastfeeding concerns
  • Lamotrigine has significant drug-drug interactions with valproic acid.
    • This is due to valproic acid competitively blocking lamotrigine's metabolism via Phase II glucoridnation, this reduces the plasma clearance and prolongs the elimination half-life of lamotrigine.
    • Never add valproic acid to a patient who is already on lamotrigine, as this can cause dramatic increases in lamotrigine levels and increase the risk for SJS (but it is OK to do it carefully the other way around – adding lamotrigine at very low doses to valproic acid)
  • Carbamazepine, phenytoin, phenobarbital, rifampin, primidone, and HIV medications (lopinavir, ritonavir, atazanavir) can induce the glucoronidation of lamotrigine.
  • GI side effects include abdominal pain, indigestion, nausea, vomiting, weakness, pain, ataxia, dizziness, headache, somnolence or insomnia, hypochloremia, double vision, unsteadiness, tremor, sedation.
  • Weight gain is less common than with other mood stabilizers.

Stevens-Johnson Syndrome

  • Lamotrigine carries a 0.3 to 1% risk of developing Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN). A benign non-serious rash occurs in 10% of patients, and is minimized by starting at low doses and increasing slowly. The benign rash usually happens in the first 4 weeks, is usually maculopapular and not vesicular, and is more frequently seen in kids.
    • The risk for SJS/TEN can be decreased significantly by starting at 25 mg, and increasingly the dose every 2 weeks by 25 mg. This can reduce the risk to as low as 1 in 5000.[3]
  • While the exact causal relation remains unclear, certain Human Leukocyte Antigen (HLA) types have been associated with the development of SJS/TEN following lamotrigine use, including HLA-B*15:02 in the Han Chinese population.[4] This is a similar mechanism in SJS from carbamazepine as well.
  • It is very important to tell all patients who take lamotrigine to report to their physician any and all skin rashes and/or mouth sores that develop.
  • If valproic acid is added to lamotrigine, this will significantly increase lamotrigine levels, because valproic acid inhibits clearance of lamotrigine in the Phase I glucoroindation pathway. Thus, never add valproic acid to lamotrigine!
  • There have been case reports of lamotrigine causing false positive phencyclidine readings on urine drug screen.[5]
  • Lamotrigine is safe in pregnancy!
  • Lamotrigine is excreted in breast milk and can be detectable in the blood of breast-fed infants.
    • Symptoms of lamotrigine ingestion in infants include poor feeding, drowsiness, rash, and apneas.