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 (Phase II)
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 (SJS)
    • There is a higher risk if someone is on concurrent valproic acid or age <16 years, and the risk increases 10-fold, to 8 in 1000
    • Always ask 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, some studies have shown that lamotrigine decreases progestin (levonorgestrel) levels by ~20%, but it is not thought to have an overall impact on contraceptive efficacy (see drug-drug interaction section below).[2]
  • Before starting patients on lamotrigine, it is important to tell them what to do if they forget to take lamotrigine.
  • If a patient has not taken lamotrigine for a period of more than five half-lives (approximately 3 to 5 days), the product monograph recommends that lamotrigine be restarted at the the lowest dose and again re-titrated upwards.[3] This is to minimize the risk for SJS.
    • The half-life of lamotrigine is 25.4 hours, but this can be affected by concomitant administration of medications such as valproic acid (which would increase the half-life of lamotrigine), and other anti-epileptic medications.
  • 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, because valproic acid inhibits clearance of lamotrigine in the Phase I glucoroindation pathway
      • This can cause dramatic increases in lamotrigine levels and increase the risk for SJS
      • However, 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, and result in lower serum levels of lamotrigine.
  • Some studies have shown that lamotrigine decreases progestin (levonorgestrel) levels by ~20%, but it is not thought to have an overall impact on contraceptive efficacy.
  • 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.
  • 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.
  • Lamotrigine carries a 0.3 to 1% risk of developing Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN).
  • 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.[4][5]
  • 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.[6]
  • It is also important to remember that 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.

Benign vs. Concerning Rashes When Starting Lamotrigine

Adapted from: Lorberg, B. et al. (2009). Lamotrigine-associated rash: to rechallenge or not to rechallenge?. The The International Journal of Neuropsychopharmacology, 12(2), 257-265.
Benign rash Concerning rash
• Peaks within days and settles in 10–14 days
• Spotty, non-confluent, non-tender
• Absence of systemic features
• Complete blood count, liver function tests, blood urea, serum creatinine, and urine analysis are within normal limits
• Confluent and widespread rash
• Purpuric and tender rash
• Associated fever, malaise, pharyngitis, lymphadenopathy, or anorexia
• Abnormalities in the laboratory test values mentioned above
• Any involvement of eyes, lips, mouth, or other mucous membranes (such as oral ulcers)
• Prominent involvement of neck or upper trunk
  • There have been case reports of lamotrigine causing false positive phencyclidine readings on urine drug screen.[7]
  • 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.