- Last edited on March 9, 2023
Lamotrigine (Lamictal)
Primer
Lamotrigine (Trade name: Lamictal) an antiepileptic and mood stabilizer used in the treatment of bipolar disorder. It is more effective for the treatment/prevention of depression than mania in bipolar disorder.
Pharmacokinetics
See also article: Introduction to Pharmacology
Pharmacokinetics of Lamotrigine
Absorption | Rapidly absorbed, Tmax = 1.4 to 4.8 hours |
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Distribution | High volume of distribution (77L), 55% bound to proteins |
Metabolism | Liver, primarily glucoroindation (Phase II) |
Elimination | Renal, approximately 70% |
Half-life | 33 hours |
See also article: Cytochrome (CYP) P450 Metabolism
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. |
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Induces | Not applicable |
Inhibits | Not applicable |
Pharmacodynamics
Mechanism of Action
- 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.
Toxicity
- In overdose, symptoms including nystagmus, ataxia, seizures, coma and intraventricular conduction delay (QRS widening).
Indications
- Bipolar I disorder (maintenance and depression phases of illness)
- Bipolar II disorder (maintenance and depression phases of illness)
- Epilepsy
Dosing
Dosing for Lamotrigine
Starting | 25mg PO daily for 2 weeks |
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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]
Formulations
- Lamotrigine comes in oral formulation.
Monitoring
- 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]
Missed Doses and Restarting
- Before starting patients on lamotrigine, it is important to tell them what to do if they forget to take lamotrigine.
- If a patient has missed or 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.
- Note that 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.
Contraindications
Absolute
- Hypersensitivity to lamotrigine
Relative
- See drug-drug interactions below
- Breastfeeding concerns
Drug-Drug Interactions
- 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.
Side Effects
Common
- 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.
Adverse Events
Stevens-Johnson Syndrome (SJS) and Toxic Epidermal Necrolysis (TEN)
See also:
- 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).
- 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]
- This is a similar mechanism in SJS from carbamazepine as well.
- 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 |
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• 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, tender, painful 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 |
Clinical Pearls
- There have been case reports of lamotrigine causing false positive phencyclidine readings on urine drug screen.[7]
Special Populations
Geriatric
See main article: Geriatric Pharmacology
Pediatric
See main article: Pediatric Pharmacology
Obstetric and Fetal
See main article: Obstetric and Fetal Pharmacology
- 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.
Medically Ill
See main article: Psychotropic Dosing in the Medically Ill
Resources
References
1)
Yatham, L. N., Kennedy, S. H., Parikh, S. V., Schaffer, A., Bond, D. J., Frey, B. N., ... & Berk, M. (2018). Canadian Network for Mood and Anxiety Treatments (CANMAT) and International Society for Bipolar Disorders (ISBD) 2018 guidelines for the management of patients with bipolar disorder. Bipolar disorders, 20(2), 97-170.
2)
Rauchenzauner, M., Deichmann, S., Pittschieler, S., Bergmann, M., Prieschl, M., Unterberger, I., ... & Luef, G. (2020). Bidirectional interaction between oral contraception and lamotrigine in women with epilepsy–Role of progestins. Seizure, 74, 89-92.
4)
Bloom, R., & Amber, K. T. (2017). Identifying the incidence of rash, Stevens-Johnson syndrome and toxic epidermal necrolysis in patients taking lamotrigine: a systematic review of 122 randomized controlled trials. Anais Brasileiros de Dermatologia, 92, 139-141.
5)
Yatham, L. N., Kennedy, S. H., Parikh, S. V., Schaffer, A., Bond, D. J., Frey, B. N., ... & Berk, M. (2018). Canadian Network for Mood and Anxiety Treatments (CANMAT) and International Society for Bipolar Disorders (ISBD) 2018 guidelines for the management of patients with bipolar disorder. Bipolar disorders, 20(2), 97-170.