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
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.
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
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

See also: The MGH Center for Women’s Mental Health - You Asked: Is There an Interaction Between Lamotrigine and Oral Contraceptives?

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)

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, 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

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.

³⁾ FDA Product Monograph: Lamictal

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.

⁶⁾ 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(1), 139-141.

⁷⁾ Geraci, M. J., Peele, J., McCoy, S. L., & Elias, B. (2010). Phencyclidine false positive induced by lamotrigine (Lamictal®) on a rapid urine toxicology screen. International journal of emergency medicine, 3(4), 327-331.

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