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LiverTox: Clinical and Research Information on Drug-Induced Liver Injury [Internet]. Bethesda (MD): National Institute of Diabetes and Digestive and Kidney Diseases; 2012-.

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LiverTox: Clinical and Research Information on Drug-Induced Liver Injury [Internet].

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Last Update: April 18, 2019.



Lamotrigine is a widely used antiseizure medication that is a rare but well known cause of idiosyncratic liver injury, that can be severe and even fatal.


Lamotrigine (la moe' tri jeen) is a phenyltriazine and belongs to an anticonvulsant class of its own. Lamotrigine is believed to inhibit the release of excitatory neurotransmitters, particularly glutamate and aspartate but may also act directly on sodium channels on neuronal cells. Lamotrigine was approved for use in the United States for epilepsy in 1994 and it is still in common use. Lamotrigine is indicated for prevention and management of partial and generalized seizures either alone or in combination with other anticonvulsant agents. Lamotrigine is also approved for use as a mood stabilizer in bipolar disorders. It is used off-label for several other conditions, including peripheral neuropathy, neuropathic pain, migraine headaches and trigeminal neuralgia. Lamotrigine is available tablets of 25, 100, 150 and 200 mg in generic formulations and under the brand name Lamictal. Pediatric formulations as chewable tablets are available in doses of 2, 5 and 25 mg. The recommended starting dose is 25 mg taken orally once daily, escalating to a maximum dose of 400 mg in two divided doses daily. Common side effects include somnolence, fatigue, nervousness, dizziness, and rash.


Prospective studies suggest that less than 1% of subjects develop elevations in serum aminotransferase levels during long term lamotrigine therapy. However, clinically apparent hepatotoxicity from lamotrigine is well known and is estimated to occur in one in 2,000 to 10,000 treated patients. The liver injury is usually part of a systemic immuno-allergic reaction (anticonvulsant hypersensitivity syndrome [AHS] or drug rash with eosinophilia and systemic symptoms [DRESS] syndrome). The latency is typically short, ranging from one to several weeks. Presenting symptoms are a diffuse maculopapular rash, followed in a few days by high fever, nausea and vomiting. The rash can develop into a systemic hypersensitivity reaction and multiorgan failure or be associated with jaundice and hepatitis. Eosinophilia is common, and facial edema, lymphadenopathy and atypical lymphocytosis can occur. The pattern of liver enzyme elevations is usually hepatocellular and severity ranges from mild-to-moderate ALT elevations accompanying the generalized hypersensitivity reaction, to an icteric hepatitis, to a severe hepatitis and acute liver failure. Liver biopsy shows portal inflammation, hepatocellular necrosis and bile duct proliferation. In some instances of severe hypersensitivity syndrome with acute multiorgan failure, the hepatic involvement may represent ischemic injury.

Lamotrigine has also been linked to rare instances of hemophagocytic lymphohistiocytosis, a rare and severre immune related reaction characterized by unremitting activation of CD8+ T cells and macrophages that causes multiorgan damage including liver injury, hepatitis and liver failure. Cases of HLH linked to lamotrigine arose within 1 to 4 weeks of starting the drug, usually in infants or children, marked clinically by fever, rash, cytopenias, hepatitis, high triglycerides and ferritin levels and bone marrow or liver histology demonstrating hemophagocytosis

Likelihood score: A (well known cause of clinically apparent liver injury).

Mechanism of Injury

The mechanism of lamotrigine hepatotoxicity is thought to be hypersensitivity or an immunological response to a metabolically generated drug-protein complex. Women, children and patients taking valproic acid appear to be more susceptible. Higher doses and rapid dose escalations have also been linked with higher incidence of lamotrigine hepatotoxicity. Genetic studies have shown little or no association of lamotrigine hepatotoxicity with specific variants, such as those associated with carbamazepine related hypersensitivity reactions.

Outcome and Management

Lamotrigine hepatotoxicity is usually rapidly reversible within a few days of the drug being stopped. In cases of multiorgan failure, disseminated intravascular consumption (DIC), rhabdomyolysis and renal failure are common. If lamotrigine is stopped promptly, recovery is expected within one to two weeks. Prolonged exposure after the appearance of symptoms may escalate the injury to result in irreversible, rapidly progressive liver failure. Corticosteroids have been used to treat lamotrigine hepatoxicity but with uncertain effectiveness. Chronic injury from lamotrigine therapy has not been reported. Lamotrigine is not an aromatic convulsant and is unrelated structurally to phenytoin and carbamazepine. However, some degree of overlap in hypersensitivity response occurs, and patients with hepatotoxicity related to lamotrigine should best avoid exposure to the aromatic anticonvulsants such as phenytoin, phenobarbital and carbamazepine.

Hemophagocytolytic lymphohistiocytosis caused by lamotrigine can be life-threatening and is usually treated with immunosuppression including corticosteroids and etoposide and occasionally with monoclonal antibody to interferon gamma (emapalumab).

Drug Class: Anticonvulsants


Case 1. Acute hepatitis-like injury due to lamotrigine.

[Modified from: Chalasani N, Bonkovsky HL, Fontana R, Lee W, Stolz A, Talwalkar J, Reddy KR, et al.; United States Drug Induced Liver Injury Network. Features and outcomes of 899 patients with drug-induced liver injury: The DILIN Prospective Study. Gastroenterology 2015; 148: 1340-52.e7. PubMed Citation]

A 27 year old female with a history of seizure disorder developed a rash with fever, itching, nausea, vomiting and fatigue 3 weeks after starting lamotrigine. The dose had been increased from 50 mg daily to 100 mg daily one week before onset of symptoms. She continued to take lamotrigine for another week before seeking medical attention, when she was found to have elevated serum aminotransferase levels and was admitted to for further evaluation. Physical examination revealed an extensive maculopapular rash and fever but no jaundice. Initially, serum ALT levels were ~25 fold elevated, but serum bilirubin levels were normal. Eosinophil counts were not available. Tests for viral hepatitis, autoimmune hepatitis and ultrasound were unremarkable. The patient had no history of alcohol or drug abuse or previous history of liver disease or drug allergy. After two days in the hospital she became jaundiced with serum bilirubin that eventually rose to 6.4 mg/dL. Over the following days, laboratory test results began to improve and were close to normal 2 weeks later.

Key Points

Medication:Lamotrigine (50→100 mg/day)
Pattern:Hepatocellular (R=56)
Severity:3+ (jaundice and hospitalization)
Latency:26 days
Recovery:Complete after 19 days
Other medications:None mentioned

Laboratory Values

Time After StartingTime After StoppingALT (U/L)Alk P (U/L)Bilirubin (mg/dL)Other
00Lamotrigine started, 50 mg daily
2 weeks0Lamotrigine increased to 100 mg
3 weeks0Rash, itching, nausea, vomiting
4 weeks01576790.4Lamotrigine stopped
2 days57051724.9
3 days41601476.6
4 days33721296.4
5 weeks5 days24601275.5Discharged
7 weeks19 days74631.2
Normal Values<42<115<1.2


A typical acute hepatitis-like injury arose after 3 weeks of lamotrigine therapy with somewhat delayed discontinuation. The timing of this reaction and the signs of hypersensitivity including fever and rash support the diagnosis and suggest an immuno-allergic etiology. Therapy with other anticonvulsants may be tolerated but monitoring for evidence of liver injury would be appropriate.



Lamotrigine – Generic, Lamictal®




Product labeling at DailyMed, National Library of Medicine, NIH


Lamotrigine chemical structure


References updated: 18 April 2019

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    (Letter expressing opinion that HLA-B*1502 screening should also be used for Asian patients planning to take lamotrigine).
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    (Genome wide association studies failed to identify any significant variation [including HLA-A*3101, previously associated with carbamazepine reactions in Europeans] associated with hypersensitivity to lamotrigine [n=46] or phenytoin [n=44]).
  • Patel PP, Gandhi AM, Desai CK, Desai MK, Dikshit RK. An analysis of drug induced Stevens-Johnson syndrome. Indian J Med Res 2012; 136: 1051-3. [PMC free article: PMC3612312] [PubMed: 23391805]
    (59 cases of drug induced Stevens Johnson syndrome were seen at a single referral center in India between 2005-2010, 25% in children, arising 1-39 days after starting drug, major causes being phenytoin [18] and nevirapine [13], 2 were attributed to lamotrigine).
  • Biton V, Shneker BF, Naritoku D, Hammer AE, Vuong A, Caldwell PT, Messenheimer JA. Long-term tolerability and safety of lamotrigine extended-release: pooled analysis of three clinical trials. Clin Drug Investig 2013; 33: 359-64. [PubMed: 23475541]
    (Pooled analysis of adverse events in 662 patients treated with extended release lamotrigine in 3 controlled trials, found no "clinically important" differences in clinical chemistry results between lamotrigine and placebo recipients).
  • Cheung YK, Cheng SH, Chan EJ, Lo SV, Ng MH, Kwan P. HLA-B alleles associated with severe cutaneous reactions to antiepileptic drugs in Han Chinese. Epilepsia 2013 May 20. [Epub ahead of print] [PubMed: 23692434]
    (HLA-B*15:02 was found in 24 of 26 [92%] Chinese patients with carbamazepine related, but only 2 of 6 [33%] with lamotrigine related Stevens Johnson syndrome versus 12% of controls).
  • Drugs for epilepsy. Treat Guidel Med Lett 2013; 11: 9-18. [PubMed: 23348233]
    (Drugs of choice for epilepsy; mentions that the adverse effects of lamotrigine include acute hepatitis and Stevens Johnson syndrome).
  • Björnsson ES, Bergmann OM, Björnsson HK, Kvaran RB, Olafsson S. Incidence, presentation and outcomes in patients with drug-induced liver injury in the general population of Iceland. Gastroenterology 2013 144: 1419-25. [PubMed: 23419359]
    (In a population based study of drug induced liver injury from Iceland, 96 cases were identified over a 2 year period, including 3 attributed to anticonvulsants: phenytoin 2 and gabapentin 1, but none attributed to lamotrigine).
  • Kaur S, Dogra A. Toxic epidermal necrolysis due to concomitant use of lamotrigine and valproic Acid. Indian J Dermatol 2013; 58: 406. [PMC free article: PMC3778793] [PubMed: 24082198]
    (Two Indian patients with epilepsy on long term valproate developed toxic epidermal necrolysis 2 and 4 weeks after starting lamotrigine, with fever and skin rash involving 30% and 60% of the body surface area [no mention of liver test abnormalities], resolving ultimately with prednisolone therapy).
  • Parveen S, Javed MA. Stevens Johnson Syndrome associated with Lamotrigine. Pak J Med Sci 2013; 29: 1450-2. [PMC free article: PMC3905385] [PubMed: 24550973]
    (58 year old Pakistani woman developed conjunctivitis, facial swelling and rash 4-6 weeks after starting lamotrigine for depression, resolving within 2 weeks of stopping; no mention of liver test abnormalities).
  • Błaszczyk B, Szpringer M, Czuczwar SJ, Lasoń W. Single centre 20 year survey of antiepileptic drug-induced hypersensitivity reactions. Pharmacol Rep 2013; 65: 399-409. [PubMed: 23744424]
    (Among 300 patients with epilepsy seen over a 10 year period at a single center in Poland, 30 developed skin rash on anticonvulsant therapy, most commonly with carbamazepine [20 of 130], phenytoin [13 of 40], lamotrigine [13 of 53] and oxcarbazepine [4 of 26]; a single case of Stevens Johnson syndrome was attributed to carbamazepine).
  • Ginory A, Chaney-Catchpole M, Demetree JM, Mayol Sabatier LM, Nguyen M. Drug reaction with eosinophilia and systemic smptoms (DRESS) in an adolescent treated with lamotrigine. J Pediatr Pharmacol Ther 2013; 18: 236-40. [PMC free article: PMC3775558] [PubMed: 24052787]
    (17 year old female developed rash, fever, fatigue and then jaundice within 3 weeks of starting lamotrigine for bipolar II disorder [bilirubin 6.5 mg/dL, ALT 2076 U/L, Alk P 455 U/L, mild eosinophilia], improving with stopping and high-dose corticosteroid therapy).
  • Hernández N, Bessone F, Sánchez A, di Pace M, Brahm J, Zapata R, A Chirino R, et al. Profile of idiosyncratic drug induced liver injury in Latin America. An analysis of published reports. Ann Hepatol 2014; 13: 231-9. [PubMed: 24552865]
    (Systematic review of literature of drug induced liver injury in Latin American countries published from 1996 to 2012 identified 176 cases, 7 [4%] of which were attributed to anticonvulsants but none to lamotrigine).
  • Chalasani N, Bonkovsky HL, Fontana R, Lee W, Stolz A, Talwalkar J, Reddy KR, et al.; United States Drug Induced Liver Injury Network. Features and outcomes of 899 patients with drug-induced liver injury: The DILIN Prospective Study. Gastroenterology 2015; 148: 1340-52.e7. [PMC free article: PMC4446235] [PubMed: 25754159]
    (Among 899 cases of drug induced liver injury enrolled in a US prospective study between 2004 and 2013, 40 [4.5%] were due to anticonvulsants including 9 [1%] due to lamotrigine, the second most common anticonvulsant cause [after phenytoin]).
  • Sultan SJ, Sameem F, Ashraf M. Drug reaction with eosinophilia and systemic symptoms: manifestations, treatment, and outcome in 17 patients. Int J Dermatol 2015; 54: 537-42. [PubMed: 24738653]
    (Among 17 patients with DRESS or drug-hypersensitivity syndrome seen at a single Indian medical center over a 4 year period, 11 were associated with anticonvulsant therapy including 6 attributed to phenytoin, 2 to phenobarbital, and 1 each to carbamazepine, oxacarbazepine and lamotrigine; all had ALT elevations and 65% were jaundiced).
  • Mehrholz D, Urban AE, Herstowska M, Nowicki R, Cubała W, Barańska-Rybak W. A retrospective study of DRESS - drug reaction with eosinophilia and systemic symptoms. Psychiatr Pol 2017; 51: 1079-93. [PubMed: 29432504]
    (Among 261 adults with cutaneous drug reactions seen at a single Polish medical center between 2004 and 2017, 10 met criteria for DRESS syndrome, including 6 attributed to carbamazepine, 1 oxycarbazepine and 2 lamotrigine).
  • Han SH, Hur MS, Youn HJ, Roh NK, Lee YW, Choe YB, Ahn KJ. Drug reaction with eosinophilia and systemic symptom syndrome induced by lamotrigine. Ann Dermatol 2017; 29: 206-9. [PMC free article: PMC5383747] [PubMed: 28392649]
    (47 year old Korean man developed rash followed by fever 3 weeks after starting lamotrigine [bilirubin 1.4 mg/dL, ALT 66 U/L, Alk P 148 U/L, eosinophils 28%], responding to methylprednisolone therapy).
  • Bunchorntavakul C, Reddy KR. Drug hepatotoxicity: newer agents. Clin Liver Dis 2017; 21: 115-34. [PubMed: 27842767]
    (Review of the hepatotoxicity of newly approved agents including lamotrigine, which causes hepatocellular injury in 1-5 of 10,000 treated patients, typically with features of hypersensitivity and cutaneous signs and which can lead to fatal acute liver failure).
  • Vidaurre J, Gedela S, Yarosz S. Antiepileptic drugs and liver disease. Pediatr Neurol 2017; 77: 23-36. [PubMed: 29097018]
    (Review of the use of anticonvulsants in patients with liver disease recommends use of agents that have little hepatic metabolism such as levetiracetam, lacosamide, topiramate, gabapentin and pregabalin; lamotrigine is problematic in that it is metabolized largely in the liver, has a high potential of drug interactions and requires dose adjustments for patients with moderate or severe cirrhosis).
  • Drugs for epilepsy. Med Lett Drugs Ther 2017; 59 (1526): 121-130. [PubMed: 28746301]
    (Concise review of drugs available for therapy of epilepsy; mentions that lamotrigine is a drug of choice for partial and generalized seizures and atypical, absence, myoclonic and atonic seizures and that adverse events include hepatitis, acute liver failure and Stevens Johnson syndrome).
  • Comparison table: some oral antiepileptic drugs. Med Lett Drugs Ther 2017; 59 (1521): e130-e136. [PubMed: 28746302]
    (Table of the major oral antiepileptic drugs in current use and listing of oral formulations, usual dosages, adverse effects, drug interactions, current indications and costs).
  • Iriki H, Ouchi T, Ito H, Sawada M, Mukai M, Nomura H, Baba Y, et al. Case of lamotrigine-induced drug adverse reaction under tocilizumab treatment with clinical and virological features of drug-induced hypersensitivity syndrome. J Dermatol 2018; 45: 738-41. [PubMed: 29569382]
    (29 year old woman with rheumatoid arthritis on tocilizumab [anti-IL6] developed rash, fever and lymphadenopathy 3 weeks after starting lamotrigine, responding to corticosteroid therapy but with mild transient ALT elevations [~120 U/L] and recurrence of rash on three occasions).
  • Tawhari I, Tawhari F, Aljuaid M. Lamotrigine-induced drug reaction with eosinophilia and systemic symptoms (DRESS) during primary Epstein-Barr virus (EBV) infection. BMJ Case Rep 2018; 2018. pii: bcr-2017-222416. [PMC free article: PMC5786957] [PubMed: 29367368]
    (21 year old man developed fever, sore throat, rash and abdominal pain 2 weeks after starting lamotrigine [bilirubin not given, ALT 506 U/L, Alk P 246 U/L, 10% atypical lymphocytes and positive heterophile antibody], resolving within 3 weeks on methylprednisolone therapy).
  • In brief: A potentially fatal immune reaction to lamotrigine. Med Lett Drugs Ther 2018; 60 (1549): 105. [PubMed: 29913474]
    (Brief summary of FDA warning of possible complication of lamotrigine therapy of hemophagocytic lymphohistiocytosis [HLH], based upon 8 cases reported to the agency arising within 24 days of starting lamotrigine).


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