Lamotrigine (Lamictal)

Indications

Bipolar Disorder (see Bipolar Disorder)

Clinical Efficacy

Seizures (see Seizures)

Clinical Efficacy

Pharmacology

Lamotrigine is a Triazine Derivative

Inhibits Release of the Excitatory Amino Acid, Glutamate
Inhibits Voltage-Sensitive Sodium Channels, Stabilizing Neuronal Membranes
Weak Inhibitory Effect on the 5-HT3 Serotonin Receptor

Metabolism

Hepatic and Renal
- Over 75% is Metabolized By Glucuronidation

Administration

Oral (PO)

Dose: XXXX

Dose Adjustment

Hepatic Dose Adjustment

Mild Hepatic Impairment
Moderate-Severe Hepatic Impairment without Ascites: decrease initial, escalation, and maintenance doses by 25%
nModerate-Severe Hepatic Impairment with Ascites: decrease initial, escalation, and maintenance doses by 50%

Renal Dose Adjustment

None Specified in Manufacturer Instructions
May Decrease Maintenance Dosage with Significant Renal Impairment

Use During Pregnancy (see Pregnancy)

xxx

Use During Breast Feeding

Concentrations of Antiseizure Medications Can Be Detected in Breastmilk of Females with Epilepsy and Plasma/Serum of Infants Exposed Via Breastmilk ((Seizure, 2022) [MEDLINE]

Adverse Effects

Allergic/Immunologic Adverse Effects

Angioedema (see Angioedema)

Epidemiology
- Angioedema Occurs in <1% of Patients

Dermatologic Adverse Effects

Drug Rash with Eosinophilia and Systemic Symptoms (DRESS Syndrome) (see Drug Rash with Eosinophilia and Systemic Symptoms)

Epidemiology
- Drug Rash with Eosinophilia and Systemic Symptoms (DRESS Syndrome) Has Been Reported (Ann Pharmacother, 2010) [MEDLINE] (BMJ Case Rep, 2015) [MEDLINE] (BMJ Case Rep, 2019) [MEDLINE] (J Dermatol, 2019) [MEDLINE]
- Risk Factors for Lamotrigine-Induced Skin Eruptions
  - Age <13 y/o
  - Concurrent Therapy with Inhibitors of Lamotrigine Metabolism (Such as Valproate)
  - Higher Initial Dose and/or Rapid Titration
  - HLA Molecular Variants (Specific to Stevens-Johnson Syndrome/Toxic Epidermal Necrolysis in Select Populations)
  - Prior Rash with Other Antiseizure Medications
  - Uridine Diphosphate-Glucuronosyltransferase (UGT) Enzyme Polymorphisms
    - May Contribute
Clinical
- Onset of Lamotrigine-Induced Skin Eruptions Occurs Between 5 Days-8 Weeks After Initiation of Therapy (Int J Neuropsychopharmacol, 2009 [MEDLINE]

Rash

Epidemiology
- Rash is Common
  - Rash Occurs in Up to 10% of Cases
- Risk Factors for Lamotrigine-Induced Skin Eruptions
  - Age <13 y/o
  - Concurrent Therapy with Inhibitors of Lamotrigine Metabolism (Such as Valproate)
  - Higher Initial Dose and/or Rapid Titration
  - HLA Molecular Variants (Specific to Stevens-Johnson Syndrome/Toxic Epidermal Necrolysis in Select Populations)
  - Prior Rash with Other Antiseizure Medications
  - Uridine Diphosphate-Glucuronosyltransferase (UGT) Enzyme Polymorphisms
    - May Contribute
Clinical
- Onset of Lamotrigine-Induced Skin Eruptions Occurs Between 5 Days-8 Weeks After Initiation of Therapy (Int J Neuropsychopharmacol, 2009 [MEDLINE]
- Benign Morbilliform Rashes with/without Pruritus

Stevens-Johnson Syndrome (SJS) (see Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis)

Epidemiology
- Cases of Stevens-Johnson Syndrome (SJS) Have Been Reported
- Risk Factors for Lamotrigine-Induced Skin Eruptions
  - Age <13 y/o
  - Concurrent Therapy with Inhibitors of Lamotrigine Metabolism (Such as Valproate)
  - Higher Initial Dose and/or Rapid Titration
  - HLA Molecular Variants (Specific to Stevens-Johnson Syndrome/Toxic Epidermal Necrolysis in Select Populations)
  - Prior Rash with Other Antiseizure Medications
  - Uridine Diphosphate-Glucuronosyltransferase (UGT) Enzyme Polymorphisms
    - May Contribute
Clinical
- Onset of Lamotrigine-Induced Skin Eruptions Occurs Between 5 Days-8 Weeks After Initiation of Therapy (Int J Neuropsychopharmacol, 2009 [MEDLINE]

Gastrointestinal/Hepatic Adverse Effects

Acute Pancreatitis (see Acute Pancreatitis)

Epidemiology
- Acute Pancreatitis Has Been Reported When Lamotrigine is Used in Combination with Vigabatrin (see Vigabatrin) (Seizure, 1994) [MEDLINE]

Drug-Induced Liver Injury (DILI)/Drug-Induced Hepatotoxicity (see Drug-Induced Hepatotoxicity)

Epidemiology
- Cases of Hepatotoxicity Have Been Reported (Am J Psychiatry, 2008) [MEDLINE]
Clinical
- Hepatitis with Increased Liver Function Tests (LFT’s)

Nausea (see Nausea and Vomiting)

Epidemiology
- Nausea Occurs in 7-14% of Patients

Hematologic Adverse Effects

Anemia (see Anemia)

Epidemiology
- XXXX

Aplastic Anemia (see xxxx)

Epidemiology
- XXXX

Disseminated Intravascular Coagulation (DIC) (see Disseminated Intravascular Coagulation)

Epidemiology
- Disseminated Intravascular Coagulation (DIC) Has Been Reported in Children Receiving Lamotrigine and Valproic Acid (Neurology, 1997) [MEDLINE]

Hemophagocytic Lymphohistiocytosis (HLH) (see Hemophagocytic Lymphohistiocytosis)

Epidemiology
- XXXX
Physiology
- Unknown Mechanism (J Med Case Rep, 2019) [MEDLINE]
  - Stimuli are Believed to Activate Circulating Macrophages, Which Phagocytose Blood Cells, Resulting in Excessive Release of Cytokines
Clinical (J Med Case Rep, 2019) [MEDLINE] (Neurology, 2019) [MEDLINE]
- Onset is Typically within the First Several Weeks (17-24 Days) After Starting Therapy
- Cytopenias
- Fever (see Fever)
- Hepatosplenomegaly (see Hepatomegaly and Splenomegaly)
- Organ Dysfunction
- Rash

Leukopenia/Neutropenia (see Leukopenia and Neutropenia)

Epidemiology
- XXXX

Pancytopenia (see Pancytopenia)

Epidemiology
- Cases Have Been Reported (J Formos Med Assoc, 2018) [MEDLINE]

Thrombocytopenia (see Thrombocytopenia)

Epidemiology
- XXXX

Neurologic Adverse Effects

Aseptic Meningitis (see Meningitis)

Epidemiology
- Does Not Appear to Be Dose-Related (Int Clin Psychopharmacol, 2009) [MEDLINE] (Neurology, 2012) [MEDLINE]
- Risk Factors
  - Presence of Collagen Vascular Disease (Epilepsia, 2005) [MEDLINE] (Epilepsia, 2009) [MEDLINE]
- Some Cases of Aseptic Meningitis are Associated with the Concurrent Development of Rash and Organ Dysfunction (Suggesting a Broader Hypersensitivity Reaction) (Neurology, 2012) [MEDLINE]
Physiology
- Immunologic Mechanism
Clinical
- Onset is Variable
  - Occurs within 1-42 Days Following Initiation of Lamotrigine
  - In 40% of Cases of Rechallenge, Recurrence Often Resulted in a More Rapid Onset (Neurology, 2012 [MEDLINE]
  - Recurrence Has Been Reported to Occur as Rapidly as 30-60 min Following Re-Exposure (Epilepsia, 2005) [MEDLINE] (Epilepsia, 2009) [MEDLINE] (Int Clin Psychopharmacol, 2009) [MEDLINE]
- Signs of Meningeal Inflammation
  - Fever (see Fever)
  - Headache (see Headache)
  - Nuchal Rigidity (see xxxx)
  - Photophobia (see Photophobia)

Central Nervous System Depression

Epidemiology
- XXXX
Clinical XXXX

Renal Adverse Effects

Hyponatremia (see Hyponatremia)

Epidemiology
- Hyponatremia Has Been Identified in Post-Marketing Studies (Innov Clin Neurosci, 2019) [MEDLINE]

Rheumatologic Adverse Effects

Peripheral Edema (see Peripheral Edema)

Epidemiology
- Peripheral Edema Occurs in 2-5% of Cases

Rhabdomyolysis (see Rhabdomyolysis)

Epidemiology
- Rhabdomyolysis Has Been Identified in Post-Marketing Studies (Ann Gen Psychiatry, 2016) [MEDLINE]

Toxicologic Adverse Effects

Serotonin Syndrome (see Serotonin Syndrome)

Epidemiology
- Serotonin Syndrome Has Been Reported When Used in Conjunction with Aripiprazole and Cocaine [MEDLINE]

Other Adverse Effects

Infection

Epidemiology
- Infection Occurs in 5% of Cases
- Herpes Zoster Infection Occurs in <1% of Cases (see Varicella-Zoster Virus)

Lamotrigine Intoxication

Clinical Manifestations

Cardiovascular Manifestations

Electrocardiographic (EKG) Changes (see Electrocardiogram)
- Clinical
  - Left Bundle Branch Block (LBBB) (see Torsade)
  - Widened QRS

Gastrointestinal Adverse Effects

Nausea/Vomiting (see Nausea and Vomiting)

Neurologic Adverse Effects

Central Nervous System Depression
- Obtundation/Coma (see Obtundation/Coma)
Paradoxical Seizures (see Seizures)

Treatment

Activated Charcoal (see Activated Charcoal): recommended due to the fact that lamotrigine undergoes enterohepatic circulation
Benzodiazepines (see Benzodiazepines): recommended for seizures
Sodium Bicarbonate (see Sodium Bicarbonate): recommended
- May Be Effective for QRS Prolongation
20% Lipid Emulsion
- Has Been Reported to Have Efficacy in Lamotrigine (Sodium Channel Blocker) Intoxication, Possibly Mediated via the Lipophilic Properties of Lamotrigine (J Emerg Med, 2012) [MEDLINE]

References

General

Lamotrigine. A review of its pharmacological properties and clinical efficacy in epilepsy. Drugs. 1993 Jul;46(1):152-76 [MEDLINE]

Administration

Concentrations of antiseizure medications in breast milk of lactating women with epilepsy: a systematic review with qualitative synthesis. Seizure: J Epilepsy. Published online March 27, 2022. doi:10.1016/j.seizure.2022.03.017 [MEDLINE]

Adverse Effects

Acute pancreatitis associated with dual vigabatrin and lamotrigine therapy. Seizure. 1994 Dec;3(4):319 [MEDLINE]
Multiorgan dysfunction and disseminated intravascular coagulation in children receiving lamotrigine and valproic acid. Neurology. 1997;49(5):1442-1444. doi:10.1212/wnl.49.5.1442 [MEDLINE]
Evaluation of lamotrigine toxicity reported to poison centers. Ann Pharmacother. 2004;38(11):1811-1815 [MEDLINE]
Recurrent severe aseptic meningitis after exposure to lamotrigine in a patient with systemic lupus erythematosus. Epilepsia. 2005;46(2):327-328. doi:10.1111/j.0013-9580.2005.43304.x [MEDLINE]
Acute hepatotoxicity associated with lamotrigine. Am J Psychiatry. 2008;165(4):539-540. doi:10.1176/appi.ajp.2007.07050728 [MEDLINE]
Lamotrigine-induced aseptic meningitis: a case report. Int Clin Psychopharmacol. 2009;24(3):159-161. doi:10.1097/YIC.0b013e32832a8edc [MEDLINE]
Recurrent lamotrigine-induced aseptic meningitis. Epilepsia. 2009;50(4):968-969. doi:10.1111/j.1528-1167.2008.01985.x [MEDLINE]
Lamotrigine-induced aseptic meningitis: a case report. Int Clin Psychopharmacol. 2009;24(3):159-161. doi:10.1097/YIC.0b013e32832a8edc [MEDLINE]
First report of lamotrigine-induced drug rash with eosinophilia and systemic symptoms syndrome with pancreatitis. Ann Pharmacother. 2010 Dec;44(12):1998-2000. doi: 10.1345/aph.1P350 [MEDLINE]
Lamotrigine and aseptic meningitis. Neurology. 2012;78(12):921-927. doi:10.1212/WNL.0b013e31824c4634 [MEDLINE]
Lamotrigine and aseptic meningitis. Neurology. 2012;78(12):921-927. doi:10.1212/WNL.0b013e31824c4634 [MEDLINE]
Lipid emulsion as rescue therapy in lamotrigine overdose. J Emerg Med. 2012 Jan;42(1):48-51. doi: 10.1016/j.jemermed.2010.11.055 [MEDLINE]
Serotonin Syndrome in the Setting of Lamotrigine, Aripiprazole, and Cocaine Use. Case Rep Med. 2015;2015:769531. doi: 10.1155/2015/769531 [MEDLINE]
Lamotrigine-induced drug reaction with eosinophilia and systemic symptoms (DRESS). BMJ Case Rep. 2015;2015:bcr2014209170. doi:10.1136/bcr-2014-209170 [MEDLINE]
Rhabdomyolysis after lamotrigine overdose: a case report and review of the literature. Ann Gen Psychiatry. 2016;15:6. doi:10.1186/s12991-016-0093-3 [MEDLINE]
Lamotrigine-induced pancytopenia in bipolar disorder. J Formos Med Assoc. 2018;117(12):1128-1129. doi:10.1016/j.jfma.2018.07.004 [MEDLINE]
Drug reaction with eosinophilia and systemic symptoms syndrome in a patient taking lamotrigine. BMJ Case Rep. 2019;12(10):e229180. doi:10.1136/bcr-2019-229180 [MEDLINE]
Drug-induced hypersensitivity syndrome/drug reaction with eosinophilia and systemic symptoms due to lamotrigine differs from that due to other drugs. J Dermatol. 2019;46(3):226-233. doi:10.1111/1346-8138.14776 [MEDLINE]
Lamotrigine-induced hemophagocytic lymphohistiocytosis with Takotsubo cardiomyopathy: a case report. J Med Case Rep. 2019;13(1):345. doi:10.1186/s13256-019-2295-1 [MEDLINE]
Hemophagocytic lymphohistiocytosis associated with the use of lamotrigine. Neurology. 2019;92(21):e2401-e2405. doi:10.1212/WNL.0000000000007517 [MEDLINE]
Severe lamotrigine-induced hyponatremia associated with takotsubo cardiomyopathy. Innov Clin Neurosci. 2019;16(7-08):32-34 [MEDLINE]