Lamotrigine (Lamictal)


Indications

Bipolar Disorder (see Bipolar Disorder)

Clinical Efficacy

  • xx

Seizures (see Seizures)

Clinical Efficacy

  • xx


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 Adjustment

Hepatic Dose Adjustment

Renal Dose Adjustment

Use During Pregnancy (see Pregnancy)

Use During Breast Feeding


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

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


Lamotrigine Intoxication

Clinical Manifestations

Cardiovascular Manifestations

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

Gastrointestinal Adverse Effects

Neurologic Adverse Effects

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

Administration

Adverse Effects