Lamotrigine use is contraindicated in patients who have demonstrated hypersensitivity to lamotrigine (e.g., rash, history of angioedema, acute urticaria, extensive pruritus, mucosal ulceration) or other life-threatening hypersensitivity or serious immune-related events. Due to life-threatening serious rash (including Stevens-Johnson syndrome and toxic epidermal necrolysis), lamotrigine carries a boxed warning stating the drug should be discontinued if rash occurs at any time during treatment. It is important to note that discontinuation of lamotrigine may not prevent progression to a higher level of severity; therefore patients should be closely monitored. Age is the only factor currently known to predict the occurrence or severity of a rash, with pediatric patients at increased risk. Other possible but unproven factors include concurrent use of valproate, exceeding the initial recommended dose, or exceeding the recommended dose titration. Almost all cases of life-threatening rash have occurred within the first 2 to 8 weeks of treatment. However, a prolonged duration of therapy should not preclude the possibility of an association to the drug. Also, caution is advised when administering lamotrigine to patients with a history of rash or allergy to other anticonvulsants, since non-serious rashes have occurred 3 times more frequently in these patients during treatment with lamotrigine than in those without this history. Lamotrigine should not be resumed following prior discontinuation due to rash unless the benefits outweigh the risks. If the drug is reintroduced and it has been 5 half-lives or longer since the last dose, the manufacturer recommends reinitiating using initial dosing recommendations. Multiorgan hypersensitivity reactions, also known as drug reaction with eosinophilia and systemic symptoms (DRESS), have occurred. Some have been fatal or life threatening. DRESS typically, although not exclusively, presents with fever, rash, and/or lymphadenopathy in association with other organ system involvement, such as hepatitis, nephritis, hematologic abnormalities, myocarditis, or myositis, sometimes resembling an acute viral infection. Eosinophilia is often present. Early manifestations of hypersensitivity (e.g., fever, lymphadenopathy) may be present even though a rash is not evident. If such signs or symptoms are present, the patient should be evaluated immediately. Discontinue lamotrigine if an alternative etiology for the signs or symptoms cannot be established. Lamotrigine may also cause hemophagocytic lymphohistiocytosis (HLH), which is a rare but serious uncontrolled immune system response that may result in hospitalization and death. Severe inflammation occurs throughout the body leading to severe problems with blood cells and organs throughout the body. HLH typically presents with a fever (greater than 101 degrees F) and rash. Other signs and symptoms may include enlarged liver with pain, tenderness, or unusual swelling over the liver area in the upper right belly, swollen lymph nodes, yellow skin or eyes, unusual bleeding, or nervous system problems (seizures, trouble walking, difficulty seeing, or other visual disturbances). A diagnosis may be established if 5 of the following symptoms from the HLH-2004 diagnostic criteria are present: fever or rash, enlarged spleen (splenomegaly), cytopenias, elevated concentrations of triglycerides or low blood concentrations of fibrinogen, high concentrations of blood ferritin, hemophagocytosis identified through bone marrow, spleen, or lymph node biopsy, decreased or absent natural killer cell activity, and elevated blood concentrations of CD25 showing prolonged immune cell activation. Evaluate patients who present with fever or rash promptly, as early recognition is necessary to improve outcomes and reduce mortality. HLH may be confused with other serious immune-system reactions such as Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS).