FDA warns that lamotrigine (Lamictal) is (HLH), a potentially life-threatening immune reaction.
The drug, which is approved for seizures and bipolar disorder, has been on the market for 24 years. For seizures, lamotrigine is used alone or in combination with other drugs in patients 2 years and older. For bipolar disorder, it's used as a maintenance therapy to delay mania, hypomania or depression.
Reviews of adverse event reports submitted to the FDA as well as cases in the literature turned up a total of eight events worldwide since 1994, five of which were confirmed as HLH. All eight involved hospitalization and one patient died.
"[HLH] can cause severe inflammation throughout the body and lead to hospitalization and death, especially if the reaction is not diagnosed and treated quickly," the agency said. "As a result, we are requiring a new warning about this risk be added to the prescribing information in the lamotrigine drug labels."
The condition is characterized by phagocytosis of blood cells and a proliferation of histiocytes in bone marrow and vital organs, including the liver, kidneys, lungs and brain. The reaction can occur within days, or weeks after starting treatment. Patients typically present with persistent fever (>101°F); a physical examination and laboratory tests are needed to diagnose HLH.
Prompt recognition and early treatment are important for improving outcomes in patients with HLH -- and for decreasing mortality, the FDA said.
A diagnosis can be established if five or more of the following signs or symptoms are identified:
- fever and rash
- enlarged spleen
- cytopenias
- elevated triglycerides or low blood levels of fibrinogen
- high levels of blood ferritin
- hemophagocytosis identified through bone marrow, spleen or lymph node biopsy
- absent or decreased natural killer (NK) cell activity
- elevated CD25 levels showing prolonged immune cell activation
Lamotrigine should be discontinued if a healthcare provider suspects HLH or another serious immune-related adverse reaction and an alternative etiology cannot be established.
"Diagnosis is often complicated because early signs and symptoms such as fever and rash are not specific," the FDA's statement noted. "HLH may also be confused with other serious immune-related adverse reactions such as Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)."
For patients who experience HLH symptoms while on lamotrigine, immediate medical attention is required. Patients who develop rash or persistent fever should seek prompt evaluation.
Other HLH signs and symptoms include pain, tenderness or swelling in the area of the liver; swollen lymph nodes; jaundice; unusual bleeding; and nervous system problems such as seizures, trouble walking, and visual difficulties or other visual disturbances.
Patients who wish to stop treatment should consult their doctor, as cessation of lamotrigine can lead to uncontrolled seizures or worsening mental health problems, depending on the reason for treatment.
This is not the first safety warning for lamotrigine since its approval. In September 2006 the FDA warned of a possible association of oral clefts in the newborns of mothers who took the drug during pregnancy (more recent reports have called this link into question), in 2008 the agency issued a safety alert related to suicidal thoughts and behavior for all anti-seizure medicines, and in 2010 a meningitis warning for lamotrigine was issued.
Another drug, alemtuzumab (Lemtrada) for relapsing-remitting multiple sclerosis, has also recently been linked with an increased risk of HLH.