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AUDIENCE: Health Professional, Patient, Pharmacy
ISSUE: The FDA is warning that the medicine lamotrigine (Lamictal) for seizures and bipolar disorder can cause a rare but very serious reaction that excessively activates the body's infection-fighting immune system. This can cause severe inflammation throughout the body and lead to hospitalization and death, especially if the reaction is not diagnosed and treated quickly. As a result, we are requiring a new warning about this risk be added to the prescribing information in the lamotrigine drug labels.
BACKGROUND: The immune system reaction, called hemophagocytic lymphohistiocytosis (HLH), causes an uncontrolled response by the immune system. HLH typically presents as a persistent fever, usually greater than 101°F, and it can lead to severe problems with blood cells and organs throughout the body such as the liver, kidneys, and lungs.
Lamotrigine is used alone or with other medicines to treat seizures in patients two years and older. It may also be used as maintenance treatment in patients with bipolar disorder to help delay the occurrence of mood episodes such as depression, mania, or hypomania. Stopping lamotrigine without first talking to a prescriber can lead to uncontrolled seizures, or new or worsening mental health problems. Lamotrigine has been approved and on the market for 24 years, and is available under the brand name Lamictal and as generics.
RECOMMENDATION: Healthcare professionals should be aware that prompt recognition and early treatment is important for improving HLH outcomes and decreasing mortality. Diagnosis is often complicated because early signs and symptoms such as fever and rash are not specific. HLH may also be confused with other serious immune-related adverse reactions such as Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS).
Evaluate patients who develop fever or rash promptly, and discontinue lamotrigine if HLH or another serious immune-related adverse reaction is suspected and an alternative etiology for the signs and symptoms cannot be established. Advise patients to seek immediate medical attention if they experience symptoms of HLH during lamotrigine treatment. A diagnosis of HLH can be established if a patient has at least five of the following eight signs or symptoms:
- fever and rash
- enlarged spleen
- elevated levels of triglycerides or low blood levels of fibrinogen
- high levels of blood ferritin
- hemophagocytosis identified through bone marrow, spleen, or lymph node biopsy
- decreased or absent Natural Killer (NK) Cell activity
- elevated blood levels of CD25 showing prolonged immune cell activation
Patients or their caregivers should contact their health care professionals right away if they experience any symptom of HLH while taking lamotrigine. HLH can occur within days to weeks after starting treatment. A physical examination and specific laboratory blood tests and other evaluations are used to diagnose HLH. Signs and symptoms of HLH include but are not limited to:
- enlarged liver; symptoms may include pain, tenderness, or unusual swelling over the liver area in the upper right belly
- swollen lymph nodes
- skin rashes
- yellow skin or eyes
- unusual bleeding
- nervous system problems, including seizures, trouble walking, difficulty seeing, or other visual disturbances
Read the patient Medication Guide, which explains the benefits and risks of lamotrigine, every time you get a new prescription because the information may change. Do not stop taking lamotrigine without talking to your health care professional first as doing so can cause serious problems.
Lamotrigine may cause rashes, including serious rashes that may need to be treated in a hospital or cause permanent disability or death. Tell your doctor if you are taking valproic acid (Depakene) or divalproex (Depakote) because taking these medications with lamotrigine may increase your risk of developing a serious rash. Also tell your doctor if you have ever developed a rash after taking lamotrigine or any other medication for epilepsy or if you are allergic to any medications for epilepsy.
Your doctor will start you on low dose of lamotrigine and gradually increase your dose, not more than once every 1 to 2 weeks. You may be more likely to develop a serious rash if you take a higher starting dose or increase your dose faster than your doctor tells you that you should. Your first doses of medication may be packaged in a starter kit that will clearly show you the right amount of medication to take each day during the first 5 weeks of your treatment. This will help you to follow your doctor's instructions as your dose is slowly increased. Be sure to take lamotrigine exactly as directed. Do not take more or less of it or take it more often than prescribed by your doctor.
Serious rashes usually develop during the first 2 to 8 weeks of treatment with lamotrigine, but can develop at any time during treatment. If you develop any of the following symptoms while you are taking lamotrigine, call your doctor immediately: rash; blistering or peeling of the skin; hives; fever; swelling of the face, throat, tongue, lips, eyes, hands, feet, ankles, or lower legs; hoarseness; difficulty breathing or swallowing; nausea; extreme tiredness; unusual bruising or bleeding; lack of energy; loss of appetite; pain in the upper right part of the stomach; yellowing of the skin or eyes; flu-like symptoms; pale skin; headache; dizziness; fast heartbeat; weakness; shortness of breath; sore throat, fever, chills, and other signs of infection; dark red or cola-colored urine; muscle weakness or aching; or painful sores in your mouth or around your eyes.
Talk to your doctor about the risks of taking lamotrigine or of giving lamotrigine to your child. Children 2-17 years of age who take lamotrigine are more likely to develop serious rashes than adults who take the medication.