The FDA has issued a drug safety communication that the epilepsy, and bipolar medication lamotrigine (Lamictal) can cause a rare, serious adverse effect known as hemophagocytic lymphohistiocytosis (HLH). HLH can cause severe inflammation throughout the body and lead to hospitalization and death. Additionally, the FDA is requiring that a new warning about the risk of HLH be added to the lamotrigine prescribing information.1
Pharmacists can play an important role in counseling patients taking lamotrigine about this adverse effect. Pharmacists can educate physicians, and other healthcare professionals about signs and symptoms of HLH, and the importance of early identification of this serious adverse effect. Treatment options for HLH include steroids, intravenous immunoglobulin, blood products, and chemotherapy.
Signs and symptoms of HLH include the following:
- Fever greater than 101°F
- Enlarged liver with symptoms of pain, tenderness, or unusual swelling over the liver area in upper right belly
- Swollen lymph nodes
- Skin rashes
- Yellow skin or eyes
- Unusual bleeding
- Nervous system problems including seizures, difficulty walking, and vision problems
Pharmacists should advise patients to seek medical attention immediately if they experience any of the above symptoms while taking lamotrigine. It is important to note that HLH can occur within days to weeks after initiating therapy. Therefore, it is especially important to target new lamotrigine prescriptions, and follow up with these patients through a phone or face-to-face consult. Pharmacists should also report possible HLH cases to the FDA’s Medwatch program, and document the lamotrigine start date, signs and symptoms, and dose.
HLH is diagnosed if a patient has at least 5 of the following 8 signs and symptoms:1
- Fever and rash
- Enlarged spleen
- Elevated triglycerides or low fibrinogen blood levels
- High levels of blood ferritin
- Hemophagocytosis identified through bone marrow, spleen, or lymph node biopsy
- Decreased or absent Natural Killer (NK) Cell activity (immune cell with enzymes that can kill tumor cells)
- Elevated blood levels of CD25 demonstrating prolonged immune cell activation
Patients diagnosed with HLH should receive a hematologist consult.
There have been 8 cases worldwide of confirmed or suspected HLH associated with lamotrigine therapy in adults and children since its approval in 1994, reported through the FDA, and medical literature.1 Two cases occurred in the United States, and 6 internationally. Five cases had confirmed HLH meeting 5 of the 8 diagnostic criteria, while 3 had suspected HLH. There were serious outcomes reported with all cases, including hospitalization, and death.
HLH symptoms began within 24 days of starting lamotrigine therapy, which establishes a temporal relationship. Doses ranged from 25 mg every other day to 250 mg once daily.1 After treatment and discontinuing lamotrigine, HLH improved in 7 cases.
The 8 cases had the following signs and symptoms:1
- Fever (8 patients)
- Thrombocytopenia (8 patients)
- Hyperferritinemia (8 patients)
- Hypofibrinogenemia (5 patients)
- Splenomegaly (3 patients)
- Anemia (3 patients)
- Hypertriglyceridemia (2 patients)
- Low or absent NK cells (1 patient)
- Neutropenia (1 patient)
- U.S. Food and Drug Administration. FDA drug safety communication: FDA warns of serious immune system reaction with seizure and mental health medicine lamotrigine (Lamictal). www.fda.gov/Drugs/DrugSafety/ucm605470.htm. Accessed May 9, 2018.