FDA Issues Warning about Seizure Medications

The FDA is warning that antiseizure medicines that contain levetiracetam (including Keppra, Keppra XR, Elepsia XR and Spritam) and clobazam (including Onfi and Sympazan) can cause a rare but serious reaction that can be life-threatening. This reaction is called drug reaction with eosinophilia and systemic symptoms (DRESS), a rare and severe drug allergy. Symptoms can include fever, rash, facial swelling, enlarged lymph nodes and kidney or liver injury. Patients with DRESS have a large number of abnormal eosinophils.

Levetiracetam is an antiseizure medicine approved for use alone or with other medicines to control certain types of seizures. It has been FDA-approved for 24 years and is available in multiple formulations under the brand names Keppra, Keppra XR, Elepsia XR, and Spritam, and as generics. Clobazam is a type of medicine called a benzodiazepine that is FDA-approved for use with other medicines to control seizures associated with a specific severe form of epilepsy called Lennox-Gastaut Syndrome.

In 2022, an estimated 12 million levetiracetam prescriptions were dispensed from U.S. outpatient pharmacies, according to IQVIA. In 2022, an estimated 779,000 clobazam prescriptions were dispensed from U.S. outpatient pharmacies.

The FDA is requiring that manufacturers add new warnings to prescribing information and medications guides. The warnings for both medications will include information about the early symptoms of DRESS such as fever or swollen lymph nodes. Additionally, for levetiracetam, an addition to the Warnings and Precautions section of the prescribing information will describe the most serious and significant potential safety issues. For clobazam, the regulatory agency is requiring a new warning specifically about DRESS to be added to the prescribing information.

The changes in labeling are a result of a review by regulators of the literature and of the FDA Adverse Event Reporting System database. This review found several cases of DRESS in children and adults worldwide, including 32 in patients treated with levetiracetam and 10 in patients treated with clobazam. Two patients treated with levetiracetam died. Most patients in these cases were hospitalized, and in the majority of cases for which the FDA had information DRESS symptoms improved when the medicines were discontinued.

The FDA had warned about the association of levetiracetam and suicidal behavior and ideation. The FDA has also warned about the risks of combining clobazam opioid pain or cough medicines and about withholding opioid addiction medicines from patients taking benzodiazepines, as well as about other rare but serious skin reactions including Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN).