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U.S. Department of Health and Human Services
National Pharmacy & Therapeutics Committee

Rare Serious Side Effect Associated with Levetiracetam and Clobazam

The FDA is warning that the anti-seizure medicines levetiracetam (brand names: Keppra®, Keppra XR®, Elepsia XR®, Spritamand®) and clobazam (brand names: Onfi® and Sympazan®) can cause a rare but serious life-threatening reaction called Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS).

  • Levetiracetam is an antiseizure medicine indicated for use alone or in combination with other medicines to control certain types of seizures in adults and children such as partial seizures, myoclonic seizures, or tonic-clonic seizures.
  • Clobazam is a benzodiazepine indicated for use in combination with other medicines to control seizures in adults and children 2 years and older who have a specific severe form of epilepsy called Lennox-Gastaut syndrome.
  • DRESS is a rare hypersensitivity reaction that may start as a rash but can quickly progress, resulting in injury to internal organs, the need for hospitalization, and even death if not diagnosed and treated quickly. Symptoms of DRESS may include:
    • fever
    • rash (not always present)
    • swollen lymph nodes
    • eosinophilia (often but not always present)
    • injury to organs (hepatitis, myocarditis, pericarditis, pancreatitis, nephritis, and pneumonitis)

Several serious cases of DRESS in children and adults were reported worldwide to the FDA through the FDA MedWatch program or discovered in the medical literature. Most patients in these cases required hospitalization and received medical treatments; two patients treated with levetiracetam died.

Levetiracetam     32 cases worldwide     est. 12 million prescriptions dispensed in U.S.
Clobazam           10 cases worldwide      est. 779,000 prescriptions dispensed in U.S.

Recommendations for Healthcare Providers

Be aware that prompt recognition and early treatment is important for improving DRESS outcomes and decreasing mortality

  • DRESS can develop 2 weeks to 8 weeks after starting the medicines, and symptoms and intensity can vary widely
  • DRESS can be confused with other serious skin reactions such as SJS and TEN
  • If DRESS is suspected, discontinue levetiracetam or clobazam immediately and restart only if an alternative etiology for the signs or symptoms cannot be established
  • Important ways to manage DRESS are early recognition, discontinuation of the offending agent as soon as possible, supportive care, and/or other interventions commonly used to treat DRESS such as systemic corticosteroids.

To help FDA track safety issues with levetiracetam, clobazam, and others, please report adverse events to the MedWatch program. Instructions for reporting can be found online at the NPTC Pharmacovigilance website - please enter "IHS" in section G of the form.

The complete Drug Safety Communication can be viewed on the FDA website.