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December 1, 2023
On November 28, 2023, the Food and Drug Administration (FDA) issued a safety warning[1] for patients taking the oral antiseizure medications levetiracetam (KEPPRA, KEPPRA XR, SPRITAM and generics)[2] and clobazam (ONFI, SYMPAZAN and generics).[3] The FDA warned that these drugs can cause a rare but serious condition called drug reaction with eosinophilia and systemic symptoms (DRESS). The FDA is requiring warnings about this risk in the prescribing information as well as the patient medication guides for both drugs.
DRESS is a multi-organ hypersensitivity reaction. The symptoms include a rash, fever, swollen lymph nodes, and face swelling. DRESS can damage organs, including the heart, kidneys, liver, lungs, and pancreas. DRESS can develop two to eight weeks after starting the medicines, can quickly progress, and can be life-threatening if not diagnosed and treated quickly.
Levetiracetam, which was approved in 1999, is indicated for use alone or in combination with other medicines to control certain types of seizures in children and adults, including partial seizures, myoclonic seizures, and tonic-clonic seizures.[4] The prescribing information already includes warnings for behavioral abnormalities including psychotic symptoms, suicidal ideation, fatigue, and coordination difficulties such as abnormal gait.
Clobazam, which was approved in 2011, is a benzodiazepine. Clobazam is indicated for use in combination with other medications to control seizures in adults and children two years or older with Lennox-Gastaut syndrome, a severe form of epilepsy.[5] Although the alert for DRESS was issued for clobazam, the FDA stated that this reaction was not associated with other medications in this class of drugs.[6]
The prescribing information for clobazam already includes a boxed warning (the most prominent warnings that the agency can require). These include a warning about the concomitant use of benzodiazepine and opioids, which may lead to respiratory depression, profound sedation, coma, and death. Use of benzodiazepines exposes users to risks of abuse, misuse and addiction, also leading to overdose and death. Abrupt discontinuation of clobazam can trigger acute withdrawal reactions that can be life-threatening.
The new warning is based on a review of DRESS cases reported to the FDA’s Adverse Event Reporting System (FAERS) database, as well as cases reported in the medical literature.[7] For levetiracetam, 32 serious cases were reported, of which three occurred in the U.S. All cases required hospitalization; for most patients, symptoms resolved once the drug was discontinued. However, two patients died. For clobazam, 10 serious cases of DRESS were reported, of which one occurred in the U.S. All 10 patients were hospitalized; in all patients, symptoms resolved once the drug was discontinued. No deaths associated with DRESS were reported.
If you are taking levetiracetam or clobazam and develop symptoms of DRESS, seek immediate medical attention, such as at an emergency room.[8] Do not stop taking levetiracetam or clobazam without talking to your clinician, as stopping these medicines suddenly can trigger uncontrolled seizures. Prompt recognition of DRESS by health care professionals and early treatment are essential to improve outcomes and decrease mortality.
To see the FDA’s warning, visit the following links:
1) https://www.fda.gov/safety/medical-product-safety-information/antiseizure-medicines-keppra-keppra-xr-elepsia-xr-spritam-levetiracetam-and-onfi-sympazan-clobazam#:~:text=ISSUE%3A%20The%20FDA%20is%20warning,not%20diagnosed%20and%20treated%20quickly.
2) https://www.fda.gov/drugs/drug-safety-and-availability/fda-warns-rare-serious-drug-reaction-antiseizure-medicines-levetiracetam-keppra-keppra-xr-elepsia-xr
References
[1] Food and Drug Administration. Antiseizure Medicines Keppra, Keppra XR, Elepsia XR, Spritam (levetiracetam) and Onfi, Sympazan (clobazam): Drug Safety Communication - FDA Warns of Rare but Serious Drug Reaction. November 28, 2023. https://www.fda.gov/safety/medical-product-safety-information/antiseizure-medicines-keppra-keppra-xr-elepsia-xr-spritam-levetiracetam-and-onfi-sympazan-clobazam. Accessed November 29, 2023.
[2] UCB. Label: levetiracetam (KEPPRA). August 2023. https://www.accessdata.fda.gov/drugsatfda_docs/label/2023/021035s113,021505s052lbl.pdf. Accessed November 29, 2023.
[3] Lundbeck. Label: clobazam (ONFI). January 2023. https://www.accessdata.fda.gov/drugsatfda_docs/label/2023/202067s007,203993s009lbl.pdf. Accessed November 29, 2023.
[4] UCB. Label: levetiracetam (KEPPRA). August 2023. https://www.accessdata.fda.gov/drugsatfda_docs/label/2023/021035s113,021505s052lbl.pdf. Accessed November 29, 2023.
[5] Lundbeck. Label: clobazam (ONFI). January 2023. https://www.accessdata.fda.gov/drugsatfda_docs/label/2023/202067s007,203993s009lbl.pdf. Accessed November 29, 2023.
[6] Food and Drug Administration. Antiseizure Medicines Keppra, Keppra XR, Elepsia XR, Spritam (levetiracetam) and Onfi, Sympazan (clobazam): Drug Safety Communication - FDA Warns of Rare but Serious Drug Reaction. November 28, 2023. https://www.fda.gov/safety/medical-product-safety-information/antiseizure-medicines-keppra-keppra-xr-elepsia-xr-spritam-levetiracetam-and-onfi-sympazan-clobazam. Accessed November 29, 2023.
[7] Food and Drug Administration. FDA Drug Safety Communication. November 28, 2023. https://www.fda.gov/drugs/drug-safety-and-availability/fda-warns-rare-serious-drug-reaction-antiseizure-medicines-levetiracetam-keppra-keppra-xr-elepsia-xr. Accessed November 30, 2023.
[8] Food and Drug Administration. Antiseizure Medicines Keppra, Keppra XR, Elepsia XR, Spritam (levetiracetam) and Onfi, Sympazan (clobazam): Drug Safety Communication - FDA Warns of Rare but Serious Drug Reaction. November 28, 2023. https://www.fda.gov/safety/medical-product-safety-information/antiseizure-medicines-keppra-keppra-xr-elepsia-xr-spritam-levetiracetam-and-onfi-sympazan-clobazam. Accessed November 29, 2023.
