Clinical Context

The exact mechanism of action of clobazam, a 1,5-benzodiazepine, is not completely understood. However, it is thought to involve potentiation of GABAergic (γ-aminobutyric acid) neurotransmission via binding at the benzodiazepine site of the GABA_A receptor.

In 2011, the US Food and Drug Administration (FDA) approved clobazam as adjunctive therapy to treat seizures that accompany Lennox-Gastaut syndrome, a severe form of epilepsy, in patients who are at least 2 years old.

According to the FDA, benzodiazepines other than clobazam generally are not associated with serious skin reactions.

Study Synopsis and Perspective

The antiseizure drug clobazam (Onfi) can trigger rare but potentially fatal skin reactions, the FDA announced. The risk for these serious skin reactions is now described in FDA-approved changes to the Onfi drug label and the patient Medication Guide.

The agency approved clobazam, a benzodiazepine, in 2011 as an add-on therapy to treat seizures that accompany a severe form of epilepsy called Lennox-Gastaut syndrome. The FDA said that other benzodiazepines generally are not associated with serious skin reactions.

For clobazam, the skin reactions to watch for are Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), which may result in permanent harm or death. Patients taking clobazam can experience these disorders at any time, but the risk increases during the first 8 weeks of treatment or when treatment resumes after it was stopped. All of the cases of these 2 adverse events identified by the FDA landed patients in the hospital, with 1 patient going blind and another dying.

The FDA advises clinicians to closely monitor patients taking clobazam for SJS and TEN, especially at the start of therapy or when the drug is reintroduced. Signs and symptoms include rashes, blistered or peeling skin, mouth sores, and hives. Clobazam should be halted at the first appearance of a rash, and if other signs and symptoms point to a serious skin reaction, the therapy should not be resumed.

Clinicians also should instruct patients taking clobazam to seek medical care immediately if they spot a rash or some other sign of hypersensitivity, according to the FDA. However, patients should not stop taking clobazam without first consulting their healthcare provider, because suddenly halting treatment on their own can trigger serious withdrawal problems such as persistent seizures, nervousness, and hallucinations.

More information on the FDA safety change regarding clobazam is available on the FDA Web site.

To report problems with clobazam, contact MedWatch, the FDA's safety information and adverse event reporting program, by telephone at 1-800-FDA-1088; by fax at 1-800-FDA-0178; online at https://www.accessdata.fda.gov/scripts/medwatch/medwatch-online.htm; with postage-paid FDA form 3500, available at http://www.fda.gov/MedWatch/getforms.htm; or by mail to MedWatch, 5600 Fishers Lane, Rockville, Maryland 20852-9787.

Laurie Barclay, MD, has contributed to this synopsis.

Clinical Implications

• The FDA announced that clobazam can cause rare skin reactions potentially resulting in permanent harm and even death. FDA-approved changes to the Onfi drug label and the patient Medication Guide now describe the risk for serious adverse skin events of SJS and TEN.
• Dermatologic signs and symptoms caused by clobazam may include rashes, blistered or peeling skin, mouth sores, and hives. SJS and TEN may occur at any time during treatment with clobazam, but the risk is highest during the first 8 weeks of treatment or when treatment is resumed after discontinuation. All cases of clobazam-induced SJS and TEN identified by the FDA required hospitalization. One of these cases resulted in blindness and a second case in death.
• Monitoring for skin reactions in patients treated with clobazam is particularly important when therapy is initiated or reintroduced. At the first appearance of a rash, clobazam should be stopped. Treatment should not be resumed if there is other evidence of a serious skin reaction. Clinicians should advise patients who experience a rash or some other sign of hypersensitivity while taking clobazam to seek medical attention immediately.

CME Test