FDA Investigates Genetic Link to Phenytoin Skin Reactions

Yael Waknine


November 25, 2008

November 25, 2008 — Patients positive for the human leukocyte antigen (HLA) allele HLA-B*1502 may be at increased risk for phenytoin-induced Stevens-Johnson syndrome and toxic epidermal necrolysis (SJS/TEN), the US Food and Drug Administration announced today.

Phenytoin is an antiepileptic drug with some structural similarity to carbamazepine, which was recently linked to an increased risk for SJS/TEN in patients positive for the allele. The allele occurs almost exclusively in individuals of Asian ancestry (Han Chinese, Filipinos, Malaysians, South Asian Indians, and Thais).

While the FDA is working to identify additional information regarding this issue, clinicians are advised to consider avoiding phenytoin and fosphenytoin as alternatives to carbamazepine therapy in patients who test positive for the allele.

However, there is not yet enough information to recommend testing for HLA-B*1502 in Asian patients for whom phenytoin treatment is contemplated, according to an alert sent from MedWatch, the FDA's safety information and adverse event reporting program.

Preliminary data published in the May 2008 issue of Epilepsia suggest that the preliminary estimate of SJS risk in allele-positive patients new to phenytoin therapy is about 3% vs 0.3% for new users overall. In the study, all 4 patients with phenytoin-associated SJS were found to be positive for the HLA-B*1502 allele compared with 18% of those in the phenytoin-tolerant group. In addition, a May 2007 article in the same journal identified a single case of SJS in a Chinese patient who tested positive for the allele.

Phenytoin and its prodrug, fosphenytoin, are used to control tonic-clonic (grand-mal) and complex-partial epileptic seizures. Phenytoin is marketed as Dilantin (Pfizer Pharmaceuticals, Inc) and Phenytek (Mylan Pharmaceuticals, Inc). Fosphenytoin is marketed as Cerebyx (Pfizer); both products are also available in generic formulations from several manufacturers.

Adverse events related to use of carbamazepine should be communicated to the FDA's MedWatch reporting program by telephone at 1-800-FDA-1088, by fax at 1-800-FDA-0178, online at http://www.fda.gov/medwatch, or by mail to 5600 Fishers Lane, Rockville, Maryland 20852-9787.


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