Recent FDA information for healthcare professionals described an increased risk of SJS/TEN with another antiepileptic drug, carbamazepine, in Asian ancestry patients with the HLA-B*1502 allele.

The FDA is working to identify additional information to evaluate the possible risk of SJS/TEN from phenytoin and fosphenytoin in patients with HLA-B*1502. Until the evaluation is completed, healthcare providers who are considering the use of phenytoin or fosphenytoin, should be aware of the risks and benefits for this drug.

Because this new data suggests a possible association between HLA-B*1502 and phenytoin or fosphenytoin-induced SJS/TEN, and because of the known association between phenytoin and SJS/TEN, healthcare providers should consider avoiding phenytoin and fosphenytoin as alternatives for carbamazepine in patients who test positive for HLA-B*1502.

Information for healthcare professionals to consider when prescribing phenytoin or fosphenytoin:

Phenytoin is an antiepileptic drug with some structural similarity to carbamazepine. Labeling for carbamazepine was recently updated to reflect an increased risk of serious skin reactions, including SJS/TEN, in Asian patients who had recently started taking carbamazepine and who tested positive for HLA-B*1502.

It is estimated that 10-15% or more of patients may carry the HLA-B*1502 allele in parts of China, Thailand, Malaysia, Indonesia, the Philippines, and Taiwan. South Asians, including Indians, appear to have an intermediate chance of having HLA-B*1502, averaging 2 to 4%, but it is higher in some groups. HLA-B*1502 appears to be present at a low frequency (<1%) in Japan and Korea.

New preliminary data suggests that phenytoin may carry a risk of serious skin reactions in some Asian patients who tested positive for HLA-B*1502, similar to the risk carried by carbamazepine. Because fosphenytoin is a prodrug and is converted to phenytoin after administration, any concern regarding this association with phenytoin is also applicable to fosphenytoin.

The carbamazepine label now recommends that testing for HLA-B*1502 be performed prior to initiating carbamazepine therapy in patients with ancestry in populations in which the allele may be present. In patients who test positive for the allele, carbamazepine should not be used unless the benefits clearly outweigh the risks.

Because this new data suggest a possible association between HLA-B*1502 and phenytoin-induced SJS, and because of the known association between phenytoin and SJS/TEN, the FDA is advising that healthcare providers consider avoiding phenytoin as an alternative to carbamazepine in patients positive for HLA-B*1502.

The possible risk of SJS from phenytoin and fosphenytoin in patients with HLA-B*1502 is still being studied; however, there is not yet enough information to recommend testing for HLA-B *1502 in Asian patients for whom phenytoin treatment is contemplated.

Of carbamazepine-treated patients who experience a serious skin reaction, over 90% have this reaction within the first few months of treatment. Patients who have been taking carbamazepine for more than a few months, without developing skin reactions, are at low risk of developing this reaction. Similarly, the risk for serious skin reaction with phenytoin therapy appears to be greatest in the first few months of therapy.

Information for patients taking phenytoin or fosphenytoin to consider:

If you have been previously prescribed carbamazepine to control seizures, then you might have had a test for a gene or “allele”, called HLA-B*1502, that can help to predict whether you might be at risk for a serious skin reaction from the drug. Phenytoin and fosphenytoin may carry a similar risk of serious skin reactions in some Asian patients who test positive for HLA-B*1502.

Having HLA-B*1502 is not abnormal, and there is no other known risk from having the allele.

Uncontrolled seizures are a serious risk. You should not stop your seizure control medication without talking with your physician. If you develop a skin rash while taking phenytoin, fosphenytoin, or carbamazepine, you should immediately contact your physician and receive advice before taking another dose of these medications. You should talk with your physician if you have any questions about phenytoin, fosphenytoin, or carbamazepine.

Patients for whom a genetic test is recommended:

Different people sometimes respond differently to drugs. Some people with Asian ancestry are at greater risk for dangerous skin reactions when first starting treatment with carbamazepine. We can test for a risk factor for such reactions, which is called HLA-B*1502, before giving carbamazepine.

Tests for HLA-B*1502 are already used to check for compatibility before tissue transplants.

Having HLA-B*1502 is not abnormal, and there is no other known risk from having it.

If you test positive for HLA-B*1502, then your doctor will take that into account for your medical care.

If you test negative for HLA-B*1502, you are at lower risk of dangerous skin reactions when first starting carbamazepine, but dangerous skin reactions could still occur, and you still should be watchful.