Information for Healthcare Professionals Phenytoin (marketed as Dilantin, Phenytek and generics) and Fosphenytoin Sodium (marketed as Cerebyx and generics)

FDA ALERT [11/24/08]: FDA is investigating new preliminary data regarding a potential increased risk of serious skin reactions including Stevens Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) from phenytoin therapy in Asian patients positive for a particular human leukocyte antigen (HLA) allele, HLA-B*1502.  This allele occurs almost exclusively in patients with ancestry across broad areas of Asia, including Han Chinese, Filipinos, Malaysians, South Asian Indians, and Thais.   Because fosphenytoin is a prodrug and is converted to phenytoin after administration, any concern regarding this association is also applicable to fosphenytoin.  Phenytoin and fosphenytoin are used to control tonic-clonic (grand mal) and complex-partial seizures in epilepsy.

A recent FDA Information for Healthcare Professionals sheet (12/12/2007) 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 described in the current prescribing information 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.

To report any unexpected adverse or serious events associated with the use of this drug, please contact the FDA MedWatch program and complete a form on line at http://www.fda.gov/medwatch/report/hcp.htm  or report by fax to 1-800-FDA-0178, by mail using the postage-paid address form provided on line, or by telephone to 1-800-FDA-1088.

Information for Healthcare Professionals to Consider when Prescribing Phenytoin or Fosphenytoin:

• Phenytoin is an antiepileptic drug with some structural similarity to another antiepileptic drug, 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 these 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.

More information can be found in the FDA Information for Healthcare Professionals sheet posted on 12/12/2007, (http://www.fda.gov/cder/drug/InfoSheets/HCP/carbamazepineHCP.htm).   

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 and control of your seizures.

 
Data Summary

The following data are currently being analyzed by FDA regarding the risk of serious skin reactions, including SJS/TEN in Asian patients positive for HLA-B*1502 who are treated with phenytoin:

• An article in the May 2008 issue of Epilepsia (Carbamazepine and phenytoin induced Stevens-Johnson syndrome is associated with HLA-B*1502 allele in Thai population) reported that the HLA-B*1502 allele was found in 4 out of 4 patients with SJS associated with phenytoin treatment in a Thai population.  In contrast, the frequency of HLA-B*1502 in the phenytoin-tolerant control group was much lower (18%).  Based on that article, a preliminary estimate of the risk for SJS in Thai patients who are new users of phenytoin and are positive for HLA-B*1502 is approximately 3%.   This compares to a risk estimate at the same epilepsy treatment center of approximately 0.3% in all new phenytoin users.  A previous article in the May 2007 issue of Epilepsia (Association between HLA-B*1502 allele and antiepileptic drug-induced cutaneous reactions in Han Chinese) reported a single case of phenytoin-associated SJS in a Chinese patient in Hong Kong who was positive for HLA-B*1502. 

Because of these new data suggesting a possible association between HLA-B*1502 and phenytoin-induced SJS/TEN, and the known association between phenytoin and SJS/TEN, consideration should be given to avoiding phenytoin as an alternative for carbamazepine in patients positive for HLA-B*1502.
Patients should not stop their seizure control medication without talking with their health care providers.  Patients should be instructed to call their physician if skin rash develops.  Patients being treated with phenytoin or carbamazepine are advised to talk with their health care providers if they have questions about phenytoin or carbamazepine and control of their seizures, or if they have questions about being tested for HLA-B*1502. 

References
Locharernkul, C. et al. (2008) Carbamazepine and phenytoin induced Stevens - Johnson syndrome is associated with the HLAB*1502 allele in Thai population. Epilepsia, Early Online Publication July 14, 2008:1-5  DOI: 10.1111/j.1528-1167.2008.01719.x.

Man C.B.L. et al.   Association between HLA-B*1502 Allele and Antiepileptic Drug-Induced Cutaneous Reactions in Han Chinese. Epilepsia 2007; 48(5):1015-8

To report any unexpected adverse or serious events associated with the use of this drug, please contact the FDA MedWatch program and complete a form on line at http://www.fda.gov/medwatch/report/hcp.htm or report by fax to 1-800-FDA-0178, by mail using the postage-paid address form provided on line, or by telephone to 1-800-FDA-1088.

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Date created: November 24, 2008

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