Medication Safety Alert

December 12, 2007

ISSUE:	Increased incidence of serious skin reactions (Stevens Johnson syndrome and toxic epidermal necrolysis) with carbamazepine among patients with the HLA-B*1502 allele which occurs almost exclusively in people with Asian ancestry
MEDICATIONS:	Carbamazepine (Carbatrol®, Equetro®, Tegretol® and generics), available as oral tablets, capsules, suspension and extended release formulations

The following was posted on FDA Med Watch alert website dated December 12, 2007:
"FDA informed healthcare professionals that dangerous or even fatal skin reactions (Stevens Johnson syndrome and toxic epidermal necrolysis), that can be caused by carbamazepine therapy, are significantly more common in patients with 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 South Asian Indians. Patients with ancestry from areas in which HLA-B*1502 is present should be screened for the HLA-B*1502 allele before starting treatment with carbamazepine. If these individuals test positive, carbamazepine should not be started unless the expected benefit clearly outweighs the increased risk of serious skin reactions. Patients who have been taking carbamazepine for more than a few months without developing skin reactions are at low risk of these events ever developing from carbamazepine. This is true for patients of any ethnicity or genotype, including patients positive for HLA-B*1502.

An excerpt of the FDA’s “Information for Healthcare Professionals” from 12/12/2007 states:
"Healthcare professionals who prescribe carbamazepine products, should be fully aware of new prescribing information in the product label and in the revised boxed warning.

The risk of Stevens Johnson syndrome (SJS)/toxic epidermal necrolysis (TEN) from carbamazepine is significantly increased in patients positive for the HLA-B*1502 allele. This allele is found almost exclusively in patients with ancestry across broad areas of Asia, including South Asian Indians. Due to wide variability in rates of HLA-B*1502 even within ethnic groups, the difficulty in ascertaining ethnic ancestry, and the likelihood of mixed ancestry, screening for HLA-B*1502 should be performed for most patients of Asian ancestry. The following figures must therefore be considered no more than a rough guide in deciding which patients to screen:

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

Patients with ancestry in at-risk populations should be screened for the HLA-B*1502 allele prior to starting carbamazepine. Patients who test positive for HLA-B*1502 should not be treated with carbamazepine unless the expected benefit clearly outweighs the increased risk of SJS/TEN. Tested patients who are found to be negative for HLA-B*1502 have a low risk of SJS/TEN from carbamazepine, but SJS/TEN can still rarely occur, so healthcare professionals should still watch for symptoms in these patients. Patients who test positive for HLA-B*1502 may be at increased risk of SJS/TEN from other antiepileptic drugs that have been associated with SJS/TEN. Therefore, in HLA-B*1502 positive patients, doctors should consider avoiding use of other antiepileptic drugs associated with SJS/TEN when alternative therapies are equally acceptable.

Over 90% of carbamazepine treated patients who will experience SJS/TEN have this reaction within the first few months of treatment. Patients of any ethnicity or genotype (including HLA-B*1502 positive) who have been taking carbamazepine for more than a few months are at low risk of SJS/TEN from carbamazepine.

Information for the patient: Physicians who are prescribing carbamazepine products should ensure that their patients or their caregivers understand the following:

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.

• If you and your doctor decide that, in your case, the benefits of starting carbamazepine outweigh possible risks, then you should watch for any sign of a rash. If you see any sign of a rash, then you should contact your doctor immediately."