FDA Issues an FDA Alert and Information for Healthcare Professionals Sheet for Carbamazepine
FDA ALERT [12/12/2007]: 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. Genetic tests for HLA-B*1502 are already available. 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 they 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. This new safety information will be reflected in updated product labeling.
This information reflects FDA's current analysis of data available to FDA concerning this drug. FDA intends to update this when additional information or analyses become available.
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.
Healthcare professionals who prescribe carbamazepine products, including Carbatrol, Equetro, Tegretol, and generic carbamazepine, should be fully aware of new prescribing information in the product label and in the revised boxed warning. Following are highlights of the important new safety information (see Drugs@FDA for full prescribing information):
- 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. Prevalence of HLA-B*1502 has
not been studied in many regions of Asia. 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.
Patients who are prescribed carbamazepine:
- 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.
The overall estimated risk of SJS/TEN associated with carbamazepine is based on countries with mainly Caucasian populations, and is fairly low, 1- to 6 per 10,000 new users (Tennis and Stern, 1997; Mockenhaupt et al., 2005). Recently, post-marketing adverse events reported to the World Health Organization (WHO) and carbamazepine manufacturers pointed to a much higher rate of SJS/TEN, about 10 times higher, in some Asian countries. Studies from Taiwan (Hung et al., 2006), Europe (Lonjou et al., 2006), and Hong Kong (Man et al., 2007), indicated that this increased risk of SJS/TEN was associated with HLA-B*1502, an inherited allelic variant of the HLA-B gene found almost exclusively in some individuals across broad areas of Asia, including South Asian Indians.
- Hung et al. (2006) in a case control study in Taiwan found that
of 59 out of 60 patients with SJS/TEN associated with carbamazepine
were positive for HLA-B*1502, far higher than the 4% incidence of
HLA-B*1502 in carbamazepine-tolerant controls. These
findings, combined with postmarketing data on cases per
patient-year exposure, suggest an initial estimate of 5% absolute
risk of SJS/TEN in HLA-B*1502 positive patients exposed to
- Lonjou et al. (2007) in a case series of European patients with
SJS/TEN associated with carbamazepine found that patients with
Asian ancestry were over-represented considering the small
percentage of Asians in the general population. Out of 12
patients, 4 were of Asian ancestry. All four were positive for
- Man et al. (2007) in a case series in patients in Hong Kong found 4 of 4 cases of SJS/TEN associated with carbamazepine in patients positive for HLA-B*1502.
HLA-B*1502 is largely absent in individuals not of Asian origin, and therefore has not been found to be a risk factor for SJS/TEN in Caucasians (Alfirevic et al., 2006).
Carbamazepine is FDA-approved for treatment of epilepsy, mania/bipolar disorder, and neuropathic pain. SJS and TEN are serious blistering reactions of the skin and mucous membranes that can be permanently disabling or fatal.
After review of the information from manufacturers as well as published studies and post-marketing adverse event reports, FDA and the manufacturers have agreed that labeling changes are needed for carbamazepine products.
Information on the association of carbamazepine and SJS/TEN, and information to guide testing for the HLAB*1502 allele in at-risk populations, has been added to the existing boxed warning, and to the sections of the labeling covering warnings, laboratory tests, and adverse reactions.
Alfirevic, A. et al. (2006) HLA-B locus in Caucasian patients with carbamazepine hypersensitivity. Pharmacogenomics, 7(6):813-818.
Hung, S.I. et al. (2006) Genetic susceptibility to carbamazepine-induced cutaneous adverse drug reactions. Pharmacogenet. Genomics, 16(4):297-306.
Lonjou, C., et al. (2006) A marker for Stevens-Johnson syndrome: ethnicity matters. Pharmacogenomics J., 6(4):265-268.
Man, C.B.L. et al. (2007) Association between HLA-B*1502 Allele and Antiepileptic Drug-Induced Cutaneous Reactions in Han Chinese. Epilepsia, 48(5):1015–1018.
Mockenhaupt, M. et al. (2005) Risk of Stevens-Johnson syndrome and toxic epidermal necrolysis in new users of antiepileptics. Neurology. 64(7):1134-1138.
Tennis, P and Stern, R.S. (1997) Risk of serious cutaneous
disorders after initiation of use of phenytoin, carbamazepine, or
sodium valproate: a record linkage study. Neurology,
Posted: December 2007