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FDA Updates Carbamazepine Label to Urge Genetic Testing for Rare Skin Reactions

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The US Food and Drug Administration last week asked sponsors to update the labeling for carbamazepine — a treatment for epilepsy, bipolar disorder, and neuropathic pain — to recommend that patients of Asian ancestry receive genetic testing to reduce an increased risk of developing rare but fatal skin reactions.
 
“Studies have found a strong association between certain serious skin reactions and an inherited variant of a gene, HLA-B*1502, an immune system gene, found almost exclusively in people with Asian ancestry,” the FDA said in a health alert. “Patients testing positive for this gene should not be treated with carbamazepine unless the benefit clearly outweighs the increased risk of these serious skin reactions.”
 
The drug is sold by Shire Pharmaceuticals as Carbatrol, by Validus Pharmaceuticals as Equetro, and by Novartis as Tegretol. There are also generic versions of the drug available.
 
The label for carbamazepine previously included a general warning for all patients of rare but sometimes life-threatening skin reactions, known as Stevens-Johnson syndrome and toxic epidermal necrolysis (SJS/TEN). These reactions can manifest themselves in the form of skin lesions, blisters, fever, and itching.
 
Upon the FDA’s request, the manufacturers of carbamazepine have agreed to add a boxed warning to the drug’s labeling highlighting that patients of Asian ancestry should get a genetic test prior to starting therapy.
 
This latest regulatory action updating carbamazepine’s label with genetic testing information follows similar actions for the anticoagulant warfarin, the acute lymphocytic leukemia drug 6-mercaptopurine, and Pfizer’s colorectal cancer agent Camptosar (irinotecan).
 
However, compared to the labeling update for irinotecan and warfarin — in which the FDA did not outright recommend genetic testing but merely explained how certain genetic polymorphisms might influence patients’ response to the drugs — the agency uses much stronger language in carbamazepine’s label. 
 
The boxed warning at the top of carbamazepine’s label states: “Patients with ancestry in genetically at-risk populations should be screened for the presence of HLA-B*1502 prior to initiating treatment with [carbamazepine]. Patients testing positive for the allele should not be treated with [the drug] unless the benefit clearly outweighs the risk.”
 
Currently “there is no test that we know of for the specific” HLA-B*1502 allele, an FDA spokesperson told Pharmacogenomics Reporter this week. “However, laboratory professionals have told FDA that they can screen for this by using general HLA typing.”
 
The FDA has approved tests for general HLA typing. According to FDA’s Center for Biologics Evaluation and Research, BD Biosciences, Dynal Biotech, GTI, One Lambda, Pel-Freez Clinical, Tepnel Lifecodes, and Texas BioGene all have 510(k)-cleared tests in this area.
 
In most cases, however, only specialized CLIA-certified labs with expertise running this type of high-complexity assay will be able to conduct testing for the HLA-B*1502 allele. “We’ve been told by labs such as Laboratory Corporation of America and Quest that they could accommodate such testing,” the FDA spokesperson said.
 
Rare, But Serious
 
According to the FDA, the agency decided to update the label for carbamazepine based on adverse-event reports, information from drug sponsors, and published studies.
 
The overall estimated risk of SJS/TEN associated with carbamazepine is based on countries with mainly Caucasian populations. The incidence in such populations is fairly low, approximately 1 to 6 cases per 10,000 new users, the FDA reported.
 
However, recent post-marketing adverse event reports to the World Health Organization and to carbamazepine manufacturers signal about a 10-fold higher rate of SJS/TEN in some Asian locales such as Taiwan and Hong Kong, as well as certain European countries. In these places, studies associated the HLA-B*1502 polymorphism with an increased risk of serious skin reactions in people of Asian descent.
 

“We’ve been told by labs such as Laboratory Corporation of America and Quest that they could accommodate such testing.”

The FDA cited several studies in support of this labeling update. For instance, Hung et al., a case control study in Taiwan, found that of 59 out of 60 patients with carbamazepine-associated SJS/TEN tested positive for HLA-B*1502, a higher incidence than the 4 percent incidence of HLA-B*1502 in carbamazepine-tolerant controls.
 
“These findings, combined with post-marketing data on cases per patient-year exposure, suggest an initial estimate of 5 percent absolute risk of SJS/TEN in HLA-B*1502 positive patients exposed to carbamazepine,” the FDA said in the health alert.
 
Similarly, Man et al., a study of patients in Hong Kong, reported that all of the four cases of SJS/TEN linked to carbamazepine occurred in patients positive for HLA-B*1502.
 
In the European study Lonjou et al., SJS/TEN cases related to carbamazepine were seen increasingly in patients of Asian ancestry in relation to the small percentage of Asians in the general population. In the study, out of 12 patients with SJS/TEN, four were of Asian ancestry. All four tested positive for HLA-B*1502.
 
Since HLA-B*1502 is not present in non-Asian populations, no allele-related risk of SJS/TEN has been found in Caucasians, the FDA said.
 
Recommendations
 
Given that between 10 to 15 percent of patients from China, Thailand, Malaysia, Indonesia, Taiwan, and the Philippines may carry the HLA-B*1502 mutation, the FDA recommends that patients in these at-risk groups be screened for the polymorphism prior to starting carbamazepine treatment.
 
Additionally, South Asians, including Indians, are found to have an “intermediate prevalence” of HLA-B*1502, averaging an incidence rate of between 2 percent to 4 percent or higher. In Japan and Korea, the HLA-B*1502 allele is found in less than 1 percent of the population.
 
“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,” the FDA said in a healthcare alert.
 
While HLA-B*1502-negative patients have a low risk of developing SJS/TEN from carbamazepine, these skin reactions can still occur in rare cases. For this reason, the FDA advises healthcare professionals to still monitor for such symptoms in HLA-B*1502-negative patients.
 
HLA-B*1502-positive patients may also be at increased risk of SJS/TEN from other antiepileptic drugs associated with the conditions. So, the FDA advises doctors to consider prescribing acceptable treatment alternatives to antiepileptic drugs associated with SJS/TEN for this group of patients.
 
Additionally, more than 90 percent of carbamazepine-treated, HLA-B*1502-positive patients who have been taking the drug for more than a few months and have not had skin reactions are at low risk of SJS/TEN from carbamazepine, the FDA states.

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