Carbamazepine - Warnings and Precautions

WARNINGS Serious Dermatologic Reactions Serious and sometimes fatal dermatologic reactions, including toxic epidermal necrolysis (TEN) and Stevens-Johnson syndrome (SJS), have been reported with carbamazepine treatment.

The risk of these events is estimated to be about 1 to 6 per 10,000 new users in countries with mainly Caucasian populations.

However, the risk in some Asian countries is estimated to be about 10 times higher.

Carbamazepine extended-release capsules should be discontinued at the first sign of a rash, unless the rash is clearly not drug-related.

If signs or symptoms suggest SJS/TEN, use of this drug should not be resumed and alternative therapy should be considered.

SJS/TEN and HLA-B*1502 Allele Retrospective case-control studies have found that in patients of Chinese ancestry there is a strong association between the risk of developing SJS/TEN with carbamazepine treatment and the presence of an inherited variant of the HLA-B gene, HLA-B*1502.

The occurrence of higher rates of these reactions in countries with higher frequencies of this allele suggests that the risk may be increased in allele-positive individuals of any ethnicity.

Across Asian populations, notable variation exists in the prevalence of HLA-B*1502.

Greater than 15% of the population is reported positive in Hong Kong, Thailand, Malaysia, and parts of the Philippines, compared to about 10% in Taiwan and 4% in North China.

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 is present in <1% of the population in Japan and Korea.

HLA-B*1502 is largely absent in individuals not of Asian origin (e.g., Caucasians, African-Americans, Hispanics, and Native Americans).

Prior to initiating carbamazepine extended-release capsules therapy, testing for HLA-B*1502 should be performed in patients with ancestry in populations in which HLA-B*1502 may be present.

In deciding which patients to screen, the rates provided above for the prevalence of HLA-B*1502 may offer a rough guide, keeping in mind the limitations of these figures due to wide variability in rates even within ethnic groups, the difficulty in ascertaining ethnic ancestry, and the likelihood of mixed ancestry.

Carbamazepine extended-release capsules should not be used in patients positive for HLA-B*1502 unless the benefits clearly outweigh the risks.

Tested patients who are found to be negative for the allele are thought to have a low risk of SJS/TEN (see WARNINGS and PRECAUTIONS/Laboratory Tests ).

Over 90% of carbamazepine treated patients who will experience SJS/TEN have this reaction within the first few months of treatment.

This information may be taken into consideration in determining the need for screening of genetically at-risk patients currently on carbamazepine extended-release capsules.

The HLA-B*1502 allele has not been found to predict risk of less severe adverse cutaneous reactions from carbamazepine, such as maculopapular eruption [MPE] or to predict Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS).

Limited evidence suggests that HLA-B*1502 may be a risk factor for the development of SJS/TEN in patients of Chinese ancestry taking other anti-epileptic drugs associated with SJS/TEN, including phenytoin.

Consideration should be given to avoiding use of other drugs associated with SJS/TEN in HLA-B*1502 positive patients, when alternative therapies are otherwise equally acceptable.

Patients should be made aware that carbamazepine extended-release capsules contains carbamazepine and should not be used in combination with any other medications containing carbamazepine.

Hypersensitivity Reactions and HLA-A*3101 Allele Retrospective case-control studies in patients of European, Korean, and Japanese ancestry have found a moderate association between the risk of developing hypersensitivity reactions and the presence of HLA-A*3101, an inherited allelic variant of the HLA-A gene, in patients using carbamazepine.

These hypersensitivity reactions include SJS/TEN, maculopapular eruptions, and Drug Reaction with Eosinophilia and Systemic Symptoms (see DRESS/Multiorgan hypersensitivity below).

HLA-A*3101 is expected to be carried by more than 15% of patients of Japanese, Native American, Southern Indian (e.g., Tamil Nadu) and some Arabic ancestry; up to about 10% in patients of Han Chinese, Korean, European, Latin American and other Indian ancestry; and up to about 5% in African-Americans and patients of Thai, Taiwanese, and Chinese (Hong Kong) ancestry.