Carbamazepine, Eslicarbazepine and Oxcarbazepine linked to potential risk of serious skin reactions associated with the HLA-A* 3101 allele


Carbamazepine ( Tegretol ) is an antiepileptic drug that is indicated for the treatment of generalised tonic clonic seizures. Carbamazepine is also licensed to treat the paroxysmal pain of trigeminal neuralgia and for the prophylaxis of manic-depressive psychosis in patients unresponsive to Lithium therapy.
Oxcarbazepine ( Trileptal ) is indicated for the treatment of partial seizures with or without secondary generalisation and is closely structurally related to Carbamazepine. Eslicarbazepine ( Zebinix ) is the active metabolite of Oxcarbazepine and indicated as adjunctive therapy in adults with partial onset seizures with or without secondary generalisation.

It is well-recognised that severe, potentially life-threatening, skin-related adverse drug reactions, including Stevens-Johnson syndrome ( SJS ) and toxic epidermal necrolysis ( TEN ), can occur rarely in association with Carbamazepine. The frequency of such skin reactions has been estimated to be about one to six cases per 10000 new users of Carbamazepine in the USA and Europe.

Human leukocyte antigens ( HLA ) are involved in some drug-specific abnormal immune responses including SJS and TEN, and the HLA allele HLA-B*1502 is known to be highly associated with Carbamazepine-induced SJS and TEN in certain Asian populations.
MHRA ( Medicines and Healthcare products Regulatory Agency ) informed health professionals in 2008 of the association between Carbamazepine-induced SJS and HLA-B*1502 in patients of Han Chinese, Hong Kong Chinese and Thai origin, with advice to screen these individuals for HLA-B*1502 before starting Carbamazepine treatment.
Since 2008, new study findings have become available suggesting an association with serious skin-related adverse drug reactions, including Stevens-Johnson syndrome, and HLA-B*1502 in other Asian populations. In addition, the clinical utility of HLA-B*1502 screening before starting Carbamazepine treatment has recently been shown in Han Chinese individuals.

More recently, a new genetic marker, HLA-A*3101, has been identified in Japanese individuals and individuals of European descent for serious Carbamazepine-induced cutaneous adverse drug reactions such as SJS, TEN, and drug rash with eosinophilia ( DRESS ), and less severe reactions such as acute generalised exanthematous pustulosis ( AGEP ) and maculopapular rash.

The frequency of HLA-A*3101 varies widely between ethnic populations, with a prevalence of 2-5% in European populations and approximately 10% in the Japanese population. The presence of the HLA-A*3101 allele may increase the risk for Carbamazepine-induced cutaneous reactions ( mostly less severe reactions ) from 5% to 26% in patients of European descent. Its absence may reduce the risk from 5% to 3.8% in patients of European descent. However, the sensitivity of the HLA-A 3101 test for SJS in European and Japanese patients is relatively low ( 5/12 cases [ 42% ] in patients of European descent and 5/6 cases [ 83% ] in Japanese patients ) when compared to the HLA-B*1502 test for SJS ( where sensitivity approaches 100% ). It is also noteworthy that the number of patients included in the HLA-A*3101 studies was small and there are no prospective studies on the clinical utility of HLA-A* 3101 testing in any population.

Currently there are insufficient data supporting a recommendation for HLA-A*3101 screening before starting Carbamazepine or chemically-related medicines. If patients of European descent or Japanese origin are known to be positive for HLA-A*3101, the use of Carbamazepine or chemically related compounds may be considered, but only after careful consideration of the expected benefits of treatment and the increased risk of serious skin conditions.

Data supporting an association of HLA-A *3101 with Oxcarbazepine and Eslicarbazepine-induced skin reactions are very limited but due to their close structural relationship with Carbamazepine and reports of hypersensitivity with cross reactivity, the advice has been extended to cover not only Carbamazepine but also these two structurally related products.

Advice for healthcare professionals

Carbamazepine is associated with a risk of potentially life-threatening skin-related adverse drug reactions, including Stevens-Johnson syndrome. If signs and symptoms suggestive of severe skin reactions appear, treatment should be withdrawn at once and alternative treatment should be considered.
The presence of the HLA-A*3101 allele may increase the risk for Carbamazepine-induced skin reactions in patients of European descent or Japanese origin. If patients of European descent or Japanese origin are known to be positive for HLA A*3101 they should only receive Carbamazepine, Oxcarbazepine, or Eslicarbazepine after careful consideration of the benefits and risks. ( Xagena )

Source: Drug Safety Update, 2012

XagenaMedicine_2012



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