Carbamazepine

Carbamazepine (brand names Tegretol, Tegretol XR, Carbatrol) is an anticonvulsant medication used primarily for the treatment of epilepsy and bipolar disorder.

It is indicated for the management of partial seizures, generalized tonic-clonic seizures, and mixed seizure patterns. Additionally, carbamazepine is approved for the acute treatment of manic or mixed episodes in bipolar disorder and for relieving trigeminal neuralgia.

Carbamazepine exerts its therapeutic effect by blocking voltage-gated sodium channels in neurons, stabilizing the inactive state of these channels, and reducing the propagation of abnormal electrical discharges in the brain.

The primary gene of interest for carbamazepine pharmacogenetics is HLA-B, which encodes a human leukocyte antigen class I protein responsible for presenting peptide antigens to the immune system.

Certain variants of HLA-B, such as HLA-B*15:02, do not affect drug metabolism or transport but can trigger inappropriate immune responses when carbamazepine is administered, leading to severe cutaneous adverse reactions. Understanding these variants helps in predicting patients at risk.

Patients who carry the HLA-B*15:02 allele have a markedly increased risk of serious skin reactions like Stevens–Johnson syndrome (SJS) or toxic epidermal necrolysis (TEN) when treated with carbamazepine, whereas non-carriers have the standard risk profile.

HLA-B*15:02 Positive (Carrier)

• Effect on drug levels: No change in metabolism but increased risk of immune-mediated reactions
• Clinical consequence: High risk of severe cutaneous adverse reactions (SJS/TEN)
• Side effects: Severe skin reactions (Stevens–Johnson syndrome and toxic epidermal necrolysis), potentially life-threatening

HLA-B*15:02 Negative (Non-carrier)

• Effect on drug levels: Typical metabolism and elimination
• Clinical consequence: Standard risk of adverse reactions
• Side effects: Common side effects such as dizziness, drowsiness, and nausea, generally of mild to moderate severity

Indeterminate/Not Available

• Effect: Unknown
• Clinical consequence: No specific guidance; follow standard dosing with clinical monitoring

HLA-B Dosing Guidelines

For patients who test positive for HLA-B*15:02 or in populations at high risk, alternative antiepileptic therapies such as valproic acid, lamotrigine, or oxcarbazepine may be considered, as well as non-pharmacologic approaches under physician guidance. These examples are provided for informational purposes only and are not medical advice.

• FDA – Table of Pharmacogenetic Associations