Carvedilol

Pharmacogenomic Information in the Context of the FDA-Approved Drug Label*

Carvedilol is indicated for the treatment of mild-to-severe chronic heart failure of ischemic or cardiomyopathic origin, to reduce cardiovascular mortality in clinically stable patients with left ventricular dysfunction following myocardial infarction, and for the management of essential hypertension. It is a nonselective beta-adrenergic blocking agent with a1-blocking activity.
Carvedilol is a racemic mixture and undergoes stereoselective first-pass metabolism. Cytochrome P450 enzymes responsible for the metabolism of both R and S-carvedilol in human liver microsomes were CYP2D6 and CYP2C9 and to a lesser extent CYP3A4, CYP2C19, CYP1A2, and CYP2E1.

Excerpts from the Carvedilol drug label:

"Retrospective analysis of side effects in clinical trials showed that poor 2D6 metabolizers had a higher rate of dizziness during up-titration, presumably resulting from vasodilating effects of the higher concentrations of the a-blocking R enantiomer."

"Carvedilol is subject to the effects of genetic polymorphism with poor metabolizers of debrisoquin (a marker for cytochrome P450 2D6) exhibiting 2- to 3-fold higher plasma concentrations of R( + )-carvedilol compared to extensive metabolizers. In contrast, plasma levels of S( - )-carvedilol are increased only about 20% to 25% in poor metabolizers, indicating this enantiomer is metabolized to a lesser extent by cytochrome P450 2D6 than R-carvedilol. The pharmacokinetics of carvedilol do not appear to be different in poor metabolizers of S-mephenytoin (patients deficient in cytochrome P450 2C19)."

(For the complete drug label text with sections containing pharmacogenetic information highlighted, see the Carvedilol drug label PDF.)