Carvedilolinteractions

CYP P450 2D6 enzyme inhibitors may increase and rifampin may decrease carvedilol levels. Hypotensive agents (e.g., reserpine, MAO inhibitors, clonidine) may increase the risk of hypotension and/or severe bradycardia. Cyclosporine or digoxin levels may increase. Both digitalis glycosides and beta-blockers slow atrioventricular conduction and decrease heart rate. Concomitant use can increase the risk of bradycardia. Amiodarone may increase carvedilol levels resulting in further slowing of the heart rate or cardiac conduction. Verapamil- or diltiazem-type calcium channel blockers may affect ECG and/or blood pressure. Insulin and oral hypoglycemics action may be enhanced.

7.1 CYP2D6 Inhibitors and

Poor Metabolizers Interactions of carvedilol with potent inhibitors of CYP2D6 isoenzyme (such as quinidine, fluoxetine, paroxetine, and propafenone) have not been studied, but these drugs would be expected to increase blood levels of the R(+) enantiomer of carvedilol. 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 alpha-blocking R(+) enantiomer.

7.2 Hypotensive

Agents Patients taking a beta-blocker and a drug that can deplete catecholamines (e.g., reserpine and monoamine oxidase inhibitors) should be observed closely for signs of hypotension and/or severe bradycardia. Concomitant administration of clonidine with a beta-blocker may cause hypotension and bradycardia. When concomitant treatment with a beta-blocker and clonidine is to be terminated, the beta-blocker should be discontinued first. Clonidine therapy can then be discontinued several days later by gradually decreasing the dosage.

7.3 Cyclosporine

Modest increases in mean trough cyclosporine concentrations were observed following initiation of carvedilol treatment in 21 renal transplant subjects suffering from chronic vascular rejection. In about 30% of subjects, the dose of cyclosporine had to be reduced in order to maintain cyclosporine concentrations within the therapeutic range, while in the remainder no adjustment was needed. On the average for the group, the dose of cyclosporine was reduced about 20% in these subjects. Due to wide interindividual variability in the dose adjustment required, it is recommended that cyclosporine concentrations be monitored closely after initiation of carvedilol therapy and that the dose of cyclosporine be adjusted as appropriate.

7.4 Digitalis

Glycosides Both digitalis glycosides and beta-blockers slow atrioventricular conduction and decrease heart rate. Concomitant use can increase the risk of bradycardia. Digoxin concentrations are increased by about 15% when digoxin and carvedilol are administered concomitantly. Therefore, increased monitoring of digoxin is recommended when initiating, adjusting, or discontinuing carvedilol phosphate extended-release capsules.

7.5 Inducers/Inhibitors of

Hepatic Metabolism Rifampin reduced plasma concentrations of carvedilol by about 70%. Cimetidine increased area under the curve (AUC) by about 30% but caused no change in C max.

7.6 Amiodarone

Amiodarone and its metabolite desethyl amiodarone, inhibitors of CYP2C9, and P-glycoprotein increased concentrations of the S(–) enantiomer of carvedilol by at least 2 fold. The concomitant administration of amiodarone or other CYP2C9 inhibitors such as fluconazole with carvedilol phosphate extended-release capsules may enhance the beta-blocking activity, resulting in further slowing of the heart rate or cardiac conduction. Patients should be observed for signs of bradycardia or heart block, particularly when one agent is added to pre-existing treatment with the other.

7.7 Calcium

Channel Blockers Conduction disturbance (rarely with hemodynamic compromise) has been observed when carvedilol phosphate extended-release capsules are co-administered with diltiazem. As with other beta-blockers, if carvedilol phosphate extended-release capsules are administered with calcium channel blockers of the verapamil or diltiazem type, it is recommended that ECG and blood pressure be monitored.

7.8 Insulin or

Oral Hypoglycemics Beta-blockers may enhance the blood-sugar-reducing effect of insulin and oral hypoglycemics. Therefore, in patients taking insulin or oral hypoglycemics, regular monitoring of blood glucose is recommended.

7.9 Proton Pump

Inhibitors There is no clinically meaningful increase in AUC and C max with concomitant administration of carvedilol extended-release capsules with pantoprazole.

7.10 Anesthesia

If treatment with carvedilol phosphate extended-release capsule is to be continued perioperatively, particular care should be taken when anesthetic agents that depress myocardial function, such as ether, cyclopropane, and trichloroethylene, are used.