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Overview: Inducers and Inhibitors of Cytochrome P450: Since carvedilol undergoes substantial oxidative metabolism, care may be required in patients receiving inducers or inhibitors of cytochrome P450, as plasma concentrations may be altered. Pre-treatment with rifampin (600 mg daily for 12 days) decreased the AUC and Cmax for carvedilol approximately 70% following a single oral dose of carvedilol. Co-administration of carvedilol and cimetidine (1000 mg/day) resulted in a 30% increase in median AUC for carvedilol. Despite the reduction in oral clearance, peak plasma concentrations of carvedilol were unchanged due to an apparent decrease in rate of absorption.
Interactions of carvedilol with strong inhibitors of CYP2D6 (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 (see Pharmacology: Pharmacokinetics: Special Populations and Conditions: Genetic Polymorphism under Actions).
Drug-Drug Interactions: Antihypertensive Agents: When administered concomitantly with other drugs that are anti-hypertensive in action or have hypotension as part of their adverse effect profile, carvedilol may have additive effects to excessively lower blood pressure.
Catecholamine-depleting agents: Patients taking both agents with β-blocking properties and a drug that can deplete catecholamines (e.g., reserpine and monoamine oxidase inhibitors) should be observed closely for evidence of hypotension and/or marked bradycardia.
Antiarrhythmics and Calcium Channel Blockers: Isolated cases of conduction disturbance (rarely with hemodynamic compromise) have been observed when carvedilol is co-administered with anti-arrhythmic agents or calcium channel blockers such as diltiazem and verapamil that can slow cardiac conduction. As with other agents with β-blocking properties, if carvedilol is to be administered orally with antiarrhythmics that slow conduction or calcium channel blockers of the verapamil or diltiazem type, it is recommended that ECG and blood pressure be monitored.
Digoxin: Following concomitant administration of carvedilol and digoxin, peak concentration of digoxin increased by approximately 30% and steady-state trough concentrations of digoxin were increased by about 15%. Both digoxin and carvedilol slow AV conduction. Therefore, increased monitoring of digoxin levels is recommended when initiating, adjusting or discontinuing carvedilol.
Clonidine: Concomitant administration of clonidine with agents with beta-blocking properties may potentiate blood pressure and heart rate lowering effects. When concomitant treatment with agents with beta-blocking properties and clonidine is to be terminated, the beta-blocking agent should be discontinued first. Clonidine therapy can then be discontinued several days later by gradually decreasing the dosage.
Cyclosporine: Modest increases in mean trough cyclosporine concentrations were observed following initiation of carvedilol treatment in 21 renal transplant patients suffering from chronic vascular rejection. In about 30% of patients, 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 patients. Due to wide inter-individual 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.
Fingolimod: Concomitant use of fingolimod with beta blockers may potentiate bradycardic effects and is not recommended. Where such co-administration is considered necessary, appropriate monitoring at treatment initiation, i.e. at least overnight monitoring, is recommended.
Nitroglycerin: The effect of carvedilol co-administration with nitroglycerin has not been studied. Carvedilol could blunt the reflex tachycardia produced by nitroglycerin through its beta-adrenergic blocking activity. When it is used with nitroglycerin in patients with angina pectoris, additional decreases in blood pressure may occur.
Insulin or Oral Hypoglycemics: Agents with beta-blocking properties 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.
Tricyclic Antidepressants: The effect of carvedilol co-administration with tricyclic antidepressants has not been studied. As an increased incidence of tremor has been observed with other drugs of this class upon co-administration of tricyclic antidepressants, the possibility of a drug interaction cannot be excluded.
Warfarin: Carvedilol (12.5 mg twice daily for 7 days) did not have an effect on warfarin-induced increase in steady-state prothrombin time ratios and did not alter the pharmacokinetics of both enantiomers of warfarin following concomitant administration with warfarin in healthy volunteers.
Drug-Food Interactions: Grapefruit Juice: Following simultaneous administration of a single dose of 25 mg of carvedilol with 300 mL of grapefruit juice (an inhibitor of CYP3A4 and CYP1A2), AUC for carvedilol was approximately 16% higher than following administration of carvedilol with 300 mL of water.
Drug-Herb Interactions: Interactions with herbal products have not been established.
Drug-Laboratory Test Interactions: Interactions with laboratory tests have not been established.
