ablish a causal relationship to drug exposure.
Blood and Lymphatic System Disorders
Aplastic anemia.
Immune System Disorders
Hypersensitivity (e.g., anaphylactic reactions, angioedema, urticaria).
Renal and Urinary Disorders
Urinary incontinence.
Respiratory, Thoracic, and Mediastinal Disorders
Interstitial pneumonitis.
Skin and Subcutaneous Tissue Disorders
Stevens-Johnson syndrome, toxic epidermal necrolysis, erythema multiforme.
7 DRUG INTERACTIONS
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 [see Clinical Pharmacology (12.3)]. 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 α‑blocking R(+) enantiomer.
7.2 Hypotensive Agents
Patients taking a β‑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 β‑blocker may cause hypotension and bradycardia. When concomitant treatment with a β‑blocker and clonidine is to be terminated, the β‑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 β‑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 COREG CR [see Clinical Pharmacology (12.5)].
7.5 Inducers/Inhibitors of Hepatic Metabolism
Rifampin reduced plasma concentrations of carvedilol by about 70% [see Clinical Pharmacology (12.5)]. Cimetidine increased area under the curve (AUC) by about 30% but caused no change in Cmax [see Clinical Pharmacology (12.5)].
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 [see Clinical Pharmacology (12.5)]. The concomitant administration of ami |
