Coreg

[Carvedilol]

Information for Patients:

Patients taking COREG should be advised of the following:

they should not interrupt or discontinue using COREG without a physician's advice.
congestive heart failure patients should consult their physician if they experience signs or symptoms of worsening heart failure such as weight gain or increasing shortness of breath.

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they may experience a drop in blood pressure when standing, resulting in dizziness and, rarely, fainting. Patients should sit or lie down when these symptoms of lowered blood pressure occur.

if patients experience dizziness or fatigue, they should avoid driving or hazardous tasks.

they should consult a physician if they experience dizziness or faintness, in case the dosage should be adjusted.

they should take COREG with food.

diabetic patients should report any changes in blood sugar levels to their physician.

contact lens wearers may experience decreased lacrimation.

Drug Interactions:

(Also see CLINICAL PHARMACOLOGY, Pharmacokinetic Drug-Drug Interactions.)

Inhibitors of CYP2D6; poor metabolizers of debrisoquin:

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 (see CLINICAL PHARMACOLOGY). 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 -blocking R(+) enantiomer.

Catecholamine-depleting agents:

Patients taking both agents with -blocking properties 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.

Clonidine:

Concomitant administration of clonidine with agents with -blocking properties may potentiate blood-pressure-and heart-rate-lowering effects. When concomitant treatment with agents with -blocking properties and clonidine is to be terminated, the -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 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.

Digoxin:

Digoxin concentrations are increased by about 15% when digoxin and carvedilol are administered concomitantly. Both digoxin and COREG slow AV conduction. Therefore, increased monitoring of digoxin is recommended when initiating, adjusting, or discontinuing COREG.

Inducers and inhibitors of hepatic metabolism:

Rifampin reduced plasma concentrations of carvedilol by about 70%. Cimetidine increased AUC by about 30% but caused no change in Cmax.

Calcium channel blockers:

Isolated cases of conduction disturbance (rarely with hemodynamic compromise) have been observed when COREG is co-administered with diltiazem. As with other agents with -blocking properties, if COREG is to be administered orally with calcium channel blockers of the verapamil or diltiazem type, it is recommended that ECG and blood pressure be monitored. Insulin or oral hypoglycemics: Agents with -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.

Carcinogenesis, Mutagenesis, Impairment of Fertility:

In 2-year studies conducted in rats given carvedilol at doses up to 75 mg/ kg/ day (12 times the maximum recommended human dose [MRHD] when compared on a mg/ m 2 basis) or in mice given up to 200 mg/ kg/ day (16 times the MRHD on a mg/ m 2 basis), carvedilol had no carcinogenic effect. Carvedilol was negative when tested in a battery of genotoxicity assays, including the Ames and the CHO/ HGPRT assays for mutagenicity and the in vitro hamster micronucleus and in vivo human lymphocyte cell tests for clastogenicity.

At doses 200 mg/ kg/ day ( 32 times the MRHD as mg/ m 2 ) carvedilol was toxic to adult rats (sedation, reduced weight gain) and was associated with a reduced number of successful matings, prolonged mating time, significantly fewer corpora lutea and implants per dam, and complete resorption of 18% of the litters. The no-observed-effect dose level for overt toxicity and impairment of fertility was 60 mg/ kg/ day (10 times the MRHD as mg/ m 2 ).

Pregnancy:

Teratogenic Effects:

Pregnancy Category C.

Studies performed in pregnant rats and rabbits given carvedilol revealed increased post-implantation loss in rats at doses of 300 mg/ kg/ day (50 times the MRHD as mg/ m 2 ) and in rabbits at doses of 75 mg/ kg/ day (25 times the MRHD as mg/ m 2 ). In the rats, there was also a decrease in fetal body weight at the maternally toxic dose of 300 mg/ kg/ day (50 times the MRHD as mg/ m 2 ), which was accompanied by an elevation in the frequency of fetuses with delayed skeletal development (missing or stunted 13th rib). In rats the no-observed-effect level for developmental toxicity was 60 mg/ kg/ day (10 times the MRHD as mg/ m 2 ); in rabbits it was 15 mg/ kg/ day (5 times the MRHD as mg/ m 2 ). There are no adequate and well-controlled studies in pregnant women. COREG should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Nursing Mothers:

It is not known whether this drug is excreted in human milk. Studies in rats have shown that carvedilol and/ or its metabolites (as well as other -blockers) cross the placental barrier and are excreted in breast milk. There was increased mortality at one week post-partum in neonates from rats treated with 60 mg/ kg/ day (10 tims the MRHD as mg/ m 2 ) and above during the last trimester through day 22 of lactation. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from -blockers, especially bradycardia, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. The effects of other -and -blocking agents have included perinatal and neonatal distress.

Pediatric Use

Safety and efficacy in patients younger than 18 years of age have not been established.

Geriatric Use

Of the 765 patients with congestive heart failure randomized to COREG in US clinical trials, 31% (235) were 65 years of age or older, and 7.3% (56) were 75 years of age or older. Of the 1,156 patients randomized to COREG in a long-term, placebo-controlled trial in severe heart failure, 47% (547) were 65 years of age or older, and 15% (174) were 75 years of age or older. Of 3,025 patients receiving COREG in congestive heart failure trials worldwide, 42% were 65 years of age or older. Of the 975 myocardial infarction patients randomized to COREG in the CAPRICORN trial, 48% (468) were 65 years of age or older, and 11% (111) were 75 years of age or older. Of the 2,065 hypertensive patients in US clinical trials of efficacy or safety who were treated with COREG, 21% (436) were 65 years of age or older. Of 3,722 patients receiving COREG in hypertension clinical trials conducted worldwide, 24% were 65 years of age or older.

With the exception of dizziness in hypertensive patients (incidence 8.8% in the elderly vs. 6% in younger patients), no overall differences in the safety or effectiveness (See Figures 2 and 4.) were observed between the older subjects and younger subjects in each of these populations. Similarly, other reported clinical experience has not identified differences in responses between the elderly and younger subjects, but greater sensitivity of some older individuals cannot be ruled out.

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