WARNINGS
Cessation of Therapy with COREG CR: Patients with coronary artery disease, who are being treated with COREG CR, should be advised against abrupt discontinuation of therapy. Severe exacerbation of angina and the occurrence of myocardial infarction and ventricular arrhythmias have been reported in angina patients following the abrupt discontinuation of therapy with β-blockers. The last 2 complications may occur with or without preceding exacerbation of the angina pectoris. As with other β-blockers, when discontinuation of COREG CR is planned, the patients should be carefully observed and advised to limit physical activity to a minimum. COREG CR should be discontinued over 1 to 2 weeks whenever possible. If the angina worsens or acute coronary insufficiency develops, it is recommended that COREG CR be promptly reinstituted, at least temporarily. Because coronary artery disease is common and may be unrecognized, it may be prudent not to discontinue COREG CR therapy abruptly even in patients treated only for hypertension or heart failure (see DOSAGE AND ADMINISTRATION).
Peripheral Vascular Disease
β-blockers can precipitate or aggravate symptoms of arterial insufficiency in patients with peripheral vascular disease. Caution should be exercised in such individuals.
Anesthesia and Major Surgery
If treatment with COREG CR is to be continued perioperatively, particular care should be taken when anesthetic agents which depress myocardial function, such as ether, cyclopropane, and trichloroethylene, are used. See OVERDOSAGE for information on treatment of bradycardia and hypertension.
Diabetes and Hypoglycemia
In general, β-blockers may mask some of the manifestations of hypoglycemia, particularly tachycardia. Nonselective β-blockers may potentiate insulin-induced hypoglycemia and delay recovery of serum glucose levels. Patients subject to spontaneous hypoglycemia, or diabetic patients receiving insulin or oral hypoglycemic agents, should be cautioned about these possibilities. In heart failure patients, there is a risk of worsening hyperglycemia (see PRECAUTIONS).
Thyrotoxicosis
β-adrenergic blockade may mask clinical signs of hyperthyroidism, such as tachycardia. Abrupt withdrawal of β-blockade may be followed by an exacerbation of the symptoms of hyperthyroidism or may precipitate thyroid storm.
PRECAUTIONS
General
In clinical trials of COREG CR in patients with hypertension (337 subjects) and in patients with left ventricular dysfunction following a myocardial infarction or heart failure (187 subjects), the profile of adverse events observed with carvedilol phosphate was generally similar to that observed with the administration of conventional carvedilol tablets. Therefore, the information included within this section is based on data from controlled clinical trials with COREG CR as well as the conventional carvedilol tablets.
In clinical trials with the conventional tablet, carvedilol caused bradycardia in about 2% of hypertensive patients, 9% of heart failure patients, and 6.5% of myocardial infarction patients with left ventricular dysfunction. Bradycardia was reported in 0.5% of patients receiving COREG CR in a study of heart failure patients and myocardial infarction patients with left ventricular dysfunction. There were no reports of bradycardia in the clinical trial of COREG CR in hypertension. However, if pulse rate drops below 55 beats/minute, the dosage of COREG CR should be reduced.
In clinical trials of primarily mild-to-moderate heart failure with the conventional carvedilol tablet, hypotension and postural hypotension occurred in 9.7% and syncope in 3.4% of patients receiving carvedilol compared to 3.6% and 2.5% of placebo patients, respectively. The risk for these events was highest during the first 30 days of dosing, corresponding to the up-titration period and was a cause for discontinuation of therapy in 0.7% of carvedilol patients, compared to 0.4% of placebo patients. In a long-term, placebo-controlled trial in severe heart failure (COPERNICUS), hypotension and postural hypotension occurred in 15.1% and syncope in 2.9% of heart failure patients receiving carvedilol compared to 8.7% and 2.3% of placebo patients, respectively. These events were a cause for discontinuation of therapy in 1.1% of carvedilol patients, compared to 0.8% of placebo patients.
In the clinical trial of COREG CR in hypertensive patients, syncope was reported in 0.3% of patients receiving COREG CR compared to 0% of patients receiving placebo. There were no reports of postural hypotension in this trial. Postural hypotension occurred in 1.8% and syncope in 0.1% of hypertensive patients receiving the conventional carvedilol tablets, primarily following the initial dose or at the time of dose increase and was a cause for discontinuation of therapy in 1% of patients.
In the CAPRICORN study of survivors of an acute myocardial infarction with left ventricular dysfunction, hypotension or postural hypotension occurred in 20.2% of patients receiving carvedilol compared to 12.6% of placebo patients. Syncope was reported in 3.9% and 1.9% of patients, respectively. These events were a cause for discontinuation of therapy in 2.5% of patients receiving carvedilol, compared to 0.2% of placebo patients.
To decrease the likelihood of syncope or excessive hypotension, treatment with COREG CR should be initiated with 10 mg once daily for heart failure patients, and at 20 mg once daily for hypertensive patients and survivors of an acute myocardial infarction with left ventricular dysfunction. Dosage should then be increased slowly, according to recommendations in the DOSAGE AND ADMINISTRATION section, and the drug should be taken with food. During initiation of therapy, the patient should be cautioned to avoid situations such as driving or hazardous tasks, where injury could result should syncope occur.
Rarely, use of carvedilol in patients with heart failure has resulted in deterioration of renal function. Patients at risk appear to be those with low blood pressure (systolic blood pressure <100 mm Hg), ischemic heart disease and diffuse vascular disease, and/or underlying renal insufficiency. Renal function has returned to baseline when carvedilol was stopped. In patients with these risk factors it is recommended that renal function be monitored during up-titration of COREG CR and the drug discontinued or dosage reduced if worsening of renal function occurs.
Worsening heart failure or fluid retention may occur during up-titration of carvedilol. If such symptoms occur, diuretics should be increased and the dose of COREG CR should not be advanced until clinical stability resumes (see DOSAGE AND ADMINISTRATION). Occasionally it is necessary to lower the dose of COREG CR or temporarily discontinue it. Such episodes do not preclude subsequent successful titration of, or a favorable response to, COREG CR. In a placebo-controlled trial of patients with severe heart failure, worsening heart failure during the first 3 months was reported to a similar degree with conventional carvedilol tablets and with placebo. When treatment was maintained beyond 3 months, worsening heart failure was reported less frequently in patients treated with carvedilol than with placebo. Worsening heart failure observed during long-term therapy is more likely to be related to the patients’ underlying disease than to treatment with carvedilol.
In patients with pheochromocytoma, an α-blocking agent should be initiated prior to the use of any β-blocking agent. Although carvedilol has both α- and β-blocking pharmacologic activities, there has been no experience with its use in this condition. Therefore, caution should be taken in the administration of carvedilol to patients suspected of having pheochromocytoma.
Agents with non-selective β-blocking activity may provoke chest pain in patients with Prinzmetal’s variant angina. There has been no clinical experience with carvedilol in thesepatients although the α-blocking activity may prevent such symptoms. However, caution should be taken in the administration of COREG CR to patients suspected of having Prinzmetal’s variant angina.
In heart failure patients with diabetes, carvedilol therapy may lead to worsening hyperglycemia, which responds to intensification of hypoglycemic therapy. It is recommended that blood glucose be monitored when dosing with COREG CR is initiated, adjusted, or discontinued.
Risk of Anaphylactic Reaction
While takingβ-blockers, patients with a history of severe anaphylactic reaction to a variety of allergens may be more reactive to repeated challenge, either accidental, diagnostic, or therapeutic. Such patients may be unresponsive to the usual doses of epinephrine used to treat allergic reaction.
Nonallergic Bronchospasm (e.g., chronic bronchitis and emphysema)
Patients with bronchospastic disease should, in general, not receive β-blockers. COREG CR may be used with caution, however, in patients who do not respond to, or cannot tolerate, other antihypertensive agents. It is prudent, if COREG CR is used, to use the smallest effective dose, so that inhibition of endogenous or exogenous β-agonists is minimized.
In clinical trials of patients with heart failure, patients with bronchospastic disease were enrolled if they did not require oral or inhaled medication to treat their bronchospastic disease. In such patients, it is recommended that COREG CR be used with caution. The dosing recommendations should be followed closely and the dose should be lowered if any evidence of bronchospasm is observed during up-titration.
Information for Patients
Patients taking COREG CR should be advised of the following:
- They should not interrupt or discontinue using COREG CR without a physician’s advice.
- 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.
- 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 not crush or chew COREG CR capsules.
- They should take COREG CR 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 α-blocking R(+) enantiomer.
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 signs of hypotension and/or severe bradycardia.
Clonidine
Concomitant administration of clonidine with agents with β-blocking properties may potentiate blood-pressure- and heart-rate-lowering effects. When concomitant treatment with agents with β-blocking properties and clonidine is to be terminated, the β-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 carvedilol slow AV conduction. Therefore, increased monitoring of digoxin is recommended when initiating, adjusting, or discontinuing COREG CR.
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 carvedilol is co-administered with diltiazem. As with other agents with β-blocking properties, if COREG CR 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 β-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/m2 basis) or in mice given up to 200 mg/kg/day (16 times the MRHD on a mg/m2 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/m2) 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/m2).
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/m2) and in rabbits at doses of 75 mg/kg/day (25 times the MRHD as mg/m2). 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/m2), 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/m2); in rabbits it was 15 mg/kg/day (5 times the MRHD as mg/m2). There are no adequate and well-controlled studies in pregnant women. COREG CR 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 β-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 times the MRHD as mg/m2) 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 β-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 α- and β-blocking agents have included perinatal and neonatal distress.
Pediatric Use
Safety and efficacy of COREG CR in patients younger than 18 years of age have not been established.
Geriatric Use
The clinical studies of COREG CR in patients with hypertension, heart failure, and left ventricular dysfunction following myocardial infarction did not include sufficient numbers of subjects 65 years of age or older to determine whether they respond differently from younger patients.
The following information is available for trials with the conventional carvedilol tablets. Of the 765 patients with heart failure randomized to carvedilol 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 carvedilol 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 carvedilol in heart failure trials worldwide, 42% were 65 years of age or older. Of the 975 myocardial infarction patients randomized to carvedilol 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 carvedilol, 21% (436) were 65 years of age or older. Of 3,722 patients receiving carvedilol 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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