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Coreg

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Coreg

Warnings
Precautions

WARNINGS

Included as part of the PRECAUTIONS section.

PRECAUTIONS

Cessation of Therapy

Patients with coronary artery disease, who are being treated with COREG (carvedilol) , 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 (carvedilol) is planned, the patients should be carefully observed and advised to limit physical activity to a minimum. COREG (carvedilol) should be discontinued over 1 to 2 weeks whenever possible. If the angina worsens or acute coronary insufficiency develops, it is recommended that COREG (carvedilol) be promptly reinstituted, at least temporarily. Because coronary artery disease is common and may be unrecognized, it may be prudent not to discontinue therapy with COREG (carvedilol) abruptly even in patients treated only for hypertension or heart failure.

Bradycardia

In clinical trials, COREG (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. If pulse rate drops below 55 beats/minute, the dosage should be reduced.

Hypotension

In clinical trials of primarily mild-to-moderate heart failure, hypotension and postural hypotension occurred in 9.7% and syncope in 3.4% of patients receiving COREG (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 patients receiving COREG (carvedilol) , 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 COREG (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 patients receiving COREG (carvedilol) , compared to 0.8% of placebo patients.

Postural hypotension occurred in 1.8% and syncope in 0.1% of hypertensive patients, 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, hypotension or postural hypotension occurred in 20.2% of patients receiving COREG (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 COREG (carvedilol) , compared to 0.2% of placebo patients.

Starting with a low dose, administration with food, and gradual up-titration should decrease the likelihood of syncope or excessive hypotension [see DOSAGE AND ADMINISTRATION]. 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.

Heart Failure/Fluid Retention

Worsening heart failure or fluid retention may occur during up-titration of carvedilol. If such symptoms occur, diuretics should be increased and the carvedilol dose should not be advanced until clinical stability resumes [see DOSAGE AND ADMINISTRATION]. Occasionally it is necessary to lower the carvedilol dose or temporarily discontinue it. Such episodes do not preclude subsequent successful titration of, or a favorable response to, carvedilol. 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 carvedilol 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.

Non-allergic Bronchospasm

Patients with bronchospastic disease (e.g., chronic bronchitis and emphysema) should, in general, not receive β-blockers. COREG (carvedilol) may be used with caution, however, in patients who do not respond to, or cannot tolerate, other antihypertensive agents. It is prudent, if COREG (carvedilol) 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 carvedilol 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.

Glycemic Control in Type 2 Diabetes

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 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 carvedilol dosing is initiated, adjusted, or discontinued. Studies designed to examine the effects of carvedilol on glycemic control in patients with diabetes and heart failure have not been conducted.

In a study designed to examine the effects of carvedilol on glycemic control in a population with mild-to-moderate hypertension and well-controlled type 2 diabetes mellitus, carvedilol had no adverse effect on glycemic control, based on HbA1c measurements [see Clinical Studies].

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.

Deterioration of Renal Function

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 carvedilol and the drug discontinued or dosage reduced if worsening of renal function occurs.

Anesthesia and Major Surgery

If treatment with COREG (carvedilol) 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].

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.

Pheochromocytoma

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.

Prinzmetal's Variant Angina

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 these patients although the α-blocking activity may prevent such symptoms. However, caution should be taken in the administration of carvedilol to patients suspected of having Prinzmetal's variant angina.

Risk of Anaphylactic Reaction

While taking β-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.

Intraoperative Floppy Iris Syndrome

Intraoperative Floppy Iris Syndrome (IFIS) has been observed during cataract surgery in some patients treated with alpha-1 blockers (COREG (carvedilol) is an alpha/beta blocker). This variant of small pupil syndrome is characterized by the combination of a flaccid iris that billows in response to intraoperative irrigation currents, progressive intraoperative miosis despite preoperative dilation with standard mydriatic drugs, and potential prolapse of the iris toward the phacoemulsification incisions. The patient's ophthalmologist should be prepared for possible modifications to the surgical technique, such as utilization of iris hooks, iris dilator rings, or viscoelastic substances. There does not appear to be a benefit of stopping alpha-1 blocker therapy prior to cataract surgery.

Patient Counseling Information

See FDA-Approved Patient Labeling.

Patient Advice

Patients taking COREG (carvedilol) should be advised of the following:

Patients should take COREG (carvedilol) with food.

  • Patients should not interrupt or discontinue using COREG (carvedilol) without a physician's advice.
  • Patients with heart failure should consult their physician if they experience signs or symptoms of worsening heart failure such as weight gain or increasing shortness of breath.
  • Patients 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 experiencing dizziness or fatigue, patients should avoid driving or hazardous tasks.
  • Patients should consult a physician if they experience dizziness or faintness, in case the dosage should be adjusted.
  • Diabetic patients should report any changes in blood sugar levels to their physician.
  • Contact lens wearers may experience decreased lacrimation.

Nonclinical Toxicology

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 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).

Use In Specific Populations

Pregnancy

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 maximum recommended human dose [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 (carvedilol) 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

Effectiveness of COREG (carvedilol) in patients younger than 18 years of age has not been established.

In a double-blind trial, 161 children (mean age 6 years, range 2 months to 17 years; 45% less than 2 years old) with chronic heart failure [NYHA class II-IV, left ventricular ejection fraction < 40% for children with a systemic left ventricle (LV), and moderate-severe ventricular dysfunction qualitatively by echo for those with a systemic ventricle that was not an LV] who were receiving standard background treatment were randomized to placebo or to 2 dose levels of carvedilol. These dose levels produced placebo-corrected heart rate reduction of 4-6 heart beats per minute, indicative of β-blockade activity. Exposure appeared to be lower in pediatric subjects than adults. After 8 months of follow-up, there was no significant effect of treatment on clinical outcomes. Adverse reactions in this trial that occurred in greater than 10% of patients treated with COREG (carvedilol) and at twice the rate of placebo-treated patients included chest pain (17% versus 6%), dizziness (13% versus 2%), and dyspnea (11% versus 0%).

Geriatric Use

Of the 765 patients with heart failure randomized to COREG (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 COREG (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 COREG (carvedilol) in heart failure trials worldwide, 42% were 65 years of age or older.

Of the 975 myocardial infarction patients randomized to COREG (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 COREG (carvedilol) , 21% (436) were 65 years of age or older. Of 3,722 patients receiving COREG (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 versus 6% in younger patients), no overall differences in the safety or effectiveness (see Figures 2 and 4 under CLINICAL PHARMACOLOGY) 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.

Last reviewed on RxList: 2/25/2011
This monograph has been modified to include the generic and brand name in many instances.

Warnings
Precautions
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