1.1 Heart Failure

COREG CR is indicated for the treatment of mild-to-severe chronic heart failure of ischemic or cardiomyopathic origin, usually in addition to diuretics, ACE inhibitors, and digitalis, to increase survival and, also, to reduce the risk of hospitalization [see Clinical Studies (14.1)].

1.2 Left Ventricular Dysfunction Following Myocardial Infarction

COREG CR is indicated to reduce cardiovascular mortality in clinically stable patients who have survived the acute phase of a myocardial infarction and have a left ventricular ejection fraction of ≤40% (with or without symptomatic heart failure) [see Clinical Studies (14.2)].

1.3 Hypertension

COREG CR is indicated for the management of essential hypertension [see Clinical Studies (14.3, 14.4)]. It can be used alone or in combination with other antihypertensive agents, especially thiazide-type diuretics [see Drug Interactions (7.2)].

2.1 Heart Failure

DOSAGE MUST BE INDIVIDUALIZED AND CLOSELY MONITORED BY A PHYSICIAN DURING UP-TITRATION. Prior to initiation of COREG CR, it is recommended that fluid retention be minimized. The recommended starting dose of COREG CR is 10 mg once daily for 2 weeks. Patients who tolerate a dose of 10 mg once daily may have their dose increased to 20, 40, and 80 mg over successive intervals of at least 2 weeks. Patients should be maintained on lower doses if higher doses are not tolerated.

Patients should be advised that initiation of treatment and (to a lesser extent) dosage increases may be associated with transient symptoms of dizziness or lightheadedness (and rarely syncope) within the first hour after dosing. Thus during these periods they should avoid situations such as driving or hazardous tasks, where symptoms could result in injury. Vasodilatory symptoms often do not require treatment, but it may be useful to separate the time of dosing of COREG CR from that of the ACE inhibitor or to reduce temporarily the dose of the ACE inhibitor. The dose of COREG CR should not be increased until symptoms of worsening heart failure or vasodilation have been stabilized.

Fluid retention (with or without transient worsening heart failure symptoms) should be treated by an increase in the dose of diuretics.

The dose of COREG CR should be reduced if patients experience bradycardia (heart rate <55 beats/minute).

Episodes of dizziness or fluid retention during initiation of COREG CR can generally be managed without discontinuation of treatment and do not preclude subsequent successful titration of, or a favorable response to, COREG CR.

2.2 Left Ventricular Dysfunction Following Myocardial Infarction

DOSAGE MUST BE INDIVIDUALIZED AND MONITORED DURING UP-TITRATION. Treatment with COREG CR may be started as an inpatient or outpatient and should be started after the patient is hemodynamically stable and fluid retention has been minimized. It is recommended that COREG CR be started at 20 mg once daily and increased after 3 to 10 days, based on tolerability, to 40 mg once daily, then again to the target dose of 80 mg once daily. A lower starting dose may be used (10 mg once daily) and/or the rate of up-titration may be slowed if clinically indicated (e.g., due to low blood pressure or heart rate, or fluid retention). Patients should be maintained on lower doses if higher doses are not tolerated. The recommended dosing regimen need not be altered in patients who received treatment with an IV or oral β-blocker during the acute phase of the myocardial infarction.

2.3 Hypertension

DOSAGE MUST BE INDIVIDUALIZED. The recommended starting dose of COREG CR is 20 mg once daily. If this dose is tolerated, using standing systolic pressure measured about one hour after dosing as a guide, the dose should be maintained for 7 to 14 days, and then increased to 40 mg once daily if needed, based on trough blood pressure, again using standing systolic pressure one hour after dosing as a guide for tolerance. This dose should also be maintained for 7 to 14 days and can then be adjusted upward to 80 mg once daily if tolerated and needed. Although not specifically studied, it is anticipated the full antihypertensive effect of COREG CR would be seen within 7 to 14 days as had been demonstrated with immediate-release carvedilol. Total daily dose should not exceed 80 mg.

Concomitant administration with a diuretic can be expected to produce additive effects and exaggerate the orthostatic component of COREG CR action.

2.4 Hepatic Impairment

COREG CR should not be given to patients with severe hepatic impairment [see Contraindications (4)].

2.5 Geriatric Use

When switching elderly patients (65 years of age or older) who are taking the higher doses of immediate-release carvedilol tablets (25 mg twice daily) to COREG CR, a lower starting dose (40 mg) of COREG CR is recommended to minimize the potential for dizziness, syncope, or hypotension [see Dosage and Administration (2)]. Patients who have switched and who tolerate COREG CR should, as appropriate, have their dose increased to after an interval of at least 2 weeks [see Use in Specific Populations (8.5)].

5.1 Cessation of Therapy

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 therapy with COREG CR abruptly even in patients treated only for hypertension or heart failure.

5.2 Bradycardia

In clinical trials with immediate-release carvedilol, bradycardia was reported 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.

5.3 Hypotension

In clinical trials of primarily mild-to-moderate heart failure with immediate-release carvedilol, 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 a trial comparing heart failure patients switched to COREG CR or maintained on immediate-release carvedilol, there was a 2-fold increase in the combined incidence of hypotension, syncope or dizziness in elderly patients (> 65 years) switched from the highest dose of carvedilol (25 mg twice daily) to COREG CR 80 mg once daily [see Dosage and Administration (2), Use in Specific Populations (8.5)].

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 immediate-release carvedilol, 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.

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 (2.1, 2.2, 2.3)]. 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.

5.4 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 dose of COREG CR should not be advanced until clinical stability resumes [see Dosage and Administration (2)]. 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 immediate-release 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.

5.5 Nonallergic Bronchospasm

Patients with bronchospastic disease (e.g., chronic bronchitis and emphysema) 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.

5.6 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 dosing with COREG CR 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 immediate-release 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 (14.4)].

5.7 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.

5.8 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 COREG CR and the drug discontinued or dosage reduced if worsening of renal function occurs.

5.9 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 (10) for information on treatment of bradycardia and hypertension].

5.10 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.

5.11 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.

5.12 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 COREG CR to patients suspected of having Prinzmetal’s variant angina.

5.13 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.

6.1 Clinical Trials Experience

Carvedilol has been evaluated for safety in patients with heart failure (mild, moderate, and severe), in patients with left ventricular dysfunction following myocardial infarction, and in hypertensive patients. The observed adverse event profile was consistent with the pharmacology of the drug and the health status of the patients in the clinical trials. Adverse events reported for each of these patient populations reflecting the use of either COREG CR or immediate-release carvedilol are provided below. Excluded are adverse events considered too general to be informative, and those not reasonably associated with the use of the drug because they were associated with the condition being treated or are very common in the treated population. Rates of adverse events were generally similar across demographic subsets (men and women, elderly and non-elderly, blacks and non-blacks). COREG CR has been evaluated for safety in a 4-week (2 weeks of immediate-release carvedilol and 2 weeks of COREG CR) clinical study (n = 187) which included 157 patients with stable mild, moderate, or severe chronic heart failure and 30 patients with left ventricular dysfunction following acute myocardial infarction. The profile of adverse events observed with COREG CR in this small, short-term study was generally similar to that observed with immediate-release carvedilol. Differences in safety would not be expected based on the similarity in plasma levels for COREG CR and immediate-release carvedilol.

6.2 Laboratory Abnormalities

Reversible elevations in serum transaminases (ALT or AST) have been observed during treatment with carvedilol. Rates of transaminase elevations (2- to 3-times the upper limit of normal) observed during controlled clinical trials have generally been similar between patients treated with carvedilol and those treated with placebo. However, transaminase elevations, confirmed by rechallenge, have been observed with carvedilol. In a long-term, placebo-controlled trial in severe heart failure, patients treated with carvedilol had lower values for hepatic transaminases than patients treated with placebo, possibly because carvedilol-induced improvements in cardiac function led to less hepatic congestion and/or improved hepatic blood flow.

Carvedilol therapy has not been associated with clinically significant changes in serum potassium, total triglycerides, total cholesterol, HDL cholesterol, uric acid, blood urea nitrogen, or creatinine. No clinically relevant changes were noted in fasting serum glucose in hypertensive patients; fasting serum glucose was not evaluated in the heart failure clinical trials.

6.3 Postmarketing Experience

The following adverse reactions have been identified during post-approval use of COREG® or COREG CR. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Reports of aplastic anemia and severe skin reactions (Stevens-Johnson syndrome, toxic epidermal necrolysis, and erythema multiforme) have been rare and received only when carvedilol was administered concomitantly with other medications associated with such reactions. Rare reports of hypersensitivity reactions (e.g., anaphylactic reaction, angioedema, and urticaria) have been received for COREG and COREG CR, including cases occurring after the initiation of COREG CR in patients previously treated with COREG. Urinary incontinence in women (which resolved upon discontinuation of the medication) and interstitial pneumonitis have been reported rarely.

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 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.

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.

7.3 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.

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 amiodarone or other CYP2C9 inhibitors such as fluconazole with COREG CR may enhance the β-blocking properties of carvedilol resulting in further slowing of the heart rate or cardiac conduction. Patients should be observed for signs of bradycardia or heart block, particularly when one agent is added to pre-existing treatment with the other.

7.7 Calcium Channel Blockers

Conduction disturbance (rarely with hemodynamic compromise) has 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.

7.8 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 [see Warnings and Precautions (5.6)].

7.9 Proton Pump Inhibitors

There is no clinically meaningful increase in AUC and Cmax with concomitant administration of carvedilol extended-release capsules with pantoprazole.

8.1 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 CR should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

8.3 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.

8.4 Pediatric Use

Effectiveness of 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% younger 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 immediate-release 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%).

8.5 Geriatric Use

The initial 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.

A randomized study (n = 405) comparing mild to severe heart failure patients switched to COREG CR or maintained on immediate-release carvedilol included 220 patients who were 65 years of age or older. In this elderly subgroup, the combined incidence of dizziness, hypotension, or syncope was 24% (18/75) in patients switched from the highest dose of immediate-release carvedilol (25 mg twice daily) to the highest dose of COREG CR (80 mg once daily) compared to 11% (4/36) in patients maintained on immediate-release carvedilol (25 mg twice daily). When switching from the higher doses of immediate-release carvedilol to COREG CR, a lower starting dose is recommended for elderly patients [see Dosage and Administration (2.5)].

The following information is available for trials with immediate-release carvedilol. 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 immediate-release 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) 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.

12.1 Mechanism of Action

Carvedilol is a racemic mixture in which nonselective β-adrenoreceptor blocking activity is present in the S(-) enantiomer and α1-adrenergic blocking activity is present in both R(+) and S(-) enantiomers at equal potency. Carvedilol has no intrinsic sympathomimetic activity.

12.2 Pharmacodynamics

12.3 Pharmacokinetics

12.4 Specific Populations

12.5 Drug-Drug interactions

Since carvedilol undergoes substantial oxidative metabolism, the metabolism and pharmacokinetics of carvedilol may be affected by induction or inhibition of cytochrome P450 enzymes.

The following drug interaction studies were performed with immediate-release carvedilol tablets.

13.1 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).

14.1 Heart Failure

A total of 6,975 patients with mild-to-severe heart failure were evaluated in placebo-controlled and active-controlled studies of immediate-release carvedilol.

Severe Heart Failure (COPERNICUS)

In a double-blind study, 2,289 patients with heart failure at rest or with minimal exertion and left ventricular ejection fraction <25% (mean 20%), despite digitalis (66%), diuretics (99%), and ACE inhibitors (89%) were randomized to placebo or carvedilol. Carvedilol was titrated from a starting dose of 3.125 mg twice daily to the maximum tolerated dose or up to 25 mg twice daily over a minimum of 6 weeks. Most subjects achieved the target dose of 25 mg. The study was conducted in Eastern and Western Europe, the United States, Israel, and Canada. Similar numbers of subjects per group (about 100) withdrew during the titration period.

The primary end point of the trial was all-cause mortality, but cause-specific mortality and the risk of death or hospitalization (total, cardiovascular [CV], or heart failure [HF]) were also examined. The developing trial data were followed by a data monitoring committee, and mortality analyses were adjusted for these multiple looks. The trial was stopped after a median follow-up of 10 months because of an observed 35% reduction in mortality (from 19.7% per patient year on placebo to 12.8% on carvedilol, hazard ratio 0.65, 95% CI 0.52 – 0.81, p = 0.0014, adjusted) (see Figure 1). The results of COPERNICUS are shown in Table 6.

Table 6. Results of COPERNICUS Trial in Patients With Severe Heart Failure

End point	Placebo (N = 1,133)	Carvedilol (N = 1,156)	Hazard ratio (95% CI)	% Reduction	Nominal p value
Mortality	190	130	0.65 (0.52 – 0.81)	35	0.00013
Mortality + all hospitalization	507	425	0.76 (0.67 – 0.87)	24	0.00004
Mortality + CV hospitalization	395	314	0.73 (0.63 – 0.84)	27	0.00002
Mortality + HF hospitalization	357	271	0.69 (0.59 – 0.81)	31	0.000004

Cardiovascular = CV; Heart failure = HF

Figure 1. Survival Analysis for COPERNICUS (intent-to-treat)

The effect on mortality was principally the result of a reduction in the rate of sudden death among patients without worsening heart failure.

Patients' global assessments, in which carvedilol-treated patients were compared to placebo, were based on pre-specified, periodic patient self-assessments regarding whether clinical status post-treatment showed improvement, worsening, or no change compared to baseline. Patients treated with carvedilol showed significant improvements in global assessments compared with those treated with placebo in COPERNICUS.

The protocol also specified that hospitalizations would be assessed. Fewer patients on immediate-release carvedilol than on placebo were hospitalized for any reason (372 versus 432, p = 0.0029), for cardiovascular reasons (246 versus 314, p = 0.0003), or for worsening heart failure (198 versus 268, p = 0.0001).

Immediate-release carvedilol had a consistent and beneficial effect on all-cause mortality as well as the combined end points of all-cause mortality plus hospitalization (total, CV, or for heart failure) in the overall study population and in all subgroups examined, including men and women, elderly and non-elderly, blacks and non-blacks, and diabetics and non-diabetics (see Figure 2).

Figure 2. Effects on Mortality for Subgroups in COPERNICUS

Although the clinical trials used twice-daily dosing, clinical pharmacologic and pharmacokinetic data provide a reasonable basis for concluding that once-daily dosing with COREG CR should be adequate in the treatment of heart failure.

14.2 Left Ventricular Dysfunction Following Myocardial Infarction

CAPRICORN was a double-blind study comparing carvedilol and placebo in 1,959 patients with a recent myocardial infarction (within 21 days) and left ventricular ejection fraction of ≤40%, with (47%) or without symptoms of heart failure. Patients given carvedilol received 6.25 mg twice daily, titrated as tolerated to 25 mg twice daily. Patients had to have a systolic blood pressure >90 mm Hg, a sitting heart rate >60 beats/minute, and no contraindication to β-blocker use. Treatment of the index infarction included aspirin (85%), IV or oral β-blockers (37%), nitrates (73%), heparin (64%), thrombolytics (40%), and acute angioplasty (12%). Background treatment included ACE inhibitors or angiotensin receptor blockers (97%), anticoagulants (20%), lipid-lowering agents (23%), and diuretics (34%). Baseline population characteristics included an average age of 63 years, 74% male, 95% Caucasian, mean blood pressure 121/74 mm Hg, 22% with diabetes, and 54% with a history of hypertension. Mean dosage achieved of carvedilol was 20 mg twice daily; mean duration of follow-up was 15 months.

All-cause mortality was 15% in the placebo group and 12% in the carvedilol group, indicating a 23% risk reduction in patients treated with carvedilol (95% CI 2% to 40%, p = 0.03), as shown in Figure 3. The effects on mortality in various subgroups are shown in Figure 4. Nearly all deaths were cardiovascular (which were reduced by 25% by carvedilol), and most of these deaths were sudden or related to pump failure (both types of death were reduced by carvedilol). Another study end point, total mortality and all-cause hospitalization, did not show a significant improvement.

There was also a significant 40% reduction in fatal or non-fatal myocardial infarction observed in the group treated with carvedilol (95% CI 11% to 60%, p = 0.01). A similar reduction in the risk of myocardial infarction was also observed in a meta-analysis of placebo-controlled trials of carvedilol in heart failure.

Figure 3. Survival Analysis for CAPRICORN (intent-to-treat)

Figure 4. Effects on Mortality for Subgroups in CAPRICORN

Although the clinical trials used twice-daily dosing, clinical pharmacologic and pharmacokinetic data provide a reasonable basis for concluding that once-daily dosing with COREG CR should be adequate in the treatment of left ventricular dysfunction following myocardial infarction.

14.3 Hypertension

A double-blind, randomized, placebo-controlled, 8-week trial evaluated the blood pressure lowering effects of COREG CR 20 mg, 40 mg, and 80 mg once daily in 338 patients with essential hypertension (sitting diastolic blood pressure [DBP] ≥90 and ≤109 mm Hg). Of 337 evaluable patients, a total of 273 patients (81%) completed the study. Of the 64 (19%) patients withdrawn from the study, 10 (3%) were due to adverse events, 10 (3%) were due to lack of efficacy; the remaining 44 (13%) withdrew for other reasons. The mean age of the patients was approximately 53 years, 66% were male, and the mean sitting systolic blood pressure (SBP) and DBP at baseline were 150 mm Hg and 99 mm Hg, respectively. Dose titration occurred at 2-week intervals.

Statistically significant reductions in blood pressure as measured by 24-hour ambulatory blood pressure monitoring (ABPM) were observed with each dose of COREG CR compared to placebo. Placebo-subtracted mean changes from baseline in mean SBP/DBP were -6.1/-4.0 mm Hg, -9.4/-7.6 mm Hg, and -11.8/-9.2 mm Hg for COREG CR 20 mg, 40 mg, and 80 mg, respectively. Placebo-subtracted mean changes from baseline in mean trough (average of hours 20-24) SBP/DBP were -3.3/-2.8 mm Hg, -4.9/-5.2 mm Hg, and -8.4/-7.4 mm Hg for COREG CR 20 mg, 40 mg, and 80 mg, respectively. The placebo-corrected trough to peak (3-7 hr) ratio was approximately 0.6 for COREG CR 80 mg. In this study, assessments of 24-hour ABPM monitoring demonstrated statistically significant blood pressure reductions with COREG CR throughout the dosing period (Figure 5).

Figure 5. Changes from Baseline in Systolic Blood Pressure and Diastolic Blood Pressure Measured by 24-Hour ABPM

Immediate-release carvedilol was studied in 2 placebo-controlled trials that utilized twice-daily dosing, at total daily doses of 12.5 to 50 mg. In these and other studies, the starting dose did not exceed 12.5 mg. At 50 mg/day, COREG reduced sitting trough (12-hour) blood pressure by about 9/5.5 mm Hg; at 25 mg/day the effect was about 7.5/3.5 mm Hg. Comparisons of trough-to-peak blood pressure showed a trough-to-peak ratio for blood pressure response of about 65%. Heart rate fell by about 7.5 beats/minute at 50 mg/day. In general, as is true for other β-blockers, responses were smaller in black than non-black patients. There were no age- or gender-related differences in response. The dose-related blood pressure response was accompanied by a dose-related increase in adverse effects [see Adverse Reactions (6)].

14.4 Hypertension With Type 2 Diabetes Mellitus

In a double-blind study (GEMINI), carvedilol, added to an ACE inhibitor or angiotensin receptor blocker, was evaluated in a population with mild-to-moderate hypertension and well-controlled type 2 diabetes mellitus. The mean HbA1c at baseline was 7.2%. COREG was titrated to a mean dose of 17.5 mg twice daily and maintained for 5 months. COREG had no adverse effect on glycemic control, based on HbA1c measurements (mean change from baseline of 0.02%, 95% CI -0.06 to 0.10, p = NS) [see Warnings and Precautions (5.6)].

17.1 Patient Advice

Patients taking COREG CR should be advised of the following:

• Patients should not interrupt or discontinue using COREG CR 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.
• Patients should not crush or chew COREG CR capsules.
• Patients 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.

17.2 FDA-Approved Patient Labeling

Patient labeling is provided as a tear-off leaflet at the end of this full prescribing information.

COREG CR and COREG are registered trademarks of GlaxoSmithKline.

TOPROL-XL is a registered trademark of the AstraZeneca group of companies.

GlaxoSmithKline

Research Triangle Park, NC 27709

©2009, GlaxoSmithKline. All rights reserved.

Relabeling and Repackaging by:
Physicians Total Care, Inc.
Tulsa, OK      74146

PHARMACIST-DETACH HERE AND GIVE INSTRUCTIONS TO PATIENT

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