Carvedilol Phosphate Extended-Release

Dosage Forms And Strengths

The hard gelatin capsules are filled with white to off-white microparticles and are available in the following strengths:

• 10 mg – white and green capsule shell printed with “GSK COREG CR” and “10 mg”
• 20 mg – white and yellow capsule shell printed with “GSK COREG CR” and “20 mg”
• 40 mg – yellow and green capsule shell printed with “GSK COREG CR” and “40 mg”
• 80 mg – white capsule shell printed with “GSK COREG CR” and “80 mg”

Storage And Handling

The hard gelatin capsules are available in the following strengths:

• 10 mg – white and green capsule shell printed with “GSK COREG CR” and “10 mg”
• 20 mg – white and yellow capsule shell printed with “GSK COREG CR” and “20 mg”
• 40 mg – yellow and green capsule shell printed with “GSK COREG CR” and “40 mg”
• 80 mg – white capsule shell printed with “GSK COREG CR” and “80 mg”

10 mg bottles of 30: NDC 0007-3370-13
20 mg bottles of 30: NDC 0007-3371-13
40 mg bottles of 30: NDC 0007-3372-13
80 mg bottles of 30: NDC 0007-3373-13

Store at 25°C (77°F); excursions 15° to 30°C (59° to 86°F). Dispense in a tight, light-resistant container.

GlaxoSmithKline, Research Triangle Park, NC 27709. Revised: October 2015

Clinical Trials Experience

Carvedilol has been evaluated for safety in subjects with heart failure (mild, moderate, and severe), in subjects with left ventricular dysfunction following myocardial infarction, and in hypertensive subjects. The observed adverse event profile was consistent with the pharmacology of the drug and the health status of the subjects in the clinical trials. Adverse events reported for each of these 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 trial (n = 187) which included 157 subjects with stable mild, moderate, or severe chronic heart failure and 30 subjects with left ventricular dysfunction following acute myocardial infarction. The profile of adverse events observed with COREG CR in this small, short-term trial 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.

The following information describes the safety experience in heart failure with immediate-release carvedilol.

Carvedilol has been evaluated for safety in heart failure in more than 4,500 subjects worldwide of whom more than 2,100 participated in placebo-controlled clinical trials. Approximately 60% of the total treated population in placebo-controlled clinical trials received carvedilol for at least 6 months and 30% received carvedilol for at least 12 months. In the COMET trial, 1,511 subjects with mild-to-moderate heart failure were treated with carvedilol for up to 5.9 years (mean: 4.8 years). Both in US clinical trials in mild-to-moderate heart failure that compared carvedilol in daily doses up to 100 mg (n = 765) with placebo (n = 437), and in a multinational clinical trial in severe heart failure (COPERNICUS) that compared carvedilol in daily doses up to 50 mg (n = 1,156) with placebo (n = 1,133), discontinuation rates for adverse experiences were similar in carvedilol and placebo subjects. In placebo-controlled clinical trials, the only cause of discontinuation greater than 1%, and occurring more often on carvedilol was dizziness (1.3% on carvedilol, 0.6% on placebo in the COPERNICUS trial).

Table 2 shows adverse events reported in subjects with mild-to-moderate heart failure enrolled in US placebo-controlled clinical trials, and with severe heart failure enrolled in the COPERNICUS trial. Shown are adverse events that occurred more frequently in drug-treated subjects than placebo-treated subjects with an incidence of greater than 3% in subjects treated with carvedilol regardless of causality. Median trial medication exposure was 6.3 months for both carvedilol and placebo subjects in the trials of mild-to-moderate heart failure, and 10.4 months in the trial of subjects with severe heart failure. The adverse event profile of carvedilol observed in the long-term COMET trial was generally similar to that observed in the US Heart Failure Trials.11

Table 2: Adverse Events (%) Occurring More Frequently with Immediate-Release Carvedilol than with Placebo in Subjects with Mild-to-Moderate Heart Failure (HF) Enrolled in US Heart Failure Trials or in Subjects with Severe Heart Failure in the COPERNICUS Trial (Incidence > 3% in Subjects Treated with Carvedilol, Regardless of Causality)

Cardiac failure and dyspnea were also reported in these trials, but the rates were equal or greater in subjects who received placebo.

The following adverse events were reported with a frequency of greater than 1% but less than or equal to 3% and more frequently with carvedilol in either the US placebo-controlled trials in subjects with mild-to-moderate heart failure, or in subjects with severe heart failure in the COPERNICUS trial.

Body as a Whole: Allergy, malaise, hypovolemia, fever, leg edema.

Cardiovascular: Fluid overload, postural hypotension, aggravated angina pectoris, AV block, palpitation, hypertension.

Central and Peripheral Nervous System: Hypesthesia, vertigo, paresthesia.

Gastrointestinal: Melena, periodontitis.

Liver and Biliary System: SGPT increased, SGOT increased.

Metabolic and Nutritional: Hyperuricemia, hypoglycemia, hyponatremia, increased alkaline phosphatase, glycosuria, hypervolemia, diabetes mellitus, GGT increased, weight loss, hyperkalemia, creatinine increased.

Musculoskeletal: Muscle cramps.

Platelet, Bleeding, and Clotting: Prothrombin decreased, purpura, thrombocytopenia.

Psychiatric: Somnolence.

Reproductive, male: Impotence.

Special Senses: Blurred vision.

Urinary System: Renal insufficiency, albuminuria, hematuria.

The following information describes the safety experience in left ventricular dysfunction following acute myocardial infarction with immediate-release carvedilol.

Carvedilol has been evaluated for safety in survivors of an acute myocardial infarction with left ventricular dysfunction in the CAPRICORN trial which involved 969 subjects who received carvedilol and 980 who received placebo. Approximately 75% of the subjects received carvedilol for at least 6 months and 53% received carvedilol for at least 12 months. Subjects were treated for an average of 12.9 months and 12.8 months with carvedilol and placebo, respectively.

The most common adverse events reported with carvedilol in the CAPRICORN trial were consistent with the profile of the drug in the US heart failure trials and the COPERNICUS trial. The only additional adverse events reported in CAPRICORN in greater than 3% of the subjects and more commonly on carvedilol were dyspnea, anemia, and lung edema. The following adverse events were reported with a frequency of greater than 1% but less than or equal to 3% and more frequently with carvedilol: flu syndrome, cerebrovascular accident, peripheral vascular disorder, hypotonia, depression, gastrointestinal pain, arthritis, and gout. The overall rates of discontinuations due to adverse events were similar in both groups of subjects. In this database, the only cause of discontinuation greater than 1%, and occurring more often on carvedilol was hypotension (1.5% on carvedilol, 0.2% on placebo).

COREG CR was evaluated for safety in an 8-week double-blind trial in 337 subjects with essential hypertension. The profile of adverse events observed with COREG CR was generally similar to that observed with immediate-release carvedilol. The overall rates of discontinuations due to adverse events were similar between COREG CR and placebo.

Table 3: Adverse Events (%) Occurring More Frequently with COREG CR than with Placebo in Subjects with Hypertension (Incidence ≥ 1% in Subjects Treated with Carvedilol, Regardless of Causality)

The following information describes the safety experience in hypertension with immediate-release carvedilol.

Carvedilol has been evaluated for safety in hypertension in more than 2,193 subjects in US clinical trials and in 2,976 subjects in international clinical trials. Approximately 36% of the total treated population received carvedilol for at least 6 months. In general, carvedilol was well tolerated at doses up to 50 mg daily. Most adverse events reported during carvedilol therapy were of mild to moderate severity. In US controlled clinical trials directly comparing carvedilol monotherapy in doses up to 50 mg (n = 1,142) with placebo (n = 462), 4.9% of carvedilol subjects discontinued for adverse events versus 5.2% of placebo subjects. Although there was no overall difference in discontinuation rates, discontinuations were more common in the carvedilol group for postural hypotension (1% versus 0). The overall incidence of adverse events in US placebo-controlled trials was found to increase with increasing dose of carvedilol. For individual adverse events this could only be distinguished for dizziness, which increased in frequency from 2% to 5% as total daily dose increased from 6.25 mg to 50 mg as single or divided doses.

Table 4 shows adverse events in US placebo-controlled clinical trials for hypertension that occurred with an incidence of greater than or equal to 1% regardless of causality, and that were more frequent in drug-treated subjects than placebo-treated subjects.

Table 4: Adverse Events (% Occurrence) in US Placebo-Controlled Hypertension Trials with Immediate-Release Carvedilol (Incidence ≥ 1% in Subjects Treated with Carvedilol, Regardless of Causality)*

Dyspnea and fatigue were also reported in these trials, but the rates were equal or greater in subjects who received placebo.

The following adverse events not described above were reported as possibly or probably related to carvedilol in worldwide open or controlled trials with carvedilol in subjects with hypertension or heart failure.

Cardiovascular: Peripheral ischemia, tachycardia.

Central and Peripheral Nervous System: Hypokinesia.

Gastrointestinal: Bilirubinemia, increased hepatic enzymes (0.2% of hypertension patients and 0.4% of heart failure patients were discontinued from therapy because of increases in hepatic enzymes) [see Laboratory Abnormalities].

Psychiatric: Nervousness, sleep disorder, aggravated depression, impaired concentration, abnormal thinking, paroniria, emotional lability.

Respiratory System: Asthma [see CONTRAINDICATIONS].

Reproductive, male: Decreased libido.

Skin and Appendages: Pruritus, rash erythematous, rash maculopapular, rash psoriaform, photosensitivity reaction.

Special Senses: Tinnitus.

Urinary System: Micturition frequency increased.

Autonomic Nervous System: Dry mouth, sweating increased.

Metabolic and Nutritional: Hypokalemia, hypertriglyceridemia.

Hematologic: Anemia, leukopenia.

The following events were reported in less than or equal to 0.1% of subjects and are potentially important: complete AV block, bundle branch block, myocardial ischemia, cerebrovascular disorder, convulsions, migraine, neuralgia, paresis, anaphylactoid reaction, alopecia, exfoliative dermatitis, amnesia, GI hemorrhage, bronchospasm, pulmonary edema, decreased hearing, respiratory alkalosis, increased BUN, decreased HDL, pancytopenia, and atypical lymphocytes.

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 subjects 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, subjects treated with carvedilol had lower values for hepatic transaminases than subjects 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 subjects; fasting serum glucose was not evaluated in the heart failure clinical trials.

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.

Aplastic anemia.

Hypersensitivity (e.g., anaphylactic reactions, angioedema, urticaria).

Urinary incontinence.

Interstitial pneumonitis.

Stevens-Johnson syndrome, toxic epidermal necrolysis, erythema multiforme.

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.

Pharmacodynamics

The basis for the beneficial effects of carvedilol in patients with heart failure and in patients with left ventricular dysfunction following an acute myocardial infarction is not known. The concentration-response relationship for β1-blockade following administration of COREG CR is equivalent (±20%) to immediate-release carvedilol tablets.

The mechanism by which β-blockade produces an antihypertensive effect has not been established.

β-adrenoreceptor blocking activity has been demonstrated in animal and human studies showing that carvedilol (1) reduces cardiac output in normal subjects; (2) reduces exercise- and/or isoproterenol-induced tachycardia; and (3) reduces reflex orthostatic tachycardia. Significant β-adrenoreceptor blocking effect is usually seen within 1 hour of drug administration.

α1-adrenoreceptor blocking activity has been demonstrated in human and animal studies, showing that carvedilol (1) attenuates the pressor effects of phenylephrine; (2) causes vasodilation; and (3) reduces peripheral vascular resistance. These effects contribute to the reduction of blood pressure and usually are seen within 30 minutes of drug administration.

Due to the α1-receptor blocking activity of carvedilol, blood pressure is lowered more in the standing than in the supine position, and symptoms of postural hypotension (1.8%), including rare instances of syncope, can occur. Following oral administration, when postural hypotension has occurred, it has been transient and is uncommon when immediate-release carvedilol is administered with food at the recommended starting dose and titration increments are closely followed [see DOSAGE AND ADMINISTRATION].

In a randomized, double-blind, placebo-controlled trial, the β1-blocking effect of COREG CR, as measured by heart rate response to submaximal bicycle ergometry, was shown to be equivalent to that observed with immediate-release carvedilol at steady state in adult subjects with essential hypertension.

In hypertensive subjects with normal renal function, therapeutic doses of carvedilol decreased renal vascular resistance with no change in glomerular filtration rate or renal plasma flow. Changes in excretion of sodium, potassium, uric acid, and phosphorus in hypertensive patients with normal renal function were similar after carvedilol and placebo.

Carvedilol has little effect on plasma catecholamines, plasma aldosterone, or electrolyte levels, but it does significantly reduce plasma renin activity when given for at least 4 weeks. It also increases levels of atrial natriuretic peptide.

Pharmacokinetics

Carvedilol is rapidly and extensively absorbed following oral administration of immediate-release carvedilol tablets, with an absolute bioavailability of approximately 25% to 35% due to a significant degree of first-pass metabolism. COREG CR extended-release capsules have approximately 85% of the bioavailability of immediate-release carvedilol tablets. For corresponding dosages [see DOSAGE AND ADMINISTRATION], the exposure (AUC, Cmax, trough concentration) of carvedilol as COREG CR extended-release capsules is equivalent to those of immediate-release carvedilol tablets when both are administered with food. The absorption of carvedilol from COREG CR is slower and more prolonged compared with the immediate-release carvedilol tablet with peak concentrations achieved approximately 5 hours after administration. Plasma concentrations of carvedilol increase in a dose-proportional manner over the dosage range of COREG CR 10 to 80 mg. Within-subject and between-subject variability for AUC and Cmax is similar for COREG CR and immediate-release carvedilol.

Effect of Food: Administration of COREG CR with a high-fat meal resulted in increases (~20%) in AUC and Cmax compared with COREG CR administered with a standard meal. Decreases in AUC (27%) and Cmax (43%) were observed when COREG CR was administered in the fasted state compared with administration after a standard meal. COREG CR should be taken with food.

In a trial with adult subjects, sprinkling the contents of the COREG CR capsule on applesauce did not appear to have a significant effect on overall exposure (AUC) compared with administration of the intact capsule following a standard meal, but did result in a decrease in Cmax (18%).

Carvedilol is more than 98% bound to plasma proteins, primarily with albumin. The plasma-protein binding is independent of concentration over the therapeutic range. Carvedilol is a basic, lipophilic compound with a steady-state volume of distribution of approximately 115 L, indicating substantial distribution into extravascular tissues.

Carvedilol is extensively metabolized. Following oral administration of radiolabelled carvedilol to healthy volunteers, carvedilol accounted for only about 7% of the total radioactivity in plasma as measured by AUC. Less than 2% of the dose was excreted unchanged in the urine. Carvedilol is metabolized primarily by aromatic ring oxidation and glucuronidation. The oxidative metabolites are further metabolized by conjugation via glucuronidation and sulfation. The metabolites of carvedilol are excreted primarily via the bile into the feces. Demethylation and hydroxylation at the phenol ring produce 3 active metabolites with β-receptor blocking activity. Based on preclinical studies, the 4'-hydroxyphenyl metabolite is approximately 13 times more potent than carvedilol for β-blockade.

Compared with carvedilol, the 3 active metabolites exhibit weak vasodilating activity. Plasma concentrations of the active metabolites are about one-tenth of those observed for carvedilol and have pharmacokinetics similar to the parent.

Carvedilol undergoes stereoselective first-pass metabolism with plasma levels of R(+)-carvedilol approximately 2 to 3 times higher than S(-)-carvedilol following oral administration of COREG CR in healthy subjects. Apparent clearance is 90 L per h and 213 L per h for R(+)- and S(-)-carvedilol, respectively.

The primary P450 enzymes responsible for the metabolism of both R(+) and S(-)-carvedilol in human liver microsomes were CYP2D6 and CYP2C9 and to a lesser extent CYP3A4, 2C19, 1A2, and 2E1. CYP2D6 is thought to be the major enzyme in the 4'- and 5'-hydroxylation of carvedilol, with a potential contribution from 3A4. CYP2C9 is thought to be of primary importance in the O-methylation pathway of S(-)-carvedilol.

Carvedilol is subject to the effects of genetic polymorphism with poor metabolizers of debrisoquin (a marker for cytochrome P450 2D6) exhibiting 2- to 3-fold higher plasma concentrations of R(+)-carvedilol compared with extensive metabolizers. In contrast, plasma levels of S(-)-carvedilol are increased only about 20% to 25% in poor metabolizers, indicating this enantiomer is metabolized to a lesser extent by cytochrome P450 2D6 than R(+)-carvedilol. The pharmacokinetics of carvedilol do not appear to be different in poor metabolizers of S-mephenytoin (patients deficient in cytochrome P450 2C19).

Specific Populations

Following administration of immediate-release carvedilol tablets, steady-state plasma concentrations of carvedilol and its enantiomers increased proportionally over the dose range in subjects with heart failure. Compared with healthy subjects, subjects with heart failure had increased mean AUC and Cmax values for carvedilol and its enantiomers, with up to 50% to 100% higher values observed in 6 subjects with NYHA class IV heart failure. The mean apparent terminal elimination half-life for carvedilol was similar to that observed in healthy subjects.

For corresponding dose levels [see DOSAGE AND ADMINISTRATION], the steady-state pharmacokinetics of carvedilol (AUC, Cmax, trough concentrations) observed after administration of COREG CR to subjects with chronic heart failure (mild, moderate, and severe) were similar to those observed after administration of immediate-release carvedilol tablets.

For corresponding dose levels [see DOSAGE AND ADMINISTRATION], the pharmacokinetics (AUC, Cmax, and trough concentrations) observed with administration of COREG CR were equivalent (±20%) to those observed with immediate-release carvedilol tablets following repeat dosing in subjects with essential hypertension.

Plasma levels of carvedilol average about 50% higher in the elderly compared with young subjects after administration of immediate-release carvedilol.

No trials have been performed with COREG CR in subjects with hepatic impairment. Compared with healthy subjects, subjects with severe liver impairment (cirrhosis) exhibit a 4- to 7-fold increase in carvedilol levels. Carvedilol is contraindicated in patients with severe liver impairment.

No trials have been performed with COREG CR in subjects with renal impairment. Although carvedilol is metabolized primarily by the liver, plasma concentrations of carvedilol have been reported to be increased in patients with renal impairment after dosing with immediate-release carvedilol. Based on mean AUC data, approximately 40% to 50% higher plasma concentrations of carvedilol were observed in hypertensive subjects with moderate to severe renal impairment compared with a control group of hypertensive subjects with normal renal function. However, the ranges of AUC values were similar for both groups. Changes in mean peak plasma levels were less pronounced, approximately 12% to 26% higher in subjects with impaired renal function.

Consistent with its high degree of plasma protein binding, carvedilol does not appear to be cleared significantly by hemodialysis.

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 trials were performed with immediate-release carvedilol tablets.

In a pharmacokinetic trial conducted in 106 Japanese subjects with heart failure, coadministration of small loading and maintenance doses of amiodarone with carvedilol resulted in at least a 2-fold increase in the steady-state trough concentrations of S(-)-carvedilol [see DRUG INTERACTIONS].

In a pharmacokinetic trial conducted in 10 healthy male subjects, cimetidine (1,000 mg per day) increased the steady-state AUC of carvedilol by 30% with no change in Cmax [see DRUG INTERACTIONS].

Following concomitant administration of carvedilol (25 mg once daily) and digoxin (0.25 mg once daily) for 14 days, steady-state AUC and trough concentrations of digoxin were increased by 14% and 16%, respectively, in 12 hypertensive subjects [see DRUG INTERACTIONS].

In 12 healthy subjects, combined administration of carvedilol (25 mg once daily) and a single dose of glyburide did not result in a clinically relevant pharmacokinetic interaction for either compound.

A single oral dose of carvedilol 25 mg did not alter the pharmacokinetics of a single oral dose of hydrochlorothiazide 25 mg in 12 subjects with hypertension. Likewise, hydrochlorothiazide had no effect on the pharmacokinetics of carvedilol.

In a pharmacokinetic trial conducted in 8 healthy male subjects, rifampin (600 mg daily for 12 days) decreased the AUC and Cmax of carvedilol by about 70% [see DRUG INTERACTIONS].

In a trial of 12 healthy subjects, combined oral administration of carvedilol 25 mg once daily and torsemide 5 mg once daily for 5 days did not result in any significant differences in their pharmacokinetics compared with administration of the drugs alone.

Carvedilol (12.5 mg twice daily) did not have an effect on the steady-state prothrombin time ratios and did not alter the pharmacokinetics of R(+)- and S(-)-warfarin following concomitant administration with warfarin in 9 healthy volunteers.

Clinical Studies

Support for the use of COREG CR extended-release capsules for the treatment of mild-to-severe heart failure and for patients with left ventricular dysfunction following myocardial infarction is based on the equivalence of pharmacokinetic and pharmacodynamic (β1-blockade) parameters between COREG CR and immediate-release carvedilol [see CLINICAL PHARMACOLOGY].

The clinical trials performed with immediate-release carvedilol in heart failure and left ventricular dysfunction following myocardial infarction are presented below.

Heart Failure

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

Carvedilol was studied in 5 multicenter, placebo-controlled trials, and in 1 active-controlled trial (COMET trial) involving subjects with mild-to-moderate heart failure.

Four US multicenter, double-blind, placebo-controlled trials enrolled 1,094 subjects (696 randomized to carvedilol) with NYHA class II-III heart failure and ejection fraction less than or equal to 0.35. The vast majority were on digitalis, diuretics, and an ACE inhibitor at trial entry. Subjects were assigned to the trials based upon exercise ability. An Australia-New Zealand double-blind, placebo-controlled trial enrolled 415 subjects (half randomized to immediate-release carvedilol) with less severe heart failure. All protocols excluded subjects expected to undergo cardiac transplantation during the 7.5 to 15 months of double-blind follow-up. All randomized subjects had tolerated a 2-week course on immediate-release carvedilol 6.25 mg twice daily.

In each trial, there was a primary end point, either progression of heart failure (1 US trial) or exercise tolerance (2 US trials meeting enrollment goals and the Australia-New Zealand trial). There were many secondary end points specified in these trials, including NYHA classification, patient and physician global assessments, and cardiovascular hospitalization. Other analyses not prospectively planned included the sum of deaths and total cardiovascular hospitalizations. In situations where the primary end points of a trial do not show a significant benefit of treatment, assignment of significance values to the other results is complex, and such values need to be interpreted cautiously.

The results of the US and Australia-New Zealand trials were as follows:

Slowing Progression of Heart Failure: One US multicenter trial (366 subjects) had as its primary end point the sum of cardiovascular mortality, cardiovascular hospitalization, and sustained increase in heart failure medications. Heart failure progression was reduced, during an average follow-up of 7 months, by 48% (P = 0.008).

In the Australia-New Zealand trial, death and total hospitalizations were reduced by about 25% over 18 to 24 months. In the 3 largest US trials, death and total hospitalizations were reduced by 19%, 39%, and 49%, nominally statistically significant in the last 2 trials. The Australia-New Zealand results were statistically borderline.

Functional Measures: None of the multicenter trials had NYHA classification as a primary end point, but all such trials had it as a secondary end point. There was at least a trend toward improvement in NYHA class in all trials. Exercise tolerance was the primary end point in 3 trials; in none was a statistically significant effect found.

Subjective Measures: Health-related quality of life, as measured with a standard questionnaire (a primary end point in 1 trial), was unaffected by carvedilol. However, patients' and investigators' global assessments showed significant improvement in most trials.

Mortality: Death was not a pre-specified end point in any trial, but was analyzed in all trials. Overall, in these 4 US trials, mortality was reduced, nominally significantly so in 2 trials.

In this double-blind trial, 3,029 subjects with NYHA class II-IV heart failure (left ventricular ejection fraction less than or equal to 35%) were randomized to receive either carvedilol (target dose: 25 mg twice daily) or immediate-release metoprolol tartrate (target dose: 50 mg twice daily). The mean age of the subjects was approximately 62 years, 80% were males, and the mean left ventricular ejection fraction at baseline was 26%. Approximately 96% of the subjects had NYHA class II or III heart failure. Concomitant treatment included diuretics (99%), ACE inhibitors (91%), digitalis (59%), aldosterone antagonists (11%), and “statin” lipid-lowering agents (21%). The mean duration of follow-up was 4.8 years. The mean dose of carvedilol was 42 mg per day.

The trial had 2 primary end points: all-cause mortality and the composite of death plus hospitalization for any reason. The results of COMET are presented in Table 5 below. All-cause mortality carried most of the statistical weight and was the primary determinant of the trial size. All-cause mortality was 34% in the subjects treated with carvedilol and was 40% in the immediate-release metoprolol group (P = 0.0017; hazard ratio = 0.83, 95% CI: 0.74 to 0.93). The effect on mortality was primarily due to a reduction in cardiovascular death. The difference between the 2 groups with respect to the composite end point was not significant (P = 0.122). The estimated mean survival was 8.0 years with carvedilol and 6.6 years with immediate-release metoprolol.

Table 5: Results of COMET

It is not known whether this formulation of metoprolol at any dose or this low dose of metoprolol in any formulation has any effect on survival or hospitalization in patients with heart failure. Thus, this trial extends the time over which carvedilol manifests benefits on survival in heart failure, but it is not evidence that carvedilol improves outcome over the formulation of metoprolol (TOPROL-XL®) with benefits in heart failure.

In a double-blind trial, 2,289 subjects with heart failure at rest or with minimal exertion and left ventricular ejection fraction less than 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 trial 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 to 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 Subjects with Severe Heart Failure

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 subjects without worsening heart failure.

Patients' global assessments, in which carvedilol-treated subjects were compared with placebo, were based on pre-specified, periodic patient self-assessments regarding whether clinical status post-treatment showed improvement, worsening, or no change compared with baseline. Subjects 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 subjects 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 trial 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.

Left Ventricular Dysfunction Following Myocardial Infarction

CAPRICORN was a double-blind trial comparing carvedilol and placebo in 1,959 subjects with a recent myocardial infarction (within 21 days) and left ventricular ejection fraction of less than or equal to 40%, with (47%) or without symptoms of heart failure. Subjects given carvedilol received 6.25 mg twice daily, titrated as tolerated to 25 mg twice daily. Subjects had to have a systolic blood pressure greater than 90 mm Hg, a sitting heart rate greater than 60 beats per 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 subjects 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 trial 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.

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 subjects with essential hypertension (sitting diastolic blood pressure [DBP] greater than or equal to 90 and less than or equal to 109 mm Hg). Of 337 evaluable subjects, a total of 273 subjects (81%) completed the trial. Of the 64 (19%) subjects withdrawn from the trial, 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 subjects 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 with 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 to 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 to 7 h) ratio was approximately 0.6 for COREG CR 80 mg. In this trial, 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 trials, the starting dose did not exceed 12.5 mg. At 50 mg per day, COREG reduced sitting trough (12-hour) blood pressure by about 9/5.5 mm Hg; at 25 mg per 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 per minute at 50 mg per day. In general, as is true for other β-blockers, responses were smaller in black than non-black subjects. 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].

Hypertension With Type 2 Diabetes Mellitus

In a double-blind trial (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].

You should not take this medication if you are allergic to carvedilol, or if you have:

• asthma, bronchitis, emphysema;
• severe liver disease; or
• a serious heart condition such as heart block, sick sinus syndrome, or slow heart rate (unless you have a pacemaker).

To make sure you can safely take carvedilol, tell your doctor if you have any of these other conditions:

• diabetes (taking carvedilol can make it harder for you to tell when you have low blood sugar);
• angina (chest pain);
• low blood pressure;
• kidney disease;
• liver disease;
• a thyroid disorder;
• pheochromocytoma (tumor of the adrenal gland);
• circulation problems (such as Raynaud's syndrome); or
• a history of allergies.

FDA pregnancy category C. It is not known whether carvedilol will harm an unborn baby. Tell your doctor if you are pregnant or plan to become pregnant while using this medication.

It is not known whether carvedilol passes into breast milk or if it could harm a nursing baby. You should not breast-feed while you are taking carvedilol.

Carvedilol may impair your thinking or reactions. Be careful if you drive or do anything that requires you to be alert.

Avoid drinking alcohol within 2 hours before or after taking extended-release carvedilol (Coreg CR). Also avoid taking medicines or other products that might contain alcohol. Alcohol may cause the carvedilol in Coreg CR to be released too quickly into the body. Check the labels of any prescription or over-the-counter medicines you take to see if they contain alcohol (also called ethanol).

Avoid getting up too fast from a sitting or lying position, or you may feel dizzy. Get up slowly and steady yourself to prevent a fall.

Your pharmacist can provide more information about carvedilol.

Remember, keep this and all other medicines out of the reach of children, never share your medicines with others, and use this medication only for the indication prescribed.

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