Coreg CR

Dosage Forms & Strengths

capsule, extended release

• 10mg
• 20mg
• 40mg
• 80mg

tablet

• 3.125mg
• 6.25mg
• 12.5mg
• 25mg

Congestive Heart Failure

Immediate release

• 3.125 mg PO q12hr for 2 weeks, then increased every 2 weeks as tolerated to 6.25 mg, 12.5 mg, or 25 mg PO twice daily
• Maximum recommended dosage (mild-to-moderate heart failure): <85 kg, 25 mg PO q12hr; >85 kg: 50 mg PO twice daily
• Maximum recommended dosage (severe heart failure): 25 mg PO twice daily

Extended release

• 10 mg/day PO; maintained for 1-2 weeks if tolerated; may be increased to 20 mg/day, 40 mg/day, or 80 mg/day PO if necessary

Hypertension

Immediate release: 6.25 mg PO twice daily initially; after 7-14 days, increased as tolerated, first to 12.5 mg PO twice daily and then to 25 mg PO twice daily

Extended release: 20 mg/day PO; maintained for 1-2 weeks if tolerated; may be increased to 40 mg/day PO if necessary; not to exceed 80 mg/day PO

Left Ventricular Dysfunction Following Myocardial Infarction

Immediate release: 3.125-6.25 mg PO q12hr initially; after 3-10 days, increased as tolerated, first to 12.5 mg PO q12hr and then to 25 mg PO q12hr (target dosage)

Extended release: 10-20 mg/day PO; increased every 3-10 days as tolerated up to 80 mg/day PO (target dosage)

Angina pectoris

25-50 mg PO twice daily

Dosing Modifications

Renal impairment: No dosage adjustments necessary

Hepatic impairment: Contraindicated in severe liver impairment

Conversion to Extended Release Form

3.125 mg twice daily: Administer 10 mg PO qDay

6.25 mg twice daily: Administer 20 mg PO qDay

12.5 mg twice daily: Administer 40 mg PO qDay

25 mg twice daily: Administer 80 mg PO qDay

Administration

To be taken with food

May break capsule and sprinkle on spoonful of applesauce; to be eaten immediately

Safety and efficacy not established

Coreg, Coreg CR

Tablets should be stored at room temperature, 15 C and 30 C (59 F and 86 F).

Coreg CR is part of the drug class:

• Alpha and beta blocking agents

Serious side effects have been reported with Coreg CR including the following:

• Acute exacerbation of coronary artery disease upon cessation of therapy: Do not abruptly discontinue Coreg CR.
• Bradycardia (slow heart rate). Tell your healthcare provider right away if you experience any new or increasing irregularities in your heart rate.
• Hypotension. Hypotension, or low blood pressure, may cause you to feel faint or dizzy. Inadequate fluid intake, excessive sweating, diarrhea, or vomiting can lead to an excessive fall in blood pressure too. Lie down if you feel faint or dizzy. Call your doctor right away.
• Worsening heart failure. Tell your healthcare provider right away if you experience any of the following symptoms:
  • sudden weight gain
  • worsening shortness of breath
  • increased swelling of your feet, legs, or abdomen
  • needing to use more pillows to go to sleep or sleeping in a recliner
  • waking from sleep to catch your breath
  • a cough that does not go away
  • new or increasing irregularities in your heart rate
• Non-allergic bronchospasm (e.g., chronic bronchitis and emphysema): Avoid using Coreg CR in patients with these conditions. 
• Diabetes: Monitor glucose as Coreg CR may mask symptoms of hypoglycemia or worsen hyperglycemia.

Coreg CR can cause you to feel dizzy, tired, or faint. Do not drive a car, use machinery, or do anything that needs you to be alert if you have these symptoms.

Do not take Coreg CR if you:

• Have severe heart failure and are hospitalized in the intensive care unit or require certain intravenous medications that help support circulation (inotropic medications)
• Are prone to asthma or other breathing problems
• Are allergic to carvedilol or to any of its ingredients
• Have a slow heartbeat or a heart that skips a beat (irregular heartbeat)
• Have liver problems

Take Coreg CR exactly as prescribed.

Coreg CR is available in controlled release capsules which are to be swallowed whole once a day with food and a full glass of water. Do not chew, divide or crush Coreg CR capsules.

If you miss a dose, take the missed dose as soon as you remember. If it is almost time for the next dose, skip the missed dose and take your next dose at the regular time. Do not take two doses of Coreg CR at the same time.

Carvedilol is in a group of drugs called beta-blockers. Beta-blockers affect the heart and circulation (blood flow through arteries and veins).

Carvedilol is used to treat heart failure and hypertension (high blood pressure). It is also used after a heart attack that has caused your heart not to pump as well.

Carvedilol may also be used for purposes not listed in this medication guide.

Take the missed dose as soon as you remember. Skip the missed dose if it is almost time for your next scheduled dose. Do not take extra medicine to make up the missed dose.

It is important that your doctor check your progress at regular visits to make sure this medicine is working properly and to allow for changes in the dose.

This medicine may cause dizziness, lightheadedness, or fainting. Make sure you know how you react to this medicine before you drive, use machines, or do anything else that could be dangerous if you are dizzy or not alert.

Dizziness, lightheadedness, or fainting may occur, especially when you get up from a lying or sitting position suddenly. These symptoms are more likely to occur when you begin taking this medicine, or when the dose is increased. Sitting or lying down may help alleviate these unwanted effects.

Before having any kind of surgery (including dental surgery or cataract surgery) or emergency treatment, tell the medical doctor or dentist in charge that you are taking this medicine. A serious eye problem called Intraoperative Floppy Iris Syndrome (IFIS) has occurred in some patients who were taking this medicine or who had recently taken this medicine when they had cataract surgery.

For diabetic patients:

• This medicine may cause changes in your blood sugar levels. Also, this medicine may cover up signs of hypoglycemia (low blood sugar), such as a rapid pulse rate. Check with your doctor if you have these problems or if you notice a change in the results of your blood or urine sugar tests.

For congestive heart failure patients:

• Check with your doctor if you have unexplained weight gain or increased shortness of breath. These may be signs of a worsening of your condition.

For patients who wear contact lenses:

• Carvedilol may cause your eyes to form tears less than they do normally. Check with your doctor if you have dry eyes.

Do not interrupt or stop taking this medicine without first checking with your doctor. Your doctor may want you to gradually reduce the amount you are taking before stopping completely. Some conditions may become worse when the medicine is stopped suddenly, which can be dangerous.

Do not take other medicines unless they have been discussed with your doctor. This includes prescription or nonprescription (over-the-counter [OTC]) medicines and herbal or vitamin supplements.

All drugs may cause side effects. However, many people have no side effects or only have minor side effects. Call your doctor or get medical help if any of these side effects or any other side effects bother you or do not go away:

• Dizziness.
• Feeling tired or weak.
• Loose stools (diarrhea).
• Headache.
• Upset stomach or throwing up.
• Weight gain.
• Joint pain.
• If you wear contact lenses, you may have fewer tears or dry eyes. Call your doctor if this bothers you.

These are not all of the side effects that may occur. If you have questions about side effects, call your doctor. Call your doctor for medical advice about side effects.

You may report side effects to the FDA at 1-800-FDA-1088. You may also report side effects at http://www.fda.gov/medwatch.

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect the rates observed in practice.

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 U.S. 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 U.S. 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 U.S. Heart Failure Trials.

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 U.S. placebo-controlled trials in subjects with mild-to-moderate heart failure or in subjects with severe heart failure in the COPERNICUS trial.

Incidence greater than 1% to less than or equal to 3%

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 U.S. 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.

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 U.S. 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 U.S. 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 U.S. 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 U.S. 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.

a  Shown are events with rate >1% rounded to nearest integer.

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.

Incidence greater than 0.1% to less than or equal to 1%

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 Adverse Reactions (6.2)].

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

Respiratory System: Asthma [see Contraindications (4)].

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.

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.

Blood and Lymphatic System Disorders

Aplastic anemia.

Immune System Disorders

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

Renal and Urinary Disorders

Urinary incontinence.

Respiratory, Thoracic, and Mediastinal Disorders

Interstitial pneumonitis.

Skin and Subcutaneous Tissue Disorders

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

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 (12.2, 12.3)].

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 U.S. 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 U.S. trial) or exercise tolerance (2 U.S. 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 U.S. and Australia‑New Zealand trials were as follows:

Slowing Progression of Heart Failure: One U.S. 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 U.S. 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 U.S. 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 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.

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.

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 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 (6)].

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 (5.6)].

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