Carvedilol

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# Overview
Carvedilol is an alpha-adrenergic blocker, beta-adrenergic blocker that is FDA approved for the {{{indicationType}}} of heart failure, left ventricular dysfunction following myocardial infarction, hypertension.   Common adverse reactions include bradyarrhythmia, hypotension, peripheral edema, abnormal weight gain, hyperglycemia, dizziness, fatigue..

# Adult Indications and Dosage

## FDA-Labeled Indications and Dosage (Adult)
- Dosing Information
- DOSAGE MUST BE INDIVIDUALIZED AND CLOSELY MONITORED BY A PHYSICIAN DURING UPTITRATION. Prior to initiation of carvedilol, it is recommended that fluid retention be minimized. The recommended starting dose of carvedilol 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 carvedilol from that of the ACE inhibitor or to reduce temporarily the dose of the ACE inhibitor. The dose of carvedilol 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 carvedilol should be reduced if patients experience bradycardia (heart rate <55 beats/minute).
Episodes of dizziness or fluid retention during initiation of carvedilol can generally be managed without discontinuation of treatment and do not preclude subsequent successful titration of, or a favorable response to, carvedilol.
- Dosing information
- DOSAGE MUST BE INDIVIDUALIZED AND MONITORED DURING UPTITRATION. Treatment with carvedilol 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 carvedilol 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 uptitration 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 blocker during the acute phase of the myocardial infarction.
- Dosing information
- DOSAGE MUST BE INDIVIDUALIZED. The recommended starting dose of carvedilol is 20 mg once daily. If this dose is tolerated, using standing systolic pressure measured about 1 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 1 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 carvedilol would be seen within 7 to 14 days as had been demonstrated with immediaterelease 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 carvedilol action.

## Off-Label Use and Dosage (Adult)

### Guideline-Supported Use
- Dosing information
- 6.25 mg bid, then titrated to a maximum of 25 mg bid

### NonGuideline-Supported Use
- Dosing information
- 25 to 50 mg twice daily
- Dosing information
- Titrate to a maximum dosage of 25 mg bid, 50 mg for patient >85 kg
- Dosing information
- 6.25 mg bid, then titrated to 25-50 mg bid
- Dosing information
- 3.125 mg bid, then titrated every 2 weeks to a maximum of 25 mg bid
- Dosing information
- 2.5 to 20 mg daily
- Dosing information
- 12.5 to 25 mg daily
- Dosing information
- 6.25 mg daily, then titrated to 12.5 mg daily
- Dosing information
- 3.125 mg bid, titrate to 25 mg bid

# Pediatric Indications and Dosage

## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding Carvedilol FDA-Labeled Indications and Dosage (Pediatric) in the drug label.

## Off-Label Use and Dosage (Pediatric)

### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Carvedilol in pediatric patients.

### NonGuideline-Supported Use
There is limited information regarding Off-Label NonGuideline-Supported Use of Carvedilol in pediatric patients.

# Contraindications
Carvedilol is contraindicated in the following conditions:
- Bronchial asthma or related bronchospastic conditions. Deaths from status asthmaticus have been reported following single doses of COREG.
- AV block (Second- or third-degree)
- Sick sinus syndrome
- Severe bradycardia (unless a permanent pacemaker is in place).
- Cardiogenic shock or who have decompensated heart failure requiring the use of intravenous inotropic therapy. Such patients should first be weaned from intravenous therapy before initiating COREG
- Severe hepatic impairment
- Serious hypersensitivity reaction (e.g., Stevens-Johnson syndrome, anaphylactic reaction, angioedema) to any component of this medication or other medications containing carvedilol.

# Warnings
- Acute exacerbation of coronary artery disease upon cessation of therapy: Do not abruptly discontinue.
- Bradycardia, hypotension, fluid retention may occur. Reduce the dose as needed.
- Non-allergic bronchospasm (e.g., chronic bronchitis and emphysema): Avoid -blockers.
- However, if deemed necessary, use with caution and at lowest effective dose.
Diabetes: Monitor glucose as -blockers may mask symptoms of hypoglycemia or worsen hyperglycemia.
Patients with coronary artery disease, who are being treated with carvedilol, should be advised against abrupt discontinuation of therapy. Severe exacerbation of angina and the occurrence of myocardial infarction and ventricular arrhythmias have been reported in angina patients following the abrupt discontinuation of therapy with -blockers. The last 2 complications may occur with or without preceding exacerbation of the angina pectoris. As with other -blockers, when discontinuation of carvedilol is planned, the patients should be carefully observed and advised to limit physical activity to a minimum. carvedilol should be discontinued over 1 to 2 weeks whenever possible. If the angina worsens or acute coronary insufficiency develops, it is recommended that carvedilol be promptly reinstituted, at least temporarily. Because coronary artery disease is common and may be unrecognized, it may be prudent not to discontinue therapy with carvedilol abruptly even in patients treated only for hypertension or heart failure.

## Bradycardia
In clinical trials, carvedilol causedbradycardia in about 2% of hypertensive subjects, 9% of heart failure subjects, and 6.5% of myocardial infarction subjects with left ventricular dysfunction. If pulse rate drops below 55 beats/minute, the dosage should be reduced.
In clinical trials of primarily mildtomoderate heart failure, hypotension and postural hypotension occurred in 9.7% and syncope in 3.4% of subjects receiving carvedilol compared with 3.6% and 2.5% of placebo subjects, respectively. The risk for these events was highest during the first 30 days of dosing, corresponding to the uptitration period and was a cause for discontinuation of therapy in 0.7% of subjects receiving carvedilol, compared with 0.4% of placebo subjects. In a longterm, placebocontrolled trial in severe heart failure (COPERNICUS), hypotension and postural hypotension occurred in 15.1% and syncope in 2.9% of heart failure subjects receiving carvedilol compared with 8.7% and 2.3% of placebo subjects, respectively. These events were a cause for discontinuation of therapy in 1.1% of subjects receiving carvedilol, compared with 0.8% of placebo subjects.
Postural hypotension occurred in 1.8% and syncope in 0.1% of hypertensive subjects, primarily following the initial dose or at the time of dose increase and was a cause for discontinuation of therapy in 1% of subjects.
In the CAPRICORN trial of survivors of an acutemyocardial infarction, hypotension or postural hypotension occurred in 20.2% of subjects receiving carvedilol compared with 12.6% of placebo subjects. Syncope was reported in 3.9% and 1.9% of subjects, respectively. These events were a cause for discontinuation of therapy in 2.5% of subjects receiving carvedilol, compared with 0.2% of placebo subjects.
Starting with a low dose, administration with food, and gradual up-titration should decrease the likelihood of syncope or excessive hypotension . 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.
Worsening heart failure or fluid retention may occur during up-titration of carvedilol. If such symptoms occur, diuretics should be increased and the carvedilol dose should not be advanced until clinical stability resumes . Occasionally it is necessary to lower the carvedilol dose or temporarily discontinue it. Such episodes do not preclude subsequent successful titration of, or a favorable response to, carvedilol. In a placebo-controlled trial of subjects with severe heart failure, worsening heart failure during the first 3 months was reported to a similar degree with carvedilol and with placebo. When treatment was maintained beyond 3 months, worsening heart failure was reported less frequently in subjects 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.
Patients with bronchospastic disease (e.g., chronic bronchitis and emphysema) should, in general, not receive -blockers. carvedilol may be used with caution, however, in patients who do not respond to, or cannot tolerate, other antihypertensive agents. It is prudent, if carvedilol is used, to use the smallest effective dose, so that inhibition of endogenous or exogenous -agonists is minimized.
In clinical trials of subjects with heart failure, subjects with bronchospastic disease were enrolled if they did not require oral or inhaled medication to treat their bronchospastic disease. In such patients, it is recommended that carvedilol be used with caution. The dosing recommendations should be followed closely and the dose should be lowered if any evidence of bronchospasm is observed during up-titration.
In general, -blockers may mask some of the manifestations of hypoglycemia, particularly tachycardia. Nonselective -blockers may potentiate insulin-induced hypoglycemia and delay recovery of serum glucose levels. Patients subject to spontaneous hypoglycemia, or diabetic patients receiving insulin or oral hypoglycemic agents, should be cautioned about these possibilities.
In heart failure patients with diabetes, carvedilol therapy may lead to worsening hyperglycemia, which responds to intensification of hypoglycemic therapy. It is recommended that blood glucose be monitored when carvedilol dosing is initiated, adjusted, or discontinued. Trials designed to examine the effects of carvedilol on glycemic control in patients with diabetes and heart failure have not been conducted.
In a trial designed to examine the effects of carvedilol on glycemic control in a population with mild-to-moderate hypertension and well-controlled type 2diabetes mellitus, carvedilol had no adverse effect on glycemic control, based on HbA1c measurements [see Carvidilol clinical studies

# Adverse Reactions

## 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 carvedilol 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 nonelderly, blacks and nonblacks). Carvedilol 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 carvedilol 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 carvedilol and immediate-release carvedilol.
Heart Failure
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 placebocontrolled clinical trials. Approximately 60% of the total treated population in placebocontrolled 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 mildtomoderate heart failure were treated with carvedilol for up to 5.9 years (mean: 4.8 years). Both in US clinical trials in mildtomoderate 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 placebocontrolled clinical trials, the only cause of discontinuation >1%, and occurring more often on carvedilol was dizziness (1.3% on carvedilol, 0.6% on placebo in the COPERNICUS trial).
The table below shows adverse events reported in subjects with mildtomoderate heart failure enrolled in US placebocontrolled clinical trials, and with severe heart failure enrolled in the COPERNICUS trial. Shown are adverse events that occurred more frequently in drugtreated subjects than placebotreated subjects with an incidence of >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 mildtomoderate 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.
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 >1% but 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.
Incidence >1% to 3%
- Body as a Whole: Allergy, malaise, hypovolemia, fever, leg edema.
- Cardiovascular: Fluid overload, orthostatic 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.
Left Ventricular Dysfunction Following Myocardial Infarction
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 >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 >1% but 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 >1%, and occurring more often on carvedilol was hypotension (1.5% on carvedilol, 0.2% on placebo).
Hypertension
Carvedilol was evaluated for safety in an 8-week double-blind trial in 337 subjects with essential hypertension. The profile of adverse events observed with carvedilol was generally similar to that observed with immediate-release carvedilol. The overall rates of discontinuations due to adverse events were similar between carvedilol 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 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 orthostatic hypotension (1% versus 0). The overall incidence of adverse events in US placebocontrolled 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.
The table below shows adverse events in US placebocontrolled clinical trials for hypertension that occurred with an incidence of 1% regardless of causality, and that were more frequent in drugtreated subjects than placebotreated subjects.
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 >0.1% 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).
Psychiatric: Nervousness, sleep disorder, aggravated depression, impaired concentration, abnormal thinking, paroniria, emotional lability.
- Respiratory System: Asthma.
- 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 0.1% of subjects and are potentially important: complete AV block, bundle branch block, myocardial ischemia, cerebrovascular disorder, seizures, 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 carvedilol. 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.

# Drug Interactions
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. 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 blocking R(+) enantiomer.
Patients taking both agents with 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 blocking properties may potentiate blood pressure and heart rate lowering effects. When concomitant treatment with agents with blocking properties and clonidine is to be terminated, the blocking agent should be discontinued first. Clonidine therapy can then be discontinued several days later by gradually decreasing the dosage.
Modest increases in mean trough cyclosporine concentrations were observed following initiation of carvedilol treatment in 21 renal transplant subjects suffering from chronic vascular rejection. In about 30% of subjects, 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 subjects. 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.
Both digitalis glycosides and 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 carvedilol.
Rifampin reduced plasma concentrations of carvedilol by about 70%. Cimetidine increased area under the curve (AUC) by about 30% but caused no change in Cmax.
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. The concomitant administration of amiodarone or other CYP2C9 inhibitors such as fluconazole with carvedilol may enhance the 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.
Conduction disturbance (rarely with hemodynamic compromise) has been observed when carvedilol is coadministered with diltiazem. As with other agents with blocking properties, if carvedilol 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.
Agents with blocking properties may enhance the bloodsugarreducing effect of insulin and oral hypoglycemics. Therefore, in patients taking insulin or oral hypoglycemics, regular monitoring of blood glucose is recommended.
There is no clinically meaningful increase in AUC and Cmax with concomitant administration of carvedilol extendedrelease capsules with pantoprazole.
If treatment with carvedilol is to be continued perioperatively, particular care should be taken when anesthetic agents which depress myocardial function, such as ether, cyclopropane, and trichloroethylene, are used.

# Use in Specific Populations

### Pregnancy
Pregnancy Category (FDA): 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  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. Carvedilol should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Pregnancy Category (AUS): 
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Carvedilol in women who are pregnant.

### Labor and Delivery
There is no FDA guidance on use of Carvedilol during labor and delivery.

### 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 -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 -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 - and -blocking agents have included perinatal and neonatal distress.

### Pediatric Use
Effectiveness of carvedilol in patients younger than 18 years 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) with chronic heart failure  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 to 6 heart beats per minute, indicative of -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 subjects treated with carvedilol and at twice the rate of placebo-treated subjects included chest pain (17% versus 6%), dizziness (13% versus 2%), and dyspnea (11% versus 0%).

### Geriatic Use
The initial clinical trials of COREG CR in subjects 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 trial (n = 405) comparing subjects with mild to severe heart failure switched to carvedilol or maintained on immediate-release carvedilol included 220 subjects 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 subjects switched from the highest dose of immediate-release carvedilol (25 mg twice daily) to the highest dose of carvedilol (80 mg once daily) compared with 11% (4/36) in subjects maintained on immediate-release carvedilol (25 mg twice daily). When switching from the higher doses of immediate-release carvedilol to carvedilol, a lower starting dose is recommended for elderly patients.
The following information is available for trials with immediate-release carvedilol. Of the 765 subjects 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 subjects randomized to carvedilol in a longterm, placebocontrolled 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 subjects receiving carvedilol in heart failure trials worldwide, 42% were 65 years of age or older. Of the 975 subjects with myocardial infarction 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 subjects 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 subjects 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 subjects (incidence 8.8% in the elderly versus 6% in younger subjects), no overall differences in the safety or effectiveness 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.

### Gender
There is no FDA guidance on the use of Carvedilol with respect to specific gender populations.

### Race
There is no FDA guidance on the use of Carvedilol with respect to specific racial populations.

### Renal Impairment
There is no FDA guidance on the use of Carvedilol in patients with renal impairment.

### Hepatic Impairment
Carvedilol is contraindicated in patients with severe liver impairment.

### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Carvedilol in women of reproductive potentials and males.

### Immunocompromised Patients
There is no FDA guidance one the use of Carvedilol in patients who are immunocompromised.

# Administration and Monitoring

### Administration
Oral

### Monitoring
DOSAGE MUST BE INDIVIDUALIZED AND CLOSELY MONITORED BY A PHYSICIAN DURING UPTITRATION.

# IV Compatibility
There is limited information regarding the compatibility of Carvedilol and IV administrations.

# Overdosage
Overdosage may cause severe hypotension, bradycardia, cardiac insufficiency, cardiogenic shock, and cardiac arrest. Respiratory problems, bronchospasms, vomiting, lapses of consciousness, and generalized seizures may also occur.
The patient should be placed in a supine position and, where necessary, kept under observation and treated under intensive-care conditions. Gastric lavage or pharmacologically induced emesis may be used shortly after ingestion. The following agents may be administered:
- For excessive bradycardia: atropine, 2 mg IV.
- To support cardiovascular function: glucagon, 5 to 10 mg IV rapidly over 30 seconds, followed by a continuous infusion of 5 mg/hour; sympathomimetics (dobutamine, isoprenaline, adrenaline) at doses according to body weight and effect.
If peripheral vasodilation dominates, it may be necessary to administer adrenaline or noradrenaline with continuous monitoring of circulatory conditions. For therapy-resistant bradycardia, pacemaker therapy should be performed. For bronchospasm, sympathomimetics (as aerosol or IV) or aminophylline IV should be given. In the event of seizures, slow IV injection of diazepam or clonazepam is recommended.
NOTE: In the event of severe intoxication where there are symptoms of shock, treatment with antidotes must be continued for a sufficiently long period of time consistent with the 7- to 10-hour half-life of carvedilol.
There is no experience of overdosage with carvedilol. Cases of overdosage with carvedilol alone or in combination with other drugs have been reported. Quantities ingested in some cases exceeded 1,000 milligrams. Symptoms experienced included low blood pressure and heart rate. Standard supportive treatment was provided and individuals recovered.

# Pharmacology

## Mechanism of Action
Carvedilol is a racemic mixture in which nonselective adrenoreceptor blocking activity is present in the S(-) enantiomer and 1adrenergic blocking activity is present in both R(+) and S(-) enantiomers at equal potency. Carvedilol has no intrinsic sympathomimetic activity.

## Structure
Carvedilol phosphate is a nonselective adrenergic blocking agent with 1-blocking activity. It is (2RS)-1-(9H-Carbazol-4-yloxy)-3-((2-(2-methoxyphenoxy)ethyl)amino)propan-2-ol phosphate salt (1:1) hemihydrate. It is a racemic mixture with the following structure:
Carvedilol phosphate is a white to almost white solid with a molecular weight of 513.5 (406.5 carvedilol free base) and a molecular formula of C24H26N2O4H3PO41/2 H2O.
COREG CR is available for once-a-day administration as controlled-release oral capsules containing 10, 20, 40, or 80 mg carvedilol phosphate. Carvedilol hard gelatin capsules are filled with carvedilol phosphate immediate-release and controlled-release microparticles that are drug-layered and then coated with methacrylic acid copolymers. Inactive ingredients include crospovidone, hydrogenated castor oil, hydrogenated vegetable oil, magnesium stearate, methacrylic acid copolymers, microcrystalline cellulose, and povidone.

## 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 1blockade following administration of carvedilol is equivalent (20%) to immediate-release carvedilol tablets.
The mechanism by which blockade produces an antihypertensive effect has not been established.
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 adrenoreceptor blocking effect is usually seen within 1 hour of drug administration.
1adrenoreceptor 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 1receptor blocking activity of carvedilol, blood pressure is lowered more in the standing than in the supine position, and symptoms of orthostatic 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.
In a randomized, double-blind, placebo-controlled trial, the 1blocking effect of carvedilol, 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. Carvedilol extended-release capsules have approximately 85% of the bioavailability of immediate-release carvedilol tablets. For corresponding dosages, the exposure (AUC, Cmax, trough concentration) of carvedilol as carvedilol extended-release capsules is equivalent to those of immediate-release carvedilol tablets when both are administered with food. The absorption of carvedilol from carvedilol 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 carvedilol 10 to 80 mg. Within-subject and between-subject variability for AUC and Cmax is similar for carvedilol and immediate-release carvedilol.
Effect of Food
Administration of carvedilol with a high-fat meal resulted in increases (~20%) in AUC and Cmax compared with carvedilol administered with a standard meal. Decreases in AUC (27%) and Cmax (43%) were observed when carvedilol was administered in the fasted state compared with administration after a standard meal. Carvedilol should be taken with food.
In a trial with adult subjects, sprinkling the contents of the carvedilol 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 receptor blocking activity. Based on preclinical studies, the 4'-hydroxyphenyl metabolite is approximately 13 times more potent than carvedilol for 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 carvedilol in healthy subjects. Apparent clearance is 90 L/h and 213 L/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).
Heart Failure
Following administration of immediate-release carvedilol tablets, steadystate 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 halflife for carvedilol was similar to that observed in healthy subjects.
For corresponding dose levels, the steady-state pharmacokinetics of carvedilol (AUC, Cmax, trough concentrations) observed after administration of carvedilol to subjects with chronic heart failure (mild, moderate, and severe) were similar to those observed after administration of immediate-release carvedilol tablets.
Hypertension
For corresponding dose levels, the pharmacokinetics (AUC, Cmax, and trough concentrations) observed with administration of carvedilol were equivalent (20%) to those observed with immediate-release carvedilol tablets following repeat dosing in subjects with essential hypertension.
Geriatric
Plasma levels of carvedilol average about 50% higher in the elderly compared with young subjects after administration of immediate-release carvedilol.
Hepatic Impairment
No trials have been performed with carvedilol in subjects with hepatic impairment. Compared with healthy subjects, subjects with severe hepatic impairment (cirrhosis) exhibit a 4- to 7-fold increase in carvedilol levels. Carvedilol is contraindicated in patients with severe liver impairment.
Renal Impairment
No trials have been performed with carvedilol 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.

## Nonclinical Toxicology
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).

# Clinical Studies
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.
Mild-to-Moderate Heart Failure
Carvedilol was studied in 5 multicenter, placebocontrolled trials, and in 1 active-controlled trial (COMET trial) involving subjects with mild-to-moderate heart failure.
Four US multicenter, doubleblind, placebocontrolled trials enrolled 1,094 subjects (696 randomized to carvedilol) with NYHA class IIIII heart failure and ejection fraction 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 AustraliaNew Zealand doubleblind, placebocontrolled trial enrolled 415 subjects (half randomized to immediaterelease carvedilol) with less severe heart failure. All protocols excluded subjects expected to undergo cardiac transplantation during the 7.5 to 15 months of doubleblind followup. All randomized subjects had tolerated a 2week course on immediaterelease 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 AustraliaNew 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 AustraliaNew 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 followup of 7 months, by 48% (P = 0.008).
In the AustraliaNew 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 AustraliaNew 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.
The COMET Trial
In this double-blind trial, 3,029 subjects with NYHA class II-IV heart failure (left ventricular ejection fraction 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.
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 with benefits in heart failure.
Severe Heart Failure (COPERNICUS)
In a double-blind trial, 2,289 subjects 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 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 allcause mortality, but causespecific mortality and the risk of death or hospitalization (total, cardiovascular , or heart failure ) 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 followup 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). The results of COPERNICUS are shown in the table below.
Cardiovascular = CV; Heart failure = HF.
Figure. 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 carvediloltreated 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 immediaterelease 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).
Immediaterelease carvedilol had a consistent and beneficial effect on allcause mortality as well as the combined end points of allcause 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 nonelderly, blacks and nonblacks, and diabetics and non-diabetics (see Figure 2).
Figure. 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.
CAPRICORN was a doubleblind trial comparing carvedilol and placebo in 1,959 subjects with a recent myocardial infarction (within 21 days) and left ventricular ejection fraction of 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 >90 mm Hg, a sitting heart rate >60 beats/minute, and no contraindication to blocker use. Treatment of the index infarction included aspirin (85%), IV or oral blockers (37%), nitrates (73%), heparin (64%), thrombolytics (40%), and acute angioplasty (12%). Background treatment included ACE inhibitors or angiotensin receptor blockers (97%), anticoagulants (20%), lipidlowering 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 followup was 15 months.
Allcause 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. Survival Analysis for CAPRICORN (Intent-to-Treat)
Figure. 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.
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  90 and 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 2week intervals.
Statistically significant reductions in blood pressure as measured by 24hour 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 24hour ABPM monitoring demonstrated statistically significant blood pressure reductions with COREG CR throughout the dosing period.
Figure. Changes from Baseline in Systolic Blood Pressure and Diastolic Blood Pressure Measured by 24-Hour ABPM
Immediaterelease carvedilol was studied in 2 placebocontrolled trials that utilized twicedaily 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/day, COREG reduced sitting trough (12hour) 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 troughtopeak blood pressure showed a troughtopeak 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 blockers, responses were smaller in black than nonblack subjects. There were no age or genderrelated differences in response. The doserelated blood pressure response was accompanied by a doserelated increase in adverse effects.
In a double-blind trial (GEMINI), carvedilol, added to an ACE inhibitor or angiotensin receptor blocker, was evaluated in a population with mildtomoderate 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).

# How Supplied
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 30s: NDC 0007-3370-13
- 20 mg 30s: NDC 0007-3371-13
- 40 mg 30s: NDC 0007-3372-13
- 80 mg 30s: NDC 0007-3373-13

## Storage
Store at 25C (77F); excursions 15 to 30C (59 to 86F).

# Images

## Drug Images

## Package and Label Display Panel

# Patient Counseling Information
COREG CR is a prescription medicine that belongs to a group of medicines called beta-blockers. COREG CR is used, often with other medicines, for the following conditions:
- to treat patients with certain types of heart failure
- to treat patients who had a heart attack that worsened how well the heart pumps
- to treat patients with high blood pressure (hypertension)
COREG CR is not approved for use in children under 18 years of age.
Do not take carvedilol if you:
- Have severe heart failure and require certain intravenous medicines that help support circulation.
- Have asthma or other breathing problems.
- Have a slow heartbeat or certain conditions that cause your heart to skip a beat (irregular heartbeat).
- Have liver problems.
- Are allergic to any of the ingredients in carvedilol. See What are the ingredients in carvedilol?
Tell your doctor about all of your medical conditions, including if you:
- Have asthma or other lung problems (such as bronchitis or emphysema).
- Have problems with blood flow in your feet and legs (peripheral vascular disease). Carvedilol can make some of your symptoms worse.
- Have diabetes.
- Have thyroid problems.
- Have a condition called pheochromocytoma.
- Have had severe allergic reactions.
- Are scheduled for surgery and will be given anesthetic agents.
- Are scheduled for cataract surgery and have taken or are currently taking carvedilol.
- Are pregnant or trying to become pregnant. It is not known if carvedilol is safe for your unborn baby. You and your doctor should talk about the best way to control your high blood pressure during pregnancy.
- Are breastfeeding. It is not known if carvedilol passes into your breast milk. You should not breastfeed while using carvedilol.
Tell your doctor about all of the medicines you take including prescription and non-prescription medicines, vitamins, and herbal supplements. Carvedilol and certain other medicines can affect each other and cause serious side effects. Carvedilol may affect the way other medicines work. Also, other medicines may affect how well carvedilol works.
Know the medicines you take. Keep a list of your medicines and show it to your doctor and pharmacist before you start a new medicine.
- Take carvedilol exactly as prescribed. Take carvedilol one time each day with food. It is important that you take carvedilol only one time each day. To lessen possible side effects, your doctor might begin with a low dose and then slowly increase the dose.
- Swallow carvedilol capsules whole. Do not chew or crush carvedilol capsules.
- If you have trouble swallowing carvedilol whole:
- The capsule may be carefully opened and the beads sprinkled over a spoonful of applesauce which should be eaten right away. The applesauce should not be warm.
- Do not sprinkle beads on foods other than applesauce.
- Do not stop taking carvedilol and do not change the amount of carvedilol you take without talking to your doctor.
- If you miss a dose of carvedilol, take your dose as soon as you remember, unless it is time to take your next dose. Take your next dose at the usual time. Do not take 2 doses at the same time.
- If you take too much carvedilol, call your doctor or poison control center right away.
Carvedilol 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.
Serious side effects of carvedilol include:
- Chest pain and heart attack if you suddenly stop taking carvedilol.
- Slow heart beat.
- Low blood pressure (which may cause dizziness or fainting when you stand up). If these happen, sit or lie down, and tell your doctor right away.
- Worsening heart failure. Tell your doctor right away if you have signs and symptoms that your heart failure may be worse, such as weight gain or increased shortness of breath.
- Changes in your blood sugar. If you have diabetes, tell your doctor if you have any changes in your blood sugar levels.
- Masking (hiding) the symptoms of low blood sugar, especially a fast heartbeat.
- New or worsening symptoms of peripheral vascular disease.
- Leg pain that happens when you walk, but goes away when you rest.
- No feeling (numbness) in your legs or feet while you are resting.
- Cold legs or feet.
- Masking the symptoms of hyperthyroidism (overactive thyroid), such as a fast heartbeat.
- Worsening of severe allergic reactions. Medicines to treat a severe allergic reaction may not work as well while you are taking carvedilol.
- Rare but serious allergic reactions (including hives or swelling of the face, lips, tongue, and/or throat that may cause difficulty in breathing or swallowing) have happened in patients who were on carvedilol. These reactions can be life-threatening.
Common side effects of carvedilol include shortness of breath, weight gain, diarrhea, and tiredness. If you wear contact lenses, you may have fewer tears or dry eyes that can become bothersome.
Call your doctor if you have any side effects that bother you or dont go away.
Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.
- Store carvedilol at less than 86F (30C).
- Safely throw away carvedilol that is out of date or no longer needed.
- Keep carvedilol and all medicines out of the reach of children.
Medicines are sometimes prescribed for conditions other than those described in patient information leaflets. Do not use carvedilol for a condition for which it was not prescribed. Do not give carvedilol to other people, even if they have the same symptoms you have. It may harm them.
This leaflet summarizes the most important information about carvedilol. If you would like more information, talk with your doctor. You can ask your doctor or pharmacist for information about carvedilol that is written for healthcare professionals.
Active ingredient: carvedilol phosphate
Inactive ingredients: crospovidone, hydrogenated castor oil, hydrogenated vegetable oil, magnesium stearate, methacrylic acid copolymers, microcrystalline cellulose, and povidone
COREG CR capsules come in the following strengths: 10 mg, 20 mg, 40 mg, 80 mg.
Blood pressure is the force of blood in your blood vessels when your heart beats and when your heart rests. You have high blood pressure when the force is too much. High blood pressure makes the heart work harder to pump blood through the body and causes damage to blood vessels. carvedilol can help your blood vessels relax so your blood pressure is lower. Medicines that lower blood pressure may lower your chance of having a stroke or heart attack.

# Precautions with Alcohol
Alcohol-Carvedilol interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.

# Brand Names
Coreg

# Look-Alike Drug Names
Carvedilol - Captopril

# Drug Shortage Status

# Price