Coreg
Carvedilol · Tablet, Film Coated · Oral
Uses
1. INDICATIONS AND USAGE COREG is an alpha-/beta-adrenergic blocking agent indicated for the treatment of: mild to severe chronic heart failure ( 1.1 ) left ventricular dysfunction following myocardial infarction in clinically stable patients ( 1.2 ) hypertension ( 1.3 ) 1.1 Heart Failure COREG is indicated for the treatment of mild-to-severe chronic heart failure of ischemic or cardiomyopathic origin, usually in addition to diuretics, ACE inhibitors, and digitalis, to increase survival and, also, to reduce the risk of hospitalization [see Drug Interactions (7.4) , Clinical Studies (14.1) ]. 1.2 Left Ventricular Dysfunction following Myocardial Infarction COREG is indicated to reduce cardiovascular mortality in clinically stable patients who have survived the acute phase of a myocardial infarction and have a left ventricular ejection fraction of less than or equal to 40% (with or without symptomatic heart failure) [see Clinical Studies (14.2) ]. 1.3 Hypertension COREG is indicated for the management of essential hypertension [see Clinical Studies (14.3 , 14.4) ]. It can be used alone or in combination with other antihypertensive agents, especially thiazide-type diuretics [see Drug Interactions (7.2) ].
Dosage and administration
2 DOSAGE AND ADMINISTRATION COREG should be taken with food to slow the rate of absorption and reduce the incidence of orthostatic effects. Take with food. Individualize dosage and monitor during up-titration. ( 2 ) Heart failure: Start at 3.125 mg twice daily and increase to 6.25, 12.5, and then 25mg twice daily over intervals of at least 2 weeks. Maintain lower doses if higher doses are not tolerated. ( 2.1 ) Left ventricular dysfunction following myocardial infarction. Start at 6.25 mg twice daily and increase to 12.5 mg then 25 mg twice daily after intervals of 3 to 10 days. A lower starting dose or slower titration may be used. ( 2.2 ) Hypertension: Start at 6.25 mg twice daily and increase if needed for blood pressure control to 12.5 mg and then 25 mg twice daily over intervals of 1 to 2 weeks. ( 2.3 ) 2.1 Heart Failure DOSAGE MUST BE INDIVIDUALIZED AND CLOSELY MONITORED BY A PHYSICIAN DURING UP-TITRATION. Prior to initiation of COREG, it is recommended that fluid retention be minimized. The recommended starting dose of COREG is 3.125 mg twice daily for 2 weeks. If tolerated, patients may have their dose increased to 6.25, 12.5, and 25 mg twice daily over successive intervals of at least 2 weeks. Patients should be maintained on lower doses if higher doses are not tolerated. A maximum dose of 50 mg twice daily has been administered to patients with mild-to-moderate heart failure weighing over 85 kg (187 lbs.). 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. During these periods, patients should avoid situations such as driving or hazardous tasks, where symptoms could result in injury. Vasodilatory symptoms often do not require treatment, but it may be useful to separate the time of dosing of COREG from that of the ACE inhibitor or to reduce temporarily the dose of the ACE inhibitor. The dose of COREG should not be increased until symptoms of worsening heart failure or vasodilation have been stabilized. Fluid retention (with or without transient worsening heart failure symptoms) should be treated by an increase in the dose of diuretics. The dose of COREG should be reduced if patients experience bradycardia (heart rate less than 55 beats per minute). Episodes of dizziness or fluid retention during initiation of COREG can generally be managed without discontinuation of treatment and do not preclude subsequent successful titration of, or a favorable response to, carvedilol. 2.2 Left Ventricular Dysfunction following Myocardial Infarction DOSAGE MUST BE INDIVIDUALIZED AND MONITORED DURING UP-TITRATION. Treatment with COREG may be started as an inpatient or outpatient and should be started after the patient is hemodynamically stable and fluid retention has been minimized. It is recommended that COREG be started at 6.25 mg twice daily and increased after 3 to 10 days, based on tolerability, to 12.5 mg twice daily, then again to the target dose of 25 mg twice daily. A lower starting dose may be used (3.125 mg twice daily) and/or the rate of up-titration may be slowed if clinically indicated (e.g., due to low blood pressure or heart rate, or fluid retention). Patients should be maintained on lower doses if higher doses are not tolerated. The recommended dosing regimen need not be altered in patients who received treatment with an IV or oral β-blocker during the acute phase of the myocardial infarction. 2.3 Hypertension DOSAGE MUST BE INDIVIDUALIZED. The recommended starting dose of COREG is 6.25 mg twice 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 12.5 mg twice 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 25 mg twice daily if tolerated and needed. The full antihypertensive effect of COREG is seen within 7 to 14 days. Total daily dose should not exceed 50 mg. Concomitant administration with a diuretic can be expected to produce additive effects and exaggerate the orthostatic component of carvedilol action. 2.4 Hepatic Impairment COREG should not be given to patients with severe hepatic impairment [see Contraindications (4) ].
Dosage forms and strengths
The white, oval, film‑coated tablets are available in the following strengths: 3.125 mg – engraved with "39" and "WP" 6.25 mg – engraved with "4140" and "WP" 12.5 mg – engraved with "4141" and "WP" 25 mg – engraved with "4142" and "WP" Tablets: 3.125 mg, 6.25 mg, 12.5 mg, 25 mg ( 3 )
Contraindications
4 CONTRAINDICATIONS COREG is contraindicated in the following conditions: Bronchial asthma or related bronchospastic conditions. Deaths from status asthmaticus have been reported following single doses of COREG. Second- or third-degree AV block. Sick sinus syndrome. Severe bradycardia (unless a permanent pacemaker is in place). Patients with 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. Patients with severe hepatic impairment. Patients with a history of a serious hypersensitivity reaction (e.g., Stevens-Johnson syndrome, anaphylactic reaction, angioedema) to any component of this medication or other medications containing carvedilol. Bronchial asthma or related bronchospastic conditions. ( 4 ) Second- or third-degree AV block. ( 4 ) Sick sinus syndrome. ( 4 ) Severe bradycardia (unless permanent pacemaker in place). ( 4 ) Patients in cardiogenic shock or decompensated heart failure requiring the use of IV inotropic therapy. (4) Severe hepatic impairment ( 2.4 , 4 ) History of serious hypersensitivity reaction (e.g., Stevens-Johnson syndrome, anaphylactic reaction, angioedema) to any component of this medication or other medications containing carvedilol. ( 4 )
Warnings and precautions
Acute exacerbation of coronary artery disease upon cessation of therapy: Do not abruptly discontinue. ( 5.1 ) Bradycardia, hypotension, worsening heart failure/fluid retention may occur. Reduce the dose as needed. ( 5.2 , 5.3 , 5.4 ) Non-allergic bronchospasm (e.g., chronic bronchitis and emphysema). Avoid β-blockers. ( 4 ) However, if deemed necessary, use with caution and at lowest effective dose. ( 5.5 ) Diabetes: May mask symptoms of hypoglycemia and alter glucose levels; monitor. ( 5.6 ) 5.1 Cessation of Therapy Patients with coronary artery disease, who are being treated with COREG, 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 patients with angina following the abrupt discontinuation of therapy with β-blockers. The last 2 complications may occur with or without preceding exacerbation of the angina pectoris. As with other β-blockers, when discontinuation of COREG is planned, the patients should be carefully observed and advised to limit physical activity to a minimum. COREG should be discontinued over 1 to 2 weeks whenever possible. If the angina worsens or acute coronary insufficiency develops, it is recommended that COREG be promptly reinstituted, at least temporarily. Because coronary artery disease is common and may be unrecognized, it may be prudent not to discontinue therapy with COREG abruptly even in patients treated only for hypertension or heart failure. 5.2 Bradycardia In clinical trials, COREG caused bradycardia in about 2% of hypertensive subjects, 9% of subjects with heart failure, and 6.5% of subjects with myocardial infarction and left ventricular dysfunction. If pulse rate drops below 55 beats per minute, the dosage should be reduced. 5.3 Hypotension In clinical trials of primarily mild‑to‑moderate heart failure, hypotension and postural hypotension occurred in 9.7% and syncope in 3.4% of subjects receiving COREG 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 up‑titration period and was a cause for discontinuation of therapy in 0.7% of subjects receiving COREG, compared with 0.4% of placebo subjects. In a long‑term, placebo‑controlled trial in severe heart failure (COPERNICUS), hypotension and postural hypotension occurred in 15.1% and syncope in 2.9% of heart failure subjects receiving COREG 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 COREG, 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 acute myocardial infarction, hypotension or postural hypotension occurred in 20.2% of subjects receiving COREG 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 COREG, 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 [see Dosage and Administration (2.1 , 2.2 , 2.3) ] . During initiation of therapy, the patient should be cautioned to avoid situations such as driving or hazardous tasks, where injury could result should syncope occur. 5.4 Heart Failure/Fluid Retention Worsening heart failure or fluid retention may occur during up-titration of carvedilol. If such symptoms occur, diuretics should be increased and the carvedilol dose should not be advanced until clinical stability resumes [see Dosage and Administration (2) ] . 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. 5.5 Non-allergic Bronchospasm Patients with bronchospastic disease (e.g., chronic bronchitis, emphysema) should, in general, not receive β-blockers. COREG may be used with caution, however, in patients who do not respond to, or cannot tolerate, other antihypertensive agents. It is prudent, if COREG is used, to use the smallest effective dose, so that inhibition of endogenous or exogenous β-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. 5.6 Effects on Blood Sugar Beta-blockers may prevent early warning signs of hypoglycemia, such as tachycardia, and increase the risk for severe or prolonged hypoglycemia at any time during treatment, especially in patients with diabetes mellitus or children and patients who are fasting (i.e., surgery, not eating regularly, or are vomiting). If severe hypoglycemia occurs, patients should be instructed to seek emergency treatment.
Side effects
Most common adverse events ( 6.1 ): Heart failure and left ventricular dysfunction following myocardial infarction (≤10%): Dizziness, fatigue, hypotension, diarrhea, hyperglycemia, asthenia, bradycardia, weight increase. Hypertension (≥5%): Dizziness. To report SUSPECTED ADVERSE REACTIONS, contact Waylis Therapeutics LLC at 1-844-200-7910 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Studies 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. COREG 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 patient populations 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). Heart Failure COREG 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 COREG for at least 6 months and 30% received COREG for at least 12 months. In the COMET trial, 1,511 subjects with mild-to-moderate heart failure were treated with COREG for up to 5.9 years (mean: 4.8 years). Both in U.S. clinical trials in mild-to- moderate heart failure that compared COREG 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 COREG 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 1 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 COREG observed in the long-term COMET trial was generally similar to that observed in the U.S. Heart Failure Trials. Table 1. Adverse Events (%) Occurring More Frequently with COREG than with Placebo in Subjects with Mild-to-Moderate Heart Failure (HF) Enrolled in U.S. Heart Failure Trials or in Subjects with Severe Heart Failure in the COPERNICUS Trial (Incidence >3% in Subjects Treated with Carvedilol, Regardless of Causality) Body System/ Adverse Event Mild-to-Moderate HF Severe HF COREG Placebo COREG Placebo (n = 765) (n = 437) (n = 1,156) (n = 1,133) Body as a Whole Asthenia 7 7 11 9 Fatigue 24 22 — — Digoxin level increased 5 4 2 1 Edema generalized 5 3 6 5 Edema dependent 4 2 — — Cardiovascular Bradycardia 9 1 10 3 Hypotension 9 3 14 8 Syncope 3 3 8 5 Angina pectoris 2 3 6 4 Central Nervous System Dizziness 32 19 24 17 Headache 8 7 5 3 Gastrointestinal Diarrhea 12 6 5 3 Nausea 9 5 4 3 Vomiting 6 4 1 2 Metabolic Hyperglycemia 12 8 5 3 Weight increase 10 7 12 11 BUN increased 6 5 — — NPN increased 6 5 — — Hypercholesterolemia 4 3 1 1 Edema peripheral 2 1 7 6 Musculoskeletal Arthralgia 6 5 1 1 Respiratory Cough increased 8 9 5 4 Rales 4 4 4 2 Vision Vision abnormal 5 2 — — 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 COREG 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.
Drug interactions
7 DRUG INTERACTIONS CYP P450 2D6 enzyme inhibitors may increase and rifampin may decrease carvedilol levels. ( 7.1 , 7.5 ) Hypotensive agents (e.g., reserpine, MAO inhibitors, clonidine) may increase the risk of hypotension and/or severe bradycardia. ( 7.4 ) Cyclosporine or digoxin levels may increase. ( 7.3 , 7.4 ) Both digitalis glycosides and β-blockers slow atrioventricular conduction and decrease heart rate. Concomitant use can increase the risk of bradycardia. ( 7.4 ) Amiodarone may increase carvedilol levels resulting in further slowing of the heart rate or cardiac conduction. ( 7.6 ) Verapamil- or diltiazem-type calcium channel blockers may affect ECG and/or blood pressure. ( 7.7 ) Insulin and oral hypoglycemics action may be enhanced. ( 7.8 ) 7.1 CYP2D6 Inhibitors and Poor Metabolizers Interactions of carvedilol with potent inhibitors of CYP2D6 isoenzyme (such as quinidine, fluoxetine, paroxetine, and propafenone) have not been studied, but these drugs would be expected to increase blood levels of the R(+) enantiomer of carvedilol [see Clinical Pharmacology (12.3) ]. Retrospective analysis of side effects in clinical trials showed that poor 2D6 metabolizers had a higher rate of dizziness during up-titration, presumably resulting from vasodilating effects of the higher concentrations of the α-blocking R(+) enantiomer. 7.2 Hypotensive Agents Patients taking a β-blocker 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 a β-blocker may cause hypotension and bradycardia. When concomitant treatment with a β-blocker and clonidine is to be terminated, the β-blocker should be discontinued first. Clonidine therapy can then be discontinued several days later by gradually decreasing the dosage. 7.3 Cyclosporine Modest increases in mean trough cyclosporine concentrations were observed following initiation of carvedilol treatment in 21 renal transplant 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. 7.4 Digitalis Glycosides Both digitalis glycosides and β-blockers slow atrioventricular conduction and decrease heart rate. Concomitant use can increase the risk of bradycardia. Digoxin concentrations are increased by about 15% when digoxin and carvedilol are administered concomitantly. Therefore, increased monitoring of digoxin is recommended when initiating, adjusting, or discontinuing COREG [see Clinical Pharmacology (12.5) ] . 7.5 Inducers/Inhibitors of Hepatic Metabolism Rifampin reduced plasma concentrations of carvedilol by about 70% [see Clinical Pharmacology (12.5) ] . Cimetidine increased AUC by about 30% but caused no change in C max [see Clinical Pharmacology (12.5) ] . 7.6 Amiodarone Amiodarone and its metabolite desethyl amiodarone, inhibitors of CYP2C9, and P- glycoprotein increased concentrations of the S(-)-enantiomer of carvedilol by at least 2 fold [see Clinical Pharmacology (12.5) ]. The concomitant administration of amiodarone or other CYP2C9 inhibitors such as fluconazole with COREG may enhance the β-blocking activity resulting in further slowing of the heart rate or cardiac conduction. Patients should be observed for signs of bradycardia or heart block, particularly when one agent is added to pre-existing treatment with the other. 7.7 Calcium Channel Blockers Conduction disturbance (rarely with hemodynamic compromise) has been observed when COREG is coadministered with diltiazem. As with other β-blockers, if COREG is administered with calcium channel blockers of the verapamil or diltiazem type, it is recommended that ECG and blood pressure be monitored. 7.8 Insulin or Oral Hypoglycemics β-blockers may enhance the blood-sugar-reducing effect of insulin and oral hypoglycemics. Therefore, in patients taking insulin or oral hypoglycemics, regular monitoring of blood glucose is recommended [see Warnings and Precautions (5.6) ]. 7.9 Anesthesia If treatment with COREG is to be continued perioperatively, particular care should be taken when anesthetic agents that depress myocardial function, such as ether, cyclopropane, and trichloroethylene, are used [see Overdosage (10) ].
Use in specific populations
8.1 Pregnancy Risk Summary Available data regarding use of COREG in pregnant women are insufficient to determine whether there are drug-associated risks of adverse developmental outcomes. There are risks to the mother and fetus associated with poorly controlled hypertension in pregnancy. The use of beta blockers during the third trimester of pregnancy may increase the risk of hypotension, bradycardia, hypoglycemia, and respiratory depression in the neonate [see Clinical Considerations ]. In animal reproduction studies, there was no evidence of adverse developmental outcomes at clinically relevant doses [see Data ]. Oral administration of carvedilol to pregnant rats during organogenesis resulted in post- implantation loss, decreased fetal body weight, and an increased frequency of delayed fetal skeletal development at maternally toxic doses that were 50 times the maximum recommended human dose (MRHD). In addition, oral administration of carvedilol to pregnant rabbits during organogenesis resulted in increased post-implantation loss at doses 25 times the MRHD [see Data ] . The estimated background risk of major birth defects and miscarriage for the indicated populations are unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Clinical Considerations Disease-Associated Maternal and/or Embryo-Fetal Risk: Hypertension in pregnancy increases the maternal risk for pre-eclampsia, gestational diabetes, premature delivery, and delivery complications (e.g., need for cesarean section and post-partum hemorrhage). Hypertension increases the fetal risk for intrauterine growth restriction and intrauterine death. Pregnant women with hypertension should be carefully monitored and managed accordingly. Fetal/Neonatal Adverse Reactions: Neonates of women with hypertension who are treated with beta-blockers during the third trimester of pregnancy may be at increased risk for hypotension, bradycardia, hypoglycemia, and respiratory depression. Observe newborns for symptoms of hypotension, bradycardia, hypoglycemia, and respiratory depression and manage accordingly. Data Animal Data: Studies performed in rats and rabbits given carvedilol during fetal organogenesis revealed increased post‑implantation loss in rats at a maternally toxic dose of 300 mg per kg per day (50 times the MRHD as mg per m2) and in rabbits (in the absence of maternal toxicity) at doses of 75 mg per kg per day (25 times the MRHD as mg per m2). In the rats, there was also a decrease in fetal body weight at 300 mg per kg per day (50 times the MRHD as mg per m2) accompanied by an increased incidence of fetuses with delayed skeletal development. In rats, the no-effect level for embryo-fetal toxicity was 60 mg per kg per day (10 times the MRHD as mg per m2); in rabbits, it was 15 mg per kg per day (5 times the MRHD as mg per m2). In a pre- and post-natal development study in rats administered carvedilol from late gestation through lactation, increased embryo-lethality was observed at a maternally toxic dose of 200 mg per kg per day (approximately 32 times the MRHD as mg per m2), and pup mortality and delays in physical growth/development were observed at 60 mg per kg per day (10 times the MRHD as mg per m2) in the absence of maternal toxicity. The no-effect level was 12 mg per kg per day (2 times the MRHD as mg per m2). Carvedilol was present in fetal rat tissue. 8.2 Lactation Risk Summary There are no data on the presence of carvedilol in human milk, the effects on the breastfed infant, or the effects on milk production. Carvedilol is present in the milk of lactating rats. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for COREG and any potential adverse effects on the breastfed infant from COREG or from the underlying maternal condition. 8.4 Pediatric Use Effectiveness of COREG 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 [NYHA class II-IV, left ventricular ejection fraction less than 40% for children with a systemic left ventricle (LV), and moderate-severe ventricular dysfunction qualitatively by echo for those with a systemic ventricle that was not an LV] who were receiving standard background treatment were randomized to placebo or to 2 dose levels of carvedilol. These dose levels produced placebo-corrected heart rate reduction of 4 to 6 heart beats per minute, indicative of β- blockade activity. Exposure appeared to be lower in pediatric subjects than adults. After 8 months of follow-up, there was no significant effect of treatment on clinical outcomes. Adverse reactions in this trial that occurred in greater than 10% of subjects treated with COREG and at twice the rate of placebo-treated subjects included chest pain (17% versus 6%), dizziness (13% versus 2%), and dyspnea (11% versus 0%). 8.5 Geriatric Use Of the 765 subjects with heart failure randomized to COREG in U.S. clinical trials, 31% (235) were aged 65 years or older, and 7.3% (56) were aged 75 years or older. Of the 1,156 subjects randomized to COREG in a long‑term, placebo‑controlled trial in severe heart failure, 47% (547) were aged 65 years or older, and 15% (174) were aged 75 years or older. Of 3,025 subjects receiving COREG in heart failure trials worldwide, 42% were aged 65 years or older. Of the 975 subjects with myocardial infarction randomized to COREG in the CAPRICORN trial, 48% (468) were aged 65 years or older, and 11% (111) were aged 75 years or older. Of the 2,065 hypertensive subjects in U.S. clinical trials of efficacy or safety who were treated with COREG, 21% (436) were aged 65 years or older.
Pregnancy
8.1 Pregnancy Risk Summary Available data regarding use of COREG in pregnant women are insufficient to determine whether there are drug-associated risks of adverse developmental outcomes. There are risks to the mother and fetus associated with poorly controlled hypertension in pregnancy. The use of beta blockers during the third trimester of pregnancy may increase the risk of hypotension, bradycardia, hypoglycemia, and respiratory depression in the neonate [see Clinical Considerations ]. In animal reproduction studies, there was no evidence of adverse developmental outcomes at clinically relevant doses [see Data ]. Oral administration of carvedilol to pregnant rats during organogenesis resulted in post- implantation loss, decreased fetal body weight, and an increased frequency of delayed fetal skeletal development at maternally toxic doses that were 50 times the maximum recommended human dose (MRHD). In addition, oral administration of carvedilol to pregnant rabbits during organogenesis resulted in increased post-implantation loss at doses 25 times the MRHD [see Data ] . The estimated background risk of major birth defects and miscarriage for the indicated populations are unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Clinical Considerations Disease-Associated Maternal and/or Embryo-Fetal Risk: Hypertension in pregnancy increases the maternal risk for pre-eclampsia, gestational diabetes, premature delivery, and delivery complications (e.g., need for cesarean section and post-partum hemorrhage). Hypertension increases the fetal risk for intrauterine growth restriction and intrauterine death. Pregnant women with hypertension should be carefully monitored and managed accordingly. Fetal/Neonatal Adverse Reactions: Neonates of women with hypertension who are treated with beta-blockers during the third trimester of pregnancy may be at increased risk for hypotension, bradycardia, hypoglycemia, and respiratory depression. Observe newborns for symptoms of hypotension, bradycardia, hypoglycemia, and respiratory depression and manage accordingly. Data Animal Data: Studies performed in rats and rabbits given carvedilol during fetal organogenesis revealed increased post‑implantation loss in rats at a maternally toxic dose of 300 mg per kg per day (50 times the MRHD as mg per m2) and in rabbits (in the absence of maternal toxicity) at doses of 75 mg per kg per day (25 times the MRHD as mg per m2). In the rats, there was also a decrease in fetal body weight at 300 mg per kg per day (50 times the MRHD as mg per m2) accompanied by an increased incidence of fetuses with delayed skeletal development. In rats, the no-effect level for embryo-fetal toxicity was 60 mg per kg per day (10 times the MRHD as mg per m2); in rabbits, it was 15 mg per kg per day (5 times the MRHD as mg per m2). In a pre- and post-natal development study in rats administered carvedilol from late gestation through lactation, increased embryo-lethality was observed at a maternally toxic dose of 200 mg per kg per day (approximately 32 times the MRHD as mg per m2), and pup mortality and delays in physical growth/development were observed at 60 mg per kg per day (10 times the MRHD as mg per m2) in the absence of maternal toxicity. The no-effect level was 12 mg per kg per day (2 times the MRHD as mg per m2). Carvedilol was present in fetal rat tissue.
Pediatric use
8.4 Pediatric Use Effectiveness of COREG 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 [NYHA class II-IV, left ventricular ejection fraction less than 40% for children with a systemic left ventricle (LV), and moderate-severe ventricular dysfunction qualitatively by echo for those with a systemic ventricle that was not an LV] who were receiving standard background treatment were randomized to placebo or to 2 dose levels of carvedilol. These dose levels produced placebo-corrected heart rate reduction of 4 to 6 heart beats per minute, indicative of β- blockade activity. Exposure appeared to be lower in pediatric subjects than adults. After 8 months of follow-up, there was no significant effect of treatment on clinical outcomes. Adverse reactions in this trial that occurred in greater than 10% of subjects treated with COREG and at twice the rate of placebo-treated subjects included chest pain (17% versus 6%), dizziness (13% versus 2%), and dyspnea (11% versus 0%).
Geriatric use
8.5 Geriatric Use Of the 765 subjects with heart failure randomized to COREG in U.S. clinical trials, 31% (235) were aged 65 years or older, and 7.3% (56) were aged 75 years or older. Of the 1,156 subjects randomized to COREG in a long‑term, placebo‑controlled trial in severe heart failure, 47% (547) were aged 65 years or older, and 15% (174) were aged 75 years or older. Of 3,025 subjects receiving COREG in heart failure trials worldwide, 42% were aged 65 years or older. Of the 975 subjects with myocardial infarction randomized to COREG in the CAPRICORN trial, 48% (468) were aged 65 years or older, and 11% (111) were aged 75 years or older. Of the 2,065 hypertensive subjects in U.S. clinical trials of efficacy or safety who were treated with COREG, 21% (436) were aged 65 years or older. Of 3,722 subjects receiving COREG in hypertension clinical trials conducted worldwide, 24% were aged 65 years 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 (see Figures 2 and 4 ) were observed between the older subjects and younger subjects in each of these populations. Similarly, other reported clinical experience has not identified differences in responses between the elderly and younger subjects, but greater sensitivity of some older individuals cannot be ruled out.
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. 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 per 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, β- 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. Cases of overdosage with COREG 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.
Description
Carvedilol is a nonselective β-adrenergic blocking agent with α1-blocking activity. It is (±)-1-(Carbazol-4-yloxy)-3-[[2-(o-methoxyphenoxy)ethyl]amino]-2-propanol. Carvedilol is a racemic mixture with the following structure: COREG is a white, oval, film-coated tablet containing 3.125 mg, 6.25 mg, 12.5 mg, or 25 mg of carvedilol. The 6.25-mg, 12.5-mg, and 25-mg tablets are TILTAB tablets. Inactive ingredients consist of colloidal silicon dioxide, crospovidone, hypromellose, lactose, magnesium stearate, polyethylene glycol, polysorbate 80, povidone, sucrose, and titanium dioxide. Carvedilol is a white to off-white powder with a molecular weight of 406.5 and a molecular formula of C24H26N2O4. It is freely soluble in dimethylsulfoxide; soluble in methylene chloride and methanol; sparingly soluble in 95% ethanol and isopropanol; slightly soluble in ethyl ether; and practically insoluble in water, gastric fluid (simulated, TS, pH 1.1), and intestinal fluid (simulated, TS without pancreatin, pH 7.5). Chemical Structure
Mechanism of action
12.1 Mechanism of Action COREG is a racemic mixture in which nonselective β-adrenoreceptor blocking activity is present in the S(-) enantiomer and α1-adrenergic blocking activity is present in both R(+) and S(-) enantiomers at equal potency. COREG has no intrinsic sympathomimetic activity.
How supplied
The white, oval, film‑coated tablets are available in the following strengths: 3.125 mg – engraved with "39" and "WP" 6.25 mg – engraved with "4140" and "WP" 12.5 mg – engraved with "4141" and "WP" 25 mg – engraved with "4142" and "WP" The 6.25-mg, 12.5-mg, and 25-mg tablets are TILTAB tablets. 3.125 mg bottles of 100: NDC 80725-139-20 6.25 mg bottles of 100: NDC 80725-140-20 12.5 mg bottles of 100: NDC 80725-141-20 25 mg bottles of 100: NDC 80725 142-20 Store below 30°C (86°F). Protect from moisture. Dispense in a tight, light‑resistant container.
Storage
Store below 30°C (86°F). Protect from moisture. Dispense in a tight, light‑resistant container.
Patient information
Advise the patient to read the FDA-approved patient labeling (Patient Information). Patients taking COREG should be advised of the following: Patients should take COREG with food. Patients should not interrupt or discontinue using COREG without a physician's advice. Patients with heart failure should consult their physician if they experience signs or symptoms of worsening heart failure such as weight gain or increasing shortness of breath. Patients may experience a drop in blood pressure when standing, resulting in dizziness and, rarely, fainting. Patients should sit or lie down when these symptoms of lowered blood pressure occur. If experiencing dizziness or fatigue, patients should avoid driving or hazardous tasks. Patients should consult a physician if they experience dizziness or faintness, in case the dosage should be adjusted. Inform patients or caregivers that there is a risk of hypoglycemia when COREG is given to patients who are fasting or who are vomiting. Instruct patients or caregivers how to monitor for signs of hypoglycemia [see Warnings and Precautions (5.6) ]. Contact lens wearers may experience decreased lacrimation. COREG, COREG CR, and TILTAB are trademarks used under license by Waylis Therapeutics LLC The other brand listed is a trademark owned by or licensed to its owner and is not owned by or licensed to Waylis Therapeutics LLC. The maker of this brand is not affiliated with and does not endorse Waylis Therapeutics LLC or its products.
Label text from the FDA structured product label by Waylis Therapeutics LLC (revised Jul 31, 2026). Long sections are shortened; the complete label is on DailyMed.
Active ingredients
- Carvedilol in 4 products
Coreg NDC products (4)
| NDC | Strength & form | Labeler | Type |
|---|---|---|---|
| 80725-139 | Carvedilol 3.125 mg/1 Tablet, Film Coated | Waylis Therapeutics LLC | NDA |
| 80725-140 | Carvedilol 6.25 mg/1 Tablet, Film Coated | Waylis Therapeutics LLC | NDA |
| 80725-141 | Carvedilol 12.5 mg/1 Tablet, Film Coated | Waylis Therapeutics LLC | NDA |
| 80725-142 | Carvedilol 25 mg/1 Tablet, Film Coated | Waylis Therapeutics LLC | NDA |
Frequently asked questions
What is Coreg used for?
1. INDICATIONS AND USAGE COREG is an alpha-/beta-adrenergic blocking agent indicated for the treatment of: mild to severe chronic heart failure ( 1.1 ) left ventricular dysfunction following myocardial infarction in clinically stable patients ( 1.2 ) hypertension ( 1.3 ) 1.1 Heart Failure COREG is indicated for the treatment of mild-to-severe chronic heart failure of ischemic or cardiomyopathic…
What are the side effects of Coreg?
Most common adverse events ( 6.1 ): Heart failure and left ventricular dysfunction following myocardial infarction (≤10%): Dizziness, fatigue, hypotension, diarrhea, hyperglycemia, asthenia, bradycardia, weight increase. Hypertension (≥5%): Dizziness. To report SUSPECTED ADVERSE REACTIONS, contact Waylis Therapeutics LLC at 1-844-200-7910 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1… See the full label for the complete list.
Who makes Coreg?
Coreg is listed by 1 labeler in the FDA NDC directory, including Waylis Therapeutics LLC.