Carvedilol Tablet 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 )
1.1Heart Failure Carvedilol
Tablets is indicated for the treatment of mild-to-severe chronic heart failure of ischemic or cardiomyopathic origin, usually in addition to diuretics, ACE inhibitors, and digitalis, to increase survival and, also, to reduce the risk of hospitalization [see Clinical Studies ( 14.1 )].
1.2Left Ventricular Dysfunction Following Myocardial Infarction Carvedilol
Tablet 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 ) ].
1.3Hypertension Carvedilol
Tablet 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 ) ].
Contraindications
Carvedilol Tablet is contraindicated in the following conditions:
Bronchial asthma or related bronchospastic conditions. Deaths from status asthmaticus have been reported following single doses of Carvedilol Tablet.
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 Carvedilol Tablet.
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 Tablet.
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: Monitor glucose as β-blockers may mask symptoms of hypoglycemia or worsen hyperglycemia. ( 5.6 )
5.1Cessation of Therapy Patients
with coronary artery disease, who are being treated with Carvedilol Tablets, should be advised against abrupt discontinuation of therapy. Severe exacerbation of angina and the occurrence of myocardial infarction and ventricular arrhythmias have been reported in angina patients following the abrupt discontinuation of therapy with β-blockers. The last 2 complications may occur with or without preceding exacerbation of the angina pectoris.
As with other β-blockers, when discontinuation of Carvedilol Tablet is planned, the patients should be carefully observed and advised to limit physical activity to a minimum. Carvedilol Tablet should be discontinued over 1 to 2 weeks whenever possible. If the angina worsens or acute coronary insufficiency develops, it is recommended that Carvedilol Tablet 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 Tablet abruptly even in patients treated only for hypertension or heart failure.
5.2Bradycardia
In clinical trials, Carvedilol Tablet caused bradycardia in about 2% of hypertensive patients, 9% of heart failure patients and 6.5% of myocardial infarction patients with left ventricular dysfunction. If pulse rate drops below 55 beats/minute, the dosage should be reduced.
5.3Hypotension
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 Carvedilol Tablets 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 Carvedilol Tablets, 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 Carvedilol Tablets 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 Tablets, compared with 0.8% of placebo subjects. Postural hypotension occurred in 1.8% and syncope in 0.1% of hypertensive patients, primarily following the initial dose or at the time of dose increase and was a cause for discontinuation of therapy in 1% of patients.
In the CAPRICORN study of survivors of an acute myocardial infarction, hypotension or postural hypotension occurred in 20.2% of patients receiving Carvedilol Tablet compared to 12.6% of placebo patients. Syncope was reported in 3.9% and 1.9% of patients, respectively. These events were a cause for discontinuation of therapy in 2.5% of patients receiving Carvedilol Tablet, compared to 0.2% of placebo patients. Starting with a low dose, administration with food, and gradual up-titration should decrease the likelihood of syncope or excessive hypotension [ see Dosage and Administration ( 2.2 , 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.
5.4Heart Failure/Fluid Retention
Worsening heart failure or fluid retention may occur during up-titration of Carvedilol Tablet. If such symptoms occur, diuretics should be increased and the Carvedilol Tablet dose should not be advanced until clinical stability resumes [ see Dosage and Administration ( 2 ) ]. Occasionally it is necessary to lower the Carvedilol Tablet 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.
5.5Non-Allergic Bronchospasm Patients
with bronchospastic disease (e.g., chronic bronchitis and emphysema) should, in general, not receive β-blockers. Carvedilol Tablet may be used with caution, however, in patients who do not respond to, or cannot tolerate, other antihypertensive agents. It is prudent, if Carvedilol Tablet is used, to use the smallest effective dose, so that inhibition of endogenous or exogenous β-agonists is minimized. In clinical trials of patients with heart failure, patients with bronchospastic disease were enrolled if they did not require oral or inhaled medication to treat their bronchospastic disease.
In such patients, it is recommended that Carvedilol Tablet 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.
5.6Glycemic Control in Type 2 Diabetes
In general, β-blockers may mask some of the manifestations of hypoglycemia, particularly tachycardia. Nonselective β-blockers may potentiate insulin-induced hypoglycemia and delay recovery of serum glucose levels. Patients subject to spontaneous hypoglycemia, or diabetic patients receiving insulin or oral hypoglycemic agents, should be cautioned about these possibilities. In heart failure patients with diabetes, carvedilol therapy may lead to worsening hyperglycemia, which responds to intensification of hypoglycemic therapy.
It is recommended that blood glucose be monitored when carvedilol dosing is initiated, adjusted, or discontinued. Studies designed to examine the effects of carvedilol on glycemic control in patients with diabetes and heart failure have not been conducted. In a study designed to examine the effects of carvedilol on glycemic control in a population with mild-to-moderate hypertension and well-controlled type 2 diabetes mellitus, carvedilol had no adverse effect on glycemic control, based on HbA1c measurements [see Clinical Studies ( 14.4 ) ].
5.7Peripheral Vascular
Disease β-blockers can precipitate or aggravate symptoms of arterial insufficiency in patients with peripheral vascular disease. Caution should be exercised in such individuals.
5.8Deterioration of Renal Function
Rarely, use of Carvedilol Tablet in patients with heart failure has resulted in deterioration of renal function. Patients at risk appear to be those with low blood pressure (systolic blood pressure less than 100 mm Hg), ischemic heart disease and diffuse vascular disease, and/or underlying renal insufficiency. Renal function has returned to baseline when Carvedilol Tablet was stopped. In patients with these risk factors it is recommended that renal function be monitored during up-titration of Carvedilol Tablet and the drug discontinued or dosage reduced if worsening of renal function occurs.
5.9Major Surgery
Chronically administered beta blocking therapy should not be routinely withdrawn prior to major surgery; however, the impaired ability of the heart to respond to reflex adrenergic stimuli may augment the risks of general anesthesia and surgical procedures.
5.10 Thyrotoxicosis β-adrenergic blocka
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Interactions
CYP P450 2D6 enzyme inhibitors may increase and rifampin may decrease Carvedilol Tablet levels. ( 7.1 , 7.5 )
Hypotensive agents (e.g., reserpine, MAO inhibitors, clonidine) may increase the risk of hypotension and/or severe bradycardia. ( 7.2 )
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 Tablet 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 )
7.1CYP2D6 Inhibitors and Poor Metabolizers Interactions of Carvedilol Tablet
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 Tablet [ 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 uptitration, presumably resulting from vasodilating effects of the higher concentrations of the α-blocking R(+) enantiomer.
7.2Hypotensive Agents
Patients taking both agents with β-blocking properties and a drug that can deplete catecholamines (e.g., reserpine and monoamine oxidase inhibitors) should be observed closely for signs of hypotension and/or severe bradycardia. Concomitant administration of clonidine with agents with β-blocking properties may potentiate blood-pressureand heart-ratelowering effects. When concomitant treatment with agents with β-blocking properties and clonidine is to be terminated, the β-blocking agent should be discontinued first.
Clonidine therapy can then be discontinued several days later by gradually decreasing the dosage.
7.3Cyclosporine
Modest increases in mean trough cyclosporine concentrations were observed following initiation of Carvedilol Tablet treatment in 21 renal transplant patients suffering from chronic vascular rejection. In about 30% of patients, the dose of cyclosporine had to be reduced in order to maintain cyclosporine concentrations within the therapeutic range, while in the remainder no adjustment was needed. On the average for the group, the dose of cyclosporine was reduced about 20% in these patients.
Due to wide interindividual variability in the dose adjustment required, it is recommended that cyclosporine concentrations be monitored closely after initiation of Carvedilol Tablet therapy and that the dose of cyclosporine be adjusted as appropriate.
7.4Digitalis 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 Tablet are administered concomitantly. Therefore, increased monitoring of digoxin is recommended when initiating, adjusting, or discontinuing Carvedilol Tablet [ see Clinical Pharmacology ( 12.5 ) ].
7.5Inducers/Inhibitors of Hepatic Metabolism
Rifampin reduced plasma concentrations of Carvedilol Tablet 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 ) ].
7.6Amiodarone Amiodarone,
and its metabolite desethyl amiodarone, inhibitors of CYP2C9 and P-glycoprotein, increased concentrations of the S(-)-enantiomer of Carvedilol Tablet by at least 2-fold [ see Clinical Pharmacology ( 12.5 ) ]. The concomitant administration of amiodarone or other CYP2C9 inhibitors such as fluconazole with Carvedilol Tablet may enhance the β-blocking properties of Carvedilol Tablet 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 preexisting treatment with the other.
7.7Calcium Channel Blockers
Conduction disturbance (rarely with hemodynamic compromise) has been observed when Carvedilol Tablets is coadministered with diltiazem. As with other agents with β-blocking properties, if Carvedilol Tablets is to be administered with calcium channel blockers of the verapamil or diltiazem type, it is recommended that ECG and blood pressure be monitored.
7.8Insulin or Oral Hypoglycemics Agents
with β-blocking properties may enhance the blood-sugar-reducing effect of insulin and oral hypoglycemics. Therefore, in patients taking insulin or oral hypoglycemics, regular monitoring of blood glucose is recommended [ see Warnings and Precautions ( 5.6 ) ].
7.9Anesthesia
If treatment with Carvedilol Tablet is to be continued perioperatively, particular care should be taken when anesthetic agents which depress myocardial function, such as ether,cyclopropane, and trichloroethylene, are used [see Overdosage ( 10 )].
Pregnancy and breastfeeding
8.1Pregnancy Pregnancy Category C.
Studies performed in pregnant rats and rabbits given Carvedilol Tablet revealed increased post-implantation loss in rats at doses of 300 mg/kg/day (50 times the maximum recommended human dose [MRHD] as mg/m 2 ) and in rabbits at doses of 75 mg/kg/day (25 times the MRHD as mg/m 2 ). 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/m 2 ), 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/m 2 ); in rabbits it was 15 mg/kg/day (5 times the MRHD as mg/m 2 ). There are no adequate and well-controlled studies in pregnant women. Carvedilol Tablet should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Adverse reactions
Most common adverse events ( 6.1 ):
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 Beximco Pharmaceuticals USA Inc. at 877-372-6093 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch
6.1Clinical Studies Experience Carvedilol
Tablet has been evaluated for safety in patients with heart failure (mild, moderate and severe), in patients with left ventricular dysfunction following myocardial infarction and in hypertensive patients. The observed adverse event profile was consistent with the pharmacology of the drug and the health status of the patients in the clinical trials. Adverse events reported for each of these patient populations 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 Carvedilol Tablets has been evaluated for safety in heart failure in more than 4,500 subjects worldwide of whom more than 2,100 participated in placebo-controlled clinical trials.
Approximately 60% of the total treated population in placebo-controlled clinical trials received Carvedilol Tablets for at least 6 months and 30% received Carvedilol Tablets for at least 12 months. In the COMET trial, 1,511 subjects with mild-to-moderate heart failure were treated with Carvedilol Tablets for up to 5.9 years (mean: 4.8 years). Both in US clinical trials in mild-to-moderate heart failure that compared Carvedilol Tablets 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 Tablets 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 >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 US placebo-controlled clinical trials, and with severe heart failure enrolled in the COPERNICUS trial. Shown are adverse events that occurred more frequently in drug-treated subjects than placebo-treated subjects with an incidence of >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 severe heart failure subjects. The adverse event profile of Carvedilol Tablets observed in the long-term COMET trial was generally similar to that observed in the US Heart Failure Trials. Table 1. Adverse Events (%) Occurring More Frequently with Carvedilol Tablet than with Placebo in Subjects with Mild-to-Moderate Heart Failure (HF) Enrolled in US Heart Failure Trials or in Subjects with Severe Heart Failure in the COPERNICUS Trial (Incidence >3% in Subjects Treated with Carvedilol, Regardless of Causality) Body System/ Adverse Event Mild-to-Moderate HF Severe HF Carvedilol Tablets Placebo Carvedilol Tablets 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 >1% but ≤3% and more frequently with Carvedilol Tablets 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, postural hypotension, aggravated angina pectoris, AV block, palpitation, hypertension.
Psychiatric: Somnolence. Reproductive, male: Impotence. Special Senses: Blurred vision. Urinary System: Renal insufficiency, albuminuria, hematuria. Left Ventricular Dysfunction Following Myocardial Infarction: Carvedilol Tablet 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 Tablet and 980 who received placebo.
Approximately 75% of the subjects received Carvedilol Tablet for at least 6 months and 53% received Carvedilol Tablet for at least 12 months. Subjects were treated for an average of 12.9 months and 12.8 months with Carvedilol Tablet and placebo, respectively. The most common adverse events reported with Carvedilol Tablets 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 greater than 1% but less than or equal to 3% and more frequently with Carvedilol Tablet: 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 patients. In this database, the only cause of discontinuation greater than 1%, and occurring more often on Carvedilol Tablet was hypotension (1.5% on Carvedilol Tablet, 0.2% on placebo). Hypertension: Carvedilol Tablet has been evaluated for safety in hypertension in more than 2,193 subjects in U.S. clinical trials and in 2,976 subjects in international clinical trials.
Approximately 36% of the total treated population received Carvedilol Tablet for at least 6 months. Most adverse events reported during therapy with Carvedilol Tablet were of mild to moderate severity. In U.S. controlled clinical trials directly comparing Carvedilol Tablet in doses up to 50 mg (n = 1,142) to placebo (n = 462), 4.9% of subjects receiving Carvedilol Tablet 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 Tablet group for postural hypotension (1% versus 0). The overall incidence of adverse events in U.S. placebo-controlled trials increased with increasing dose of Carvedilol Tablet. For individual adverse events this could only be disting
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Composition
Active ingredients
CARVEDILOL 3.125MG
Strengths and forms
The FDA lists each strength of a product separately; these pages share one label.
Prognia shows this product information for reference and learning. It is not treatment advice and can lag behind the official text. Always check the current product information and local protocols before prescribing.
