Generic: CARVEDILOL
alpha-Adrenergic Blocker [EPC]
1. INDICATIONS AND USAGE Carvedilol tablets, USP is an alpha/beta-adrenergic blocking agent indicated for the treatment of: • Left ventricular dysfunction following myocardial infarction in clinically stable patients( 1.1 ) • Hypertension( 1.2 ) 1.1 Left Ventricular Dysfunction Following Myocardial Infarction Carvedilol tablets, USP are indicated to reduce cardiovascular mortality in clinically stable patients who have survived the acute phase of a myocardial infarction and have a left ventricul...
1. INDICATIONS AND USAGE Carvedilol tablets, USP is an alpha/beta-adrenergic blocking agent indicated for the treatment of: • Left ventricular dysfunction following myocardial infarction in clinically stable patients( 1.1 ) • Hypertension( 1.2 ) 1.1 Left Ventricular Dysfunction Following Myocardial Infarction Carvedilol tablets, USP are 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 ≤40% (with or without symptomatic heart failure) [see Clinical Studies (14.1)]. 1.2 Hypertension Carvedilol tablets, USP are indicated for the management of essential hypertension [see Clinical Studies (14.2)] . It can be used alone or in combination with other antihypertensive agents, especially thiazide-type diuretics [see Drug Interactions (7.2)].
5. 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 symp...
5. 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 ) 5.1 Cessation 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 tablets is planned, the patients should be carefully observed and advised to limit physical activity to a minimum. Carvedilol tablets should be discontinued over 1 to 2 weeks whenever possible. If the angina worsens or acute coronary insufficiency develops, it is recommended that carvedilol tablets 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. 5.2 Bradycardia In clinical trials, carvedilol tablets caused bradycardia in about 2% of hypertensive 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. 5.3 Hypotension 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 tablets 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 tablets, 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 (2.1, 2.2)]. 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. 5.5 Non-allergic Bronchospasm Patients with bronchospastic disease (e.g., chronic bronchitis and emphysema) should, in general, not receive β-blockers. Carvedilol tablets may be used with caution, however, in patients who do not respond to, or cannot tolerate, other antihypertensive agents. It is prudent, if carvedilol tablets are used, to use the smallest effective dose, so that inhibition of endogenous or exogenous β-agonists is minimized. In clinical trials, 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 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 Glycemic 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. 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) ]. 5.7 Peripheral 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. 5.8 Deterioration of Renal Function Rarely, use of carvedilol 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 <100 mm Hg), ischemic heart disease and diffuse vascular disease, and/or underlying renal insufficiency. Renal function has returned to baseline when carvedilol was stopped. In patients with these risk factors it is recommended that renal function be monitored during up-titration of carvedilol and the drug discontinued or dosage reduced if worsening of renal function occurs. 5.9 Major 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 blockade may mask clinical signs of hyperthyroidism, such as tachycardia. Abrupt withdrawal of β-blockade may be followed by an exacerbation of the symptoms of hyperthyroidism or may precipitate thyroid storm. 5.11 Pheochromocytoma In patients with pheochromocytoma, an α-blocking agent should be initiated prior to the use of any β-blocking agent. Although carvedilol has both α- and β-blocking pharmacologic activities, there has been no experience with its use in this condition. Therefore, caution should be taken in the administration of carvedilol to patients suspected of having pheochromocytoma. 5.12 Prinzmetal’s Variant Angina Agents with non-selective β-blocking activity may provoke chest pain in patients with Prinzmetal's variant angina. There has been no clinical experience with carvedilol in these patients although the α-blocking activity may prevent such symptoms. However, caution should be taken in the administration of carvedilol to patients suspected of having Prinzmetal's variant angina. 5.13 Risk of Anaphylactic Reaction While taking β-blockers, patients with a history of severe anaphylactic reaction to a variety of allergens may be more reactive to repeated challenge, either accidental, diagnostic, or therapeutic. Such patients may be unresponsive to the usual doses of epinephrine used to treat allergic reaction. 5.14 Intraoperative Floppy Iris Syndrome Intraoperative Floppy Iris Syndrome (IFIS) has been observed during cataract surgery in some patients treated with alpha-1 blockers (carvedilol is an alpha/beta blocker). This variant of small pupil syndrome is characterized by the combination of a flaccid iris that billows in response to intraoperative irrigation currents, progressive intraoperative miosis despite preoperative dilation with standard mydriatic drugs, and potential prolapse of the iris toward the phacoemulsification incisions. The patient's ophthalmologist should be prepared for possible modifications to the surgical technique, such as utilization of iris hooks, iris dilator rings, or viscoelastic substances. There does not appear to be a benefit of stopping alpha-1 blocker therapy prior to cataract surgery.
6. 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 Zydus Pharmaceuticals USA Inc. at 1-877-993-8779 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Studies Experience Carvedilol tablets have been evaluated for safety in patients wit...
6. 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 Zydus Pharmaceuticals USA Inc. at 1-877-993-8779 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Studies Experience Carvedilol tablets have been evaluated for safety 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). Left Ventricular Dysfunction Following Myocardial Infarction: Carvedilol tablets have been evaluated for safety in survivors of an acute myocardial infarction with left ventricular dysfunction in the CAPRICORN trial which involved 969 patients who received carvedilol tablets and 980 who received placebo. Approximately 75% of the patients received carvedilol tablets for at least 6 months and 53% received carvedilol tablets for at least 12 months. Patients were treated for an average of 12.9 months and 12.8 months with carvedilol tablets and placebo, respectively. The following adverse events were reported with a frequency of >1% but ≤3% and more frequently with carvedilol tablets: 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 >1%, and occurring more often on carvedilol was hypotension (1.5% on carvedilol, 0.2% on placebo). Hypertension: Carvedilol tablets have been evaluated for safety in hypertension in more than 2,193 patients in US clinical trials and in 2,976 patients in international clinical trials. Approximately 36% of the total treated population received carvedilol tablets for at least 6 months. Most adverse events reported during therapy with carvedilol tablets were of mild to moderate severity. In US controlled clinical trials directly comparing carvedilol tablets in doses up to 50 mg (n = 1,142) to placebo (n = 462), 4.9% of patients receiving carvedilol tablets discontinued for adverse events versus 5.2% of placebo patients. Although there was no overall difference in discontinuation rates, discontinuations were more common in the carvedilol group for postural hypotension (1% versus 0). The overall incidence of adverse events in US placebo-controlled trials increased with increasing dose of carvedilol tablets. 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. Table 1 shows adverse events in US placebo-controlled clinical trials for hypertension that occurred with an incidence of >1% regardless of causality, and that were more frequent in drug-treated patients than placebo-treated patients. Table 1 Adverse Events (%) Occurring in US Placebo-Controlled Hypertension Trials (Incidence ≥1%, Regardless of Causality) Shown are events with rate >1% rounded to nearest integer. Carvedilol Tablets Placebo (n = 1,142) (n = 462) Cardiovascular Bradycardia 2 - Postural hypotension 2 - Peripheral edema 1 - Central Nervous System Dizziness 6 5 Insomnia 2 1 Gastrointestinal Diarrhea 2 1 Hematologic Thrombocytopenia 1 - Metabolic Hypertriglyceridemia 1 - Dyspnea and fatigue were also reported in these studies, but the rates were equal or greater in patients who received placebo. The following adverse events not described above were reported as possibly or probably related to carvedilol tablets in worldwide open or controlled trials with carvedilol tablets in patients with hypertension. 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 were discontinued from therapy because of increases in hepatic enzymes) [see Adverse Reactions (6.2)]. Psychiatric: Nervousness, sleep disorder, aggravated depression, impaired concentration, abnormal thinking, paroniria, emotional lability. Respiratory System: Asthma [see CONTRAINDICATIONS (4)]. Reproductive, male: Decreased libido. Skin and Appendages: Pruritus, rash erythematous, rash maculopapular, rash psoriaform, photosensitivity reaction. Special Senses: Tinnitus. Urinary System: Micturition frequency increased. Autonomic Nervous System: Dry mouth, sweating increased. Metabolic and Nutritional: Hypokalemia, hypertriglyceridemia. Hematologic: Anemia, leukopenia. The following events were reported in ≤0.1% of patients and are potentially important: Complete AV block, bundle branch block, myocardial ischemia, cerebrovascular disorder, convulsions, migraine, neuralgia, paresis, anaphylactoid reaction, alopecia, exfoliative dermatitis, amnesia, GI hemorrhage, bronchospasm, pulmonary edema, decreased hearing, respiratory alkalosis, increased BUN, decreased HDL, pancytopenia, and atypical lymphocytes. 6.2 Laboratory Abnormalities Reversible elevations in serum transaminases (ALT or AST) have been observed during treatment with carvedilol tablets. Rates of transaminase elevations (2- to 3-times the upper limit of normal) observed during controlled clinical trials have generally been similar between patients treated with carvedilol tablets and those treated with placebo. However, transaminase elevations, confirmed by rechallenge, have been observed with carvedilol tablets. In a long-term, placebo-controlled trial in severe heart failure, patients treated with carvedilol tablets had lower values for hepatic transaminases than patients treated with placebo, possibly because improvements in cardiac function induced by carvedilol led to less hepatic congestion and/or improved hepatic blood flow. Carvedilol tablets have 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 patients. 6.3 Postmarketing Experience The following adverse reactions have been identified during post-approval use of carvedilol tablets. 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.
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