FDA label 3dfaa85f-a57a-373f-e054-00144ff88e88

WARNINGS AND PRECAUTIONS 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 angina patients following the abrupt discontinuation of therapy withThe last 2 complications may occur with or without preceding exacerbation of the angina pectoris. As with otherwhen 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. Bradycardia In clinical trials, COREG caused bradycardia in about 2 percent of hypertensive patients, 9 percent of heart failure patients, and 6.5 percent of myocardial infarction patients with left ventricular dysfunction. If pulse rate drops below 55 beats/minute, the dosage should be reduced. Hypotension In clinical trials of primarily mild-to-moderate heart failure, hypotension and postural hypotension occurred in 9.7 percent and syncope in 3.4 percent of patients receiving COREG compared to 3.6 percent and 2.5 percent of placebo patients, 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 percent of patients receiving COREG, compared to 0.4 percent of placebo patients. In a long-term, placebo-controlled trial in severe heart failure (COPERNICUS), hypotension and postural hypotension occurred in 15.1 percent and syncope in 2.9 percent of heart failure patients receiving COREG compared to 8.7 percent and 2.3 percent of placebo patients, respectively. These events were a cause for discontinuation of therapy in 1.1 percent of patients receiving COREG, compared to 0.8 percent of placebo patients. Postural hypotension occurred in 1.8 percent and syncope in 0.1 percent 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 percent of patients. In the CAPRICORN study of survivors of an acute myocardial infarction, hypotension or postural hypotension occurred in 20.2 percent of patients receiving COREG compared to 12.6 percent of placebo patients. Syncope was reported in 3.9 percent and 1.9 percent of patients, respectively. These events were a cause for discontinuation of therapy in 2.5 percent of patients receiving COREG, compared to 0.2 percent 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]. 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. 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 ]. 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 patients 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 patients 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. Non-allergic Bronchospasm Patients with bronchospastic disease (e.g., chronic bronchitis and emphysema) should, in general, not receiveCOREG 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 exogenousis 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 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. Glycemic Control in Type 2 Diabetes In general,may mask some of the manifestations of hypoglycemia, particularly tachycardia. Nonselectivemay 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]. Peripheral Vascular Disease can precipitate or aggravate symptoms of arterial insufficiency in patients with peripheral vascular disease. Caution should be exercised in such individuals. 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 greater then 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. Anesthesia and Major Surgery If treatment with COREG 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 for information on treatment of bradycardia and hypertension]. Thyrotoxicosis blockade may mask clinical signs of hyperthyroidism, such as tachycardia. Abrupt withdrawal ofmay be followed by an exacerbation of the symptoms of hyperthyroidism or may precipitate thyroid storm. Pheochromocytoma In patients with pheochromocytoma, anagent should be initiated prior to the use of anyagent. Although carvedilol has bothandpharmacologic 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. Prinzmetal's Variant Angina Agents with non-selectiveactivity may provoke chest pain in patients with Prinzmetal's variant angina. There has been no clinical experience with carvedilol in these patients although theactivity may prevent such symptoms. However, caution should be taken in the administration of carvedilol to patients suspected of having Prinzmetal's variant angina. Risk of Anaphylactic Reaction While takingpatients 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.

ADVERSE REACTIONS Clinical Studies Experience COREG 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 COREG has been evaluated for safety in heart failure in more than 4,500 patients worldwide of whom more than 2,100 participated in placebo-controlled clinical trials. Approximately 60 percent of the total treated population in placebo-controlled clinical trials received COREG for at least 6 months and 30 percent received COREG for at least 12 months. In the COMET trial, 1,511 patients with mild-to-moderate heart failure were treated with COREG for up to 5.9 years (mean 4.8 years). Both in US clinical trials in mild-to-moderate heart failure that compared COREG in daily doses up to 100 mg (n = 765) to 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 patients. In placebo-controlled clinical trials, the only cause of discontinuation less then1 percent, and occurring more often on carvedilol was dizziness (1.3 percent on carvedilol, 0.6 percent on placebo in the COPERNICUS trial). Table 1 shows adverse events reported in patients 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 patients than placebo-treated patients with an incidence of less then 3 percent in patients treated with carvedilol regardless of causality. Median study medication exposure was 6.3 months for both carvedilol and placebo patients in the trials of mild-to-moderate heart failure, and 10.4 months in the trial of severe heart failure patients. The adverse event profile of COREG observed in the long-term COMET study was generally similar to that observed in the US Heart Failure Trials. Table 1. Adverse Events (percent) Occurring More Frequently With COREG Than With Placebo in Patients With Mild-to-Moderate Heart Failure (HF) Enrolled in US Heart Failure Trials or in Patients With Severe Heart Failure in the COPERNICUS Trial (Incidence greater then3 percent in Patients Treated With Carvedilol, Regardless of Causality) Mild-to-Moderate HFSevere HFCOREGPlaceboCOREGPlacebo(n = 765)(n = 437)(n = 1,156)(n = 1,133)Body as a WholeAsthenia77119Fatigue2422Digoxin level increased5421Edema generalized5365Edema dependent42CardiovascularBradycardia91103Hypotension93148Syncope3385Angina pectoris2364Central Nervous SystemDizziness32192417Headache8753GastrointestinalDiarrhea12653Nausea9543Vomiting6412MetabolicHyperglycemia12853Weight increase1071211BUN increased65NPN increased65Hypercholesterolemia4311Edema peripheral2176MusculoskeletalArthralgia6511RespiratoryCough increased8954Rales4442VisionVision abnormal52Cardiac failure and dyspnea were also reported in these studies, but the rates were equal or greater in patients who received placebo. The following adverse events were reported with a frequency of less then 1 percent but greater then 3 percent and more frequently with COREG in either the US placebo-controlled trials in patients with mild-to-moderate heart failure, or in patients with severe heart failure in the COPERNICUS trial. Incidence less then 1percent to greater then 3 percent 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. Left Ventricular Dysfunction Following Myocardial Infarction COREG has 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 COREG and 980 who received placebo. Approximately 75 percent of the patients received COREG for at least 6 months and 53 percent received COREG for at least 12 months. Patients were treated for an average of 12.9 months and 12.8 months with COREG and placebo, respectively. The most common adverse events reported with COREG 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 less then 3 percent of the patients and more commonly on carvedilol were dyspnea, anemia, and lung edema. The following adverse events were reported with a frequency of less then 1 percent but greater then 3 percent and more frequently with COREG: 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 less then 1 percent, and occurring more often on carvedilol was hypotension (1.5 percent on carvedilol, 0.2 percent on placebo). Hypertension COREG has 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 percent of the total treated population received COREG for at least 6 months. Most adverse events reported during therapy with COREG were of mild to moderate severity. In US controlled clinical trials directly comparing COREG in doses up to 50 mg (n = 1,142) to placebo (n = 462), 4.9 percent of patients receiving COREG discontinued for adverse events versus 5.2 percent of placebo patients. Although there was no overall difference in discontinuation rates, discontinuations were more common in the carvedilol group for postural hypotension (1 percent versus 0). The overall incidence of adverse events in US placebo-controlled trials increased with increasing dose of COREG. For individual adverse events this could only be distinguished for dizziness, which increased in frequency from 2 percent to 5 percent as total daily dose increased from 6.25 mg to 50 mg. Table 2 shows adverse events in US placebo-controlled clinical trials for hypertension that occurred with an incidence of less then 1 percent regardless of causality, and that were more frequent in drug-treated patients than placebo-treated patients. Table 2. Adverse Events (percent) Occurring in US Placebo-Controlled Hypertension Trials (Incidence less then1percent, Regardless of Causality) COREGPlacebo(n = 1,142)(n = 462)CardiovascularBradycardia2Postural hypotension2Peripheral edema1Central Nervous SystemDizziness65Insomnia21GastrointestinalDiarrhea21HematologicThrombocytopenia1MetabolicHypertriglyceridemia1Shown are events with rate less then1 percent rounded to nearest integer. 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 COREG in worldwide open or controlled trials with COREG in patients with hypertension or heart failure. Incidence less then 0.1 percent to greater then1 percent Cardiovascular: Peripheral ischemia, tachycardia. Central and Peripheral Nervous System: Hypokinesia. Gastrointestinal: Bilirubinemia, increased hepatic enzymes (0.2 percent of hypertension patients and 0.4 percent of heart failure patients were discontinued from therapy because of increases in hepatic enzymes) [see Adverse Reactions]. Psychiatric: Nervousness, sleep disorder, aggravated depression, impaired concentration, abnormal thinking, paroniria, emotional lability. Respiratory System: Asthma [see Contraindications]. 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 greater then 0.1 percent 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. Laboratory Abnormalities Reversible elevations in serum transaminases (ALT or AST) have been observed during treatment with COREG. 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 COREG and those treated with placebo. However, transaminase elevations, confirmed by rechallenge, have been observed with COREG. In a long-term, placebo-controlled trial in severe heart failure, patients treated with COREG had lower values for hepatic transaminases than patients treated with placebo, possibly because improvements in cardiac function induced by COREG led to less hepatic congestion and/or improved hepatic blood flow. Postmarketing Experience The following adverse reactions have been identified during post-approval use of COREG. 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. Reports of aplastic anemia and severe skin reactions (Stevens-Johnson syndrome, toxic epidermal necrolysis, and erythema multiforme) have been rare and received only when carvedilol was administered concomitantly with other medications associated with such reactions. Rare reports of hypersensitivity reactions (e.g., anaphylactic reaction, angioedema, and urticaria) have been received for COREG and COREG CR, including cases occurring after the initiation of COREG CR in patients previously treated with COREG. Urinary incontinence in women (which resolved upon discontinuation of the medication) and interstitial pneumonitis have been reported rarely.