6 ADVERSE REACTIONS The safety profile of COREG CR was similar to that observed for immediate-release carvedilol. Most common adverse events seen with immediate-release carvedilol (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 GlaxoSmithKline at 1-888-825-5249 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials 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. Carvedilol has been evaluated for safety in subjects with heart failure (mild, moderate, and severe), in subjects with left ventricular dysfunction following myocardial infarction, and in hypertensive subjects. The observed adverse event profile was consistent with the pharmacology of the drug and the health status of the subjects in the clinical trials. Adverse events reported for each of these populations reflecting the use of either COREG CR or immediate-release carvedilol are provided below. Excluded are adverse events considered too general to be informative, and those not reasonably associated with the use of the drug because they were associated with the condition being treated or are very common in the treated population. Rates of adverse events were generally similar across demographic subsets (men and women, elderly and non‑elderly, blacks and non‑blacks). COREG CR has been evaluated for safety in a 4-week (2 weeks of immediate-release carvedilol and 2 weeks of COREG CR) clinical trial (n = 187) which included 157 subjects with stable mild, moderate, or severe chronic heart failure and 30 subjects with left ventricular dysfunction following acute myocardial infarction. The profile of adverse events observed with COREG CR in this small, short-term trial was generally similar to that observed with immediate-release carvedilol. Differences in safety would not be expected based on the similarity in plasma levels for COREG CR and immediate-release carvedilol. Heart Failure The following information describes the safety experience in heart failure with immediate-release carvedilol. Carvedilol has been evaluated for safety in heart failure in more than 4,500 subjects worldwide of whom more than 2,100 participated in placebo‑controlled clinical trials. Approximately 60% of the total treated population in placebo‑controlled clinical trials received carvedilol for at least 6 months and 30% received carvedilol for at least 12 months. In the COMET trial, 1,511 subjects with mild‑to‑moderate heart failure were treated with carvedilol for up to 5.9 years (mean: 4.8 years). Both in U.S. clinical trials in mild‑to‑moderate heart failure that compared carvedilol in daily doses up to 100 mg (n = 765) with placebo (n = 437), and in a multinational clinical trial in severe heart failure (COPERNICUS) that compared carvedilol in daily doses up to 50 mg (n = 1,156) with placebo (n = 1,133), discontinuation rates for adverse experiences were similar in carvedilol and placebo subjects. In 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 2 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 carvedilol observed in the long-term COMET trial was generally similar to that observed in the U.S. Heart Failure Trials. Table 2. Adverse Events (%) Occurring More Frequently with Immediate-Release Carvedilol than with Placebo in Subjects with MildtoModerate 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 Carvedilol Placebo Carvedilol 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 carvedilol 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. Left Ventricular Dysfunction following Myocardial Infarction The following information describes the safety experience in left ventricular dysfunction following acute myocardial infarction with immediate-release carvedilol. Carvedilol has been evaluated for safety in survivors of an acute myocardial infarction with left ventricular dysfunction in the CAPRICORN trial which involved 969 subjects who received carvedilol and 980 who received placebo. Approximately 75% of the subjects received carvedilol for at least 6 months and 53% received carvedilol for at least 12 months. Subjects were treated for an average of 12.9 months and 12.8 months with carvedilol and placebo, respectively. The most common adverse events reported with carvedilol in the CAPRICORN trial were consistent with the profile of the drug in the U.S. heart failure trials and the COPERNICUS trial. The only additional adverse events reported in CAPRICORN in greater than 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: flu syndrome, cerebrovascular accident, peripheral vascular disorder, hypotonia, depression, gastrointestinal pain, arthritis, and gout. The overall rates of discontinuations due to adverse events were similar in both groups of subjects. In this database, the only cause of discontinuation greater than 1% and occurring more often on carvedilol was hypotension (1.5% on carvedilol, 0.2% on placebo). Hypertension COREG CR was evaluated for safety in an 8-week double-blind trial in 337 subjects with essential hypertension. The profile of adverse events observed with COREG CR was generally similar to that observed with immediate-release carvedilol. The overall rates of discontinuations due to adverse events were similar between COREG CR and placebo. Table 3. Adverse Events (%) Occurring More Frequently with COREG CR than with Placebo in Subjects with Hypertension (Incidence ≥1% in Subjects Treated with Carvedilol, Regardless of Causality) Adverse Event COREG CR (n = 253) Placebo (n = 84) Nasopharyngitis 4 0 Dizziness 2 1 Nausea 2 0 Edema peripheral 2 1 Nasal congestion 1 0 Paresthesia 1 0 Sinus congestion 1 0 Diarrhea 1 0 Insomnia 1 0 The following information describes the safety experience in hypertension with immediate-release carvedilol. Carvedilol has been evaluated for safety in hypertension in more than 2,193 subjects in U.S. clinical trials and in 2,976 subjects in international clinical trials. Approximately 36% of the total treated population received carvedilol for at least 6 months. In general, carvedilol was well tolerated at doses up to 50 mg daily. Most adverse events reported during carvedilol therapy were of mild to moderate severity. In U.S. controlled clinical trials directly comparing carvedilol monotherapy in doses up to 50 mg (n = 1,142) with placebo (n = 462), 4.9% of carvedilol subjects discontinued for adverse events versus 5.2% of placebo subjects. Although there was no overall difference in discontinuation rates, discontinuations were more common in the carvedilol group for postural hypotension (1% versus 0). The overall incidence of adverse events in U.S. placebo‑controlled trials was found to increase with increasing dose of carvedilol. For individual adverse events this could only be distinguished for dizziness, which increased in frequency from 2% to 5% as total daily dose increased from 6.25 mg to 50 mg as single or divided doses. Table 4 shows adverse events in U.S. placebo‑controlled clinical trials for hypertension that occurred with an incidence of greater than or equal to 1% regardless of causality and that were more frequent in drug‑treated subjects than placebo‑treated subjects. Table 4. Adverse Events (% Occurrence) in U.S. Placebo-Controlled Hypertension Trials with Immediate-Release Carvedilol (Incidence ≥1% in Subjects Treated with Carvedilol, Regardless of Causality)a Adverse Event Carvedilol (n = 1,142) Placebo (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 — a Shown are events with rate >1% rounded to nearest integer. Dyspnea and fatigue were also reported in these trials, but the rates were equal or greater in subjects who received placebo. The following adverse events not described above were reported as possibly or probably related to carvedilol in worldwide open or controlled trials with carvedilol in subjects with hypertension or heart failure. Incidence greater than 0.1% to less than or equal to 1% Cardiovascular: Peripheral ischemia, tachycardia. Central and Peripheral Nervous System: Hypokinesia. Gastrointestinal: Bilirubinemia, increased hepatic enzymes (0.2% of hypertension patients and 0.4% of heart failure patients were discontinued from therapy because of increases in hepatic enzymes) [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 less than or equal to 0.1% of subjects 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 carvedilol. Rates of transaminase elevations (2 to 3 times the upper limit of normal) observed during controlled clinical trials have generally been similar between subjects treated with carvedilol and those treated with placebo. However, transaminase elevations, confirmed by rechallenge, have been observed with carvedilol. In a long-term, placebo-controlled trial in severe heart failure, subjects treated with carvedilol had lower values for hepatic transaminases than subjects treated with placebo, possibly because carvedilol-induced improvements in cardiac function led to less hepatic congestion and/or improved hepatic blood flow. Carvedilol therapy has not been associated with clinically significant changes in serum potassium, total triglycerides, total cholesterol, HDL cholesterol, uric acid, blood urea nitrogen, or creatinine. No clinically relevant changes were noted in fasting serum glucose in hypertensive subjects; fasting serum glucose was not evaluated in the heart failure clinical trials. 6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of COREG or COREG CR. 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.