1 ): Heart failure and left ventricular dysfunction following myocardial infarction (≥10%): Dizziness, fatigue, hypotension, diarrhea, hyperglycemia, asthenia, bradycardia, weight increase. Hypertension (≥5%): Dizziness. gov/medwatch.
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.
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 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 for at least 6 months and 30% received carvedilol for at least 12 months. 8 years). S. 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.
6% on placebo in the COPERNICUS trial). 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.
4 months in the trial of subjects with severe heart failure. S. Heart Failure Trials. Table 1. 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 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.
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 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 tablets for at least 12 months. 8 months with carvedilol and placebo, respectively. 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. 2% on placebo). S. clinical trials and in 2,976 subjects in international clinical trials. Approximately 36% of the total treated population received Carvedilol.
Most adverse events reported during therapy with carvedilol tablets were of mild to moderate severity. S. 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).
S. placebo‑controlled trials increased with increasing dose of carvedilol. 25 mg to 50 mg. 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 2. S. Placebo-Controlled Hypertension Trials (Incidence ≥1%, Regardless of Causality) a Body System/ Adverse Event CARVEDILOL 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 — 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.
1% to less than or equal to 1% Cardiovascular: Peripheral ischemia, tachycardia.
Central and Peripheral Nervous System:
Hypokinesia. 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. 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 tablets. 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 improvements in cardiac function induced by carvedilol led to less hepatic congestion and/or improved hepatic blood flow.
Carvedilol 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 patients; fasting serum glucose was not evaluated in the heart failure clinical trials.
2 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. , 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.