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Clinical Studies Experience

COREG (carvedilol) 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 (carvedilol) 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% of the total treated population in placebo-controlled clinical trials received COREG (carvedilol) for at least 6 months and 30% received COREG (carvedilol) for at least 12 months. In the COMET trial, 1,511 patients with mild-to-moderate heart failure were treated with COREG (carvedilol) for up to 5.9 years (mean 4.8 years). Both in US clinical trials in mild-to-moderate heart failure that compared COREG (carvedilol) 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 (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 patients. 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 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 > 3% 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 (carvedilol) observed in the long-term COMET study was generally similar to that observed in the US Heart Failure Trials.

Table 1: Adverse Events (%) Occurring More Frequently With COREG (carvedilol) 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 > 3% in Patients Treated With Carvedilol, Regardless of Causality)

  Mild-to-Moderate HF Severe HF
COREG
(n = 765)
Placebo
(n = 437)
COREG
(n = 1,156)
Placebo
(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 studies, but the rates were equal or greater in patients who received placebo.

The following adverse events were reported with a frequency of > 1% but ≤ 3% and more frequently with COREG (carvedilol) 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 > 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.

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 (carvedilol) 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 (carvedilol) and 980 who received placebo. Approximately 75% of the patients received COREG (carvedilol) for at least 6 months and 53% received COREG (carvedilol) for at least 12 months. Patients were treated for an average of 12.9 months and 12.8 months with COREG (carvedilol) and placebo, respectively.

The most common adverse events reported with COREG (carvedilol) 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 patients and more commonly on carvedilol were dyspnea, anemia, and lung edema. The following adverse events were reported with a frequency of > 1% but ≤ 3% and more frequently with COREG (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 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

COREG (carvedilol) 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% of the total treated population received COREG (carvedilol) for at least 6 months. Most adverse events reported during therapy with COREG (carvedilol) were of mild to moderate severity. In US controlled clinical trials directly comparing COREG (carvedilol) in doses up to 50 mg (n = 1,142) to placebo (n = 462), 4.9% of patients receiving COREG (carvedilol) 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 COREG (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.

Table 2 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 2: Adverse Events (%) Occurring in US Placebo-Controlled Hypertension Trials (Incidence ≥ 1%, Regardless of Causality)*

  COREG
(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
* Shown are events with rate > 1% 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 (carvedilol) in worldwide open or controlled trials with COREG (carvedilol) in patients with hypertension or heart failure.

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 and 0.4% of heart failure patients were discontinued from therapy because of increases in hepatic enzymes).

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 ≤ 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.

Laboratory Abnormalities

Reversible elevations in serum transaminases (ALT or AST) have been observed during treatment with COREG (carvedilol) . 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 (carvedilol) and those treated with placebo. However, transaminase elevations, confirmed by rechallenge, have been observed with COREG (carvedilol) . In a long-term, placebo-controlled trial in severe heart failure, patients treated with COREG (carvedilol) had lower values for hepatic transaminases than patients treated with placebo, possibly because improvements in cardiac function induced by COREG (carvedilol) led to less hepatic congestion and/or improved hepatic blood flow.

COREG (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.

Postmarketing Experience

The following adverse reactions have been identified during post-approval use of COREG (carvedilol) . 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 (carvedilol) and COREG (carvedilol) CR®, including cases occurring after the initiation of COREG (carvedilol) CR in patients previously treated with COREG (carvedilol) . Urinary incontinence in women (which resolved upon discontinuation of the medication) and interstitial pneumonitis have been reported rarely.