pms-Carvedilol Adverse Reactions

Overview: Mild to Moderate Heart Failure - Controlled Trials: The most frequent adverse experiences reported in the double-blind phase of the US clinical trial experience (see Table 6) in patients with mild to moderate heart failure treated with carvedilol were dizziness (32.4%), fatigue (23.9%), dyspnea (21.3%), upper respiratory infection (18.3%) cardiac failure (15.3%) and chest pain (14.4%).
During the double-blind phase of six US placebo controlled trials, adverse experiences rated as serious were reported in 22.4% of patients treated with carvedilol and 31.8% in the placebo group. The most serious adverse experiences reported with carvedilol were cardiac failure (5.6%), syncope (1.8%), bradycardia (1.6%), hypotension (1.3%), myocardial infarction (0.9%), acute renal failure (0.8%), and AV block (0.7%).
Of the 1202 patients who received randomized treatment in these trials, 5.4% of patients treated with carvedilol withdrew because of adverse experiences compared with 8.0% of placebo patients. Bradycardia, fatigue, hypotension, dizziness and dyspnea were the most commonly reported adverse experiences leading to discontinuation in patients treated with carvedilol (see Table 6).
Six deaths occurred in 1319 patients enrolled in the screening phase (3 to 4 weeks), 11 deaths occurred in 1313 patients challenged with carvedilol (2 to 4 weeks). There were 8 deaths (3/765 carvedilol; 5/437 placebo) during up titration phase (2 to 6 weeks) and 47 deaths (20/765 carvedilol; 27/437 placebo) during the maintenance phase (up to 12 months) of the studies.
Withdrawals due to worsening heart failure in U.S placebo controlled trials were as follows: during challenge 1.4% of patients (18/1313 for 2 to 4 weeks); during up-titration 0.9% (7/765) of patients treated with carvedilol and 0% (0/437) of placebo patients (2 to 6 weeks); during the maintenance phase 0.7% (5/765) of patients treated with carvedilol and 2.3% (10/437) of placebo patients (up to 12 months).
Worsening renal function, including acute renal failure (see Table 6), has been seen in some patients (carvedilol 9.5% and placebo 7.6%). Patients at greatest risk include those with pre-existing renal insufficiency, hypotension and ischemic cardiomyopathy, previous renal insufficiency due to ACE inhibitors, diffuse vascular disease, or evidence of renal artery stenosis.
Severe Heart Failure - Controlled Trials: The most frequent adverse experiences reported in a clinical trial in patients with severe heart failure treated with carvedilol were dizziness (24.1%), hypotension (13.9%) and upper respiratory infection (13.6%) (see Table 7). Median study exposure was 10.4 months for both carvedilol and placebo patients.
Clinical Trial Adverse Drug Reactions: Because clinical trials are conducted under very specific conditions the adverse reaction rates observed in the clinical trials may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug. Adverse drug reaction information from clinical trials is useful for identifying drug-related adverse events and for approximating rates.
Mild to Moderate Heart Failure - Controlled Trials: In six US placebo controlled trials, 1313 patients were challenged with carvedilol over a 2 - 4 week period. Of these patients, 1202 were randomized to double blind treatment with carvedilol (n=765) or placebo (n=437). 92.5% of those treated with carvedilol reported at least one adverse experience.
Adverse experiences rated as severe in intensity during the double-blind phase of these trials were reported in 24.3% of patients treated with carvedilol. The most frequent severe adverse experiences were cardiac failure (2.9%), fatigue (2.2%), dizziness (2.0%), dyspnea (1.8%), and syncope (1.7%).
Table 6 shows adverse events reported in patients with mild to moderate heart failure enrolled in U.S. placebo-controlled clinical trials. Shown are adverse events that occurred more frequently in carvedilol-treated patients than placebo-treated patients with an incidence >1% regardless of causality. Median study medication exposure was 6.3 months for carvedilol and placebo patients. (See Table 6.)

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In addition to the events in Table 6, the following events occurred in more than 1% of patients treated with carvedilol but rates were equal to, or more common in, placebo-treated patients: asthenia, cardiac failure, flatulence, anorexia, dyspepsia, palpitation, ventricular tachycardia, atrial fibrillation, extrasystoles, bilirubinemia, hyperkalemia, arthritis, angina pectoris, insomnia, depression, amnesia, anemia, viral infection, dyspnea, coughing, respiratory disorder, pneumonia, rhinitis, rash, pruritus, and leg cramps.
Adverse experiences related to laboratory parameters reported in greater than 1% of patients are in Table 6. Adverse experiences related to laboratory parameters reported in ≤1% but more than 0.1% of patients included increased hepatic enzymes (0.4% of congestive heart failure patients were discontinued from therapy because of increases in hepatic enzymes; see Hepatic: Hepatic Impairment under Precautions), hypokalemia, hypertriglyceridemia, anemia, leukopenia.
Severe Heart Failure - Controlled Trial: In a clinical trial in severe heart failure that compared carvedilol in daily doses of 50 mg (n=1156) with placebo (n=1133), 9.4% of patients treated with carvedilol discontinued treatment for adverse experiences versus 11.2% of placebo patients.
Table 7 shows adverse events reported in patients with severe heart failure enrolled in multinational placebo-controlled clinical trial. Shown are adverse events that occurred more frequently in carvedilol-treated patients than placebo-treated patients with an incidence >1% regardless of causality. (See Table 7.)

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In addition to the events in Table 7, when compared with placebo, carvedilol-treated patients had fewer of the following adverse events related to the cardiovascular system and occurring in or equal to 2% of patients: sudden death, atrial fibrillation, chest pain, congestive heart failure, heart failure, peripheral vascular disorder, unstable angina pectoris and ventricular tachycardia. Other adverse experiences occurring in greater or equal to 2% but reported less frequently in carvedilol-treated patients include: abdominal pain, pain in the extremity, hypokalemia, lung edema, pneumonia, abnormal kidney function and urinary tract infection.
Less Common Clinical Trials Adverse Drug Reactions (˂ 1%): Hypertension and Heart Failure - Open and Controlled Trials: The following adverse events were reported as possibly or probably related in worldwide open or controlled trials with carvedilol in patients with hypertension or congestive heart failure at an incidence of > 0.1% to ≤ 1%: Cardiovascular: Peripheral ischemia, tachycardia.
Central and Peripheral Nervous System: Hypokinesia.
General: Substernal chest pain, edema.
Psychiatric: Sleep disorder, aggravated depression, impaired concentration, abnormal thinking, paroniria, emotional lability.
Respiratory System: Asthma.
Reproductive, Male: Decreased libido.
Skin and Appendages: Pruritus, rash erythematous, rash maculopapular, rash psoriaform, photosensitivity reaction.
Special Senses: Tinnitus.
Urinary System: Micturition frequency.
Autonomic Nervous System: Dry mouth, sweating increased.
Metabolic and Nutritional: Diabetes mellitus.
The following adverse events were reported as possibly or probably related in worldwide open or controlled trials with carvedilol in patients with hypertension or congestive heart failure at an incidence of ≤ 0.1%, 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, decreased HDL, pancytopenia, and atypical lymphocytes.
Post-Market Adverse Drug Reactions: 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. Urinary incontinence in women (which resolved upon discontinuation of the medication) and interstitial pneumonitis have been reported rarely.