Carvedilol

aggravated depression, emotional lability, impaired concentration, nervousness, paroniria (morbid dreams), somnolence.

elevated serum ALT, AST, bilirubin, alkaline phosphatase and/or GGT levels.

anemia, decreased prothrombin, leucopenia, purpura, thrombocytopenia.

muscle cramps.

alopecia, pruritus, erythematous rash, exfoliative dermatitis, maculopapular rash, psoriaform rash, photosensitivity.

diabetes mellitus, hyperuricemia, hypoglycemia, hyponatremia, glycosuria, hypervolemia, hypokalemia, weight loss, hyperkalemia.

bronchospasm.

decreased libido, male impotence.

aggravated angina pectoris, AV block, bundle branch block, complete AV block, fluid overload, myocardial ischemia, postural hypotension, palpitation, hypertension, peripheral ischemia.

The pattern and frequency of adverse events in elderly patients with heart failure was similar to that reported in younger patients with heart failure enrolled in clinical trials. However, because plasma levels of carvedilol are generally higher in elderly individuals the maximum tolerated dose may be lower in elderly patients than in younger patients.

In pediatric patients with heart failure there was no difference in the percentage of patients who experienced improvement, worsening or no change in clinical status after 8 months of treatment with carvedilol or placebo in a randomized, double-blind, multicentre trial [Carvedilol for children and adolescents with heart failure: a randomized controlled trial. JAMA 2007;298(10):1171-9]. There was a possible beneficial trend in children with a systemic left ventricle (i.e., those with congenital heart defects resulting in an absent or poorly functioning left ventricle), but not in those without a systemic left ventricle.

Plasma levels are approximately 50% higher in elderly than in younger patients.

Carvedilol undergoes extensive hepatic metabolism including significant first-pass metabolism. Thus, the bioavailability of carvedilol may be increased in patients with hepatic dysfunction.

Severe bradycardia may occur after initiating treatment with carvedilol. The dosage should be reduced or the drug withdrawn in such cases.

Pregnancy category C. Post-implantation loss of pregnancy has been observed in animals treated with carvedilol. Use of beta blockers during pregnancy has been associated with persistent bradycardia, hypotension and intrauterine growth retardation. Neonatal hypoglycemia has been reported in infants after maternal use of beta blockers at parturition or during breast-feeding.

Caution with anesthetic agents that depress myocardial function.

Beta blockers may mask the clinical signs of hyperthyroidism, particularly tachycardia. Abrupt withdrawal of a beta blocker may result in an exacerbation of hyperthyroidism and may precipitate thyroid storm.

Blood pressure, heart rate electrocardiogram, serum creatinine and liver function tests in all patients, and blood sugar in patients with diabetes or those at risk of developing diabetes.

Hypotension including postural hypotension may be precipitated by carvedilol. Hypotension is more likely to occur during initiation of treatment; thus, it is important to follow the dosage recommendations (see Dosage and Administration).

Patients may experience dizziness and syncope after the initiation of carvedilol. Patients should be counseled to avoid driving or operating potentially dangerous machinery if they experience dizziness upon initiation of carvedilol or after dosage adjustments.

Beta blockers may mask some of the signs of hypoglycemia, particularly autonomic signs such as tachycardia, in patients with diabetes. Beta blockers may lead to worsening hyperglycemia.

Worsening of renal function may occur upon initiation of carvedilol in patients with heart failure. Patients with pre-existing renal insufficiency, hypotension (systolic blood pressure <100 mm Hg), ischemic heart disease and/or diffuse vascular disease are at increased risk of worsening renal function. Renal function should be monitored before and after initiating treatment with carvedilol and after increasing the dose. If clinically significant worsening of renal function occurs during treatment with carvedilol the dose should be reduced or treatment withdrawn.

Carvedilol is not approved for use in children, although the drug has been evaluated in children with heart failure aged 3 months to 18 years in clinical trials. The safety and efficacy of carvedilol in this setting is not well established.

Carvedilol may antagonize the action of epinephrine when the latter is used to treat allergic reactions. Larger than usual doses of epinephrine may be required to treat anaphylaxis.

The area under the plasma concentration vs time curve (AUC) is higher in elderly subjects aged 65 to 76 years compared with younger subjects aged 18 to 43 years. In elderly individuals the mean AUC of S(−) carvedilol was 50% higher and that of R(+) carvedilol 23% higher than that in younger individuals.

The volume of distribution of carvedilol is estimated to be 115 L indicating extensive extravascular distribution. Plasma concentrations of carvedilol are dose proportional after oral administration. At therapeutic doses carvedilol is highly bound (>98%) to plasma proteins (primarily albumin) in a concentration independent manner. Plasma levels of R(+) carvedilol are generally 2 to 3 times higher than those of S(−) carvedilol after oral administration.

Peak plasma concentrations of carvedilol occur approximately 1 hour after oral administration to fasting individuals. The absolute bioavailability of the drug ranges from 25% to 35% because of extensive first-pass metabolism. When administered with food the rate of absorption is reduced, but the extent of absorption is unchanged.

Carvedilol is a nonselective beta-adrenergic receptor antagonist with alpha₁-antagonist activity. The potency of the drug is 10-fold greater at beta-adrenergic than alpha-adrenergic receptors. Carvedilol produces bradycardia through its beta₁-antagonist activity, and hypotension primarily through its alpha₁-adrenergic antagonist activity. Beta₁-blockade prevents reflex tachycardia in response to the decrease in systemic vascular resistance. The drug also inhibits release of renin mediated via beta-adrenergic receptors.

The beta₁-receptor antagonist activity of carvedilol is attributable primarily to the S(−) enantiomer and the alpha₁-receptor antagonist activity of the drug is primarily associated with the R(+) enantiomer.

In patients with heart failure, carvedilol has been shown to significantly reduce heart rate, blood pressure, pulmonary artery pressure and pulmonary capillary wedge pressure. After 3 months of administration there were significant reductions in heart rate, pulmonary artery pressure, right atrial pressure, systemic vascular resistance, and a significant increase in stroke volume index.

Carvedilol undergoes extensive hepatic metabolism mediated predominantly by CYP2D6 and CYP2C9 and to a lesser extent by CYP1A2, CYP2E1 and CYP3A4. Carvedilol has three major and one minor pharmacologically active metabolites all of which exist as 2 enantiomers. The metabolites are produced at differing rates by the same CYP isozymes. S(−) carvedilol is metabolized more rapidly than R(+) carvedilol in vitro and in vivo. The metabolites are present in concentrations that are 10 to 50 times lower than the parent enantiomers.

Carvedilol undergoes stereoselective hepatic metabolism mediated by CYP2D6. Poor metabolizers of debrisoquin (i.e., those with low CYP2D6 activity) have plasma levels of R(+) carvedilol that are 2 to 3 times higher than those in extensive metabolizers of debrisoquin.

Biliary-fecal excretion is the major elimination pathway for the metabolites of carvedilol. Less than 2% of an administered oral dose of carvedilol is excreted unchanged in the urine. The mean elimination half-life (t½) of R(+) carvedilol is 5 to 9 hours and that of S(−) carvedilol is 7 to 11 hours.

In patients with hepatic cirrhosis the absolute bioavailability of carvedilol is 4 times higher than in healthy volunteers and the median C_max and AUC values are increased by 4-fold to 7-fold.