No

Alpha-/Beta- Blocker

Management of hypertension; can be used alone or in combination with other agents, especially thiazide-type diuretics; mild to moderate heart failure (NYHA Class II-III) following standardized therapy.

C (per manufacturer);D (in 2nd and 3rd trimesters, based on expert analysis)

Clinical effects on the fetus: Use during pregnancy only if the potential benefit justifies the risk

Breast-feeding/lactation: Possible excretion in breast milk; avoid administration in lactating women, if possible

Hypersensitivity to carvedilol or any component; patients with NYHA Class IV decompensated cardiac failure requiring intravenous therapy; bronchial asthma or related bronchospastic conditions; second- or third-degree AV block (except in patients with a functioning artificial pacemaker); sick sinus syndrome (except in patients with a functioning artificial pacemaker); cardiogenic shock; severe bradycardia; severe hepatic impairment; pregnancy (2nd and 3rd trimesters)

Initiate cautiously and monitor for possible deterioration in CHF. Adjustment of other medications (ACE inhibitors and/or diuretics) may be required. Discontinue therapy if any evidence of liver injury occurs. Use caution in patients with PVD (can aggravate arterial insufficiency). Use caution with concurrent use of beta-blockers and either verapamil or diltiazem; bradycardia or heart block can occur. Patients with bronchospastic disease should not receive beta-blockers. Use cautiously in diabetics because it can mask prominent hypoglycemic symptoms. Can mask signs of thyrotoxicosis. Use care with anesthetic agents that decrease myocardial function.

Note: Frequency ranges include data from hypertension and heart failure trials. Higher rates of adverse reactions have generally been noted in patients with congestive heart failure. However, the frequency of adverse effects associated with placebo is also increased in this population. Events occurring at a frequency > placebo in clinical trials:

Cardiovascular: Chest pain (14.4%)

Central nervous system: Dizziness (6.2% to 32.4%), fatigue (4.3% to 23.9%)

Endocrine & metabolic: Hyperglycemia (12.2%)

Gastrointestinal: Diarrhea (11.8%)

Respiratory: Upper respiratory tract infection (18.3%)

1% to 10%:

Cardiovascular: Bradycardia (2.1% to 8.8%), hypotension (8.5%), generalized edema (5.1%), syncope (3.4%), hypertension (2.9%), AV block (2.9%), lower extremity edema (1.4% to 2.2%), angina (aggravated) (2.0%), postural hypotension (1.8%)

Central nervous system: Pain (8.6%), headache (8.1%), fever (3.1%), paresthesia (2.0%), somnolence (1.8%), insomnia (1.6%), malaise, hypesthesia, vertigo

Endocrine & metabolic: Weight gain (9.7%), gout (6.3%), hypercholesterolemia (4.1%), dehydration (2.1%), hypervolemia (2.0%), hypertriglyceridemia (1.2%), hyperuricemia, hypoglycemia, hyponatremia

Gastrointestinal: Nausea (8.5%), abdominal pain (1.4% to 7.2%), vomiting (6.3%), diarrhea (2.2%), melena, periodontitis

Genitourinary: Urinary tract infection (1.8% to 3.1%), hematuria (2.9%), impotence

Hematologic: Thrombocytopenia (1.1% to 2.0%), decreased prothrombin, purpura

Hepatic: Increased transaminases, increased alkaline phosphatase

Neuromuscular & skeletal: Back pain (2.3% to 6.9%), arthralgia (6.4%), myalgia (3.4%)

Ocular: Abnormal vision (5.0%)

Renal: Increased BUN (6.0%), abnormal renal function, albuminuria, glycosuria

Respiratory: Sinusitis (5.4%), bronchitis (5.4%), pharyngitis (1.5% to 3.1%), rhinitis (2.1%), dyspnea (1.4%)

Miscellaneous: Infection (2.2%), injury (2.9% to 5.9%), increased sweating (2.9%), viral infection (1.8%), allergy, sudden death

<1% (Limited to important or life-threatening symptoms): Peripheral ischemia, tachycardia, hypokinesis, bilirubinemia, elevated hepatic enzymes (hypertension: 0.2%; congestive heart failure: 0.4%), nervousness, sleep disorder, aggravated depression, impaired concentration, abnormal thinking, paranoia, emotional lability, asthma, decreased libido (male), pruritus, erythematous rash, maculopapular rash, psoriaform rash, photosensitivity, tinnitus, micturition frequency, xerostomia, increased sweating, hypokalemia, diabetes mellitus, hypertriglyceridemia, anemia, leukopenia, AV block (complete), bundle branch block, myocardial ischemia, cerebrovascular disorder, convulsion, migraine, neuralgia, paresis, anaphylactoid reaction, alopecia, exfoliative dermatitis, amnesia, GI hemorrhage, bronchospasm, pulmonary edema, decreased hearing, respiratory alkalosis, increased BUN, decreased HDL cholesterol, pancytopenia, atypical lymphocytes.

Additional events from clinical trials in heart failure patients occurring at a frequency >2% but equal to or less than the frequency reported in patients receiving placebo: Asthenia, cardiac failure, flatulence, dyspepsia, palpitation, hyperkalemia, arthritis, depression, anemia, coughing, rash, leg cramps, chest pain, dyspepsia, headache, nausea, pain, sinusitis, upper respiratory infection.

Postmarketing case reports: Aplastic anemia (rare): All events occurred in patients receiving other medications capable of causing this effect; Stevens-Johnson syndrome.

Symptoms of intoxication include cardiac disturbances, CNS toxicity, bronchospasm, hypoglycemia, and hyperkalemia. The most common cardiac symptoms include hypotension and bradycardia; atrioventricular block, intraventricular conduction disturbances, cardiogenic shock, and asystole may occur with severe overdose, especially with membrane-depressant drugs (eg, propranolol); CNS effects include convulsions, coma, and respiratory arrest which are commonly seen with propranolol and other membrane-depressant and lipid-soluble drugs.

Treatment includes symptomatic treatment of seizures, hypotension, hyperkalemia, and hypoglycemia; bradycardia and hypotension resistant to atropine, isoproterenol, or pacing may respond to glucagon; wide QRS defects caused by the membrane-depressant poisoning may respond to hypertonic sodium bicarbonate; repeat-dose charcoal, hemoperfusion, or hemodialysis may be helpful in removal of only those beta-blockers with a small V_d, long half-life, or low intrinsic clearance (acebutolol, atenolol, nadolol, sotalol)

CYP2C, 2C9, 2D6 substrate

Alpha-blockers (prazosin, terazosin): Concurrent use of beta-blockers may increase risk of orthostasis.

Clonidine: Hypertensive crisis after or during withdrawal of either agent.

Cyclosporin blood levels may be increased by carvedilol.

Digoxin blood levels may be increased.

Fluoxetine may increase carvedilol blood levels.

Paroxetine may increase carvedilol blood levels.

Rifampin may decrease in carvedilol blood concentration.

Insulin and oral hypoglycemics: Carvedilol may masks symptoms of hypoglycemia.

Salicylates may reduce the antihypertensive effects of beta-blockers.

NSAIDs (ibuprofen, indomethacin, naproxen, piroxicam) may reduce the antihypertensive effects of beta-blockers.

Verapamil or diltiazem may have synergistic or additive pharmacological effects when taken concurrently with beta-blockers.

Glucagon: Carvedilol may blunt the hyperglycemic action of glucagon.

Sulfonylureas: Beta-blockers may alter response to hypoglycemic agents.

Drugs which slow AV conduction (digoxin): Effects may be additive with beta-blockers.

As a racemic mixture, carvedilol has nonselective beta-adrenoreceptor and alpha-adrenergic blocking activity at equal potency. No intrinsic sympathomimetic activity has been documented. Associated effects include reduction of cardiac output, exercise- or beta agonist-induced tachycardia, reduction of reflex orthostatic tachycardia, vasodilation, decreased peripheral vascular resistance (especially in standing position), decreased renal vascular resistance, reduced plasma renin activity, and increased levels of atrial natriuretic peptide.

Onset of effect: Within 1-2 hours

Absorption: Rapid; food decreases the rate but not the extent of absorption; administration with food minimizes risks of orthostatic hypotension

Metabolism: First-pass metabolism; extensively metabolized primarily by aromatic ring oxidation and glucuronidation (2% excreted unchanged); three active metabolites (4-hydroxphenyl metabolite is 13 times more potent than parent drug); plasma concentrations in the elderly and those with cirrhotic liver disease are 50% and 4-7 times higher, respectively

Bioavailability: 25% to 35%

Half-life: 7-10 hours

Elimination: Primarily via bile into feces

Adults: Oral:

Congestive heart failure: 3.125 mg twice daily for 2 weeks; if this dose is tolerated, may increase to 6.25 mg twice daily. Double the dose every 2 weeks to the highest dose tolerated by patient. (Prior to initiating therapy, other heart failure medications should be stabilized.)

Maximum recommended dose:

<85 kg: 25 mg twice daily

>85 kg: 50 mg twice daily

Angina pectoris (unlabeled use): 25-50 mg twice daily

Idiopathic cardiomyopathy (unlabeled use): 6.25-25 mg twice daily

Dosing adjustment in renal impairment: None necessary

Dosing adjustment in hepatic impairment: Use is contraindicated in liver dysfunction.

Should be administered with food to minimize the risk of hypotension

Heart rate, blood pressure (base need for dosage increase on trough blood pressure measurements and for tolerance on standing systolic pressure 1 hour after dosing)

Hypertension: Beta-blocker therapy in the treatment of hypertension has been associated with improved cardiovascular outcomes. This class of drug is beneficial for elderly patients with hypertension. A recent UKPDS study showed that beta-blocker therapy (atenolol) was as effective as an ACE inhibitor in reducing cardiovascular events and that the benefits of therapy were related more to the degree of antihypertensive efficacy rather than the class of drug used.

Myocardial infarction: Beta-blockers, in general without intrinsic sympathomimetic activity (ISA), have been shown to decrease morbidity and mortality when initiated in the acute treatment of myocardial infarction and continued long-term. In this setting, therapy should be avoided in patients with hypotension, cardiogenic shock, or heart block.

Surgery: Atenolol has also been shown to improve cardiovascular outcomes when used in the perioperative period in patients with underlying cardiovascular disease who are undergoing noncardiac surgery. Bisoprolol in high-risk patients undergoing vascular surgery reduced the perioperative incidence of death from cardiac causes and nonfatal myocardial infarction.

Atrial fibrillation: Beta-blocker therapy provides effective rate control in patients with atrial fibrillation.

Angina: Beta-blockers are effective in the treatment of angina as monotherapy or when combined with nitrates and/or calcium channel blockers. In patients with severe intractable angina requiring negative cardiac chronotropic medications, pacemaker placement has been carried out to maintain heart rate in the setting of large doses of beta-blockers and/or calcium channel blockers. Beta-blockers are ineffective in the treatment of pure vasospastic (Prinzmetal) angina.

Withdrawal: Beta-blocker therapy should not be withdrawn abruptly, but gradually tapered to avoid acute tachycardia and hypertension.

Heart failure: Carvedilol is a nonselective beta-blocker with alpha-blocking and antioxidant properties. It is the only beta-blocker approved for the treatment of heart failure. Beta-blocker therapy, without intrinsic sympathomimetic activity (ISA), should be initiated in patients with stable congestive heart failure (NYHA Class II-III). To date, carvedilol, sustained release metoprolol, and bisoprolol have demonstrated a beneficial effect on morbidity and mortality. It is important that beta-blocker therapy be instituted initially at very low doses with gradual and very careful titration. Because carvedilol has alpha-adrenergic blocking effects, it may lower blood pressure to a greater extent. The definitive clinical benefits of the antioxidant property are not known at this time.

May cause fatigue, insomnia, confusion, and nightmare and clinically look like a major depression

Fluoxetine and paroxetine may increase carvedilol's (a CYP2D6 substrate) serum levels

Use with caution, epinephrine has interacted with noncardioselective beta-blockers to result in initial hypertensive episode followed by bradycardia

Noncardioselective beta-blockers (ie, propranolol, nadolol) enhance the pressor response to epinephrine, resulting in hypertension and bradycardia. Many nonsteroidal anti-inflammatory drugs, such as ibuprofen and indomethacin, can reduce the hypotensive effect of beta-blockers after 3 or more weeks of therapy with the NSAID. Short-term NSAID use (ie, 3 days) requires no special precautions in patients taking beta-blockers.

Take exactly as directed. Do not increase, decrease, or adjust dosage without consulting prescriber. Take pulse daily, prior to medication; follow prescriber's instruction about holding medication. Do not take with antacids and avoid alcohol or OTC medications (eg, cold remedies) without consulting prescriber. If diabetic, monitor serum glucose closely (may alter glucose tolerance or mask signs of hypoglycemia). May cause fatigue, dizziness, or postural hypotension; use caution when changing position from lying or sitting to standing, when driving, or climbing stairs until response to medication is known. May cause alteration in sexual performance (reversible). Report unresolved swelling of extremities, difficulty breathing or new cough, unresolved fatigue, unusual weight gain, unresolved constipation, or unusual muscle weakness. Pregnancy/breast-feeding precautions: Inform prescriber if you are or intend to be pregnant. Do not breast-feed.

Minimize risk of bradycardia with initiation of treatment with a low dose, slow upward titration, and administration with food; decrease dose if pulse rate drops <55 beats per minute

Tablet: 3.125 mg, 6.25 mg, 12.5 mg, 25 mg

Packer M, Bristow MR, Cohn JN, et al, "The Effect of Carvedilol on Morbidity and Mortality in Patients With Chronic Heart Failure," N Engl J Med, 1996, 334(21):1349-55.