Home > Medical Reference > Complementary Medicine

Carvedilol


Pronunciation

 (KAR ve dil ole)


U.S. Brand Names

 Coreg®


Generic Available

 No


Canadian Brand Names

 Coreg®


Use

 Mild to severe heart failure of ischemic or cardiomyopathic origin (usually in addition to standardized therapy); left ventricular dysfunction following myocardial infarction (MI); management of hypertension


Use - Unlabeled/Investigational

 Angina pectoris


Pregnancy Risk Factor

 C (manufacturer); D (2nd and 3rd trimesters - expert analysis)


Pregnancy Implications

 No data available on whether carvedilol crosses the placenta; beta-blockers have been associated with persistent bradycardia, hypotension, and IUGR; IUGR probably related to maternal hypertension. Cases of neonatal hypoglycemia have been reported following maternal use of beta-blockers at parturition or during breast-feeding. Use during pregnancy only if the potential benefit justifies the risk.


Lactation

 Excretion in breast milk unknown/contraindicated


Contraindications

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


Warnings/Precautions

 Initiate cautiously and monitor for possible deterioration in patient status (including symptoms of CHF). Adjustment of other medications (ACE inhibitors and/or diuretics) may be required. In severe chronic heart failure, trial patients were excluded if they had cardiac-related rales, ascites, or a serum creatinine >2.8 mg/dL. Patients should be advised to avoid driving or other hazardous tasks during initiation of therapy due to the risk of syncope. Avoid abrupt discontinuation (may be associated with angina, arrhythmia, or myocardial infarction), particularly in patients with coronary artery disease; dose should be tapered over 1-2 weeks with close monitoring. Manufacturer recommends discontinuation of therapy if liver injury occurs (confirmed by laboratory testing). Use caution in patients with PVD (can aggravate arterial insufficiency). Use caution with concurrent use of 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. May mask signs of thyrotoxicosis. Use care with anesthetic agents that decrease myocardial function. Safety and efficacy in children <18 years of age have not been established.


Adverse Reactions

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

>10%:

Cardiovascular: Hypotension (9% to 14%)

Central nervous system: Dizziness (6% to 32%), fatigue (4% to 24%)

Endocrine & metabolic: Hyperglycemia (5% to 12%), weight gain (10% to 12%)

Gastrointestinal: Diarrhea (2% to 12%)

Neuromuscular & skeletal: Weakness (11%)

1% to 10%:

Cardiovascular: Bradycardia (2% to 10%), hypertension (3%), AV block (3%), angina (2% to 6%), postural hypotension (2%), syncope (3% to 8%), dependent edema (4%), palpitation, peripheral edema (1% to 7%), generalized edema (5% to 6%)

Central nervous system: Headache (5% to 8%), fever (3%), paresthesia (2%), somnolence (2%), insomnia (2%), malaise, hypesthesia, vertigo

Endocrine & metabolic: Alkaline phosphatase increased, gout (6%), hypercholesterolemia (4%), dehydration (2%), hyperkalemia (3%), hypervolemia (2%), hypertriglyceridemia (1%), hyperuricemia, hypoglycemia, hyponatremia

Gastrointestinal: Nausea (4% to 9%), vomiting (6%), melena, periodontitis

Genitourinary: Hematuria (3%), impotence

Hematologic: Thrombocytopenia (1% to 2%), decreased prothrombin, purpura

Hepatic: Transaminases increased

Neuromuscular & skeletal: Back pain (2% to 7%), arthralgia (6%), myalgia (3%), muscle cramps

Ocular: Blurred vision (3% to 5%)

Renal: Increased BUN (6%), abnormal renal function, albuminuria, glycosuria, increased creatinine (3%), kidney failure

Respiratory: Rhinitis (2%), increased cough (5%)

Miscellaneous: Injury (3% to 6%), allergy, sudden death

<1%: Abnormal thinking, aggravated depression, alopecia, amnesia, anaphylactoid reaction, anemia, asthma, atypical lymphocytes, AV block (complete), bilirubinemia, bronchospasm, bundle branch block, cerebrovascular disorder, convulsion, diabetes mellitus, diaphoresis increased, emotional lability, erythematous rash, exfoliative dermatitis, GI hemorrhage, HDL-cholesterol decreased, hearing decreased, hypokalemia, hypokinesis, impaired concentration, leukopenia, libido decreased (male), maculopapular rash, micturition (increased), migraine, myocardial ischemia, nervousness, neuralgia, pancytopenia, paranoia, paresis, peripheral ischemia, photosensitivity, pruritus, psoriaform rash, pulmonary edema, respiratory alkalosis, sleep disorder, tachycardia, tinnitus, xerostomia

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


Overdosage/Toxicology

 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 (commonly seen with propranolol and other membrane-depressant and lipid-soluble drugs). Treatment is symptom-directed and supportive. Carvedilol does not appear to be significantly cleared by hemodialysis.


Drug Interactions

 Substrate of CYP1A2 (minor), 2C8/9 (major), 2D6 (major), 2E1 (minor), 3A4 (minor)

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

Antacids: May decrease absorption of beta-blockers.

Calcium channel blockers (nondihydropyridine): May enhance hypotensive effects of beta-blockers.

Cholestyramine: May decrease absorption of beta-blockers.

Cimetidine: May increase carvedilol blood levels.

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

Colestipol: May decrease absorption of beta-blockers.

Cyclosporine: Carvedilol may increase the blood levels of cyclosporine.

CYP2C8/9 inducers: May decrease the levels/effects of carvedilol. Example inducers include carbamazepine, phenobarbital, phenytoin, rifampin, rifapentine, and secobarbital.

CYP2C8/9 inhibitors: May increase the levels/effects of carvedilol. Example inhibitors include delavirdine, fluconazole, gemfibrozil, ketoconazole, nicardipine, NSAIDs, pioglitazone, and sulfonamides.

CYP2D6 inhibitors: May increase the levels/effects of carvedilol. Example inhibitors include chlorpromazine, delavirdine, fluoxetine, miconazole, paroxetine, pergolide, quinidine, quinine, ritonavir, and ropinirole.

Digoxin: Carvedilol may increase the blood levels of digoxin.

Disopyramide: May exacerbate heart failure or enhance bradycardic effect of beta-blockers.

Glucagon: Carvedilol may blunt the hyperglycemic action of glucagon.

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

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

Penicillins (ampicillin): May possibly decrease beta-blocker effect.

Salicylates: May reduce the antihypertensive effects of beta-blockers.

Sulfonylureas: Beta blockers may alter response to hypoglycemic agents.

Theophylline: Carvedilol may diminish (antagonize) the bronchodilatory effect of theophylline derivatives.

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

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


Ethanol/Nutrition/Herb Interactions

 Herb/Nutraceutical: Avoid dong quai if using for hypertension (has estrogenic activity). Avoid ephedra, yohimbe, ginseng (may worsen hypertension). Avoid garlic (may have increased antihypertensive effect).


Stability

 Store at 30°C (86°F).


Mechanism of Action

 As a racemic mixture, carvedilol has nonselective beta-adrenoreceptor and alpha-adrenergic blocking activity. No intrinsic sympathomimetic activity has been documented. Associated effects in hypertensive patients 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. In CHF, associated effects include decreased pulmonary capillary wedge pressure, decreased pulmonary artery pressure, decreased heart rate, decreased systemic vascular resistance, increased stroke volume index, and decreased right arterial pressure (RAP).


Pharmacodynamics/Kinetics

Onset of action: 1-2 hours

Peak antihypertensive effect: ~1-2 hours

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

Distribution: Vd: 115 L

Protein binding: >98%, primarily to albumin

Metabolism: Extensively hepatic, via CYP2C9, 2D6, 3A4, and 2C19 (2% excreted unchanged); three active metabolites (4-hydroxyphenyl metabolite is 13 times more potent than parent drug for beta-blockade); first-pass effect; 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 elimination: 7-10 hours

Excretion: Primarily feces


Dosage

 Oral: Adults: Reduce dosage if heart rate drops to <55 beats/minute.

Hypertension: 6.25 mg twice daily; if tolerated, dose should be maintained for 1-2 weeks, then increased to 12.5 mg twice daily. Dosage may be increased to a maximum of 25 mg twice daily after 1-2 weeks. Maximum dose: 50 mg/day

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 and fluid retention minimized.)

Maximum recommended dose:

Mild to moderate heart failure:

<85 kg: 25 mg twice daily

>85 kg: 50 mg twice daily

Severe heart failure: 25 mg twice daily

Left ventricular dysfunction following MI: Initial 3.125-6.25 mg twice daily; increase dosage incrementally (ie, from 6.25 to 12.5 mg twice daily) at intervals of 3-10 days, based on tolerance, to a target dose of 25 mg twice daily. Note : Should be initiated only after patient is hemodynamically stable and fluid retention has been minimized.

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

Dosing adjustment in renal impairment: None necessary

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


Administration

 Administer with food.


Monitoring Parameters

 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); renal studies, BUN, liver function


Test Interactions

 Increased hepatic enzymes, BUN, NPN, alkaline phosphatase; decreased HDL


Dietary Considerations

 Should be taken with food to minimize the risk of orthostatic hypotension.


Patient Education

 Inform prescriber of all prescriptions, OTC medications, or herbal products you are taking, and any allergies you have. Do not take any new medication during therapy unless approved by prescriber. Take exactly as directed. Do not alter dose or discontinue without consulting prescriber. Take pulse daily, prior to medication; follow prescriber's instruction about holding medication. If you have diabetes, monitor serum glucose closely (drug may alter glucose tolerance or mask signs of hypoglycemia). You may experience fatigue, dizziness, or postural hypotension (use caution when changing position from lying or sitting to standing, driving, or climbing stairs until response to medication is known); alteration in sexual performance (reversible); or diarrhea (buttermilk, boiled milk, or yogurt may help). Report unresolved swelling of extremities; respiratory difficulty or new cough; unresolved fatigue; unusual weight gain (>5 lb/week); unresolved constipation or diarrhea; or unusual muscle weakness. Pregnancy/breast-feeding precautions: Inform prescriber if you are pregnant. Do not get pregnant while taking this medications. Consult prescriber for appropriate contraceptive use. Do not breast-feed.


Additional Information

 Fluid retention during therapy should be treated with an increase in diuretic dosage.


Anesthesia and Critical Care Concerns/Other Considerations

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.


Cardiovascular Considerations

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. 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.


Dental Health: Effects on Dental Treatment

 Key adverse event(s) related to dental treatment: Postural hypotension and periodontitis. Noncardioselective beta-blockers 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.


Dental Health: Vasoconstrictor/Local Anesthetic Precautions

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


Mental Health: Effects on Mental Status

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


Mental Health: Effects on Psychiatric Treatment

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


Dosage Forms

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


References

Antman EM, Anbe SC, Alpert JS, et al, "ACC/AHA Guidelines for the Management of Patients With ST-Elevation Myocardial Infarction - Executive Summary: A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Revise the 1999 Guidelines for the Management of Patients With Acute Myocardial Infarction)," Circulation, 2004, 110:588-636. Available at: http://www.circulationaha.org/cgi/content/full/110/5/588. Last accessed October 26, 2004.

Bristow MR, Gilbert EM, Abraham WT, et al, "Carvedilol Produces Dose-Related Improvements in Left Ventricular Function and Survival in Subjects With Chronic Heart Failure," Circulation , 1996, 94(11):2807-16.

Colucci WS, Packer M, Bristow MR, et al, "Carvedilol Inhibits Clinical Progression in Patients With Mild Symptoms of Heart Failure. U.S Carvedilol Heart Failure Study Group," Circulation , 1996, 94(11):2800-6.

Dargie HJ, "Effect of Carvedilol on Outcome After Myocardial Infarction in Patients With Left-Ventricular Dysfunction: The CAPRICORN Randomised Trial," Lancet , 2001, 357(9266):1385-90.

Gibbons RJ, Abrams J, Chatterjee K, et al, "ACC/AHA 2002 Guideline Update for the Management of Patients With Chronic Stable Angina - Summary Article: A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee on the Management of Patients With Chronic Stable Angina)," J Am Coll Cardiol , 2003, 41(1):159-68.

Hunt SA, Baker DW, and Chin MH, et al, "ACC/AHA Guidelines for the Evaluation and Management of Chronic Heart Failure in the Adult. A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee to Revise the 1995 Guidelines for the Evaluation and Management of Heart Failure)," Circulation , 2001, 104(24):2996-3007.

Macdonald PS, Keogh AM, Aboyoun CL, et al, "Tolerability and Efficacy of Carvedilol in Patients With New York Heart Association Class IV Heart Failure," J Am Coll Cardiol , 1999, 33(4):924-31.

Mokhlesi B, Leikin JB, Murray P, et al, "Adult Toxicology in Critical Care: Part II: Specific Poisonings," Chest , 2003, 123(3):897-922.

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.

Packer M, Coats AJ, Fowler MB, et al, "Effect of Carvedilol on Survival in Severe Chronic Heart Failure," N Engl J Med , 2001, 344(22):1651-8.

Packer M, Colucci WS, Sackner-Bernstein JD, et al, "Double-Blind, Placebo-Controlled Study of the Effects of Carvedilol in Patients With Moderate to Severe Heart Failure. The PRECISE Trial. Prospective Randomized Evaluation of Carvedilol on Symptoms and Exercise," Circulation , 1996, 94(11):2793-9.

"Randomised, Placebo-Controlled Trial of Carvedilol in Patients With Congestive Heart Failure Due to Ischaemic Heart Disease. Australia/New Zealand Heart Failure Research Collaborative Group," Lancet , 1997, 349(9049):375-80.


International Brand Names

 Betaplex® (CL); Bidecar® (AR); Biocard® (IE); Cardilol® (BR); Cardiol® (FI); CarLich® (DE); Carloc® (IN, ZA); Carvecard® (DE); Carved® (DO); Carvedigamma® (DE); Carvedilol-1A Pharma® (DE); Carvedilol AbZ® (DE); Carvedilol AL® (DE); Carvedilol AWD® (DE); Carvedilol beta® (DE); carvedilol-corax® (DE); Carvedilol dura® (DE); Carvedilol Gea® (DK, FI); Carvedilol Heumann® (DE); Carvedilol Hexal® (DE); Carvedilol-Isis® (DE); Carvedilol-ratiopharm® (DE); Carvedilol Sandoz® (DE); Carvedilol STADA® (DE); Carvedilol von ct® (DE); Carvedilol Wolff® (DE); Carvelol® (HR); Carve-Q® (DE); Carve TAD® (DE); Carvetrend (HR); Carvil® (IN); Carvipress® (IT); Co-Dilatrend® (AT); Coreg® (BR, CA, CR, DO, GT, HN, PA, SV); Coritensil® (AR); Coropres® (ES); Coryol® (PL, SI); Dilatrend® (AR, AT, AU, BR, CH, CL, CO, CZ, DE, HU, IT, MX, NZ, PL, RO, RU, SG, SI, TH, YU, ZA); Dilbloc® (PT, ZA); Dimetil® (DE); Dimitone® (BE, DK, IL, LU); Divelol® (BR); Eucardic® (GB, IE, NL); Filten® (AR); Hybridil® (AT); Isobloc® (AR); Karvedilol® (YU); Karvileks® (YU); Kredex® (BE, FR, LU, NL, NO, PL, RO, SE); Querto® (DE); Talliton® (HU); V-Bloc® (ID); Veraten® (AR); Vivacor® (PL)


A.D.A.M., Inc. is accredited by URAC, also known as the American Accreditation HealthCare Commission (www.urac.org). URAC's accreditation program is the first of its kind, requiring compliance with 53 standards of quality and accountability, verified by independent audit. A.D.A.M. is among the first to achieve this important distinction for online health information and services. Learn more about A.D.A.M.'s editorial process . A.D.A.M. is also a founding member of Hi-Ethics (www.hiethics.com) and subscribes to the principles of the Health on the Net Foundation (www.hon.ch).

The information provided herein should not be used during any medical emergency or for the diagnosis or treatment of any medical condition. A licensed medical professional should be consulted for diagnosis and treatment of any and all medical conditions. Call 911 for all medical emergencies. Links to other sites are provided for information only -- they do not constitute endorsements of those other sites. © 1997-2007 A.D.A.M., Inc. Any duplication or distribution of the information contained herein is strictly prohibited.
adam.com