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Carvedilol

Class: beta-Adrenergic Blocking Agents
VA Class: CV100
Chemical Name: 1-(9H-Carbazol-4-yloxy)-3-[[2-(2-methoxyphenoxy)ethyl]amino]-2-propanol
Molecular Formula: C24H26N2O4
CAS Number: 72956-09-3
Brands: Coreg, Coreg CR

Medically reviewed by Drugs.com. Last updated on Feb 8, 2021.

Introduction

Nonselective β-adrenergic blocking agent (β-blocker) with selective α1-adrenergic blocking activity.

Uses for Carvedilol

Hypertension

Management of hypertension, alone or in combination with other classes of antihypertensive agents.

β-Blockers generally not preferred for first-line therapy of hypertension according to current evidence-based hypertension guidelines, but may be considered in patients who have a compelling indication (e.g., prior MI, ischemic heart disease, heart failure) for their use or as add-on therapy in those who do not respond adequately to the preferred drug classes (ACE inhibitors, angiotensin II receptor antagonists, calcium-channel blockers, or thiazide diuretics). Carvedilol is one of several β-blockers (including bisoprolol, metoprolol succinate, metoprolol tartrate, nadolol, propranolol, and timolol) recommended by a 2017 ACC/AHA multidisciplinary hypertension guideline as first-line therapy for hypertension in patients with stable ischemic heart disease/angina.

Individualize choice of therapy; consider patient characteristics (e.g., age, ethnicity/race, comorbidities, cardiovascular risk) as well as drug-related factors (e.g., ease of administration, availability, adverse effects, cost).

The 2017 ACC/AHA hypertension guideline classifies BP in adults into 4 categories: normal, elevated, stage 1 hypertension, and stage 2 hypertension. (See Table 1.)

Source: Whelton PK, Carey RM, Aronow WS et al. 2017 ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ASH/ASPC/NMA/PCNA guideline for the prevention, detection, evaluation, and management of high blood pressure in adults: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. Hypertension. 2018;71:e13-115.

Individuals with SBP and DBP in 2 different categories (e.g., elevated SBP and normal DBP) should be designated as being in the higher BP category (i.e., elevated BP).

Table 1. ACC/AHA BP Classification in Adults1200

Category

SBP (mm Hg)

DBP (mm Hg)

Normal

<120

and

<80

Elevated

120–129

and

<80

Hypertension, Stage 1

130–139

or

80–89

Hypertension, Stage 2

≥140

or

≥90

The goal of hypertension management and prevention is to achieve and maintain optimal control of BP. However, the BP thresholds used to define hypertension, the optimum BP threshold at which to initiate antihypertensive drug therapy, and the ideal target BP values remain controversial.

The 2017 ACC/AHA hypertension guideline generally recommends a target BP goal (i.e., BP to achieve with drug therapy and/or nonpharmacologic intervention) of <130/80 mm Hg in all adults regardless of comorbidities or level of atherosclerotic cardiovascular disease (ASCVD) risk. In addition, an SBP goal of <130 mm Hg generally is recommended for noninstitutionalized ambulatory patients ≥65 years of age with an average SBP of ≥130 mm Hg. These BP goals are based upon clinical studies demonstrating continuing reduction of cardiovascular risk at progressively lower levels of SBP.

Other hypertension guidelines generally have based target BP goals on age and comorbidities. Guidelines such as those issued by the JNC 8 expert panel generally have targeted a BP goal of <140/90 mm Hg regardless of cardiovascular risk and have used higher BP thresholds and target BPs in elderly patients compared with those recommended by the 2017 ACC/AHA hypertension guideline.

Some clinicians continue to support previous target BPs recommended by JNC 8 due to concerns about the lack of generalizability of data from some clinical trials (e.g., SPRINT study) used to support the 2017 ACC/AHA hypertension guideline and potential harms (e.g., adverse drug effects, costs of therapy) versus benefits of BP lowering in patients at lower risk of cardiovascular disease.

Consider potential benefits of hypertension management and drug cost, adverse effects, and risks associated with the use of multiple antihypertensive drugs when deciding a patient's BP treatment goal.

For decisions regarding when to initiate drug therapy (BP threshold), the 2017 ACC/AHA hypertension guideline incorporates underlying cardiovascular risk factors. ASCVD risk assessment is recommended by ACC/AHA for all adults with hypertension.

ACC/AHA currently recommend initiation of antihypertensive drug therapy in addition to lifestyle/behavioral modifications at an SBP ≥140 mm Hg or DBP ≥90 mm Hg in adults who have no history of cardiovascular disease (i.e., primary prevention) and a low ASCVD risk (10-year risk <10%).

For secondary prevention in adults with known cardiovascular disease or for primary prevention in those at higher risk for ASCVD (10-year risk ≥10%), ACC/AHA recommend initiation of antihypertensive drug therapy at an average SBP ≥130 mm Hg or an average DBP ≥80 mm Hg.

Adults with hypertension and diabetes mellitus, chronic kidney disease (CKD), or age ≥65 years are assumed to be at high risk for cardiovascular disease; ACC/AHA state that such patients should have antihypertensive drug therapy initiated at a BP ≥130/80 mm Hg. Individualize drug therapy in patients with hypertension and underlying cardiovascular or other risk factors.

In stage 1 hypertension, experts state that it is reasonable to initiate drug therapy using the stepped-care approach in which one drug is initiated and titrated and other drugs are added sequentially to achieve the target BP. Initiation of antihypertensive therapy with 2 first-line agents from different pharmacologic classes recommended in adults with stage 2 hypertension and average BP >20/10 mm Hg above BP goal.

Black hypertensive patients generally tend to respond better to monotherapy with calcium-channel blockers or thiazide diuretics than to β-blockers. However, diminished response to β-blockers is largely eliminated when administered concomitantly with a thiazide diuretic.

Heart Failure

Management of mild to severe (NYHA class II–IV) heart failure of ischemic or cardiomyopathic origin (usually in conjunction with other heart failure therapies [e.g., cardiac glycosides, diuretics, ACE inhibitors]). Used to increase survival and to reduce the risk of hospitalization.

The American College of Cardiology Foundation (ACCF), AHA, and the Heart Failure Society of America (HFSA) recommend therapy with an ACE inhibitor, angiotensin II receptor antagonist, or angiotensin receptor-neprilysin inhibitor (ARNI) in conjunction with a β-blocker, and an aldosterone antagonist in selected patients, to reduce morbidity and mortality in patients with symptomatic heart failure and reduced left ventricular ejection fraction (LVEF) (ACCF/AHA stage C heart failure).

Initiate a clinical-trial proven β-blocker (bisoprolol, carvedilol, extended-release metoprolol succinate) to reduce the risk of death in patients with chronic heart failure; benefits shown with these β-blockers not considered indicative of a β-blocker class effect.

Experts recommend that β-blockers be used in conjunction with ACE inhibitors in all patients who have asymptomatic heart failure (i.e., structural heart disease but no signs or symptoms; ACCF/AHA stage B heart failure) with reduced LVEF.

Left Ventricular Dysfunction After Acute MI

Secondary prevention following acute MI in clinically stable patients with left ventricular ejection fraction ≤40% (with or without symptomatic heart failure).

Administration within 21 days following MI associated with reductions in cardiovascular mortality and reinfarction.

Experts recommend β-blocker therapy in all patients with left ventricular systolic dysfunction and prior MI; a β-blocker with proven mortality benefit (bisoprolol, carvedilol, or metoprolol succinate) is preferred.

Carvedilol Dosage and Administration

General

  • Poor CYP2D6 metabolizers have a higher rate of dizziness during titration with increasing dosage. (See Special Populations under Pharmacokinetics.)

BP Monitoring and Treatment Goals

  • Monitor BP regularly (i.e., monthly) during therapy and adjust dosage of the antihypertensive drug until BP controlled.

  • If unacceptable adverse effects occur, discontinue drug and initiate another antihypertensive agent from a different pharmacologic class.

  • If adequate BP response not achieved with a single antihypertensive agent, either increase dosage of single drug or add a second drug with demonstrated benefit and preferably a complementary mechanism of action (e.g., ACE inhibitor, angiotensin II receptor antagonist, calcium-channel blocker, thiazide diuretic). Many patients will require ≥2 drugs from different pharmacologic classes to achieve BP goal; if goal BP still not achieved, add a third drug.

Heart Failure

  • Prior to initiation of therapy, minimize fluid retention and stabilize patients who are receiving treatment that includes a cardiac glycoside, diuretic, and/or an ACE inhibitor.

  • Initiate therapy and adjust subsequent dosage under very close medical supervision in a clinical setting; risk of cardiac decompensation and/or severe hypotension is highest during the initial 30 days of therapy.

  • Prior to increasing dosage, determine response and tolerance, including assessment of declining cardiovascular status, vasodilation (e.g., dizziness, lightheadedness, symptomatic hypotension), and bradycardia. Observe for manifestations of hypotension (e.g., dizziness or light-headedness) for 1 hour after administration of the initial increased dose.

Left Ventricular Dysfunction After Acute MI

  • Prior to initiation of therapy, minimize fluid retention and stabilize patients hemodynamically.

  • Individualize dosage and monitor during titration.

  • Initiate therapy and adjust subsequent dosage under very close medical supervision in a clinical setting.

  • May initiate on inpatient or outpatient basis after hemodynamically stable and fluid retention is minimized.

  • Not necessary to alter recommended dosage if IV or oral β-blocker was used during treatment of acute MI.

Administration

Administer orally.

Oral Administration

Administer carvedilol immediate-release tablets with food to decrease the risk of orthostatic hypotension. (See Absorption under Pharmacokinetics.)

In patients receiving concomitant ACE inhibitor therapy, administer 2 hours prior to ACE inhibitor to reduce manifestations of vasodilation.

Administer carvedilol phosphate extended-release capsules with food; administration with food has been shown to increase the bioavailability of the extended-release capsules. (See Absorption under Pharmacokinetics.)

Administer extended-release capsules once daily in the morning and swallow whole; do not crush or chew the capsule and/or its contents or take in divided doses.

Alternatively, may carefully open the extended-release capsules and sprinkle the entire contents over a spoonful of applesauce, immediately prior to administration. Do not use warm applesauce; consume the drug and applesauce mixture in entirety. Do not store the drug and applesauce mixture for future use. Absorption of the beads sprinkled on foods other than applesauce has not been studied.

Dosage

Adults

Patients whose conditions are controlled with immediate-release carvedilol tablets alone or in combination with other drugs may be switched to carvedilol phosphate extended-release capsules. Subsequent titration to higher or lower dosages may be necessary and should be guided by the patient's clinical response.

Table 2. Dosage Conversion from Carvedilol Immediate-Release Tablets to Carvedilol Phosphate Extended-Release Capsules59

Daily Dosage of Carvedilol Immediate-Release Tablets

Initial Dosage of Carvedilol Phosphate Extended-Release Capsules

6.25 mg (3.125 mg twice daily)

10 mg once daily

12.5 mg (6.25 mg twice daily)

20 mg once daily

25 mg (12.5 mg twice daily)

40 mg once daily

50 mg (25 mg twice daily)

80 mg once daily

Hypertension

In hypertensive patients with left ventricular dysfunction, follow the usual heart failure dosages and instructions (instead of those for hypertension); includes patients with heart failure who already are receiving a cardiac glycoside, diuretic, and/or an ACE inhibitor. Such patients generally depend (at least in part) on β-adrenergic stimulation to maintain cardiovascular compensation.

Additive effects (e.g., hypotensive response, including increased orthostatic hypotension) may occur with concomitant carvedilol and diuretic therapy.

Oral

Conventional tablets: Initially, 6.25 mg twice daily for 7–14 days. If required, increase to 12.5 mg twice daily for 7–14 days. Dosage may be increased as tolerated to a maximum of 25 mg twice daily. Some experts state usual dosage range is 12.5–50 mg daily, administered in 2 divided doses.

Extended-release capsules: Initially, 20 mg once daily for 7–14 days. If required, increase gradually (usually increasing dosage every 7–14 days) up to a maximum of 80 mg once daily. Some experts state usual dosage range is 20–80 mg once daily.

Maintain dosage for 7–14 days between increments; full antihypertensive effect of each dosage level occurs within 7–14 days.

Evaluate response and tolerance to the initial dosage and subsequent dosage adjustments by measurement of standing systolic pressure 1 hour after administration.

Heart Failure

If deterioration of heart failure is evident during titration, increase dosage of the concurrent diuretic; do not escalate β-blocker dosage until symptoms (e.g., fluid retention) have stabilized.

If heart failure manifestations do not resolve in response to an increase in diuretic dosage, consider decreasing dosage or temporarily discontinuing carvedilol.

Occurrence of increased heart failure manifestations during initiation or dosage titration that require dosage decreases or discontinuance should not prevent future consideration of resuming therapy with or increasing dosage of carvedilol.

If vasodilation occurs, consider decreasing diuretic or ACE inhibitor dosage; if this does not improve circulatory status, decrease carvedilol dosage. Separating the time of dosing of carvedilol from that of the ACE inhibitor also may reduce vasodilatory symptoms.

If worsening heart failure or vasodilation occurs, do not increase carvedilol dosage until cardiovascular status is stable.

If bradycardia (heart rate <55 bpm) occurs, reduce carvedilol dosage.

Oral

Conventional tablets: Initiate at very low dosage, usually 3.125 mg twice daily for 2 weeks. If initial dosage is tolerated, increase dosage to 6.25 mg twice daily for 2 weeks.

Extended-release capsules: Initiate at very low dosage, usually 10 mg once daily for 2 weeks. If initial dosage is tolerated, increase dosage to 20 mg once daily.

If necessary, dosage of carvedilol as the immediate-release tablets and carvedilol phosphate as extended-release capsules may then be doubled every 2 weeks (with strict adherence to the monitoring regimen) to highest tolerated dosage.

Maximum dosage of carvedilol as the immediate-release tablets is 50 mg daily (in patients weighing <85 kg) and 100 mg daily (in those weighing >85 kg). Maximum dosage of carvedilol phosphate as extended-release capsules is 80 mg once daily.

Evaluate response and tolerance to the initial dosage and subsequent dosage adjustments by observing patient in a clinical setting for manifestations of hypotension (e.g., dizziness or light-headedness) for 1 hour after administration of the initial dose (or the initial dose at the increased dosage).

Left Ventricular Dysfunction After Acute MI
Oral

Conventional tablets: Initially, usually 6.25 mg twice daily for 3–10 days. If tolerated, increase to 12.5 mg twice daily for 3–10 days, and then increase to 25 mg twice daily (target dose). In patients with low BP, heart rate, or fluid retention, initiate at 3.125 mg twice daily and/or slow the rate of titration.

Extended-release capsules: Initially, usually 20 mg once daily for 3–10 days. If tolerated, increase to 40 mg once daily for 3–10 days, and then increase to 80 mg once daily (target dose). In patients with low BP, heart rate, or fluid retention, initiate at 10 mg once daily and/or slow the rate of titration.

Maintain dosage for 3–10 days between increments to assess tolerance.

If higher dosage is not tolerated, maintain on lower dosage.

Optimal duration of therapy remains to be clearly established. Experts generally recommend long-term therapy in post-MI patients with left ventricular systolic dysfunction.

Prescribing Limits

Adults

Hypertension

Initial dosage: maximum 6.25 mg twice daily as immediate-release tablets or 20 mg once daily as carvedilol phosphate extended-release capsules (to minimize hypotension, syncope).

Maximum 50 mg daily as immediate-release tablets or 80 mg once daily as carvedilol phosphate extended-release capsules.

Heart Failure

Initial dosage: maximum 3.125 mg twice daily as immediate-release tablets or 10 mg once daily as carvedilol phosphate extended-release capsules (to minimize hypotension, syncope).

Patients weighing <85 kg: maximum 25 mg daily as immediate-release tablets.

Patients weighing >85 kg: maximum 50 mg daily as immediate-release tablets.

Maximum 80 mg once daily as carvedilol phosphate extended-release capsules.

Left Ventricular Dysfunction Following MI

Initial dosage: maximum 6.25 mg twice daily as immediate-release tablets or 20 mg once daily as carvedilol phosphate extended-release capsules (to minimize hypotension, syncope).

Maximum (target dose): 25 mg twice daily as immediate-release tablets or 80 mg once daily as carvedilol phosphate extended-release capsules.

Special Populations

Hepatic Impairment

Not recommended for use in patients with clinical manifestations of hepatic impairment or severe impairment. (See Contraindications.)

Renal Impairment

No specific dosage adjustment recommendations.

If a deterioration in renal function is detected in heart failure patients, decrease dosage or discontinue carvedilol.

Geriatric Patients

Reduced initial dosage may be necessary because of increased risk of orthostatic hypotension and limited experience in patients ≥75 years of age.

Cautions for Carvedilol

Contraindications

  • Bronchial asthma or related bronchospastic conditions.

  • Second or third degree AV block.

  • Sick sinus syndrome or severe bradycardia (unless permanent pacemaker is in place).

  • Cardiogenic shock or decompensated heart failure requiring IV inotropic therapy; initiate carvedilol only after weaned from IV therapy.

  • Clinically manifest or otherwise severe hepatic impairment.

  • History of serious hypersensitivity reaction (e.g., Stevens-Johnson syndrome, anaphylactic reaction, angioedema) to carvedilol or any ingredient in the formulation.

Warnings/Precautions

Warnings

Abrupt Withdrawal of Therapy

Abrupt discontinuance may exacerbate angina symptoms or precipitate MI or ventricular arrhythmias in patients with CAD, or may precipitate thyroid storm in patients with thyrotoxicosis. When carvedilol is discontinued in patients with CAD or suspected thyrotoxicosis, observe the patient carefully; advise patients with CAD to temporarily limit their physical activity.

Because CAD is common and may be undiagnosed, also avoid abrupt withdrawal in patients receiving carvedilol for other conditions (e.g., hypertension).

In all patients, gradually decrease dosage over 1–2 weeks and monitor patients carefully. If exacerbation of angina occurs or acute coronary insufficiency develops, reinstitute therapy promptly, at least temporarily.

Peripheral Vascular Disease

Possible precipitation or aggravation of arterial insufficiency in patients with peripheral vascular disease. Use with caution.

Anesthesia and Major Surgery

Use with caution in patients undergoing major surgery involving general anesthesia agents that cause myocardial depression (e.g., ether, cyclopropane, trichloroethylene). (See Specific Drugs under Interactions.)

Diabetes and Hypoglycemia

β-Blockers may mask some of the manifestations of hypoglycemia (e.g., tachycardia). Nonselective β-blockers (e.g., carvedilol) are more likely to potentiate insulin-induced hypoglycemia and delay recovery of serum glucose concentrations.

Risk of worsening hyperglycemia in patients with heart failure and diabetes mellitus; monitor blood glucose when initiating, adjusting, or discontinuing carvedilol.

Thyrotoxicosis

β-Adrenergic blockade may mask clinical signs of hyperthyroidism (e.g., tachycardia). Abrupt withdrawal of β-blockade may be followed by an exacerbation of symptoms of hyperthyroidism or precipitate thyroid storm.

General Precautions

Carvedilol shares the toxic potentials of β-blockers and α1-adrenergic blocking agents; observe the usual precautions of these agents.

Bradycardia

May cause bradycardia; reduce dosage if heart rate is <55 bpm.

Hypotension

May cause hypotension, postural hypotension, or syncope. Risk is highest in first 30 days of therapy in patients with heart failure. To decrease risk of orthostatic hypotension, administer with food and strictly adhere to the usual starting dose and titration recommendations. (See Dosage and Administration.)

Pheochromocytoma

Use with caution in patients suspected of having pheochromocytoma; initiate α-adrenergic blocking agent before using any β-blocker. Although carvedilol has both α- and β-blocking pharmacologic activities, there has been no experience with its use in this condition; use with caution.

Prinzmetal’s Variant Angina

Nonselective β-blockers may provoke chest pain in patients with Prinzmetal’s variant angina; use with caution.

History of Anaphylactic Reactions

Possible increased reactivity to a variety of allergens; patients may be unresponsive to usual doses of epinephrine used to treat anaphylactic reactions.

Bronchospastic Disease

Bronchospasm reported rarely; deaths secondary to status asthmaticus have been reported following single doses of carvedilol. In general, use of β-blockers not recommended in patients with bronchospastic disease (e.g., chronic bronchitis, emphysema). (See Contraindications under Cautions.)

Use carvedilol with caution in patients who do not respond to or are intolerant to other antihypertensive drugs. Use lowest possible dosage to minimize inhibition of endogenous or exogenous β-agonists. If bronchospasm occurs, reduce dosage.

Use with caution and strict adherence to recommendations regarding dosage titration in patients with heart failure and bronchospastic disease. If any evidence of bronchospasm occurs during titration of carvedilol, reduce dosage.

Specific Populations

Pregnancy

Category C.

Crosses the placenta in rats. Perinatal and neonatal distress have been reported with other α- and β-blocking agents.

Lactation

Distributed into milk in rats; not known whether distributed into human milk. Discontinue nursing or the drug.

Pediatric Use

Safety and efficacy not established in children <18 years of age.

In a clinical trial in pediatric patients (mean age 6 years; range 2 months to 17 years) with chronic heart failure (NYHA class II–IV), carvedilol resulted in β-blockade activity as demonstrated by a placebo-corrected heart rate reduction of 4–6 beats per minute; however, no clinically important effect on treatment outcome was observed after 8 months of follow-up. Common adverse effects included chest pain, dizziness, and dyspnea.

Geriatric Use

No substantial differences in safety or efficacy relative to younger adults, but possibility exists of increased sensitivity to carvedilol in some individuals.

Hepatic Impairment

Not recommended for use in patients with manifestations of hepatic impairment or severe hepatic impairment. (See Contraindications.)

Renal Impairment

Monitor renal function in patients with low BP (SBP <100 mm Hg), ischemic heart disease and diffuse vascular disease, and/or underlying renal insufficiency, especially during the initial titration period. If a deterioration in renal function is detected, decrease dosage or discontinue carvedilol.

Common Adverse Effects

Patients with heart failure receiving immediate-release carvedilol tablets: Dizziness, headache, fatigue, asthenia, arthralgia, hypotension, bradycardia, generalized edema, diarrhea, nausea, vomiting, hyperglycemia, weight gain, increased BUN, increased nonprotein nitrogen (NPN), increased cough, abnormal vision.

Patients with left ventricular dysfunction following MI receiving immediate-release carvedilol tablets: Similar to those in patients receiving the drug for the treatment of heart failure. Anemia, dyspnea, pulmonary edema also reported.

Patients with hypertension receiving immediate-release carvedilol tablets: Dizziness, bradycardia, diarrhea, insomnia, postural hypotension.

Patients with hypertension receiving extended-release carvedilol phosphate capsules: Nasopharyngitis, dizziness, nausea, peripheral edema.

Interactions for Carvedilol

Metabolized by CYP isoenzymes, principally CYP2D6 and CYP2C9; to a lesser extent by CYP3A4, CYP2C19, CYP1A2, CYP2E1.

Drugs Affecting Hepatic Microsomal Enzymes

Potent inhibitors of CYP2D6 (e.g., fluoxetine, paroxetine, propafenone, quinidine): potential pharmacokinetic interaction (increased plasma concentrations of R(+)-carvedilol); however interactions with carvedilol have not been studied.

Specific Drugs

Drug

Interaction

Comments

Anesthetics, general (myocardial depressant [e.g., ether, cyclopropane, trichloroethylene])

Potential for increased risk of hypotension and heart failure

Use with caution

Antidiabetic agents (oral and parenteral [e.g., insulin])

Possible increased hypoglycemic effect

Regularly monitor blood glucose concentrations

Calcium-channel blocking agents (e.g., verapamil, diltiazem)

Possible conduction disturbance, rarely with hemodynamic compromise

Monitor BP and ECG with concomitant use with diltiazem or verapamil

Cardiac glycosides (e.g., digoxin)

Potential pharmacokinetic and pharmacodynamic interaction. Increased digoxin concentrations; possible additive negative effects on AV conduction and increased risk of bradycardia

Monitor digoxin carefully when carvedilol dosage is initiated, adjusted, or discontinued

Catecholamine-depleting agents (e.g., reserpine, MAO inhibitors)

Potential additive effects (e.g., hypotension, bradycardia)

Monitor closely for symptoms (e.g., vertigo, syncope, postural hypotension)

Cimetidine

Potential decreased carvedilol metabolism and increased bioavailability (AUC) of carvedilol (e.g., by 30%)

No apparent change in peak plasma concentration of carvedilol

Clonidine

Potential additive effects (e.g., hypotension, bradycardia)

If used concomitantly, exercise caution when discontinuing therapy; discontinue carvedilol therapy first and then discontinue clonidine by gradual downward titration starting several days thereafter

Cyclosporine

Possible increased cyclosporine concentrations

Monitor cyclosporine concentrations closely during carvedilol dosage titration; adjust cyclosporine dosage as necessary

Fluoxetine

Potential pharmacokinetic and pharmacodynamic interaction: increased plasma concentrations of R(+)-carvedilol may result in increased α-adrenergic blockade effects (vasodilation)

Glyburide

Pharmacokinetic interaction unlikely

Hydrochlorothiazide

Pharmacokinetic interaction unlikely

Pantoprazole

No clinically important increases in AUC and peak plasma concentrations of carvedilol reported with concomitant administration of carvedilol and pantoprazole

Paroxetine

Potential pharmacokinetic and pharmacodynamic interaction: increased plasma concentrations of R(+)-carvedilol may result in increased α-adrenergic blockade effects (vasodilation)

Propafenone

Potential pharmacokinetic interaction: increased plasma concentrations of R(+)-carvedilol may result in increased α-adrenergic blockade effects (vasodilation)

Quinidine

Potential pharmacokinetic interaction: increased plasma concentrations of R(+)-carvedilol may result in increased α-adrenergic blockade effects (vasodilation)

Rifampin

Potential increased carvedilol metabolism and decreased peak plasma concentration and AUC of carvedilol

Torsemide

Pharmacokinetic interaction unlikely

Warfarin

No effect on steady-state prothrombin times or warfarin pharmacokinetics

Carvedilol Pharmacokinetics

Absorption

Bioavailability

Rapidly and extensively absorbed; absolute bioavailability following oral administration of immediate-release tablets is 25–35%. Bioavailability of carvedilol phosphate extended-release capsules is approximately 85% that of the immediate-release tablets.

Onset

Following oral administration as immediate-release tablets, dose-dependent hypotensive effect occurs in approximately 30 minutes; maximum effect occurs in 1.5–7 hours.

Following oral administration as immediate-release tablets, clinically important β-adrenergic blocking activity usually occurs within 1 hour and α1-adrenergic blocking effects generally occur within 30 minutes.

Absorption of carvedilol following administration of carvedilol phosphate extended-release capsules is slower and more prolonged compared with carvedilol immediate-release tablets; peak plasma concentrations are achieved approximately 5 hours after oral administration of the extended-release capsules.

Food

Food decreases absorption rate (i.e., increases time to peak plasma concentration), but not extent (i.e., no effect on bioavailability) of absorption of carvedilol immediate-release tablets. Administration with food increases the extent of absorption of carvedilol when administered as carvedilol phosphate extended-release capsules. When administered with food in corresponding dosages (see Dosage under Dosage and Administration), equivalent drug exposure is achieved with carvedilol immediate release tablets and carvedilol extended-release capsules.

Administration with food may be used to decrease risk of orthostatic hypotension.

Special Populations

Increased plasma concentrations in individuals with CYP2D6 deficiency (poor metabolizers); results in increased α-adrenergic effects (vasodilation) and increased rate of dizziness during dosage titration.

Increased peak plasma concentrations and AUCs (up to 50–100%) in heart failure patients.

Increased plasma concentrations (50%) in elderly patients compared with younger adults.

Substantially increased plasma concentrations (about 4- to 7-fold) in patients with cirrhosis.

Increased plasma concentrations in patients with moderate or severe renal impairment; AUCs are similar to those in patients with normal renal function.

Distribution

Extent

Substantial distribution into extravascular tissues.

Crosses the placenta and is distributed into milk in rats.

Plasma Protein Binding

>98%.

Elimination

Metabolism

Substantial, stereoselective first-pass metabolism.

Extensively metabolized; phenol ring demethylation and hydroxylation produce 3 metabolites with β-adrenergic blocking activity and (weak) vasodilating activity. Plasma concentrations of active metabolites are about 10% those of carvedilol. 4’-Hydroxyphenyl metabolite is 13 times more potent than carvedilol for β-adrenergic blocking activity.

Elimination Route

Excreted principally in the feces as metabolites; <2% excreted in urine unchanged.

Half-life

7–10 hours. 5–9 hours for R(+)-carvedilol, and 7–11 hours for S(-)-carvedilol.

Special Populations

In heart failure patients, mean half-life was similar to that in normal individuals.

Excretion apparently is not substantially affected by hemodialysis.

Stability

Storage

Oral

Tablets

Tight, light-resistant containers below 30°C.

Capsules

Tight, light-resistant containers at 25°C (may be exposed to 15–30°C).

Actions

  • Nonselective β-blocker with selective α1-adrenergic blocking activity.

  • Racemic mixture: S(-)-carvedilol has nonselective β-adrenergic blocking activity. S(-)- and R(+)-carvedilol have equal α-adrenergic blocking activity.

  • Principally blocks β-adrenergic receptor stimulation within myocardium (β1-receptors) and bronchial and vascular smooth muscle (β2-receptors), and to a lesser extent α1-receptors within vascular smooth muscle.

  • Does not exhibit intrinsic sympathomimetic (β1-agonist) activity and possesses only weak membrane-stabilizing (local anesthetic) activity.

  • Hypotensive effect apparently results from α1-adrenergic blockade, reduced sympathetic tone, reduced total peripheral resistance, vasodilation (both arterial and venous).

  • Mechanism of beneficial effects in the treatment of heart failure has not been fully elucidated; combined adrenergic effects (especially vasodilation), may ameliorate the negative inotropic effects that could otherwise lead to myocardial dysfunction in the compensating heart failure patient.

  • Mechanism of beneficial effect in left ventricular dysfunction following acute MI has not been established.

Advice to Patients

  • Importance of taking medication exactly as prescribed.

  • Importance of taking with food.

  • Importance of not interrupting or discontinuing therapy without consulting clinician.

  • When discontinuing therapy, importance of advising patients to temporarily limit physical activity.

  • Importance of advising patients to sit or lie down and avoid hazardous tasks (e.g., driving) if dizziness or fatigue occur.

  • Importance of informing clinician if dizziness or faintness from decreased BP occurs; dosage adjustment may be necessary.

  • Importance of diabetic patients informing clinician if changes in blood glucose concentrations occur. Importance of warning patients receiving insulin or oral hypoglycemic agents, or those subject to spontaneous hypoglycemia about these potential effects.

  • Importance of immediately informing clinician at the first sign or symptom (e.g., weight gain, shortness of breath) of heart failure.

  • Importance of informing contact lens wearers that they may experience decreased lacrimation.

  • Importance of advising patients undergoing major surgery to inform anesthesiologist or dentist that they are receiving the drug.

  • Importance of informing clinicians of existing or contemplated therapy, including prescription and OTC drugs.

  • Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.

  • Importance of informing patient of other important precautionary information. (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name

Carvedilol

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Tablets, film-coated

3.125 mg*

Carvedilol Tablets

Coreg

GlaxoSmithKline

6.25 mg*

Carvedilol Tablets

Coreg Tiltabs

GlaxoSmithKline

12.5 mg*

Carvedilol Tablets

Coreg Tiltabs

GlaxoSmithKline

25 mg*

Carvedilol Tablets

Coreg Tiltabs

GlaxoSmithKline

Carvedilol Phosphate

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Capsules, extended-release

10 mg (with 12.5% immediate-release and 87.5% extended-release)

Coreg CR

GlaxoSmithKline

20 mg (with 12.5% immediate-release and 87.5% extended-release)

Coreg CR

GlaxoSmithKline

40 mg (with 12.5% immediate-release and 87.5% extended-release)

Coreg CR

GlaxoSmithKline

80 mg (with 12.5% immediate-release and 87.5% extended-release)

Coreg CR

GlaxoSmithKline

AHFS DI Essentials™. © Copyright 2021, Selected Revisions February 18, 2019. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, Maryland 20814.

† Use is not currently included in the labeling approved by the US Food and Drug Administration.

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