Carvedilol

Pharmacologic Category

Antihypertensive; Beta-Blocker With Alpha-Blocking Activity

Dosing: Adult

Angina, chronic stable (off-label use):

Note: For vasospastic angina, beta-blockers are not recommended; other agents (eg, calcium channel blockers, nitrates) are preferred. For nonvasospastic angina, guidelines recommend titrating dose to a resting heart rate of 55 to 60 beats per minute (ACCF/AHA [Fihn 2012]), while other experts recommend a target of 60 to 70 beats per minute (Kannam 2019).

Immediate release: Oral: Initial: 12.5 mg twice daily; increase dose as tolerated to desired effect; usual dosage range: 25 to 50 mg twice daily (Hauf-Zachariou 1997; Weiss 1998).

Atrial fibrillation/flutter, maintenance of ventricular rate control (off-label use):

Note: Initiate cautiously in patients with concomitant heart failure. Avoid in patients with decompensated heart failure; electrical cardioversion preferred in these patients (AHA/ACC/HRS [January 2014]; AHA [Neumar 2010]).

Immediate release: Oral: Usual dosage range: 3.125 to 25 mg twice daily (AHA/ACC/HRS [January 2014]).

Heart failure with reduced ejection fraction, including left ventricular dysfunction following myocardial infarction:

Note: Initiate only in stable patients. In hospitalized patients, volume status should be optimized and IV diuretics, vasodilators, and inotropic agents successfully discontinued. Use caution when initiating in patients with New York Heart Association class IV symptoms or recent heart failure exacerbation (particularly in those who required inotropes during their hospital stay) (ACCF/AHA [Yancy 2013]; Meyer 2019).

Immediate release: Oral: Initial: 3.125 mg twice daily for 2 weeks, then up-titrate gradually (eg, doubling the dose every ≥2 weeks) to the recommended or maximum tolerated dose while monitoring for signs and symptoms of heart failure (ACC/AHA [Yancy 2017]; ACCF/AHA [Yancy 2013]; Packer 1996; Packer 2001).

Maximum recommended dose:

≤85 kg: 25 mg twice daily.

>85 kg: 50 mg twice daily.

Extended release: Oral: Initial: 10 mg once daily for 2 weeks, then up-titrate gradually (eg, doubling the dose every ≥2 weeks) to the maximum tolerated dose while monitoring for signs and symptoms of heart failure; maximum dose: 80 mg/day (ACC/AHA [Yancy 2017]; ACCF/AHA [Yancy 2013]).

Hypertension (alternative agent):

Note: Not recommended in the absence of specific comorbidities (eg, arrhythmia ischemic heart disease, heart failure with reduced ejection fraction) (ACC/AHA [Whelton 2018]).

Immediate release: Oral: Initial: 6.25 mg twice daily; titrate in ≥1-week intervals as needed based on patient response; usual dosage range: 6.25 to 25 mg twice daily; maximum dose: 50 mg/day (ACC/AHA [Whelton 2018]).

Extended release: Oral: Initial: 20 mg once daily; titrate in ≥1-week intervals as needed based on patient response; usual dosage range: 20 to 80 mg/day; maximum dose: 80 mg/day (ACC/AHA [Whelton 2018]).

Myocardial infarction, early treatment and secondary prevention (alternative agent) (off-label use):

Note: An oral beta-blocker is recommended within the first 24 hours for most patients (ACCF/AHA [O'Gara 2013]). Patients who do not receive a beta-blocker within 24 hours of myocardial infarction due to contraindications should be reevaluated for secondary prevention at a later date. The optimal duration of therapy is unknown; some experts treat for a minimum of 3 years and continue longer for patients with high-risk features (eg, cardiogenic shock, heart failure, chronic kidney disease) at initial presentation (Rosenson 2019).

Immediate release: Oral: Initial: 3.125 to 6.25 mg twice daily; titrate dose based on heart rate and blood pressure as tolerated up to 25 mg twice daily (Dargie 2001).

Variceal hemorrhage prophylaxis, primary (alternative agent) (off-label use):

Immediate release: Oral: Initial: 3.125 mg twice daily or 6.25 mg once daily; titrate according to resting heart rate (target 55 to 60 beats per minute) while maintaining blood pressure (eg, systolic blood pressure ≥90 mm Hg) to a maximum dose of 6.25 mg twice daily (AASLD [Garcia-Tsao 2017]; Bañares 2002; Bhardwaj 2017; Reiberger 2013; Sanyal 2019; Tripathi 2009).

Conversion from immediate release to extended release (Coreg CR):

Current dose IR tablets 3.125 mg twice daily: Convert to ER capsules 10 mg once daily.

Current dose IR tablets 6.25 mg twice daily: Convert to ER capsules 20 mg once daily.

Current dose IR tablets 12.5 mg twice daily: Convert to ER capsules 40 mg once daily.

Current dose IR tablets 25 mg twice daily: Convert to ER capsules 80 mg once daily.

* See Dosage and Administration in AHFS Essentials for additional information.

Dosing: Geriatric

Refer to adult dosing. Consider lower initial doses and titrate to response (ACCF/AHA [Aronow 2011]).

Dosing: Renal Impairment: Adult

No dosage adjustment necessary; not significantly cleared by hemodialysis

Dosing: Hepatic Impairment: Adult

Mild to moderate impairment: There are no dosage adjustments provided in the manufacturer’s labeling.

Severe impairment: Use is contraindicated.

Dosing: Pediatric

Note: Immediate release and extended release products are not interchangeable on a mg:mg basis due to pharmacokinetic differences. Individualize dosage for each patient; monitor patients closely during initiation and upwards titration of dose; reduce dosage for hypotension or bradycardia (adolescents ≥ 18 years: 55 bpm; younger patients may alternate target). Pharmacokinetic data suggests a faster carvedilol elimination in young pediatric patients (< 3.5 years) which may require more frequent dosing (3 times daily) and a higher target dose per kg (Laer, 2002; Shaddy, 2007).

Heart failure: Prior to initiating therapy, other CHF medications should be stabilized and fluid retention minimized.

Infants, Children, and Adolescents ≤ 17 years: Limited data available, efficacy results variable; optimal dose not established: Oral: Immediate release tablets: Initial: Reported mean: 0.075-0.08 mg/kg/dose twice daily; titrate as tolerated; may increase dose by typically 50% every 2 weeks; usual reported maintenance (target) dose range: 0.3-0.75 mg/kg/dose twice daily; the usual titration time to reach target dose was 11-14 weeks (Bruns, 2001; Rusconi, 2004); maximum daily dose: 50 mg/day. Dosing based on two retrospective analyses of a total 70 pediatric patients (age range: 3 months to 19 years) which showed improvement in left ventricular function and heart failure symptoms (67% to 68% of patients showed improvement in NYHA class). However, in a large, a multicenter, double-blind, placebo-controlled, dose-finding trial in 161 pediatric patients (treatment group: n=103, median age range: 33-43 months), a lower target dose range of 0.2-0.4 mg/kg/dose twice daily did not result in a statistical difference in composite clinical end point scores compared to placebo; the authors suggested multiple factors for negative efficacy findings including that the study may have been underpowered due to unexpected, high improvement of the placebo-arm; a subset analysis suggests ventricular morphology may play a role in efficacy (Shaddy, 2007).

Adolescents ≥18 years:

Immediate release tablets: Oral: Initial: 3.125 mg twice daily for 2 weeks; if tolerated, may increase to 6.25 mg twice daily. May double the dose every 2 weeks to the highest dose tolerated by patient.

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

Extended release capsules: Oral: Initial: 10 mg once daily for 2 weeks; if tolerated, may double the dose (eg, 20 mg, 40 mg) every 2 weeks up to 80 mg once daily; maintain on lower dose if higher dose is not tolerated

Hypertension: Adolescents ≥18 years:

Immediate release tablets: Oral: Initial: 6.25 mg twice daily; if tolerated, dose should be maintained for 1-2 weeks, then increased to 12.5 mg twice daily; maximum daily dose: 50 mg/day

Extended release capsules: Oral: Initial: 20 mg once daily; if tolerated, dose should be maintained for 1-2 weeks, then increased to 40 mg once daily if necessary; maximum daily dose: 80 mg/day

Left ventricular dysfunction following MI: Adolescents ≥ 18 years: Note: Initiate only after patient is hemodynamically stable and fluid retention has been minimized.

Immediate release tablets: Oral: Initial: 3.125-6.25 mg twice daily; increase dosage incrementally (eg, from 6.25 to 12.5 mg twice daily) at intervals of 3-10 days, as tolerated, to a target dose of 25 mg twice daily

Extended release capsules: Oral: Initial: 10-20 mg once daily; increase dosage incrementally at intervals of 3-10 days, as tolerated, to a target dose of 80 mg once daily

Conversion from immediate release to extended release (Coreg CR®): Adolescents ≥ 18 years:

Current dose immediate release tablets 3.125 mg twice daily: Convert to extended release capsules 10 mg once daily

Current dose immediate release tablets 6.25 mg twice daily: Convert to extended release capsules 20 mg once daily

Current dose immediate release tablets 12.5 mg twice daily: Convert to extended release capsules 40 mg once daily

Current dose immediate release tablets 25 mg twice daily: Convert to extended release capsules 80 mg once daily

Dosing: Renal Impairment: Pediatric

No adjustment required. Note: Mean AUCs were 40% to 50% higher in adult patients with moderate to severe renal dysfunction who received immediate release carvedilol, but the ranges of AUCs were similar to patients with normal renal function

Hemodialysis: Hemodialysis does not significantly clear carvedilol.

Dosing: Hepatic Impairment: Pediatric

Mild to moderate impairment (Child-Pugh class A or B): There are no dosage adjustments provided in manufacturer's labeling; use with caution; monitor for symptoms of drug-induced toxicity.

Severe impairment (Child-Pugh class C): Use is contraindicated as drug is extensively metabolized by the liver. Note: Adult patients with severe cirrhotic liver disease achieved carvedilol serum concentrations four- to sevenfold higher than normal patients following a single dose of immediate release carvedilol

Use: Labeled Indications

Heart failure with reduced ejection fraction, including left ventricular dysfunction following myocardial infarction: Treatment of mild to severe chronic heart failure of ischemic or cardiomyopathic origin or left ventricular dysfunction following myocardial infarction (clinically stable with left ventricular ejection fraction ≤40%).

Hypertension: Management of hypertension. Note: Beta-blockers are not recommended as first-line therapy (ACC/AHA [Whelton 2018]).

* See Uses in AHFS Essentials for additional information.

Use: Off-Label: Adult

Angina, chronic stableLevel of Evidence [G]

Based on the 2012 American College of Cardiology Foundation (ACCF)/American Heart Association (AHA) guideline for the diagnosis and management of patients with stable ischemic heart disease, a beta-blocker is recommended, in the absence of contraindications, for the treatment of chronic stable angina.

Atrial fibrillation/flutter, maintenance of ventricular rate controlLevel of Evidence [B, G]

Data from a randomized, double-blind, placebo-controlled trial support the use of carvedilol (with or without digoxin) in the management of atrial fibrillation in patients with heart failure ^Ref.

Based on the 2014 AHA/American College of Cardiology (ACC)/Heart Rhythm Society guideline for the management of patients with atrial fibrillation, the use of beta-blockers for ventricular rate control in patients with atrial fibrillation is effective and recommended for this condition, especially in patients with heart failure.

Myocardial infarction, early treatment and secondary preventionLevel of Evidence [G]

According to the 2013 ACCF/AHA guideline for the management of ST-elevation myocardial infarction and the 2014 AHA/ACC guideline for the management of patients with non-ST-elevation acute coronary syndromes, an oral beta-blocker should be initiated within the first 24 hours unless the patient has signs of heart failure, evidence of a low-output state, an increased risk for cardiogenic shock, or other contraindications.

Variceal hemorrhage prophylaxis, primaryLevel of Evidence [B, G]

Data from clinical trials support the use of carvedilol for primary prophylaxis of variceal hemorrhage ^Ref.

Based on the 2017 American Association for the Study of Liver Diseases guidelines on the management of portal hypertensive bleeding in cirrhosis, use of carvedilol is an effective and recommended option for primary prophylaxis of variceal hemorrhage.

Level of Evidence Definitions

Level of Evidence Scale

Clinical Practice Guidelines

Arrhythmias:

AHA/ACC/HRS, "2017 AHA/ACC/HRS Guideline for Management of Patients with Ventricular Arrhythmias and the Prevention of Sudden Cardiac Death," October 2017

AHA/ACC/HRS, "2019 AHA/ACC/HRS Focused Update of the 2014 AHA/ACC/HRS Guideline for the Management of Patients with Atrial Fibrillation," January 2019

AHA/ACC/HRS, "2014 AHA/ACC/HRS Guideline for the Management of Patients with Atrial Fibrillation," March 2014

Canadian Cardiovascular Society, "2016 Focused Update of the Canadian Cardiovascular Society Guidelines for the Management of Atrial Fibrillation," 2016

Heart Failure:

ACC/AHA/HFSA, "Focused Update of the 2013 ACCF/AHA Guideline for the Management of Heart Failure," August 2017

ACC/AHA/HFSA, “2016 ACC/AHA/HFSA Focused Update on New Pharmacological Therapy for Heart Failure,” May 2016

ACCF/AHA, “2013 ACCF/AHA Guideline for the Management of Heart Failure,” June 2013

Hypertension:

"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," November 2017.

"ACCF/AHA Expert Consensus Document on Hypertension in the Elderly," 2011

AHA/ACC/CDC, “AHA/ACC/CDC Science Advisory: An Effective Approach to High Blood Pressure Control” November 2013

ASH/ISH “Clinical Practice Guidelines for the Management of Hypertension in the Community: A Statement by the American Society of Hypertension and the International Society of Hypertension,” January 2014

Canadian Cardiovascular Society, “2012 Heart Failure Management Guidelines Update: Focus on Acute and Chronic Heart Failure,” 2012

Eighth Joint National Committee (JNC 8), "2014 Evidence-based Guideline for the Management of High Blood Pressure in Adults," December 2013

Ischemic Heart Disease:

ACC/AHA/AATS/PCNA/SCAI/STS, "2014 Focused Update of the Guideline for the Diagnosis and Management of Patients with Stable Ischemic Heart Disease," July 2014

ACCF/AHA/ACP/AATS/PCNA/SCAI/STS, “2012 Guideline for the Diagnosis and Management of Patients with Stable Ischemic Heart Disease,” November 2012

ACCF/AHA, “2013 ACCF/AHA Guideline for the Management of ST-Elevation Myocardial Infarction,” December 2012

AHA/ACC, "2014 AHA/ACC Guideline for the Management of Patients with Non-ST-Elevation Acute Coronary Syndromes,” September 2014

Surgery:

ACC/AHA, “2014 ACC/AHA Guideline on Perioperative Cardiovascular Evaluation and Management of Patients Undergoing Noncardiac Surgery,” August 2014

Valvular Heart Disease:

AHA/ACC, “2014 AHA/ACC Guideline for the Management of Patients with Valvular Heart Disease,” March 2014

Administration: Oral

Administer with food to minimize the risk of orthostatic hypotension. Extended-release capsules and its contents should not be crushed, chewed, or divided. Capsules may be opened and its contents sprinkled on applesauce for immediate use.

Administration: Pediatric

Oral:

Immediate-release tablets: Administer with food to decrease the risk of orthostatic hypotension.

Extended-release capsules: Administer with food, preferably in the morning; do not crush or chew capsule; swallow whole; do not take in divided doses. Capsule may be opened and contents sprinkled on a spoonful of applesauce; swallow applesauce/medication mixture immediately; do not chew; do not store for later use; do not use warm applesauce; do not sprinkle capsule contents on food other than applesauce; drink fluids after dose to make sure mixture is completely swallowed.

Dietary Considerations

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

Storage/Stability

Coreg: Store at <30°C (<86°F). Protect from moisture.

Coreg CR: Store at 25°C (77°F); excursions permitted to 15°C to 30°C (59°F to 86°F). Protect from light.

Extemporaneously Prepared

A 1.25 mg/mL carvedilol oral suspension may be made with tablets and one of two different vehicles (Ora-Blend or 1:1 mixture of Ora-Sweet and Ora-Plus). Crush five 25 mg tablets in a mortar and reduce to a fine powder; add 15 mL of purified water and mix to a uniform paste. Mix while adding chosen vehicle in incremental proportions to almost 100 mL; transfer to a calibrated amber bottle, rinse mortar with vehicle, and add quantity of vehicle sufficient to make 100 mL. Label “shake well”. Stable for 84 days when stored in amber prescription bottles at room temperature (Loyd, 2006).

Carvedilol oral liquid suspensions (0.1 mg/mL and 1.67 mg/mL) made from tablets, water, Ora-Plus, and Ora-Sweet were stable for 12 weeks when stored in glass amber bottles at room temperature (25°C). Use one 3.125 mg tablet for the 0.1 mg/mL suspension or two 25 mg tablets for the 1.67 mg/mL suspension; grind the tablet(s) and compound a mixture with 5 mL of water, 15 mL Ora-Plus, and 10 mL Ora-Sweet. Final volume of each suspension: 30 mL; label “shake well” (data on file, GlaxoSmithKline, Philadelphia, PA: DOF #132 [Note: Manufacturer no longer disseminates this document]).

Loyd A Jr, “Carvedilol 1.25 mg/mL Oral Suspension,” Int J Pharm Compounding, 2006, 10(3):220.

Medication Patient Education with HCAHPS Considerations

What is this drug used for?

• It is used to treat heart failure (weak heart).

• It is used to treat high blood pressure.

• It is used to help heart function after a heart attack.

• It may be given to you for other reasons. Talk with the doctor.

Frequently reported side effects of this drug

• Loss of strength and energy

• Diarrhea

• Headache

• Nausea

• Vomiting

• Weight gain

• Joint pain

• Contact lens discomfort

Other side effects of this drug: Talk with your doctor right away if you have any of these signs of:

• Heart problems like cough or shortness of breath that is new or worse, swelling of the ankles or legs, abnormal heartbeat, weight gain of more than five pounds in 24 hours, dizziness, or passing out.

• Severe dizziness

• Passing out

• Unable to pass urine

• Change in amount of urine passed

• Chest pain

• Slow heartbeat

• Vision changes

• Signs of a significant reaction like wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat.

Note: This is not a comprehensive list of all side effects. Talk to your doctor if you have questions.

Consumer Information Use and Disclaimer: This information should not be used to decide whether or not to take this medicine or any other medicine. Only the healthcare provider has the knowledge and training to decide which medicines are right for a specific patient. This information does not endorse any medicine as safe, effective, or approved for treating any patient or health condition. This is only a brief summary of general information about this medicine. It does NOT include all information about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to this medicine. This information is not specific medical advice and does not replace information you receive from the healthcare provider. You must talk with the healthcare provider for complete information about the risks and benefits of using this medicine.

Medication Safety Issues

Sound-alike/look-alike issues:

Contraindications

Serious hypersensitivity to carvedilol or any component of the formulation; 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

Documentation of allergenic cross-reactivity for drugs alpha/beta adrenergic blocking agents is limited. However, because of similarities in chemical structure and/or pharmacologic actions, the possibility of cross-sensitivity cannot be ruled out with certainty.

Canadian labeling: Additional contraindications (not in US labeling): Severe hypotension; primary obstructive valvular heart disease; mental incapacity (eg, severe Alzheimer disease, alcoholism, drug abuse), unless closely supervised by an appropriate caregiver.

Warnings/Precautions

Concerns related to adverse effects:

• Anaphylactic reactions: Use caution with history of severe anaphylaxis to allergens; patients taking beta-blockers may become more sensitive to repeated challenges. Treatment of anaphylaxis (eg, epinephrine) in patients taking beta-blockers may be ineffective or promote undesirable effects.

• Bradycardia: May occur; reduce dosage if heart rate drops to <55 beats/minute.

• Floppy iris syndrome: Intraoperative floppy iris syndrome has been observed in cataract surgery patients who were on or were previously treated with alpha₁-blockers; there appears to be no benefit in discontinuing alpha-blocker therapy prior to surgery. Instruct patients to inform ophthalmologist of carvedilol use when considering eye surgery.

• Hypotension/syncope: Symptomatic hypotension with or without syncope may occur with carvedilol (usually within the first 30 days of therapy); close monitoring of patient is required especially with initial dosing and dosing increases; blood pressure must be lowered at a rate appropriate for the patient's clinical condition. Initiation with a low dose, gradual up-titration, and administration with food may help to decrease the occurrence of hypotension or syncope. Advise patients to avoid driving or other hazardous tasks during initiation of therapy due to the risk of syncope.

Disease-related concerns:

• Angina: Use with caution in patients suspected of having vasospastic angina.

• Bronchospastic disease: In general, patients with bronchospastic disease should not receive beta-blockers; if used at all, should be used cautiously with close monitoring.

• Diabetes: Use with caution in patients with diabetes mellitus; may potentiate hypoglycemia and/or mask signs and symptoms (eg, sweating, anxiety, tachycardia). In patients with heart failure and diabetes, use of carvedilol may worsen hyperglycemia; may require adjustment of antidiabetic agents.

• Heart failure (HF): Heart failure patients may experience a worsening of renal function (rare); risk factors include ischemic heart disease, diffuse vascular disease, underlying renal dysfunction, and/or systolic BP <100 mm Hg. Initiate cautiously, titrate gradually, and monitor for possible deterioration in patient status (eg, symptoms of HF). Worsening heart failure or fluid retention may occur during upward titration; dose reduction or temporary discontinuation may be necessary. Adjustment of other medications (ACE inhibitors and/or diuretics) may also be required.

• Hepatic impairment: Use with caution in patients with mild to moderate hepatic impairment; use is contraindicated in patients with severe hepatic impairment.

• Myasthenia gravis: Use with caution in patients with myasthenia gravis.

• Peripheral vascular disease (PVD): May precipitate or aggravate symptoms of arterial insufficiency in patients with PVD; use with caution and monitor for progression of arterial obstruction.

• Pheochromocytoma (untreated): Use with caution; adequate alpha-blockade should be initiated prior to use of any beta-blocker.

• Psoriasis: Beta-blocker use has been associated with induction or exacerbation of psoriasis, but cause and effect have not been firmly established.

• Thyroid disease: May mask signs of hyperthyroidism (eg, tachycardia). If hyperthyroidism is suspected, carefully manage and monitor; abrupt withdrawal may exacerbate symptoms of hyperthyroidism or precipitate thyroid storm.

Concurrent drug therapy issues:

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

Special populations:

• Elderly: Bradycardia may be observed more frequently in elderly patients (>65 years of age); dosage reductions may be necessary.

Dosage form specific issues:

• Polysorbate 80: Some dosage forms may contain polysorbate 80 (also known as Tweens). Hypersensitivity reactions, usually a delayed reaction, have been reported following exposure to pharmaceutical products containing polysorbate 80 in certain individuals (Isaksson 2002; Lucente 2000; Shelley 1995). Thrombocytopenia, ascites, pulmonary deterioration, and renal and hepatic failure have been reported in premature neonates after receiving parenteral products containing polysorbate 80 (Alade 1986; CDC 1984). See manufacturer's labeling.

Other warnings/precautions:

• Abrupt withdrawal: Beta-blocker therapy should not be withdrawn abruptly (particularly in patients with CAD), but gradually tapered to avoid acute tachycardia, hypertension, and/or ischemia. Severe exacerbation of angina, ventricular arrhythmias, and myocardial infarction (MI) have been reported following abrupt withdrawal of beta-blocker therapy. Temporary and prompt resumption of beta-blocker therapy may be indicated with worsening of angina or acute coronary insufficiency.

• Major surgery: Chronic beta-blocker therapy should not be routinely withdrawn prior to major surgery.

* See Cautions in AHFS Essentials for additional information.

Geriatric Considerations

Due to alterations in the beta-adrenergic autonomic nervous system, beta-adrenergic blockade may result in less hemodynamic response than seen in younger adults. In US trials conducted by the manufacturer, hypertension patients who were elderly (>65%) had a higher incidence of dizziness (8.8% vs 6%) than seen in younger patients. No other differences noted between young and old in these trials.

Pregnancy Considerations

Exposure to beta-blockers during pregnancy may increase the risk for adverse events in the neonate. If maternal use of a beta-blocker is needed, fetal growth should be monitored during pregnancy and the newborn should be monitored for 48 hours after delivery for bradycardia, hypoglycemia, and respiratory depression (ESC [Regitz-Zagrosek 2018]).

Chronic maternal hypertension is also associated with adverse events in the fetus/infant. Chronic maternal hypertension may increase the risk of birth defects, low birth weight, premature delivery, stillbirth, and neonatal death. Actual fetal/neonatal risks may be related to duration and severity of maternal hypertension. Untreated chronic hypertension may also increase the risks of adverse maternal outcomes, including gestational diabetes, preeclampsia, delivery complications, stroke, and myocardial infarction (ACOG 203 2019).

When treatment of chronic hypertension in pregnancy is indicated, agents other than carvedilol are preferred (ACOG 203 2019; ESC [Regitz-Zagrosek 2018]; Magee 2014). Females with preexisting hypertension may continue their medication during pregnancy unless contraindications exist (ESC [Regitz-Zagrosek 2018]). Carvedilol may be considered for use in pregnant patients with heart failure (ESC [Regitz-Zagrosek 2018]).

Breast-Feeding Considerations

It is not known if carvedilol is present in breast milk.

According to the manufacturer, the decision to continue or discontinue breastfeeding during therapy should consider the risk of infant exposure, the benefits of breastfeeding to the infant, and benefits of treatment to the mother. Use of a beta-blocker other than carvedilol may be preferred in a lactating female (Anderson 2017; Ito 2000).

Lexicomp Pregnancy & Lactation, In-Depth

• Carvedilol

Briggs' Drugs in Pregnancy & Lactation

• Carvedilol

Adverse Reactions

>10%:

Cardiovascular: Hypotension (≤20%), orthostatic hypotension (≤20%)

Central nervous system: Dizziness (2% to 32%), fatigue (24%)

Endocrine & metabolic: Weight gain (10% to 12%), hyperglycemia (5% to 12%)

Gastrointestinal: Diarrhea (1% to 12%)

Neuromuscular & skeletal: Asthenia (11%)

1% to 10%:

Cardiovascular: Bradycardia (≤10%), syncope (≤8%), peripheral edema (1% to 7%), angina pectoris (6%), edema (5% to 6%), atrioventricular block (>1% to ≤3%), cerebrovascular accident (>1% to ≤3%), exacerbation of angina pectoris (>1% to ≤3%), hypertension (>1% to ≤3%), lower extremity edema (>1% to ≤3%), palpitations (>1% to ≤3%), peripheral vascular disease (>1% to ≤3%), peripheral ischemia (≤1%), tachycardia (≤1%)

Central nervous system: Headache (5% to 8%), depression (>1% to ≤3%), drowsiness (>1% to ≤3%), hypoesthesia (>1% to ≤3%), hypotonia (>1% to ≤3%), malaise (>1% to ≤3%), vertigo (>1% to ≤3%), paresthesia (1% to ≤3%), insomnia (1% to 2%), abnormality in thinking (≤1%), emotional lability (≤1%), exacerbation of depression (≤1%), lack of concentration (≤1%), nervousness (≤1%), nightmares (≤1%), sleep disorder (≤1%)

Dermatologic: Diaphoresis (≤1%), erythematous rash (≤1%), maculopapular rash (≤1%), pruritus (≤1%), psoriasiform eruption (≤1%), skin photosensitivity (≤1%)

Endocrine & metabolic: Increased nonprotein nitrogen (6%), dependent edema (4%), hypercholesterolemia (4%), albuminuria (>1% to ≤3%), diabetes mellitus (>1% to ≤3%), glycosuria (>1% to ≤3%), gout (>1% to ≤3%), hyperkalemia (>1% to ≤3%), hyperuricemia (>1% to ≤3%), hypervolemia (>1% to ≤3%), hypoglycemia (>1% to ≤3%), hyponatremia (>1% to ≤3%), hypovolemia (>1% to ≤3%), impotence (>1% to ≤3%), increased gamma-glutamyl transferase (>1% to ≤3%), weight loss (>1% to ≤3%), decreased libido (≤1%), hypertriglyceridemia (≤1%), hypokalemia (≤1%)

Gastrointestinal: Nausea (2% to 9%), vomiting (6%), melena (>1% to ≤3%), periodontitis (>1% to ≤3%), gastrointestinal pain (1% to ≤3%), xerostomia (≤1%)

Genitourinary: Hematuria (>1% to ≤3%), urinary frequency (≤1%)

Hematologic & oncologic: Hypoprothrombinemia (>1% to ≤3%), nonthrombocytopenic purpura (>1% to ≤3%), thrombocytopenia (1% to ≤3%), leukopenia (≤1%)

Hepatic: Increased serum alanine aminotransferase (>1% to ≤3%), increased serum alkaline phosphatase (>1% to ≤3%), increased serum aspartate aminotransferase (>1% to ≤3%), hyperbilirubinemia (≤1%), increased liver enzymes (≤1%)

Hypersensitivity: Hypersensitivity reaction (>1% to ≤3%)

Neuromuscular & skeletal: Arthralgia (6%), arthritis (>1% to ≤3%), muscle cramps (>1% to ≤3%), hypokinesia (≤1%)

Ophthalmic: Visual disturbance (5%), blurred vision (>1% to ≤3%)

Otic: Tinnitus (≤1%)

Renal: Increased blood urea nitrogen (≤6%), increased serum creatinine (>1% to ≤3%), renal insufficiency (>1% to ≤3%)

Respiratory: Increased cough (5%), nasopharyngitis (4%), rales (4%), dyspnea (>3%), flu-like symptoms (>1% to ≤3%), nasal congestion (1%), paranasal sinus congestion (1%), asthma (≤1%)

Miscellaneous: Fever (>1% to ≤3%)

Frequency not defined:

Hematologic & oncologic: Anemia

Respiratory: Pulmonary edema

<1%, postmarketing, and/or case reports: Abnormal lymphocytes, alopecia, anaphylactoid shock, anaphylaxis, angioedema, aplastic anemia, amnesia, auditory impairment, bronchospasm, bundle branch block, cerebrovascular disease, complete atrioventricular block, decreased HDL cholesterol, erythema multiforme, exfoliative dermatitis, gastrointestinal hemorrhage, interstitial pneumonitis, ischemic heart disease, migraine, neuralgia, pancytopenia, paresis, respiratory alkalosis, seizure, Stevens-Johnson syndrome, toxic epidermal necrolysis, urinary incontinence

* See Cautions in AHFS Essentials for additional information.

Allergy and Idiosyncratic Reactions

• Beta-Blocker Allergy

Toxicology

• Beta-Blockers

Metabolism/Transport Effects

Substrate of CYP1A2 (minor), CYP2C9 (minor), CYP2D6 (major), CYP2E1 (minor), CYP3A4 (minor), P-glycoprotein/ABCB1; Note: Assignment of Major/Minor substrate status based on clinically relevant drug interaction potential; Inhibits P-glycoprotein/ABCB1

Drug Interactions Open Interactions

Abiraterone Acetate: May increase the serum concentration of CYP2D6 Substrates (High risk with Inhibitors). Management: Avoid concurrent use of abiraterone with CYP2D6 substrates that have a narrow therapeutic index whenever possible. When concurrent use is not avoidable, monitor patients closely for signs/symptoms of toxicity. Risk D: Consider therapy modification

Acetylcholinesterase Inhibitors: May enhance the bradycardic effect of Beta-Blockers. Risk C: Monitor therapy

Afatinib: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Afatinib. Management: Reduce afatinib by 10 mg if not tolerated. Some non-US labeling recommends avoiding combination if possible. If used, administer the P-gp inhibitor simultaneously with or after the dose of afatinib. Risk D: Consider therapy modification

Ajmaline: May increase the serum concentration of CYP2D6 Substrates (High risk with Inhibitors). Risk C: Monitor therapy

Alfuzosin: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy

Alpha1-Blockers: Beta-Blockers may enhance the orthostatic hypotensive effect of Alpha1-Blockers. The risk associated with ophthalmic products is probably less than systemic products. Risk C: Monitor therapy

Alpha2-Agonists: May enhance the AV-blocking effect of Beta-Blockers. Sinus node dysfunction may also be enhanced. Beta-Blockers may enhance the rebound hypertensive effect of Alpha2-Agonists. This effect can occur when the Alpha2-Agonist is abruptly withdrawn. Management: Closely monitor heart rate during treatment with a beta blocker and clonidine. Withdraw beta blockers several days before clonidine withdrawal when possible, and monitor blood pressure closely. Recommendations for other alpha2-agonists are unavailable. Exceptions: Apraclonidine. Risk D: Consider therapy modification

Amifostine: Blood Pressure Lowering Agents may enhance the hypotensive effect of Amifostine. Management: When amifostine is used at chemotherapy doses, blood pressure lowering medications should be withheld for 24 hours prior to amifostine administration. If blood pressure lowering therapy cannot be withheld, amifostine should not be administered. Risk D: Consider therapy modification

Aminoquinolines (Antimalarial): May decrease the metabolism of Beta-Blockers. Risk C: Monitor therapy

Amiodarone: May enhance the bradycardic effect of Beta-Blockers. Possibly to the point of cardiac arrest. Amiodarone may increase the serum concentration of Beta-Blockers. Risk C: Monitor therapy

Amphetamines: May diminish the antihypertensive effect of Antihypertensive Agents. Risk C: Monitor therapy

Antipsychotic Agents (Phenothiazines): May enhance the hypotensive effect of Beta-Blockers. Beta-Blockers may decrease the metabolism of Antipsychotic Agents (Phenothiazines). Antipsychotic Agents (Phenothiazines) may decrease the metabolism of Beta-Blockers. Risk C: Monitor therapy

Antipsychotic Agents (Second Generation [Atypical]): Blood Pressure Lowering Agents may enhance the hypotensive effect of Antipsychotic Agents (Second Generation [Atypical]). Risk C: Monitor therapy

Asunaprevir: May increase the serum concentration of CYP2D6 Substrates (High risk with Inhibitors). Risk D: Consider therapy modification

Barbiturates: May decrease the serum concentration of Beta-Blockers. Risk C: Monitor therapy

Barbiturates: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy

Benperidol: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy

Beta2-Agonists: Beta-Blockers (Nonselective) may diminish the bronchodilatory effect of Beta2-Agonists. Risk X: Avoid combination

Betrixaban: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Betrixaban. Management: Decrease the adult betrixaban dose to an initial single dose of 80 mg followed by 40 mg once daily if combined with a P-glycoprotein inhibitor. Risk D: Consider therapy modification

Bilastine: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Bilastine. Management: Consider alternatives when possible; bilastine should be avoided in patients with moderate to severe renal insufficiency who are receiving p-glycoprotein inhibitors. Risk D: Consider therapy modification

Bradycardia-Causing Agents: May enhance the bradycardic effect of other Bradycardia-Causing Agents. Risk C: Monitor therapy

Brentuximab Vedotin: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Brentuximab Vedotin. Specifically, concentrations of the active monomethyl auristatin E (MMAE) component may be increased. Risk C: Monitor therapy

Brigatinib: May diminish the antihypertensive effect of Antihypertensive Agents. Brigatinib may enhance the bradycardic effect of Antihypertensive Agents. Risk C: Monitor therapy

Brimonidine (Topical): May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy

Bromperidol: Blood Pressure Lowering Agents may enhance the hypotensive effect of Bromperidol. Bromperidol may diminish the hypotensive effect of Blood Pressure Lowering Agents. Risk X: Avoid combination

Bupivacaine: Beta-Blockers may increase the serum concentration of Bupivacaine. Risk C: Monitor therapy

Calcium Channel Blockers (Nondihydropyridine): May enhance the hypotensive effect of Beta-Blockers. Bradycardia and signs of heart failure have also been reported. Calcium Channel Blockers (Nondihydropyridine) may increase the serum concentration of Beta-Blockers. Exceptions: Bepridil. Risk C: Monitor therapy

Cardiac Glycosides: Beta-Blockers may enhance the bradycardic effect of Cardiac Glycosides. Risk C: Monitor therapy

Celiprolol: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Celiprolol. Risk C: Monitor therapy

Ceritinib: Bradycardia-Causing Agents may enhance the bradycardic effect of Ceritinib. Management: If this combination cannot be avoided, monitor patients for evidence of symptomatic bradycardia, and closely monitor blood pressure and heart rate during therapy. Exceptions are discussed in separate monographs. Risk D: Consider therapy modification

Cholinergic Agonists: Beta-Blockers may enhance the adverse/toxic effect of Cholinergic Agonists. Of particular concern are the potential for cardiac conduction abnormalities and bronchoconstriction. Risk C: Monitor therapy

Cimetidine: May increase the serum concentration of Carvedilol. Risk C: Monitor therapy

CloBAZam: May increase the serum concentration of CYP2D6 Substrates (High risk with Inhibitors). Risk C: Monitor therapy

Cobicistat: May increase the serum concentration of CYP2D6 Substrates (High risk with Inhibitors). Risk C: Monitor therapy

Colchicine: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Colchicine. Colchicine distribution into certain tissues (e.g., brain) may also be increased. Management: Colchicine is contraindicated in patients with impaired renal or hepatic function who are also receiving a p-glycoprotein inhibitor. In those with normal renal and hepatic function, reduce colchicine dose as directed. See full monograph for details. Risk D: Consider therapy modification

CycloSPORINE (Systemic): Carvedilol may increase the serum concentration of CycloSPORINE (Systemic). Risk D: Consider therapy modification

CYP2C9 Inhibitors (Moderate): May increase the serum concentration of Carvedilol. Specifically, concentrations of the S-carvedilol enantiomer may be increased. Risk C: Monitor therapy

CYP2D6 Inhibitors (Moderate): May decrease the metabolism of CYP2D6 Substrates (High risk with Inhibitors). Risk C: Monitor therapy

CYP2D6 Inhibitors (Strong): May decrease the metabolism of CYP2D6 Substrates (High risk with Inhibitors). Risk D: Consider therapy modification

Dabigatran Etexilate: P-glycoprotein/ABCB1 Inhibitors may increase serum concentrations of the active metabolite(s) of Dabigatran Etexilate. Risk C: Monitor therapy

Dacomitinib: May increase the serum concentration of CYP2D6 Substrates (High risk with Inhibitors). Management: Avoid concurrent use of dacomitinib with CYP2D6 subtrates that have a narrow therapeutic index. Risk D: Consider therapy modification

Darunavir: May increase the serum concentration of CYP2D6 Substrates (High risk with Inhibitors). Risk C: Monitor therapy

Dexmethylphenidate: May diminish the therapeutic effect of Antihypertensive Agents. Risk C: Monitor therapy

Diazoxide: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy

Digoxin: May enhance the bradycardic effect of Carvedilol. Carvedilol may increase the serum concentration of Digoxin. Risk C: Monitor therapy

Dipyridamole: May enhance the bradycardic effect of Beta-Blockers. Risk C: Monitor therapy

Disopyramide: May enhance the bradycardic effect of Beta-Blockers. Beta-Blockers may enhance the negative inotropic effect of Disopyramide. Risk C: Monitor therapy

DOXOrubicin (Conventional): P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of DOXOrubicin (Conventional). Management: Seek alternatives to P-glycoprotein inhibitors in patients treated with doxorubicin whenever possible. One U.S. manufacturer (Pfizer Inc.) recommends that these combinations be avoided. Risk D: Consider therapy modification

Dronedarone: May enhance the bradycardic effect of Beta-Blockers. Dronedarone may increase the serum concentration of Beta-Blockers. This likely applies only to those agents that are metabolized by CYP2D6. Management: Use lower initial beta-blocker doses; adequate tolerance of the combination, based on ECG findings, should be confirmed prior to any increase in beta-blocker dose. Risk D: Consider therapy modification

DULoxetine: Blood Pressure Lowering Agents may enhance the hypotensive effect of DULoxetine. Risk C: Monitor therapy

Edoxaban: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Edoxaban. Management: See full monograph for details. Reduced doses are recommended for patients receiving edoxaban for venous thromboembolism in combination with certain P-gp inhibitors. Similar dose adjustment is not recommended for edoxaban use in atrial fibrillation. Risk D: Consider therapy modification

EPINEPHrine (Nasal): Beta-Blockers (with Alpha-Blocking Properties) may diminish the therapeutic effect of EPINEPHrine (Nasal). Risk C: Monitor therapy

EPINEPHrine (Oral Inhalation): Beta-Blockers (with Alpha-Blocking Properties) may diminish the therapeutic effect of EPINEPHrine (Oral Inhalation). Risk C: Monitor therapy

Epinephrine (Racemic): Beta-Blockers (with Alpha-Blocking Properties) may diminish the therapeutic effect of Epinephrine (Racemic). Risk C: Monitor therapy

EPINEPHrine (Systemic): Beta-Blockers (with Alpha-Blocking Properties) may diminish the therapeutic effect of EPINEPHrine (Systemic). Risk C: Monitor therapy

Erdafitinib: May increase the serum concentration of P-glycoprotein/ABCB1 Substrates. Risk C: Monitor therapy

Ergot Derivatives: Beta-Blockers may enhance the vasoconstricting effect of Ergot Derivatives. Exceptions: Nicergoline. Risk D: Consider therapy modification

Everolimus: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Everolimus. Risk C: Monitor therapy

Fexinidazole [INT]: Bradycardia-Causing Agents may enhance the arrhythmogenic effect of Fexinidazole [INT]. Risk X: Avoid combination

Fingolimod: Beta-Blockers may enhance the bradycardic effect of Fingolimod. Management: Avoid the concomitant use of fingolimod and beta-blockers if possible. If coadministration is necessary, patients should have overnight continuous ECG monitoring conducted after the first dose of fingolimod. Monitor patients for bradycardia. Risk D: Consider therapy modification

Floctafenine: May enhance the adverse/toxic effect of Beta-Blockers. Risk X: Avoid combination

Grass Pollen Allergen Extract (5 Grass Extract): Beta-Blockers may enhance the adverse/toxic effect of Grass Pollen Allergen Extract (5 Grass Extract). More specifically, Beta-Blockers may inhibit the ability to effectively treat severe allergic reactions to Grass Pollen Allergen Extract (5 Grass Extract) with epinephrine. Some other effects of epinephrine may be unaffected or even enhanced (e.g., vasoconstriction) during treatment with Beta-Blockers. Risk D: Consider therapy modification

Herbs (Hypertensive Properties): May diminish the antihypertensive effect of Antihypertensive Agents. Risk C: Monitor therapy

Herbs (Hypotensive Properties): May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy

Hypotension-Associated Agents: Blood Pressure Lowering Agents may enhance the hypotensive effect of Hypotension-Associated Agents. Risk C: Monitor therapy

Imatinib: May increase the serum concentration of CYP2D6 Substrates (High risk with Inhibitors). Risk C: Monitor therapy

Insulins: Beta-Blockers may enhance the hypoglycemic effect of Insulins. Risk C: Monitor therapy

Ivabradine: Bradycardia-Causing Agents may enhance the bradycardic effect of Ivabradine. Risk C: Monitor therapy

Lacosamide: Bradycardia-Causing Agents may enhance the AV-blocking effect of Lacosamide. Risk C: Monitor therapy

Larotrectinib: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Larotrectinib. Risk C: Monitor therapy

Lasmiditan: May increase the serum concentration of P-glycoprotein/ABCB1 Substrates. Risk X: Avoid combination

Lefamulin: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Lefamulin. Management: Avoid concomitant use of lefamulin tablets with P-glycoprotein/ABCB1 inhibitors. If concomitant use is required, monitor for lefamulin adverse effects. Risk D: Consider therapy modification

Levodopa-Containing Products: Blood Pressure Lowering Agents may enhance the hypotensive effect of Levodopa-Containing Products. Risk C: Monitor therapy

Lidocaine (Systemic): Beta-Blockers may increase the serum concentration of Lidocaine (Systemic). Risk C: Monitor therapy

Lidocaine (Topical): Beta-Blockers may increase the serum concentration of Lidocaine (Topical). Risk C: Monitor therapy

Lormetazepam: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy

Lumacaftor and Ivacaftor: May decrease the serum concentration of P-glycoprotein/ABCB1 Substrates. Lumacaftor and Ivacaftor may increase the serum concentration of P-glycoprotein/ABCB1 Substrates. Risk C: Monitor therapy

Lumefantrine: May increase the serum concentration of CYP2D6 Substrates (High risk with Inhibitors). Risk C: Monitor therapy

Mepivacaine: Beta-Blockers may increase the serum concentration of Mepivacaine. Risk C: Monitor therapy

Methacholine: Beta-Blockers may enhance the adverse/toxic effect of Methacholine. Risk C: Monitor therapy

Methoxyflurane: May enhance the hypotensive effect of Beta-Blockers. Risk C: Monitor therapy

Methylphenidate: May diminish the antihypertensive effect of Antihypertensive Agents. Risk C: Monitor therapy

Midodrine: May enhance the bradycardic effect of Bradycardia-Causing Agents. Risk C: Monitor therapy

Molsidomine: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy

Naftopidil: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy

Naldemedine: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Naldemedine. Risk C: Monitor therapy

Naloxegol: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Naloxegol. Risk C: Monitor therapy

NiCARdipine: May enhance the hypotensive effect of Carvedilol. NiCARdipine may precipitate signs of heart failure in susceptible patients on Carvedilol NiCARdipine may increase the serum concentration of Carvedilol. Risk C: Monitor therapy

Nicergoline: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy

Nicorandil: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy

NIFEdipine: May enhance the hypotensive effect of Beta-Blockers. NIFEdipine may enhance the negative inotropic effect of Beta-Blockers. Risk C: Monitor therapy

Nitroprusside: Blood Pressure Lowering Agents may enhance the hypotensive effect of Nitroprusside. Risk C: Monitor therapy

Nonsteroidal Anti-Inflammatory Agents: May diminish the antihypertensive effect of Beta-Blockers. Risk C: Monitor therapy

Obinutuzumab: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Management: Consider temporarily withholding blood pressure lowering medications beginning 12 hours prior to obinutuzumab infusion and continuing until 1 hour after the end of the infusion. Risk D: Consider therapy modification

Opioids (Anilidopiperidine): May enhance the bradycardic effect of Beta-Blockers. Opioids (Anilidopiperidine) may enhance the hypotensive effect of Beta-Blockers. Risk C: Monitor therapy

Panobinostat: May increase the serum concentration of CYP2D6 Substrates (High risk with Inhibitors). Risk C: Monitor therapy

PAZOPanib: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of PAZOPanib. Risk X: Avoid combination

Peginterferon Alfa-2b: May decrease the serum concentration of CYP2D6 Substrates (High risk with Inhibitors). Peginterferon Alfa-2b may increase the serum concentration of CYP2D6 Substrates (High risk with Inhibitors). Risk C: Monitor therapy

Pentoxifylline: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy

Perhexiline: CYP2D6 Substrates (High risk with Inhibitors) may increase the serum concentration of Perhexiline. Perhexiline may increase the serum concentration of CYP2D6 Substrates (High risk with Inhibitors). Risk C: Monitor therapy

P-glycoprotein/ABCB1 Inducers: May decrease the serum concentration of P-glycoprotein/ABCB1 Substrates. P-glycoprotein inducers may also further limit the distribution of p-glycoprotein substrates to specific cells/tissues/organs where p-glycoprotein is present in large amounts (e.g., brain, T-lymphocytes, testes, etc.). Risk C: Monitor therapy

P-glycoprotein/ABCB1 Inhibitors: May increase the serum concentration of P-glycoprotein/ABCB1 Substrates. P-glycoprotein inhibitors may also enhance the distribution of p-glycoprotein substrates to specific cells/tissues/organs where p-glycoprotein is present in large amounts (e.g., brain, T-lymphocytes, testes, etc.). Risk C: Monitor therapy

P-glycoprotein/ABCB1 Substrates: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of P-glycoprotein/ABCB1 Substrates. P-glycoprotein inhibitors may also enhance the distribution of p-glycoprotein substrates to specific cells/tissues/organs where p-glycoprotein is present in large amounts (e.g., brain, T-lymphocytes, testes, etc.). Exceptions: Loperamide. Risk C: Monitor therapy

Pholcodine: Blood Pressure Lowering Agents may enhance the hypotensive effect of Pholcodine. Risk C: Monitor therapy

Phosphodiesterase 5 Inhibitors: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy

Propafenone: May increase the serum concentration of Beta-Blockers. Propafenone possesses some independent beta blocking activity. Risk C: Monitor therapy

Prostacyclin Analogues: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy

Prucalopride: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Prucalopride. Risk C: Monitor therapy

Quinagolide: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy

QuiNINE: May increase the serum concentration of CYP2D6 Substrates (High risk with Inhibitors). Risk C: Monitor therapy

Ranolazine: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Ranolazine. Risk C: Monitor therapy

Ranolazine: May increase the serum concentration of P-glycoprotein/ABCB1 Substrates. Risk C: Monitor therapy

Regorafenib: May enhance the bradycardic effect of Beta-Blockers. Risk C: Monitor therapy

Reserpine: May enhance the hypotensive effect of Beta-Blockers. Risk C: Monitor therapy

Rifamycin Derivatives: May decrease the serum concentration of Beta-Blockers. Exceptions: Rifabutin. Risk C: Monitor therapy

RifAXIMin: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of RifAXIMin. Risk C: Monitor therapy

Rivastigmine: May enhance the bradycardic effect of Beta-Blockers. Risk X: Avoid combination

Ruxolitinib: May enhance the bradycardic effect of Bradycardia-Causing Agents. Management: Ruxolitinib Canadian product labeling recommends avoiding use with bradycardia-causing agents to the extent possible. Risk C: Monitor therapy

Selective Serotonin Reuptake Inhibitors: May increase the serum concentration of Beta-Blockers. Exceptions: Citalopram; Escitalopram; FluvoxaMINE. Risk C: Monitor therapy

Silodosin: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Silodosin. Risk C: Monitor therapy

Siponimod: Bradycardia-Causing Agents may enhance the bradycardic effect of Siponimod. Management: Avoid coadministration of siponimod with drugs that may cause bradycardia. Risk D: Consider therapy modification

Sulfonylureas: Beta-Blockers may enhance the hypoglycemic effect of Sulfonylureas. Cardioselective beta-blockers (eg, acebutolol, atenolol, metoprolol, and penbutolol) may be safer than nonselective beta-blockers. All beta-blockers appear to mask tachycardia as an initial symptom of hypoglycemia. Ophthalmic beta-blockers are probably associated with lower risk than systemic agents. Risk C: Monitor therapy

Talazoparib: Carvedilol may increase the serum concentration of Talazoparib. Management: If concurrent use cannot be avoided, reduce talazoparib dose to 0.75 mg once daily. After a period of 3 to 5 times the half-life of carvedilol, increase the talazoparib dose to the dose used before initiation of carvedilol. Risk D: Consider therapy modification

Tegaserod: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Tegaserod. Risk C: Monitor therapy

Terlipressin: May enhance the bradycardic effect of Bradycardia-Causing Agents. Risk C: Monitor therapy

Theophylline Derivatives: Beta-Blockers (Nonselective) may diminish the bronchodilatory effect of Theophylline Derivatives. Risk C: Monitor therapy

Tofacitinib: May enhance the bradycardic effect of Bradycardia-Causing Agents. Risk C: Monitor therapy

Topotecan: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Topotecan. Risk X: Avoid combination

Ubrogepant: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Ubrogepant. Management: Use an initial ubrogepant dose of 50 mg and second dose (if needed) of 50 mg when used with a P-gp inhibitor. Risk D: Consider therapy modification

Venetoclax: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Venetoclax. Management: Consider a venetoclax dose reduction by at least 50% in patients requiring concomitant treatment with P-glycoprotein (P-gp) inhibitors. Risk D: Consider therapy modification

VinCRIStine (Liposomal): P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of VinCRIStine (Liposomal). Risk X: Avoid combination

Yohimbine: May diminish the antihypertensive effect of Antihypertensive Agents. Risk C: Monitor therapy

Food Interactions

Food decreases rate but not extent of absorption. Management: Administration with food minimizes risks of orthostatic hypotension.

Test Interactions

May lead to false-positive aldosterone/renin ratio (ARR) (Funder 2016).

Genes of Interest

• Angiotensin I Converting Enzyme 1
• Beta-1 Receptor
• Beta-2 Receptor
• Carvedilol
• G Protein-Coupled Receptor Kinase 5
• P-Glycoprotein

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; blood glucose in diabetics; in patients with increased risk for developing renal dysfunction, monitor during dosage titration.

Hypertension: The 2017 Guideline for the Prevention, Detection, Evaluation, and Management of High Blood Pressure in Adults (ACC/AHA [Whelton 2018]):

Confirmed hypertension and known CVD or 10-year ASCVD risk ≥10%: Target blood pressure <130/80 mm Hg is recommended.

Confirmed hypertension without markers of increased ASCVD risk: Target blood pressure <130/80 mm Hg may be reasonable.

Advanced Practitioners Physical Assessment/Monitoring

Blood pressure and heart rate should be assessed prior to and following first dose and any change in dose. Caution patients with diabetes to monitor glucose levels closely (beta-blockers may alter glucose tolerance).

Nursing Physical Assessment/Monitoring

Take blood pressure and heart rate prior to and following first dose and with any change in dosage. Caution patients with diabetes to monitor glucose levels closely (beta-blockers may alter glucose tolerance).

Dosage Forms: US

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Capsule Extended Release 24 Hour, Oral, as phosphate:

Coreg CR: 10 mg, 20 mg, 40 mg, 80 mg

Generic: 10 mg, 20 mg, 40 mg, 80 mg

Tablet, Oral:

Coreg: 3.125 mg, 6.25 mg, 12.5 mg, 25 mg

Generic: 3.125 mg, 6.25 mg, 12.5 mg, 25 mg

Dosage Forms: Canada

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Tablet, Oral:

Generic: 3.125 mg, 6.25 mg, 12.5 mg, 25 mg

Anatomic Therapeutic Chemical (ATC) Classification

• C07AG02

Generic Available (US)

Yes

Pricing: US

Capsule ER 24 Hour Therapy Pack (Carvedilol Phosphate ER Oral)

10 mg (per each): $9.91 - $10.32

20 mg (per each): $9.91 - $10.32

40 mg (per each): $9.91 - $10.32

80 mg (per each): $9.91 - $10.32

Capsule ER 24 Hour Therapy Pack (Coreg CR Oral)

10 mg (per each): $11.01

20 mg (per each): $11.01

40 mg (per each): $11.01

80 mg (per each): $11.01

Tablets (Carvedilol Oral)

3.125 mg (per each): $0.03 - $2.14

6.25 mg (per each): $0.03 - $2.14

12.5 mg (per each): $0.03 - $2.14

25 mg (per each): $0.03 - $2.14

Tablets (Coreg Oral)

3.125 mg (per each): $5.93

6.25 mg (per each): $5.93

12.5 mg (per each): $5.93

25 mg (per each): $5.93

Disclaimer: A representative AWP (Average Wholesale Price) price or price range is provided as reference price only. A range is provided when more than one manufacturer's AWP price is available and uses the low and high price reported by the manufacturers to determine the range. The pricing data should be used for benchmarking purposes only, and as such should not be used alone to set or adjudicate any prices for reimbursement or purchasing functions or considered to be an exact price for a single product and/or manufacturer. Medi-Span expressly disclaims all warranties of any kind or nature, whether express or implied, and assumes no liability with respect to accuracy of price or price range data published in its solutions. In no event shall Medi-Span be liable for special, indirect, incidental, or consequential damages arising from use of price or price range data. Pricing data is updated monthly.

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 atrial pressure (RAP).

Pharmacodynamics/Kinetics

Onset of action: Antihypertensive effect: Alpha-blockade: Within 30 minutes; Beta-blockade: Within 1 hour

Peak antihypertensive effect: ~1 to 2 hours

Absorption: Oral: Rapid and extensive, but with large first pass effect; first pass effect is stereoselective with R(+) enantiomer achieving plasma concentrations 2 to 3 times higher than S(-) enantiomer; delayed with food

Distribution: V_d: 115 L; distributes into extravascular tissues

Protein binding: >98%, primarily to albumin

Metabolism: Extensively (98%) hepatic, via CYP2C9, 2D6, 3A4, 2C19, 1A2, and 2E1 (2% excreted unchanged); metabolized predominantly by aromatic ring oxidation and glucuronidation; oxidative metabolites undergo conjugation via glucuronidation and sulfation; three active metabolites (4-hydroxyphenyl metabolite is 13 times more potent than parent drug for beta-blockade, however, active metabolites achieve plasma concentrations of only 1/10 of those for carvedilol); first-pass effect; plasma concentrations in the elderly and those with cirrhotic liver disease are 50% and 4 to 7 times higher, respectively. Metabolism is subject to genetic polymorphism; CYP2D6 poor metabolizers have a 2- to 3-fold higher plasma concentration of the R(+) enantiomer and a 20% to 25% increase in the S(-) enantiomer compared to extensive metabolizers.

Bioavailability: Immediate release: ~25% to 35% (due to significant first-pass metabolism); Extended release: ~85% of immediate release; high-fat meal increases AUC and C_max ~20%; bioavailability is increased in patients with CHF

Half-life elimination:

Infants and Children 6 weeks to 3.5 years (n=8): 2.2 hours (Läer 2002)

Children and Adolescents 5.5 to 19 years (n=7): 3.6 hours (Läer 2002)

Adults 7 to 10 hours; some have reported lower values: Adults 24 to 37 years (n=9): 5.2 hours (Läer 2002)

R(+)-carvedilol: 5 to 9 hours

S(-)-carvedilol: 7 to 11 hours

Time to peak, plasma: Extended release: ~5 hours

Excretion: Primarily feces; urine (<2%, unchanged)

Pharmacodynamics/Kinetics: Additional Considerations

Renal function impairment: Plasma concentrations may be higher (40% to 50% in moderate to severe renal impairment).

Hepatic function impairment: Severe hepatic impairment (cirrhosis) patients have a 4- to 7-fold increase in concentrations.

Geriatric: Plasma levels are about 50% higher.

Heart failure: AUC and C_max increased up to 100%.

Local Anesthetic/Vasoconstrictor Precautions

Carvedilol is a nonselective beta-blocker, but also has alpha-adrenergic blocking actions. No intrinsic sympathomimetic activity has been documented for carvedilol. Unlike other nonselective beta-blockers such as propranolol, with which epinephrine has interacted with to result in initial hypertensive episode followed by tachycardia, any interaction with carvedilol and vasoconstrictor to result in hypertensive episode would not be expected. There is no information available to require special precautions.

Effects on Dental Treatment

Key adverse event(s) related to dental treatment: Frequent occurrence of orthostatic hypotension has been reported (use caution with sudden changes in position during and after dental treatment). Infrequent occurrence of periodontitis and xerostomia (normal salivary flow resumes upon discontinuation) have been reported. Rare occurrence of erythema multiforme and Stevens-Johnson syndrome have also been reported.

Note: 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.

Effects on Bleeding

No information available to require special precautions

Related Information

• Beta-Blockers
• Inhibitors and Inducers of P-glycoprotein
• Oral Medications That Should Not Be Crushed or Altered

FDA Approval Date

September 14, 1995

References

Alade SL, Brown RE, Paquet A. Polysorbate 80 and E-Ferol toxicity. Pediatrics. 1986;77(4):593-597.[PubMed 3960626]

American College of Obstetricians and Gynecologists (ACOG). ACOG practice bulletin no. 203: chronic hypertension in pregnancy. Obstet Gynecol. 2019;133(1):e26-e50.[PubMed 30575676]

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Brand Names: International

Alvelol (KR); Arlec (TR); Artist (JP); Avernol (ET, MT, TR); Avidol (BD); Betacard (PH); Betaplex (CL); Bicol (TR); Blorec (ID); Cadil (HR); Caraca-12.5 (ZW); Caraten (TH); Carbloxal (ID); Carca-3 (ZW); Carca-6 (ZW); Cardilol (EG, JO, PH); Cardine (SY); Cardiol (FI, MY); Cardiostad (UA); Cardipres (PH); Cardivas (IN, VN); Cardoz (LK, TZ); Cargen (KR); Carloc (ZA); Carlov (PK); Carsantin (VN); Carved (BD); Carvedexxon (IL); Carvedil (EC); Carvedlol (KR); Carvelmed (VN); Carvelol (KR, NZ); Carvena (EG); Carvepen (SG); Carveta (KR); Carveta XR (PH); Carvetop (PH); Carvetrend (UA); Carvidex (MT, TR, UA); Carvidil (RU); Carvidol (CN, ET, JO, SA); Carvil (LK); Carvilar (DO); Carvo (TW); Cavel (MY); Coreg (BB, BM, BR, BS, BZ, GY, JM, SR, TT); Coritensil (AR); Coronis (ET); Coropres (ES); Corubin (EC); Coryol (CO, CR, GT, NI, PA, RO, SV); Dicarz (AU); Dilabloc (PH); Dilapress (LK); Dilatrend (AE, AR, AT, AU, BF, BG, BH, BJ, CH, CI, CL, CN, CY, CZ, DE, EC, EE, EG, ET, GH, GM, GN, GR, HK, HR, HU, IT, JO, KE, KR, KW, LB, LR, MA, ML, MR, MU, MW, MX, MY, NE, NG, NO, NZ, PE, PH, PL, PY, QA, RO, SA, SC, SD, SG, SL, SN, TH, TN, TR, TW, TZ, UG, UY, VE, VN, ZM, ZW); Dilatrend SR (KR); Dilbloc (PT); Dilgard (BD); Dimitone (DK); Duobloc (PH); Epicarve (EG); Eucardic (GB, NL); Gladycor (MT); Glovedol (PH); Ictus (BR); Karter (KR); Karvedil (BD); Karvex (EG); Karvil (ET, PH, ZW); Kredex (AU, BE, FR, LU, SE); Longcardio (TW); Normotride (ES); Querto (DE); Riacavilol (SA); Scodilol (VN); Syntrend (TW); Talliton (BB, BM, BS, BZ, GY, HK, JM, SR, TT, UA); Tocarlol (TH); Udilol (TW); V-Bloc (ID); Vacodil (MY); Vasodilren (KR); Vedilol (AU, KR); Volirop (AU); Xetin (PY); Xicard (PH); Ziclar (PY)

Last Updated 3/12/20