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Carvedilol

Pronunciation

Pronunciation

(KAR ve dil ole)

Dosage Forms

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

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

Brand Names: U.S.

  • Coreg
  • Coreg CR

Pharmacologic Category

  • Antihypertensive
  • Beta-Blocker With Alpha-Blocking Activity

Pharmacology

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).

Absorption

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

Vd: 115 L; distributes into extravascular tissues

Metabolism

Extensively (98%) hepatic, via CYP2D6, 2C9, 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.

Excretion

Primarily feces; urine (<2%, unchanged)

Onset of Action

Antihypertensive effect: Alpha-blockade: Within 30 minutes; Beta-blockade: Within 1 hour. Peak antihypertensive effect: ~1 to 2 hours

Time to Peak

Extended release: ~5 hours

Half-Life Elimination

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

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

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

R(+)-carvedilol: 5 to 9 hours

S(-)-carvedilol: 7 to 11 hours

Protein Binding

>98%, primarily to albumin

Special Populations: Renal Function Impairment

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

Special Populations: Hepatic Function Impairment

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

Special Populations: Elderly

Plasma levels are about 50% higher

Special Populations Note

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

Use: Labeled Indications

Hypertension: Management of hypertension.

The 2014 guideline for the management of high blood pressure in adults (Eighth Joint National Committee [JNC 8]) recommends initiation of pharmacologic treatment to lower blood pressure for the following patients (JNC 8 [James, 2013]):

• Patients ≥60 years of age, with systolic blood pressure (SBP) ≥150 mm Hg or diastolic blood pressure (DBP) ≥90 mm Hg. Goal of therapy is SBP <150 mm Hg and DBP <90 mm Hg.

• Patients <60 years of age, with SBP ≥140 mm Hg or DBP ≥90 mm Hg. Goal of therapy is SBP <140 mm Hg and DBP <90 mm Hg.

• Patients ≥18 years of age with diabetes, with SBP ≥140 mm Hg or DBP ≥90 mm Hg. Goal of therapy is SBP <140 mm Hg and DBP <90 mm Hg.

• Patients ≥18 years of age with chronic kidney disease (CKD), with SBP ≥140 mm Hg or DBP ≥90 mm Hg. Goal of therapy is SBP <140 mm Hg and DBP <90 mm Hg.

In patients with CKD, regardless of race or diabetes status, the use of an ACE inhibitor (ACEI) or angiotensin receptor blocker (ARB) as initial therapy is recommended to improve kidney outcomes. In the general non-black population (without CKD) including those with diabetes, initial antihypertensive treatment should consist of a thiazide-type diuretic, calcium channel blocker, ACEI, or ARB. In the general black population (without CKD) including those with diabetes, initial antihypertensive treatment should consist of a thiazide-type diuretic or a calcium channel blocker instead of an ACEI or ARB.

Heart failure: Mild to severe chronic heart failure of ischemic or cardiomyopathic origin (usually in addition to standard therapy [eg, diuretics, ACE inhibitors]).

The ACCF/AHA 2013 heart failure guidelines recommend the use of 1 of the 3 beta blockers (ie, bisoprolol, carvedilol, or extended-release metoprolol succinate) for all patients with recent or remote history of MI or ACS and reduced ejection fraction (rEF) to reduce mortality, for all patients with rEF to prevent symptomatic HF (even if no history of MI), and for all patients with current or prior symptoms of HF with reduced ejection fraction (HFrEF), unless contraindicated, to reduce morbidity and mortality (Yancy, 2013).

Left ventricular dysfunction following myocardial infarction (MI): Left ventricular dysfunction following MI (clinically stable with LVEF ≤40%)

Use: Unlabeled

Angina pectoris, atrial fibrillation (rate control)

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.

Dosing: Adult

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

Hypertension: Oral:

Immediate release: 6.25 mg twice daily; if tolerated, dose should be maintained for 1 to 2 weeks, then increased to 12.5 mg twice daily. If necessary, dosage may be increased to a maximum of 25 mg twice daily after 1 to 2 weeks. Usual dosage range (ASH/ISH [Weber, 2014]): 6.25 to 25 mg twice daily.

Extended release: Initial: 20 mg once daily, if tolerated, dose should be maintained for 1 to 2 weeks then increased to 40 mg once daily if necessary; if this dose is tolerated, maintain for 1 to 2 weeks then, if necessary, increase to 80 mg once daily; maximum dose: 80 mg once daily

Heart failure: Oral: Note: Initiate only in stable patients or hospitalized patients after volume status has been optimized and IV diuretics, vasodilators, and inotropic agents have all been successfully discontinued. Caution should be used when initiating in patients who required inotropes during their hospital course. Increase dose gradually and monitor for congestive signs and symptoms of HF making every effort to achieve target dose shown to be effective (HFSA [Lindenfeld, 2010]; Packer, 1996; ACCF/AHA [Yancy, 2013])

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

Maximum recommended dose:

Mild-to-moderate heart failure:

<85 kg: 25 mg twice daily

>85 kg: 50 mg twice daily

Severe heart failure: 25 mg twice daily (Packer, 2001)

Extended release: Initial: 10 mg once daily for 2 weeks; if the dose is tolerated, increase dose to 20 mg, 40 mg, and 80 mg over successive intervals of at least 2 weeks. Maintain on lower dose if higher dose is not tolerated. Note: The 2013 ACCF/AHA heart failure guidelines recommend a maximum dose of 80 mg once daily (Yancy, 2013).

Left ventricular dysfunction following MI: Oral: Note: Should be initiated only after patient is hemodynamically stable and fluid retention has been minimized.

Immediate release: Initial 3.125 to 6.25 mg twice daily; increase dosage incrementally (ie, from 6.25 to 12.5 mg twice daily) at intervals of 3 to 10 days, based on tolerance, to a target dose of 25 mg twice daily. Note: The 2013 ACCF/AHA heart failure guidelines recommend a maximum dose of 50 mg twice daily (Yancy, 2013].

Extended release: Initial: Extended release: Initial: 10 to 20 mg once daily; increase dosage incrementally at intervals of 3 to 10 days, based on tolerance, to a target dose of 80 mg once daily.

Angina pectoris (off-label use): Oral: Immediate release: 25 to 50 mg twice daily

Atrial fibrillation (rate control) (off-label use): Usual maintenance dose: 3.125 to 25 mg twice daily (AHA/ACC/HRS [January, 2014]). In patients with heart failure, the initial dose of 3.125 mg twice daily may be increased at 2-week intervals to a target dose of 25 mg twice daily (50 mg twice daily for patients weighing >85 kg) (Khand, 2003)

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

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: Geriatric

Refer to adult dosing. In the management of hypertension, consider lower initial doses and titrate to response (Aronow, 2011).

Dosing: Renal Impairment

No dosage adjustment necessary; not significantly cleared by hemodialysis

Dosing: Hepatic Impairment

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

Severe impairment: Use is contraindicated.

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.

Administration

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.

Dietary Considerations

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

Storage

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.

Drug Interactions

Abiraterone Acetate: May increase the serum concentration of CYP2D6 Substrates. 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. Consider therapy modification

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

Afatinib: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Afatinib. Management: Per US labeling: reduce afatinib by 10mg if not tolerated. Per Canadian labeling: avoid combination if possible; if used, administer the P-gp inhibitor simultaneously with or after the dose of afatinib. Consider therapy modification

Ajmaline: May increase the serum concentration of CYP2D6 Substrates. Monitor therapy

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

Alpha-/Beta-Agonists (Direct-Acting): Beta-Blockers may enhance the vasopressor effect of Alpha-/Beta-Agonists (Direct-Acting). Epinephrine used as a local anesthetic for dental procedures will not likely cause clinically relevant problems. Some beta-adrenoceptor mediated effects of Alpha-/Beta-Agonists (Direct-Acting), including anti-anaphylactic effects of epinephrine, may be diminished by Beta-Blockers. Management: Cardioselective beta-blockers and lower doses of epinephrine may confer a more limited risk. Patients who may require acute subcutaneous epinephrine (e.g., bee sting kits) should probably avoid beta blockers. Exceptions: Dipivefrin. Consider therapy modification

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. 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. 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. Consider therapy modification

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

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

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

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

Asunaprevir: May increase the serum concentration of CYP2D6 Substrates. Consider therapy modification

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

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

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

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

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

Bretylium: May enhance the bradycardic effect of Bradycardia-Causing Agents. Bretylium may also enhance atrioventricular (AV) blockade in patients receiving AV blocking agents. Monitor therapy

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

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

Cardiac Glycosides: Beta-Blockers may enhance the bradycardic effect of Cardiac Glycosides. 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. Avoid combination

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. Management: Administer these agents in combination with caution, and monitor for conduction disturbances. Avoid methacholine with any beta blocker due to the potential for additive bronchoconstriction. Monitor therapy

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

Cobicistat: May increase the serum concentration of CYP2D6 Substrates. 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. Consider therapy modification

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

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

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

CYP2D6 Inhibitors (Moderate): May decrease the metabolism of CYP2D6 Substrates. Monitor therapy

CYP2D6 Inhibitors (Strong): May decrease the metabolism of CYP2D6 Substrates. Consider therapy modification

Dabigatran Etexilate: P-glycoprotein/ABCB1 Inhibitors may increase serum concentrations of the active metabolite(s) of Dabigatran Etexilate. Management: Dabigatran dose reductions may be needed. Specific recommendations vary considerably according to US vs Canadian labeling, specific P-gp inhibitor, renal function, and indication for dabigatran treatment. Refer to full monograph or dabigatran labeling. Consider therapy modification

Darunavir: May increase the serum concentration of CYP2D6 Substrates. Monitor therapy

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

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

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

Disopyramide: May enhance the bradycardic effect of Beta-Blockers. Beta-Blockers may enhance the negative inotropic effect of Disopyramide. 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. 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. Consider therapy modification

DULoxetine: Blood Pressure Lowering Agents may enhance the hypotensive effect of DULoxetine. 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 inhibitors. Similar dose adjustment is not recommended for edoxaban use in atrial fibrillation. Consider therapy modification

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

Everolimus: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Everolimus. Management: Everolimus dose reductions are required for patients being treated for subependymal giant cell astrocytoma or renal cell carcinoma. See prescribing information for specific dose adjustment and monitoring recommendations. Consider therapy modification

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. Consider therapy modification

Floctafenine: May enhance the adverse/toxic effect of Beta-Blockers. 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. Consider therapy modification

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

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

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

Imatinib: May increase the serum concentration of CYP2D6 Substrates. Monitor therapy

Insulin: Beta-Blockers may enhance the hypoglycemic effect of Insulin. Monitor therapy

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

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

Levodopa: Blood Pressure Lowering Agents may enhance the hypotensive effect of Levodopa. Monitor therapy

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

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

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

Lumefantrine: May increase the serum concentration of CYP2D6 Substrates. Monitor therapy

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

Methacholine: Beta-Blockers may enhance the adverse/toxic effect of Methacholine. Avoid combination

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

Midodrine: Beta-Blockers may enhance the bradycardic effect of Midodrine. Monitor therapy

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

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

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

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

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

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

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

Nonsteroidal Anti-Inflammatory Agents: May diminish the antihypertensive effect of Beta-Blockers. 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. Consider therapy modification

Panobinostat: May increase the serum concentration of CYP2D6 Substrates. Management: Avoid concurrent use of sensitive CYP2D6 substrates when possible, particularly those substrates with a narrow therapeutic index. Consider therapy modification

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

Peginterferon Alfa-2b: May decrease the serum concentration of CYP2D6 Substrates. Peginterferon Alfa-2b may increase the serum concentration of CYP2D6 Substrates. Monitor therapy

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

Perhexiline: CYP2D6 Substrates may increase the serum concentration of Perhexiline. Perhexiline may increase the serum concentration of CYP2D6 Substrates. 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.). 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.). 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.). Monitor therapy

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

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

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

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

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

QuiNINE: May increase the serum concentration of CYP2D6 Substrates. Monitor therapy

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

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

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

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

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

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

Rivastigmine: May enhance the bradycardic effect of Beta-Blockers. 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. Monitor therapy

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

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

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. Monitor therapy

Theophylline Derivatives: Beta-Blockers (Nonselective) may diminish the bronchodilatory effect of Theophylline Derivatives. Consider therapy modification

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

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

Venetoclax: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Venetoclax. Management: Reduce the venetoclax dose by at least 50% in patients requiring these combinations. Consider therapy modification

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

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

Adverse Reactions

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

>10%:

Cardiovascular: Hypotension (9% to 20%)

Central nervous system: Dizziness (2% to 32%), fatigue (4% to 24%)

Endocrine & metabolic: Hyperglycemia (5% to 12%)

Gastrointestinal: Diarrhea (1% to 12%), weight gain (10% to 12%)

Neuromuscular & skeletal: Weakness (7% to 11%)

1% to 10%:

Cardiovascular: Bradycardia (2% to 10%), syncope (3% to 8%), peripheral edema (1% to 7%), generalized edema (5% to 6%), angina (1% to 6%), dependent edema (≤4%), AV block, cerebrovascular accident, hypertension, hyper-/hypovolemia, orthostatic hypotension, palpitation

Central nervous system: Headache (5% to 8%), depression, fever, hypoesthesia, hypotonia, insomnia, malaise, somnolence, vertigo

Endocrine & metabolic: Hypercholesterolemia (1% to 4%), hypertriglyceridemia (1%), diabetes mellitus, gout, hyperkalemia, hyperuricemia, hypoglycemia, hyponatremia

Gastrointestinal: Nausea (2% to 9%), vomiting (1% to 6%), abdominal pain, melena, periodontitis, weight loss

Genitourinary: Impotence

Hematologic: Anemia, prothrombin decreased, purpura, thrombocytopenia

Hepatic: Alkaline phosphatase increased (1% to 3%), GGT increased, transaminases increased

Neuromuscular & skeletal: Back pain (2% to 7%), arthralgia (1% to 6%), arthritis, muscle cramps, paresthesia

Ocular: Blurred vision (1% to 5%)

Renal: BUN increased (≤6%), nonprotein nitrogen increased (6%), albuminuria, creatinine increased, glycosuria, hematuria, renal insufficiency

Respiratory: Cough (5% to 8%), nasopharyngitis (4%), rales (4%), dyspnea (>3%), pulmonary edema (>3%), rhinitis (2%), nasal congestion (1%), sinus congestion (1%)

Miscellaneous: Injury (3% to 6%), allergy, flu-like syndrome, sudden death

<1% (Limited to important or life-threatening): Anaphylactoid reaction, alopecia, angioedema, aplastic anemia, amnesia, asthma, bronchospasm, bundle branch block, cholestatic jaundice, concentration decreased, diaphoresis, erythema multiforme, exfoliative dermatitis, GI hemorrhage, HDL decreased, hearing decreased, hyperbilirubinemia, hypersensitivity reaction, hypokalemia, hypokinesia, interstitial pneumonitis, leukopenia, libido decreased, migraine, myocardial ischemia, nervousness, neuralgia, nightmares, pancytopenia, paresis, peripheral ischemia, photosensitivity, pruritus, rash (erythematous, maculopapular, and psoriaform), respiratory alkalosis, seizure, Stevens-Johnson syndrome, tachycardia, tinnitus, toxic epidermal necrolysis, urinary incontinence, urticaria, xerostomia

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 Prinzmetal variant 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 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.

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.

Pregnancy Risk Factor

C

Pregnancy Considerations

Adverse events have been observed in animal reproduction studies. Adverse events, such as fetal/neonatal bradycardia, hypoglycemia, and reduced birth weight, have been observed following in utero exposure to beta-blockers as a class. Adequate facilities for monitoring infants at birth is generally recommended.

Untreated chronic maternal hypertension and preeclampsia are also associated with adverse events in the fetus, infant, and mother (ACOG 2015; Magee 2014). Although beta-blockers may be used when treatment of hypertension or heart failure in pregnancy is indicated, agents other than carvedilol are preferred (ACOG 2013; ESC [Regitz-Zagrosek 2011]; Magee 2014).

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Patient may experience loss of strength and energy, diarrhea, headache, nausea, vomiting, weight gain, joint pain, or contact lens discomfort. Have patient report immediately to prescriber signs of heart problems (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, urinary retention, change in amount of urine passed, angina, bradycardia, or vision changes (HCAHPS).

• Educate patient about signs of a significant reaction (eg, 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. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for health care professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience, and judgment in diagnosing, treating, and advising patients.

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