Bisoprolol (Monograph)

Brand name: Zebeta
Drug class: alpha-Adrenergic Blocking Agents
VA class: CV100

Medically reviewed by Drugs.com on Apr 10, 2024. Written by ASHP.

Introduction

β₁-selective adrenergic blocking agent (β-blocker).⁶⁰⁰ ^a

Uses for Bisoprolol

Hypertension

Management of hypertension as monotherapy or in combination with other classes of antihypertensive agents.¹ ² ³ ⁴ ⁵ ⁶ ⁷ ¹²⁰⁰

β-Blockers generally not preferred for first-line therapy of hypertension according to current evidence-based hypertension guidelines, but may be considered in patients who have a compelling indication (e.g., prior MI, ischemic heart disease, heart failure) for their use or as add-on therapy in those who do not respond adequately to the preferred drug classes (ACE inhibitors, angiotensin II receptor antagonists, calcium-channel blockers, or thiazide diuretics).⁶⁷ ⁵⁰¹ ⁵⁰² ⁵⁰³ ⁵⁰⁴ ⁵¹⁵ ⁵²³ ⁵²⁴ ⁵²⁷ ⁸⁰⁰ ¹²⁰⁰ Bisoprolol is one of several β-blockers (including carvedilol, metoprolol succinate, metoprolol tartrate, nadolol, propranolol, and timolol) recommended by a 2017 ACC/AHA multidisciplinary hypertension guideline as first-line therapy for hypertension in patients with stable ischemic heart disease/angina.¹²⁰⁰

Individualize choice of therapy; consider patient characteristics (e.g., age, ethnicity/race, comorbidities, cardiovascular risk) as well as drug-related factors (e.g., ease of administration, availability, adverse effects, cost).⁵⁰¹ ⁵⁰² ⁵⁰³ ⁵⁰⁴ ⁵¹⁵ ¹²⁰⁰ ¹²⁰¹

The 2017 ACC/AHA hypertension guideline classifies BP in adults into 4 categories: normal, elevated, stage 1 hypertension, and stage 2 hypertension.¹²⁰⁰ (See Table 1.)

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

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

Table 1. ACC/AHA BP Classification in Adults1200
Category	SBP (mm Hg)		DBP (mm Hg)
Normal	<120	and	<80
Elevated	120–129	and	<80
Hypertension, Stage 1	130–139	or	80–89
Hypertension, Stage 2	≥140	or	≥90

The goal of hypertension management and prevention is to achieve and maintain optimal control of BP.¹²⁰⁰ However, the BP thresholds used to define hypertension, the optimum BP threshold at which to initiate antihypertensive drug therapy, and the ideal target BP values remain controversial.⁵⁰¹ ⁵⁰³ ⁵⁰⁴ ⁵⁰⁵ ⁵⁰⁶ ⁵⁰⁷ ⁵⁰⁸ ⁵¹⁵ ⁵²³ ⁵²⁶ ⁵³⁰ ¹²⁰⁰ ¹²⁰¹ ¹²⁰⁷ ¹²⁰⁹ ¹²²² ¹²²³ ¹²²⁹

The 2017 ACC/AHA hypertension guideline generally recommends a target BP goal (i.e., BP to achieve with drug therapy and/or nonpharmacologic intervention) <130/80 mm Hg in all adults regardless of comorbidities or level of atherosclerotic cardiovascular disease (ASCVD) risk.¹²⁰⁰ In addition, an SBP goal of <130 mm Hg generally is recommended for noninstitutionalized ambulatory patients ≥65 years of age with an average SBP of ≥130 mm Hg.¹²⁰⁰ These BP goals are based upon clinical studies demonstrating continuing reduction of cardiovascular risk at progressively lower levels of SBP.¹²⁰⁰ ¹²⁰² ¹²¹⁰

Other hypertension guidelines generally have based target BP goals on age and comorbidities.⁵⁰¹ ⁵⁰⁴ ⁵³⁶ Guidelines such as those issued by the JNC 8 expert panel generally have targeted a BP goal of <140/90 mm Hg regardless of cardiovascular risk and have used higher BP thresholds and target BPs in elderly patients⁵⁰¹ ⁵⁰⁴ compared with those recommended by the 2017 ACC/AHA hypertension guideline.¹²⁰⁰

Some clinicians continue to support previous target BPs recommended by JNC 8 due to concerns about the lack of generalizability of data from some clinical trials (e.g., SPRINT study) used to support the 2017 ACC/AHA hypertension guideline and potential harms (e.g., adverse drug effects, costs of therapy) versus benefits of BP lowering in patients at lower risk of cardiovascular disease.¹²²² ¹²²³ ¹²²⁴ ¹²²⁹

Consider potential benefits of hypertension management and drug cost, adverse effects, and risks associated with the use of multiple antihypertensive drugs when deciding a patient's BP treatment goal.¹²⁰⁰ ¹²²⁰ ¹²²⁹

For decisions regarding when to initiate drug therapy (BP threshold), the 2017 ACC/AHA hypertension guideline incorporates underlying cardiovascular risk factors.¹²⁰⁰ ¹²⁰⁷ ASCVD risk assessment is recommended by ACC/AHA for all adults with hypertension.¹²⁰⁰

ACC/AHA currently recommend initiation of antihypertensive drug therapy in addition to lifestyle/behavioral modifications at an SBP ≥140 mm Hg or DBP ≥90 mm Hg in adults who have no history of cardiovascular disease (i.e., primary prevention) and a low ASCVD risk (10-year risk <10%).¹²⁰⁰

For secondary prevention in adults with known cardiovascular disease or for primary prevention in those at higher risk for ASCVD (10-year risk ≥10%), ACC/AHA recommend initiation of antihypertensive drug therapy at an average SBP ≥130 mm Hg or an average DBP ≥80 mm Hg.¹²⁰⁰

Adults with hypertension and diabetes mellitus, chronic kidney disease (CKD), or age ≥65 years are assumed to be at high risk for cardiovascular disease; ACC/AHA state that such patients should have antihypertensive drug therapy initiated at a BP ≥130/80 mm Hg.¹²⁰⁰ Individualize drug therapy in patients with hypertension and underlying cardiovascular or other risk factors.⁵⁰² ¹²⁰⁰

In stage 1 hypertension, experts state that it is reasonable to initiate drug therapy using the stepped-care approach in which one drug is initiated and titrated and other drugs are added sequentially to achieve the target BP.¹²⁰⁰ Initiation of antihypertensive therapy with 2 first-line agents from different pharmacologic classes recommended in adults with stage 2 hypertension and average BP >20/10 mm Hg above BP goal.¹²⁰⁰

Black hypertensive patients generally tend to respond better to monotherapy with calcium-channel blockers or thiazide diuretics than to β-blockers.⁴⁵ ⁵³ ⁵⁴ ⁵⁰¹ ⁵⁰⁴ ¹²⁰⁰ However, diminished response to β-blockers is largely eliminated when administered concomitantly with a thiazide diuretic.⁵⁰⁰

Heart Failure

Management of mild to moderately severe (NYHA class II or III) heart failure^{† [off-label]} of ischemic or cardiomyopathic origin in conjunction with other heart failure therapies (e.g., cardiac glycosides, diuretics, ACE inhibitors).²³ ²⁴ ²⁵ ²⁶ ²⁷ ²⁸ ²⁹ ³⁰ ³¹ ³² ³³ ³⁴ ³⁵ ³⁶ ³⁷ ³⁸ ⁵²⁴ ⁸⁰⁰

The American College of Cardiology Foundation (ACCF), AHA, and the Heart Failure Society of America (HFSA) recommend therapy with an ACE inhibitor, angiotensin II receptor antagonist, or angiotensin receptor-neprilysin inhibitor (ARNI) in conjunction with a β-blocker, and an aldosterone antagonist in selected patients, to reduce morbidity and mortality in patients with symptomatic heart failure and reduced left ventricular ejection fraction (LVEF) (ACCF/AHA stage C heart failure).⁸⁰⁰

Initiate a clinical-trial proven β-blocker (bisoprolol, carvedilol, extended-release metoprolol succinate) to reduce the risk of death in patients with chronic heart failure; benefits shown with these β-blockers not considered indicative of a β-blocker class effect.⁵²⁴

Experts recommend that β-blockers also be used in conjunction with ACE inhibitors in all patients who have asymptomatic heart failure^{† [off-label]} (i.e., structural heart disease but no signs or symptoms; ACCF/AHA stage B heart failure) with reduced LVEF.⁵²⁴ ⁸⁰⁰

Bisoprolol Dosage and Administration

General

Individualize dosage according to patient response and tolerance.³ ¹⁸
If long-term therapy is discontinued, reduce dosage gradually over a period of about 1–2 weeks.¹ ² ²⁰ (See Abrupt Withdrawal of Therapy under Cautions.)

BP Monitoring and Treatment Goals

Monitor BP regularly (i.e., monthly) during therapy and adjust dosage of the antihypertensive drug until BP controlled.¹²⁰⁰
If unacceptable adverse effects occur, discontinue drug and initiate another antihypertensive agent from a different pharmacologic class.¹²¹⁶
If adequate BP response not achieved with a single antihypertensive agent, either increase dosage of single drug or add a second drug with demonstrated benefit and preferably a complementary mechanism of action (e.g., ACE inhibitor, angiotensin II receptor antagonist, calcium-channel blocker, thiazide diuretic).¹²⁰⁰ ¹²¹⁶ Many patients will require ≥2 drugs from different pharmacologic classes to achieve BP goal; if goal BP still not achieved, add a third drug.¹²⁰⁰ ¹²¹⁶

Administration

Oral Administration

Administer orally;¹ ² ³ ⁴ ⁵ ⁶ ⁷ absorption does not appear to be affected by food.¹ ² ³ ⁴ ⁶ ⁷

Dosage

Available as bisoprolol fumarate; dosage expressed in terms of the fumarate.¹ ² ³

Pediatric Patients

Hypertension† [off-label]

Bisoprolol/Hydrochlorothiazide Fixed-combination Therapy

Oral

Some experts have recommended an initial dosage of 2.5 mg of bisoprolol fumarate and 6.25 mg of hydrochlorothiazide daily.⁵² If needed, dosage may be increased to 10 mg of bisoprolol fumarate and 6.25 mg of hydrochlorothiazide once daily.⁵²

Adults

Hypertension

Bisoprolol Therapy

Oral

Initially, 2.5–5 mg once daily.¹ ³ ⁵ ¹⁸ ²¹

May increase dosage gradually, generally at intervals of ≥2 weeks,³ ¹⁸ based on BP response up to maximum of 20 mg daily.¹ ² ³ ¹⁸

Some experts state usual dosage range is 2.5–10 mg once daily.¹²⁰⁰

Bisoprolol/Hydrochlorothiazide Fixed-combination Therapy

Oral

Patients in whom BP is not adequately controlled by monotherapy with bisoprolol fumarate 2.5–20 mg daily or those who respond adequately to a hydrochlorothiazide dosage of 50 mg daily but experience problematic potassium loss can switch to a fixed-combination preparation containing bisoprolol and hydrochlorothiazide.² ³

Can use the fixed combination as a substitute for the individually titrated drugs.⁶⁰⁰

Alternatively, may initiate antihypertensive therapy with the fixed-combination preparation containing bisoprolol fumarate 2.5 mg and hydrochlorothiazide 6.25 mg daily.² ³

Heart Failure† [off-label]

Oral

Initially, 1.25 mg daily⁴⁰ for 2–4 weeks or less suggested in adults with mild to moderately severe heart failure.²² ³⁰ ⁵²⁴

If tolerated, increase to 2.5 mg daily for 2–4 weeks; subsequent dosages can be doubled every 2–4 weeks.²² ³⁰

If deterioration (usually transient) occurs during titration, increase dosage of concurrent diuretic⁴⁰ ⁵²⁴ and decrease dosage of β-blocker or temporarily discontinue β-blocker as appropriate.⁵²⁴ Do not continue dosage titration until symptoms of worsening heart failure have stabilized.⁵²⁴ Initial difficulty in dosage titration should not preclude subsequent attempts to successfully titrate the dosage.⁴⁰

Reduce dosage in patients with heart failure who experience symptomatic bradycardia (e.g., dizziness) or 2nd or 3rd degree heart block.⁵²⁴

Prescribing Limits

Pediatric Patients

Hypertension† [off-label]

Bisoprolol/Hydrochlorothiazide Fixed-combination Therapy

Oral

Some experts have stated that the maximum dosage is 10 mg of bisoprolol fumarate and 6.25 mg of hydrochlorothiazide daily.⁵²

Adults

Hypertension

Bisoprolol Therapy

Oral

Maximum is 20 mg daily.¹ ² ³

Bisoprolol/Hydrochlorothiazide Fixed-combination Therapy

Oral

Dosage generally should not exceed bisoprolol fumarate 20 mg and hydrochlorothiazide 12.5 mg daily.² ³

Heart Failure†

Oral

Maximum dosage recommended by ACCF and AHA: 10 mg once daily.⁵²⁴

Special Populations

Hepatic Impairment

Hepatitis or cirrhosis: Initially 2.5 mg once daily.¹ Increase dosage with caution.¹ ³

Renal Impairment

Cl_cr <40 mL/minute: Initially 2.5 mg daily.¹ Increase dosage with caution.¹ ³

Cl_cr <20 mL/minute per 1.73 m²: Generally, maximum 10 mg once daily.⁴ ⁶ ⁸ ^a

Hemodialysis: Apparently not removed by dialysis; supplemental dose is not required after dialysis;³

Bisoprolol/hydrochlorothiazide fixed combination: Discontinue if progressive renal impairment develops.²

Geriatric Patients

Dosage adjustment not required unless appreciable renal or hepatic impairment is present.¹ ²

Bronchospastic Disease

Initially, 2.5 mg daily;¹ ³ use the possible lowest dosage.¹

Cautions for Bisoprolol

Contraindications

Patients with sinus bradycardia, heart block greater than first degree, cardiogenic shock, or overt heart failure.¹ ²
Hypersensitivity to bisoprolol fumarate, any ingredient in the formulation, or sulfonamides.²

Warnings/Precautions

Warnings

Heart Failure

Possible precipitation of heart failure.¹ ²

Avoid use in overt heart failure;¹ ² may use cautiously in patients with well-compensated heart failure (e.g., those controlled with cardiac glycosides and/or diuretics).¹ ²

Adequate treatment (e.g., with a cardiac glycoside and/or diuretic) and close observation recommended if signs or symptoms of impending heart failure occur; if heart failure continues, discontinue therapy, gradually if possible.¹ ² ²² ⁴⁰

Abrupt Withdrawal of Therapy

Abrupt discontinuance of therapy is not recommended as it may exacerbate symptoms or precipitate MI or ventricular arrhythmias in patients with CAD.¹ ² Gradually decrease dosage over 1–2 weeks and monitor patients carefully.¹ ² ³ ¹⁹ ²⁰ If manifestations of withdrawal (exacerbation of angina or hypotension) occur, increase dosage or reinstitute therapy, at least temporarily.¹ ² ³

Peripheral Vascular Disease

Possible precipitation or aggravation of symptoms of arterial insufficiency; use with caution.¹ ²

Bronchospastic Disease

Generally should not be used in patients with bronchospastic disease,¹ ² but may be used with caution in such patients who do not respond to or cannot tolerate alternative treatment.¹ ²

Administer the lowest effective dosage (initially 2.5 mg once daily);¹ ² a bronchodilator (e.g. a β₂-adrenergic agonist) should be available.¹ ²

Major Surgery

Use with caution in patients undergoing major surgery involving general anesthesia.¹ ² Use particular care if anesthetics that depress the myocardium (e.g., cyclopropane, ether, trichloroethylene) are used.¹ ² (See Specific Drugs under Interactions.)

Diabetes and Hypoglycemia

Possible decreased signs and symptoms of hypoglycemia (e.g., tachycardia).¹ ²

Use with caution in patients with diabetes mellitus receiving hypoglycemic drugs.¹ ²

Thyrotoxicosis

Signs of hyperthyroidism (e.g., tachycardia) may be masked.¹ ² Possible exacerbation of hyperthyroidism or precipitation of thyroid storm if therapy is abruptly withdrawn; carefully monitor patients having or suspected of developing thyrotoxicosis.¹ ²

General Precautions

History of Anaphylactic Reactions

Possible increased reactivity to repeated, accidental, diagnostic, or therapeutic challenges with a variety of allergens while taking β-blockers.¹ ² Such patients may be unresponsive to usual doses of epinephrine.¹ ²

Other Precautions

Shares the toxic potentials of β-blockers; observe the usual precautions of these agents.¹ ² In addition, when used in fixed-combination with hydrochlorothiazide, consider the cautions, precautions, and contraindications associated with thiazide diuretics.¹ ²

Specific Populations

Pregnancy

Category C.¹ ²

Lactation

Not known whether bisoprolol fumarate is distributed into human milk.¹ ² Use with caution.¹

Pediatric Use

Safety and efficacy not established in children;¹ ² however, some experts have recommended the use of bisoprolol fumarate/hydrochlorothiazide fixed combination in hypertensive children (1–17 years of age).⁵²

Geriatric Use

Safety and efficacy profiles in geriatric individuals are similar to those in younger adults.¹ ²

Hepatic Impairment

In patients with hepatitis or cirrhosis, reduce initial dosage and adjust dosage cautiously.¹ ³ (See Hepatic Impairment under Dosage and Administration.)

Renal Impairment

Cl_cr <40 mL/minute: Threefold increase in half-life;¹ ² reduce initial dosage and adjust dosage cautiously.¹ ³ (See Renal Impairment under Dosage and Administration.)

Common Adverse Effects

Fatigue, headache, diarrhea, peripheral edema, and upper respiratory tract infection.¹ ²

Drug Interactions

Not metabolized by isoenzyme CYP2D6.

Specific Drugs

Drug	Interaction	Comments
β-Blockers		Do not use with other β- blockers¹ ²
Catecholamine-depleting drugs (e.g., reserpine, guanethidine)	Possible additive effects with concurrent use¹ ²	Monitor closely for excessive decreases in sympathetic activity¹ ²
Calcium-channel blocking agents (e.g., verapamil, diltiazem])	Potential for additive negative effects on AV nodal conduction	Use with caution¹ ²
Cimetidine	No clinically important pharmacokinetic interaction¹ ²
Clonidine	β-Adrenergic blockade may exacerbate rebound hypertension which may occur following clonidine discontinuance ^a	Discontinue β-blockers several days before withdrawal of clonidine ¹ ²
Digoxin	No clinically important pharmacokinetic interaction
Disopyramide	Potential for additive negative effects on AV nodal conduction¹ ²	Use with caution¹ ²
Myocardial depressant general anesthetics (e.g., ether, cyclopropane, trichloroethylene)	Increased risk of hypotension and heart failure¹ ²	Use with caution¹ ² ⁴¹
Rifampin	Potential for increased clearance and decreased elimination half-life of bisoprolol¹ ²	Initial dosage adjustments of bisoprolol are not necessary¹ ²
Thiazide diuretics	No clinically important pharmacokinetic interaction¹ ²
Warfarin	No effect on prothrombin time with stable warfarin dosage¹ ²

Bisoprolol Pharmacokinetics

Absorption

Bioavailability

About 80%.¹ ²

Onset

In healthy individuals, decreased tachycardia (exercise- and isoproterenol-induced) occurs within 1–4 hours.¹ ²

Duration

In normal individuals, decreased tachycardia generally persists for 24 hours.¹ ²

Food

Food does not appear to affect absorption.¹

Distribution

Extent

Not known whether distributed into human milk.¹ ²

Plasma Protein Binding

About 30%.¹ ²

Elimination

Metabolism

Not metabolized by CYP2D6.¹ ²

20% first-pass metabolism.¹ ²

Elimination Route

Excreted in urine as unchanged drug (50%) and as inactive metabolites; less than 2% excreted in feces.¹ ²

Half-life

9–12 hours.¹ ²

Special Populations

In patients with cirrhosis, half-life is more variable and substantially prolonged (range: 8.3–21.7 hours).¹ ²

In renal impairment (Cl_cr <40 mL/minute), threefold increase in half-life.¹ (See Renal Impairment under Dosage and Administration.)

In geriatrics, half-life slightly increased due to decreased renal function.¹ ²

Stability

Storage

Oral

Tablets

Tight containers at 20–25°C.¹

Tablets (Bisoprolol Fumarate and Hydrochlorothiazide)

Tight containers at 20–25°C.²

Actions

Inhibits response to adrenergic stimuli by competitively blocking β₁-adrenergic receptors within the myocardium.¹ Blocks β₂-adrenergic receptors within the bronchial and vascular smooth muscle only at high doses.¹ ² ³ ⁴ ⁷
Decreases resting and exercise-stimulated heart rate and cardiac output, decreases isoproterenol-induced tachycardia, prolongs sinus node recovery time, refractory period of the AV node, and AV nodal conduction (with rapid atrial stimulation).¹ ²
No intrinsic sympathomimetic activity or membrane-stabilizing effect on the heart.¹ ²
Reduces blood pressure by decreasing cardiac output, decreasing sympathetic outflow from the CNS, and or suppressing renin release.¹ ²

Advice to Patients

Importance of taking medication exactly as prescribed.¹
Importance of not interrupting or discontinuing therapy without consulting clinician.¹ ²
Importance of informing clinician at the first sign or symptom of heart failure, excessive bradycardia, or if any difficulty in breathing occurs.¹ ²
Importance of informing anesthesiologist or dentist that they are receiving bisoprolol therapy prior to undergoing major surgery.¹ ²
Importance of informing patients with diabetes that the drug may mask signs and symptoms of hypoglycemia, including increased heart rate.¹ ²
Importance of avoiding some activities (e.g., operating machinery or driving a motor vehicle or those requiring mental alertness).¹ ²
Importance of informing clinicians of existing or contemplated therapy, including prescription and OTC drugs.¹ ²
Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.¹ ²
Importance of informing patients of other important precautionary information. (See Cautions.)

Preparations

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

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

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

Bisoprolol Fumarate
Routes	Dosage Forms	Strengths	Brand Names	Manufacturer
Oral	Tablets, film-coated	5 mg*	Bisoprolol Fumarate Tablets
			Zebeta (scored)	Barr
		10 mg*	Bisoprolol Fumarate Tablets
			Zebeta	Barr

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

Bisoprolol Fumarate and Hydrochlorothiazide
Routes	Dosage Forms	Strengths	Brand Names	Manufacturer
Oral	Tablets, film-coated	2.5 mg with Hydrochlorothiazide 6.25 mg*	Bisoprolol Fumarate and Hydrochlorothiazide Tablets
			Ziac	Barr
		5 mg with Hydrochlorothiazide 6.25 mg*	Bisoprolol Fumarate and Hydrochlorothiazide Tablets
			Ziac	Barr
		10 mg with Hydrochlorothiazide 6.25 mg*	Bisoprolol Fumarate and Hydrochlorothiazide Tablets
			Ziac	Barr

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

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a. AHFS Drug Information 2019. McEvoy GK, ed. Bisoprolol. American Society of Health-System Pharmacists; 2019:.

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