Skip to main content

Bisoprolol

Class: beta-Adrenergic Blocking Agents
VA Class: CV100
Chemical Name: 2-Propanol, 1-(4-((2-(1-methylethoxy)ethoxy)methyl)phenoxy)-3-((1-methylethyl)amino),(±),(E)-2-butenedioate (2:1) (salt)
Molecular Formula: C18H31NO4•½C4H4O4
CAS Number: 104344-23-2
Brands: Zebeta

Medically reviewed by Drugs.com on Feb 8, 2021. Written by ASHP.

Introduction

β1-selective adrenergic blocking agent (β-blocker).

Uses for Bisoprolol

Hypertension

Management of hypertension as monotherapy or in combination with other classes of antihypertensive agents.

β-Blockers generally not preferred for first-line therapy of hypertension according to current evidence-based hypertension guidelines, but may be considered in patients who have a compelling indication (e.g., prior MI, ischemic heart disease, heart failure) for their use or as add-on therapy in those who do not respond adequately to the preferred drug classes (ACE inhibitors, angiotensin II receptor antagonists, calcium-channel blockers, or thiazide diuretics). 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.

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

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

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

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

Table 1. ACC/AHA BP Classification in Adults1200

Category

SBP (mm Hg)

DBP (mm Hg)

Normal

<120

and

<80

Elevated

120–129

and

<80

Hypertension, Stage 1

130–139

or

80–89

Hypertension, Stage 2

≥140

or

≥90

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

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

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

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

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

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

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

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

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

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

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

Heart Failure

Management of mild to moderately severe (NYHA class II or III) heart failure of ischemic or cardiomyopathic origin in conjunction with other heart failure therapies (e.g., cardiac glycosides, diuretics, ACE inhibitors).

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

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

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

Bisoprolol Dosage and Administration

General

  • Individualize dosage according to patient response and tolerance.

  • If long-term therapy is discontinued, reduce dosage gradually over a period of about 1–2 weeks. (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.

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

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

Administration

Oral Administration

Administer orally; absorption does not appear to be affected by food.

Dosage

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

Pediatric Patients

Hypertension†
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. If needed, dosage may be increased to 10 mg of bisoprolol fumarate and 6.25 mg of hydrochlorothiazide once daily.

Adults

Hypertension
Bisoprolol Therapy
Oral

Initially, 2.5–5 mg once daily.

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

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

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.

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

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

Heart Failure†
Oral

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

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

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

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

Prescribing Limits

Pediatric Patients

Hypertension†
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.

Adults

Hypertension
Bisoprolol Therapy
Oral

Maximum is 20 mg daily.

Bisoprolol/Hydrochlorothiazide Fixed-combination Therapy
Oral

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

Heart Failure†
Oral

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

Special Populations

Hepatic Impairment

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

Renal Impairment

Clcr <40 mL/minute: Initially 2.5 mg daily. Increase dosage with caution.

Clcr <20 mL/minute per 1.73 m2: Generally, maximum 10 mg once daily.

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

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

Geriatric Patients

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

Bronchospastic Disease

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

Cautions for Bisoprolol

Contraindications

  • Patients with sinus bradycardia, heart block greater than first degree, cardiogenic shock, or overt heart failure.

  • Hypersensitivity to bisoprolol fumarate, any ingredient in the formulation, or sulfonamides.

Warnings/Precautions

Warnings

Heart Failure

Possible precipitation of heart failure.

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

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.

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. Gradually decrease dosage over 1–2 weeks and monitor patients carefully. If manifestations of withdrawal (exacerbation of angina or hypotension) occur, increase dosage or reinstitute therapy, at least temporarily.

Peripheral Vascular Disease

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

Bronchospastic Disease

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

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

Major Surgery

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

Diabetes and Hypoglycemia

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

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

Thyrotoxicosis

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

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. Such patients may be unresponsive to usual doses of epinephrine.

Other Precautions

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

Specific Populations

Pregnancy

Category C.

Lactation

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

Pediatric Use

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

Geriatric Use

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

Hepatic Impairment

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

Renal Impairment

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

Common Adverse Effects

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

Interactions for Bisoprolol

Not metabolized by isoenzyme CYP2D6.

Specific Drugs

Drug

Interaction

Comments

β-Blockers

Do not use with other β- blockers

Catecholamine-depleting drugs (e.g., reserpine, guanethidine)

Possible additive effects with concurrent use

Monitor closely for excessive decreases in sympathetic activity

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

Potential for additive negative effects on AV nodal conduction

Use with caution

Cimetidine

No clinically important pharmacokinetic interaction

Clonidine

β-Adrenergic blockade may exacerbate rebound hypertension which may occur following clonidine discontinuance

Discontinue β-blockers several days before withdrawal of clonidine

Digoxin

No clinically important pharmacokinetic interaction

Disopyramide

Potential for additive negative effects on AV nodal conduction

Use with caution

Myocardial depressant general anesthetics (e.g., ether, cyclopropane, trichloroethylene)

Increased risk of hypotension and heart failure

Use with caution

Rifampin

Potential for increased clearance and decreased elimination half-life of bisoprolol

Initial dosage adjustments of bisoprolol are not necessary

Thiazide diuretics

No clinically important pharmacokinetic interaction

Warfarin

No effect on prothrombin time with stable warfarin dosage

Bisoprolol Pharmacokinetics

Absorption

Bioavailability

About 80%.

Onset

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

Duration

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

Food

Food does not appear to affect absorption.

Distribution

Extent

Not known whether distributed into human milk.

Plasma Protein Binding

About 30%.

Elimination

Metabolism

Not metabolized by CYP2D6.

20% first-pass metabolism.

Elimination Route

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

Half-life

9–12 hours.

Special Populations

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

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

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

Stability

Storage

Oral

Tablets

Tight containers at 20–25°C.

Tablets (Bisoprolol Fumarate and Hydrochlorothiazide)

Tight containers at 20–25°C.

Actions

  • Inhibits response to adrenergic stimuli by competitively blocking β1-adrenergic receptors within the myocardium. Blocks β2-adrenergic receptors within the bronchial and vascular smooth muscle only at high doses.

  • 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).

  • No intrinsic sympathomimetic activity or membrane-stabilizing effect on the heart.

  • Reduces blood pressure by decreasing cardiac output, decreasing sympathetic outflow from the CNS, and or suppressing renin release.

Advice to Patients

  • Importance of taking medication exactly as prescribed.

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

  • Importance of informing clinician at the first sign or symptom of heart failure, excessive bradycardia, or if any difficulty in breathing occurs.

  • Importance of informing anesthesiologist or dentist that they are receiving bisoprolol therapy prior to undergoing major surgery.

  • Importance of informing patients with diabetes that the drug may mask signs and symptoms of hypoglycemia, including increased heart rate.

  • Importance of avoiding some activities (e.g., operating machinery or driving a motor vehicle or those requiring mental alertness).

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

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

  • Importance of informing 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

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

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

Show article references