Bisoprolol is a β1-selective adrenergic blocking agent (β-blocker).
Bisoprolol is used in the management of hypertension.1, 2, 3, 4, 5, 6, 7, 1200 The drug also has been used in the management of heart failure†.30, 524
The choice of a β-adrenergic blocking agent (β-blocker) depends on numerous factors, including pharmacologic properties (e.g., relative β-selectivity, intrinsic sympathomimetic activity, membrane-stabilizing activity, lipophilicity), pharmacokinetics, intended use, and adverse effect profile, as well as the patient's coexisting disease states or conditions, response, and tolerance.14, 45, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66 While specific pharmacologic properties and other factors may appropriately influence the choice of a β-blocker in individual patients,1235 evidence of clinically important differences among the agents in terms of overall efficacy and/or safety is limited. 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66 Patients who do not respond to or cannot tolerate one β-blocker may be successfully treated with a different agent.57, 58, 59, 60, 63, 65, 66
Bisoprolol is used alone or in combination with other classes of antihypertensive agents in the management of hypertension.1, 2, 3, 4, 5, 6, 7, 1200
Current evidence-based practice guidelines for the management of hypertension in adults generally recommend the use of drugs from 4 classes of antihypertensive agents (angiotensin-converting enzyme [ACE] inhibitors, angiotensin II receptor antagonists, calcium-channel blockers, and thiazide diuretics).501, 502, 503, 504, 1200 Most guidelines no longer recommend β-blockers as first-line therapy for hypertension because of the lack of established superiority over other recommended drug classes and evidence from at least one study demonstrating that β-blockers may be less effective than angiotensin II receptor antagonists in preventing cardiovascular death, myocardial infarction (MI), or stroke.67, 501, 503, 504, 515, 1200 However, therapy with a β-blocker may still be considered in hypertensive 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.501, 502, 503, 504, 523, 524, 527, 800, 1200 (See Considerations for Drug Therapy in Patients with Underlying Cardiovascular and Other Risk Factors under Uses: Hypertension, in Atenolol 24:24 and in Metoprolol 24:24.) Ultimately, choice of antihypertensive therapy should be individualized, considering the clinical characteristics of the patient (e.g., age, ethnicity/race, comorbid conditions, cardiovascular risk factors) as well as drug-related factors (e.g., ease of administration, availability, adverse effects, costs).501, 502, 503, 504, 515, 1200, 1201
A 2017 multidisciplinary hypertension guideline of the American College of Cardiology (ACC), American Heart Association (AHA), and a number of other professional organizations generally recommends a target blood pressure goal (i.e., blood pressure to achieve with drug therapy and/or nonpharmacologic intervention) of less than 130/80 mm Hg in all patients regardless of comorbidities or level of atherosclerotic cardiovascular disease (ASCVD) risk.1200 In addition, a systolic blood pressure goal of less than 130 mm Hg generally is recommended for noninstitutionalized ambulatory patients 65 years of age or older with an average systolic blood pressure of at least 130 mm Hg.1200 These blood pressure goals are based upon clinical studies demonstrating continuing reduction of cardiovascular risk at progressively lower levels of systolic blood pressure.1200, 1202, 1210 Previous hypertension guidelines, such as those from an expert panel of the Eighth Joint National Committee on the Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 8), generally have recommended initiation of antihypertensive treatment in patients with a systolic blood pressure of at least 140 mm Hg or diastolic blood pressure of at least 90 mm Hg, targeted a blood pressure goal of less than 140/90 mm Hg regardless of cardiovascular risk, and used higher systolic blood pressure thresholds and targets in geriatric patients501, 504, 536 compared with those recommended by the 2017 ACC/AHA hypertension guideline.1200 The blood pressure thresholds used to define hypertension, the optimum blood pressure threshold at which to initiate antihypertensive drug therapy, and the ideal target blood pressure values remain controversial.501, 503, 504, 505, 506, 507, 508, 515, 523, 526, 530, 1200, 1201, 1207, 1209, 1222, 1223, 1229
Most patients with hypertension, especially black patients, will require at least 2 antihypertensive drugs to achieve adequate blood pressure control.1200 In general, black hypertensive patients tend to respond better to monotherapy with thiazide diuretics or calcium-channel blocking agents than to monotherapy with β-blockers.45, 53, 54, 501, 504, 1200 Although β-blockers have lowered blood pressure in all races studied, monotherapy with these agents has produced a smaller reduction in blood pressure in black hypertensive patients; however, this population difference in response does not appear to occur during combined therapy with a β-blocker and a thiazide diuretic.500 (See Race under Hypertension: Other Special Considerations for Antihypertensive Drug Therapy, in Uses in Atenolol 24:24 and Metoprolol 24:24.)
For additional information on the role of β-blockers in the management of hypertension, see Uses: Hypertension, in Atenolol 24:24 and in Metoprolol 24:24. For information on overall principles and expert recommendations for treatment of hypertension, see Uses: Hypertension, in Adults, in the Thiazides General Statement 40:28.20. For information on overall principles and expert recommendations for treatment of hypertension in pediatric patients, see Uses: Hypertension in Pediatric Patients, in the Thiazides General Statement 40:28.20.
Bisoprolol has been used (usually in conjunction with other heart failure therapies) in the management of mild to severe (New York Heart Association [NYHA] class II-IV) heart failure† of ischemic or cardiomyopathic origin to increase survival and to reduce the risk of hospitalization.23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 41, 524, 800 Current guidelines for the management of heart failure in adults generally recommend a combination of drug therapies to reduce morbidity and mortality, including neurohormonal antagonists (e.g., ACE inhibitors, angiotensin II receptor antagonists, angiotensin receptor-neprilysin inhibitors [ARNIs], β-blockers, aldosterone receptor antagonists) that inhibit the detrimental compensatory mechanisms in heart failure.524, 701, 703, 800 Additional agents (e.g., cardiac glycosides, diuretics, sinoatrial modulators [i.e., ivabradine]) added to a heart failure treatment regimen in selected patients have been associated with symptomatic improvement of heart failure and/or reduction in heart failure-related hospitalizations.524, 800 Experts recommend that all asymptomatic patients with reduced left ventricular ejection fraction (LVEF) (American College of Cardiology Foundation [ACCF]/American Heart Association [AHA] stage B heart failure) receive therapy with an ACE inhibitor and a β-blocker to prevent symptomatic heart failure and reduce morbidity and mortality.524, 800 In patients with prior or current symptoms of chronic heart failure and reduced LVEF (ACCF/AHA stage C heart failure), ACCF, AHA, and the Heart Failure Society of America (HFSA) recommend inhibition of the renin-angiotensin-aldosterone (RAA) system with an ACE inhibitor, angiotensin II receptor antagonist, or ARNI in conjunction with a β-blocker, and an aldosterone antagonist in selected patients, to reduce morbidity and mortality.800 While ACE inhibitors have been the preferred drugs for inhibition of the RAA system because of their established benefits in patients with heart failure and reduced ejection fraction, some evidence indicates that therapy with an ARNI (sacubitril/valsartan) may be more effective than ACE inhibitor therapy (enalapril) in reducing cardiovascular death and heart failure-related hospitalization in such patients.702, 800 ACCF, AHA, and HFSA recommend that patients with chronic symptomatic heart failure and reduced LVEF (NYHA class II or III) who are able to tolerate an ACE inhibitor or angiotensin II receptor antagonist be switched to therapy containing an ARNI to further reduce morbidity and mortality.800
Because of its favorable effects on survival and disease progression, therapy with a clinical trial-proven β-blocker (bisoprolol, carvedilol, extended-release metoprolol succinate) should be initiated as soon as the patient is diagnosed with heart failure and reduced LVEF.524 While bisoprolol, carvedilol, and extended-release metoprolol have been effective in reducing the risk of death in patients with chronic heart failure, these positive findings should not be considered indicative of a β-blocker class effect.524 Even when symptoms are mild or improve with other therapies, β-blocker therapy should not be delayed until symptoms return or the disease progresses.524 Despite concerns about β-blockade potentially masking some signs of hypoglycemia,22 patients with diabetes mellitus may be particularly likely to experience a reduction in morbidity and mortality with the use of β-blockers.22, 33 If a patient cannot tolerate a β-blocker or if increasing the β-blocker dosage to optimal levels is ineffective, ivabradine should be considered an alternative or additional treatment option.701, 709, 710, 800 Some evidence suggests that ivabradine is effective in reducing hospitalizations related to heart failure, but unlike β-blockers, ivabradine has not been shown to reduce cardiovascular mortality.707, 708, 710, 711, 712 (See Uses: Heart Failure, in Ivabradine 24:04.92.)
In individualizing the decision to use a β-blocker, clinicians should consider that clinical studies establishing the effects of these drugs on morbidity and mortality excluded patients who were hospitalized or had unstable symptoms and enrolled few patients with current or recent NYHA class IV symptoms.22, 32, 39, 40 The efficacy of β-blockers in such patients is not known,22, 32, 39 and they may be at particular risk of deterioration following initiation of therapy with β-blockers.22
The beneficial effects of β-blockers in the management of heart failure are thought to result principally from inhibition of the effects of the sympathetic nervous system.22 Although the specific effects on the heart and circulation that are responsible for progression of heart failure remain to be established, sympathetic activity can increase ventricular volumes and pressure secondary to peripheral vasoconstriction and by impairing sodium excretion by the kidneys.22 Other sympathetic effects (e.g., induction of cardiac hypertrophy, arrhythmogenic activity) also may be involved.22 Collective experience indicates that long-term therapy with β-blockers, like that with ACE inhibitors, can reduce heart failure symptoms and improve clinical status in patients with chronic heart failure and also can decrease the risk of death as well as the combined risk of death and hospitalization.32, 34, 39, 41, 524 These beneficial effects were demonstrated in patients already receiving an ACE inhibitor, suggesting that combined inhibition of the renin-angiotensin system and sympathetic nervous system can produce additive effects.22, 524
β-Blockers should not be used in patients with acutely decompensated heart failure requiring IV inotropic therapy and those with substantial fluid retention requiring intensive diuresis.22, 524 In the absence of hemodynamic instability or contraindications, it has been recommended that patients with heart failure and a reduced ejection fraction who are hospitalized for a symptomatic exacerbation continue to receive maintenance treatment with standard oral therapy for heart failure (e.g., β-blocker, ACE inhibitor).524 Withholding of or reduction in β-blocker therapy should be considered only in patients hospitalized after recent initiation or increase in β-blocker therapy or in those with marked volume overload or low/marginal cardiac output.524 Initiation of β-blocker therapy in hospitalized patients is recommended once the patient's condition is stabilized (i.e., after optimization of volume status and successful discontinuance of IV diuretics, vasodilators, and inotropic agents).524 Caution should be used when initiating β-blockers in patients who have required inotrope therapy during hospitalization.524
Bisoprolol fumarate is administered orally.1, 2, 3, 4, 5, 6, 7 GI absorption of the drug does not appear to be affected by food.1, 3, 4, 6, 7
Adjustment of dosage of bisoprolol-containing therapy based solely on age does not appear to be necessary in geriatric patients, unless appreciable renal or hepatic impairment is present.1, 2 (See Dosage and Administration: Dosage in Renal and Hepatic Impairment.)
For the management of hypertension in adults, the usual initial dosage of bisoprolol fumarate is 2.5-5 mg once daily.1, 3, 5, 18, 21 Because the β1-adrenergic blocking selectivity of bisoprolol fumarate is not absolute (diminishing with increasing dose), the drug should be used cautiously in patients with bronchospastic disease, initiating therapy at a dosage of 2.5 mg once daily.1, 3 Such reduced initial dosage also occasionally may be appropriate for other patients.1 In patients whose blood pressure is not controlled adequately with the initial bisoprolol fumarate dosage, dosage can be increased gradually as tolerated, generally at intervals of at least18 2 weeks,3 up to a maximum of 20 mg daily.1, 2, 3, 18 Some experts state the usual dosage range is 2.5-10 mg once daily.1200
The manufacturer states that modification of bisoprolol fumarate dosage generally is not necessary in geriatric patients with normal renal and hepatic function.1, 3
Bisoprolol/Hydrochlorothiazide Fixed-combination Therapy
The commercially available preparations containing bisoprolol fumarate in fixed combination with hydrochlorothiazide may be used in adults who do not respond adequately to bisoprolol fumarate dosages of 2.5-20 mg daily or in those who respond adequately to a hydrochlorothiazide dosage of 50 mg daily but who experience severe potassium depletion.2, 3 Such fixed combinations also may be used in patients who have been receiving the drugs separately, provided that the optimum maintenance dosage corresponds to the ratio in the commercial combination preparation.600 Unfortunately, because all commercially available fixed combinations of bisoprolol fumarate and hydrochlorothiazide contain the diuretic in the same relatively low dose of 6.25 mg, multiple tablets with relatively low doses of bisoprolol fumarate may be needed to achieve the optimum ratio required; employing multiple tablets may reduce the simplification in dosing and gains in compliance intended with substitution of the fixed combination for the individual drugs.2, 3
Alternatively, antihypertensive therapy in adults can be initiated with the fixed-combination preparation containing bisoprolol fumarate and hydrochlorothiazide, employing the lowest available dosage (i.e., 2.5 and 6.25 mg, respectively, daily).2, 3, 21 The manufacturer recommends that dosage with the fixed combination not exceed 20 mg of bisoprolol fumarate and 12.5 mg of hydrochlorothiazide (i.e., 2 tablets of the 10/6.25-mg fixed combination) daily.2, 3
Although safety and efficacy remain to be fully established in pediatric patients, some experts have recommended pediatric dosages for hypertension based on clinical experience. If bisoprolol fumarate in fixed combination with hydrochlorothiazide is used for the management of hypertension in children†, these experts have recommended an initial dosage of 2.5 mg of bisoprolol fumarate and 6.25 mg of hydrochlorothiazide once daily.52 Such experts have suggested that dosage may be increased as necessary to a maximum dosage of 10 mg of bisoprolol fumarate and 6.25 mg of hydrochlorothiazide once daily.52
Blood Pressure Monitoring and Treatment Goals
Blood pressure should be monitored regularly (i.e., monthly) during therapy and dosage of the antihypertensive drug adjusted until blood pressure is controlled.1200 If an adequate blood pressure response is not achieved, the dosage may be increased or another antihypertensive agent with demonstrated benefit and preferably with a complementary mechanism of action (e.g., angiotensin-converting enzyme [ACE] inhibitor, angiotensin II receptor antagonist, calcium-channel blocker, thiazide diuretic) may be added; if target blood pressure is still not achieved with the use of 2 antihypertensive agents, a third drug may be added.1200, 1216 (See Uses: Hypertension.) In patients who develop unacceptable adverse effects with bisoprolol, the drug should be discontinued and another antihypertensive agent from a different pharmacologic class should be initiated.1200, 1216
The goal of hypertension management and prevention is to achieve and maintain optimal control of blood pressure.1200 However, the optimum blood pressure threshold for initiating antihypertensive drug therapy and specific treatment goals remain controversial.505, 506, 507, 508, 515, 523, 530, 1201, 1207, 1209, 1222 While previous hypertension guidelines have based target blood pressure goals on age and comorbidities,501, 504, 536 the 2017 American College of Cardiology/American Heart Association (ACC/AHA) hypertension guideline incorporates underlying cardiovascular risk into decision making regarding treatment and generally recommends the same target blood pressure (i.e., less than 130/80 mm Hg) for all adults.1200 Many patients will require at least 2 drugs from different pharmacologic classes to achieve this blood pressure goal; the potential benefits of hypertension management and drug cost, adverse effects, and risks associated with the use of multiple antihypertensive drugs also should be considered when deciding a patient's blood pressure treatment goal.1200, 1220
For additional information on target levels of blood pressure and on monitoring therapy in the management of hypertension, see Blood Pressure Monitoring and Treatment Goals under Dosage: Hypertension, in Dosage and Administration in the Thiazides General Statement 40:28.20.
Prior to initiation of therapy with a β-blocker for heart failure†, patients who are receiving treatment that includes a cardiac glycoside, diuretic, and/or an angiotensin-converting enzyme (ACE) inhibitor should be stabilized.22, 40 Because of the potential for severe adverse effects (e.g., hypotension, bradycardia, fluid retention, worsening of heart failure),524 initiation of β-blocker therapy for heart failure and subsequent dosage adjustments should occur under very close medical supervision.36, 524 (See Heart Failure under Dosage and Administration: Dosage, in Carvedilol 24:24.) Treatment with a β-blocker should be initiated at a very low dosage (e.g., a bisoprolol fumarate dosage of 1.25 mg daily for 2-4 weeks or less has been recommended, although the lowest dose strength currently available in the US is 5 mg).22, 30, 524 It has been recommended that if the patient tolerates the initial dosage, bisoprolol fumarate dosage may be increased to 2.5 mg daily for 2-4 weeks and subsequent dosage then can be doubled every 2-4 weeks if tolerated.22, 30 If deterioration of heart failure (usually transient) becomes evident during titration of β-blocker therapy, the dosage of the concurrent diuretic should be increased40, 524 and the dosage of the β-blocker not escalated until manifestations of worsening heart failure (e.g., fluid retention) have stabilized.524 Should patients with heart failure experience symptomatic bradycardia (e.g., dizziness) or second- or third-degree heart block, the dosage of the β-blocker should be reduced.524 Initial difficulty in titrating the dosage of a β-blocker should not preclude subsequent attempts to successfully titrate the dosage.40
It should be recognized that symptomatic improvement may not be evident for 2-3 months after initiating therapy.22, 40 However, β-blockade may reduce the risk of disease progression even if symptomatic improvement is not evident.524 In clinical trials, dosages were not adjusted according to response but instead were increased as tolerated to a prespecified target dose (e.g., 5-10 mg once daily).22, 40 The maximum dosage of bisoprolol fumarate recommended by the American College of Cardiology Foundation (ACCF) and the American Heart Association (AHA) for the management of chronic heart failure is 10 mg once daily.524
Abrupt withdrawal of bisoprolol may exacerbate angina symptoms and/or precipitate myocardial infarction and ventricular arrhythmias in patients with coronary artery disease, or may precipitate thyroid storm in patients with thyrotoxicosis.1, 2 Therefore, patients receiving bisoprolol (especially those with ischemic heart disease) should be warned not to interrupt or discontinue therapy without consulting their clinician.1, 2 Because coronary artery disease is common and may be undiagnosed, abrupt withdrawal also should be avoided in patients receiving bisoprolol for other conditions (e.g., hypertension).1, 2 When bisoprolol is discontinued in patients with coronary artery disease or suspected thyrotoxicosis, the patient should be observed carefully; patients with coronary artery disease should be advised to temporarily limit their physical activity.1, 2 If exacerbation of angina occurs or acute coronary insufficiency develops after bisoprolol therapy is interrupted or discontinued, treatment with the drug should be reinstituted, at least temporarily.1, 2
If bisoprolol fumarate therapy, alone or combined with hydrochlorothiazide, is to be discontinued, dosage should be reduced gradually in a deliberate and progressive manner, if possible.1, 2, 3, 19 When such cessation of therapy is planned, the manufacturer recommends that therapy with the drug be withdrawn gradually over approximately 2 weeks.1, 2, 20 Patients should be monitored closely during this period and, if manifestations of withdrawal (e.g., angina, exacerbation of hypertension) develop, dosage should be increased or the drug reinstituted, at least temporarily.1, 2, 3
Dosage in Renal and Hepatic Impairment
Since pharmacokinetics of bisoprolol may be altered in patients with renal impairment (i.e., creatinine clearance less than 40 mL/minute) or hepatic impairment, the manufacturer states that bisoprolol fumarate should be initiated at 2.5 mg daily in such patients.1 If needed, dosage of bisoprolol fumarate should be increased with caution.1, 3 Limited data indicate that patients with severe renal impairment (i.e., creatinine clearances less than 20 mL/minute per 1.73 m2) generally should not receive bisoprolol fumarate dosages exceeding 10 mg once daily.4, 6, 8 Since limited data suggest that the drug is not removed by dialysis, the manufacturer states that patients undergoing dialysis do not require a supplemental dose afterward.1, 3 If progressive renal impairment develops in any patient receiving bisoprolol fumarate in fixed combination with hydrochlorothiazide, the manufacturer recommends that the combination be discontinued.2
Bisoprolol is a β1-selective adrenergic blocking agent.1, 2, 3, 6 Bisoprolol is related structurally to acebutolol, atenolol, and metoprolol in that the drugs contain substituents in the para position of the benzene ring; the presence of large substituents in the para position is believed to account in part for the selective β1-adrenergic blocking effect of these drugs.13, 14, 15, 16, 17 The commercially available drug is a racemic mixture of the 2 optical isomers; however, only the l -isomer of bisoprolol has substantial β-adrenergic blocking activity.1, 6, 12 The drug does not exhibit the intrinsic sympathomimetic activity seen with pindolol or the membrane-stabilizing activity possessed by propranolol or pindolol.1, 3, 4, 6, 7, 12 At low dosages, bisoprolol selectively inhibits response to adrenergic stimuli by competitively blocking cardiac β1-adrenergic receptors, while having little effect on the β2-adrenergic receptors of bronchial and vascular smooth muscle.1, 2, 3, 4, 7, 12 At high doses (e.g., 20 mg or higher), the selectivity of bisoprolol on β1-adrenergic receptors usually diminishes, and the drug will competitively inhibit β1- and β2-adrenergic receptors.1, 2, 3, 4, 7 The drug is commercially available as the fumarate.1, 2, 3
Additional Information
SumMon® (see Users Guide). For additional information on this drug until a more detailed monograph is developed and published, the manufacturer's labeling should be consulted. It is essential that the labeling be consulted for detailed information on the usual cautions, precautions, and contraindications.
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.
Routes | Dosage Forms | Strengths | Brand Names | Manufacturer |
|---|---|---|---|---|
Oral | Tablets, film-coated | 5 mg* | Bisoprolol Fumarate Tablets | |
Zebeta® (scored) | ||||
10 mg* | Bisoprolol Fumarate Tablets | |||
Zebeta® | Barr |
* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name
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 |
* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name
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40. Hunt SA, Baker DW, Chin MH et al. ACC/AHA guidelines for the management of chronic heart failure in the adult: A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee to Revise the 1995 Guidelines for the Evaluation and Management of Heart Failure). J Am Coll Cardiol . 2001. From ACC website. [Web]
41. Hjalmarson A, Goldstein S, Fagerberg B et al. Effects of controlled-release metoprolol on total mortality, hospitalizations, and well-being in patients with heart failure: the Metoprolol CR/XL Randomized Intervention Trial in Congestive Heart Failure (MERIT-HF). JAMA . 2000; 283:1295-1302. [PubMed 10714728]
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