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Generic Name: Bisoprolol Fumarate
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

Introduction

β1-selective adrenergic blocking agent.600 a

Uses for Zebeta

Hypertension

Management of hypertension as monotherapy or in combination with other classes of antihypertensive agents.1 2 3 4 5 6 7 500

β-Blockers generally not preferred for initial management of hypertension, 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

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Black hypertensive patients generally tend to respond better to monotherapy with calcium-channel blockers or thiazide diuretics than to β-blockers.45 53 54 500 501 504 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 of ischemic or cardiomyopathic origin in conjunction with cardiac glycosides, diuretics, and ACE inhibitors.22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38

Bisoprolol, carvedilol, and extended-release metoprolol succinate have been shown to be effective in reducing the risk of death in patients with chronic heart failure; however, these positive findings should not be considered indicative of β-adrenergic blocking agent class effect.55

Zebeta 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

  • Carefully monitor BP during initial titration or subsequent upward adjustment in dosage.500 501

  • When available, use evidence-based dosing information (i.e., dosages shown in randomized controlled trials to reduce complications of hypertension) to determine target dosages; target dosages usually can be achieved within 2–4 weeks but may take up to several months.501

  • Goal is to achieve and maintain optimal control of BP; individualize specific target BP based on consideration of multiple factors, including patient age and comorbidities, and currently available evidence from clinical studies.500 501

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
Bisoprolol/Hydrochlorothiazide Fixed-combination Therapy
Oral

Some experts state that the initial dosage is 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 recommend a usual dosage range of 2.5–10 mg daily.500

If intolerable adverse effects occur, consider dosage reduction; if adverse effects worsen or fail to resolve, may need to discontinue and switch to another antihypertensive drug class.501

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
Oral

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

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 and decrease dosage of β -blocker or temporarily discontinue β -blocker.40 Do not continue dosage titration until symptoms of worsening heart failure have stabilized.40 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.40

Prescribing Limits

Pediatric Patients

Hypertension
Bisoprolol/Hydrochlorothiazide Fixed-combination Therapy
Oral

Some experts state 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 recommended by ACC and AHA: 10 mg once daily.40

Special Populations

Hepatic Impairment

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

Renal Impairment

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

Clcr <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 Zebeta

Contraindications

  • Patients with sinus bradycardia, heart block greater than first degree, cardiogenic shock, or overt cardiac failure.1 2

  • Hypersensitivity to bisoprolol fumarate, any ingredient in the formulation, or sulfonamides.2

Warnings/Precautions

Warnings

Cardiac 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 cardiac failure occur; if cardiac 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 recommend 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

Clcr <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

Interactions for Zebeta

Not metabolized by isoenzyme CYP2D6.

Specific Drugs

Drug

Interaction

Comments

β-Adrenergic blocking agents

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

Zebeta 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 (Clcr <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 congestive cardiac 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.

* 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

Comparative Pricing

This pricing information is subject to change at the sole discretion of DS Pharmacy. This pricing information was updated 02/2015. Actual costs to patients will vary depending on the use of specific retail or mail-order locations and health insurance copays.

Bisoprolol Fumarate 10MG Tablets (UNICHEM PHARMACEUTICALS): 30/$37.99 or 90/$95.97

Bisoprolol Fumarate 5MG Tablets (UNICHEM PHARMACEUTICALS): 30/$35.99 or 90/$92.98

Bisoprolol-Hydrochlorothiazide 10-6.25MG Tablets (SANDOZ): 30/$22.99 or 90/$59.97

Bisoprolol-Hydrochlorothiazide 2.5-6.25MG Tablets (UNICHEM PHARMACEUTICALS): 90/$59.99 or 180/$105.97

Bisoprolol-Hydrochlorothiazide 5-6.25MG Tablets (UNICHEM PHARMACEUTICALS): 90/$19.96 or 180/$39.92

Zebeta 10MG Tablets (TEVA/WOMENS HEALTH): 30/$114.43 or 90/$337.86

Zebeta 5MG Tablets (TEVA/WOMENS HEALTH): 30/$114.43 or 90/$337.86

Ziac 10-6.25MG Tablets (TEVA/WOMENS HEALTH): 30/$113.99 or 90/$322.99

Ziac 2.5-6.25MG Tablets (TEVA/WOMENS HEALTH): 30/$114.63 or 90/$319.88

Ziac 5-6.25MG Tablets (TEVA/WOMENS HEALTH): 30/$115.00 or 90/$318.98

AHFS DI Essentials. © Copyright, 2004-2015, Selected Revisions February 17, 2015. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

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

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