Zebeta - Drug Monograph

Introduction

Zebeta (bisoprolol fumarate) is a cardioselective beta-1 adrenergic receptor blocking agent used primarily in the management of hypertension and heart failure. As a second-generation beta-blocker, it offers improved selectivity for cardiac beta-1 receptors compared to non-selective beta-blockers, potentially resulting in fewer pulmonary and metabolic side effects.

Mechanism of Action

Bisoprolol competitively blocks beta-1 adrenergic receptors in the heart and vascular smooth muscle. This inhibition results in:

• Decreased heart rate (negative chronotropy)
• Reduced myocardial contractility (negative inotropy)
• Slowed atrioventricular conduction
• Decreased cardiac output
• Reduced renin secretion from the kidneys

The drug's high beta-1 selectivity (approximately 75:1 ratio of beta-1 to beta-2 affinity) distinguishes it from non-selective beta-blockers, though this selectivity diminishes at higher doses.

Indications

FDA-approved indications:

• Management of hypertension (alone or in combination with other antihypertensive agents)
• Chronic stable heart failure (NYHA Class II-III) with reduced ejection fraction, in combination with ACE inhibitors, diuretics, and optionally digitalis

Off-label uses may include:

• Stable angina pectoris
• Supraventricular arrhythmias
• Migraine prophylaxis

Dosage and Administration

• Initial dose: 2.5-5 mg once daily
• Maintenance dose: 2.5-10 mg once daily
• Maximum dose: 20 mg daily (though doses >10 mg provide little additional benefit)

• Initial dose: 1.25 mg once daily
• Titration: Double dose every 2-4 weeks as tolerated
• Target maintenance dose: 10 mg once daily

• Renal impairment: CrCl <40 mL/min - start with 2.5 mg daily
• Hepatic impairment: Use with caution; consider lower starting dose
• Geriatric patients: Initiate at lower end of dosing range
• Pediatric patients: Safety and effectiveness not established

Pharmacokinetics

Contraindications

• Severe bradycardia (heart rate <50 bpm)
• Heart block greater than first degree (without permanent pacemaker)
• Cardiogenic shock
• Decompensated cardiac failure
• Sick sinus syndrome
• Severe bronchial asthma or severe COPD
• Hypersensitivity to bisoprolol or any component of the formulation

Warnings and Precautions

• May precipitate heart failure in patients with compensated cardiac function
• Abrupt withdrawal may cause exacerbation of angina or myocardial infarction
• Can mask signs of hypoglycemia in diabetics
• May reduce effectiveness of glucagon in treating hypoglycemia

• Although cardioselective, caution required in patients with bronchospastic disease
• Beta-1 selectivity is dose-dependent and may be lost at higher doses

• Can exacerbate symptoms of peripheral arterial insufficiency

• Chronic beta-blocker therapy should generally be continued perioperatively
• Consideration for anesthetic agents that depress myocardial function

• May mask signs of hyperthyroidism
• Can cause depression or sleep disturbances
• Use with caution in patients with psoriasis

Drug Interactions

• Verapamil, diltiazem: Additive bradycardia and AV block
• Digoxin: Enhanced bradycardic effect
• Clonidine: Exaggerated rebound hypertension upon withdrawal
• Antiarrhythmics (Class I): Increased risk of arrhythmias
• Insulin and oral hypoglycemics: Masked hypoglycemic symptoms, altered glucose metabolism

• CYP3A4 inhibitors (ketoconazole, macrolides): May increase bisoprolol levels
• NSAIDs: May decrease antihypertensive effect
• Sympathomimetics: Mutual antagonism of effects

Adverse Effects

• Fatigue (3-11%)
• Dizziness (6-10%)
• Headache (6-9%)
• Bradycardia (3-7%)
• Diarrhea (3-6%)
• Cold extremities (2-5%)

• Heart failure exacerbation
• Bronchospasm
• Depression
• Sexual dysfunction
• Worsening of peripheral vascular disease
• Hypoglycemia
• Vision disturbances

Monitoring Parameters

• Blood pressure and heart rate
• ECG (assess for conduction abnormalities)
• Renal and hepatic function
• Blood glucose in diabetics
• Signs/symptoms of heart failure

• Blood pressure at each visit until controlled, then periodically
• Heart rate (ensure >50 bpm)
• Signs of fluid retention or heart failure exacerbation
• Respiratory status in patients with pulmonary disease
• Mental status changes
• Peripheral circulation

• Hypertension: BP <140/90 mmHg (individualized based on patient factors)
• Heart failure: Improved functional status, reduced hospitalizations

Patient Education

• Take medication at the same time each day, with or without food
• Do not abruptly discontinue medication without physician guidance
• Rise slowly from sitting/lying position to minimize dizziness
• Monitor weight regularly and report sudden increases
• Report any shortness of breath, excessive fatigue, or swelling
• Inform all healthcare providers about bisoprolol use
• Use caution with alcohol and other sedating medications
• Diabetic patients should monitor blood glucose regularly
• Be aware that medication may affect ability to drive or operate machinery
• Store at room temperature away from moisture and heat

• Take as soon as remembered unless close to next dose
• Do not double doses

References

1. Frishman WH. Bisoprolol: a new beta-adrenoceptor blocking agent. Am J Cardiol. 1991;67(16):43D-46D. 2. FDA Prescribing Information: Zebeta (bisoprolol fumarate). 2021. 3. The Cardiac Insufficiency Bisoprolol Study II (CIBIS-II). Lancet. 1999;353(9146):9-13. 4. Williams B, et al. 2018 ESC/ESH Guidelines for the management of arterial hypertension. Eur Heart J. 2018;39(33):3021-3104. 5. Yancy CW, et al. 2017 ACC/AHA/HFSA Focused Update of the 2013 ACCF/AHA Guideline for the Management of Heart Failure. J Am Coll Cardiol. 2017;70(6):776-803. 6. McDonagh TA, et al. 2021 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure. Eur Heart J. 2021;42(36):3599-3726. 7. Lexicomp Online, Lexi-Drugs. Bisoprolol. Wolters Kluwer Clinical Drug Information, Inc. 2023. 8. Micromedex Solutions. Bisoprolol. Truven Health Analytics, Inc. 2023.