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Nebivolol Hydrochloride

Class: beta-Adrenergic Blocking Agents
Chemical Name: (1RS,1′RS)-1,1′-[(2RS,2′SR)-bis(6-fluoro-3,4-dihydro-2H-1-benzopyran-2-yl)]- 2,2′-iminodiethanol hydrochloride
Molecular Formula: C22H25F2NO4•HCl
CAS Number: 152520-56-4
Brands: Bystolic

Medically reviewed by Drugs.com. Last updated on Jan 28, 2019.

Introduction

β-adrenergic blocking agent (β-blocker).1 2 3 4 5 6 7 8 9 10 11 20 24

Uses for Nebivolol Hydrochloride

Hypertension

Management of hypertension (alone or in combination with other classes of antihypertensive agents).1 2 3 4 5 6 10 11 24 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).29 501 502 503 504 515 523 524 527 800 1200 A 2017 ACC/AHA multidisciplinary hypertension guideline states that β-blockers used for ischemic heart disease that are also effective in lowering BP include bisoprolol, carvedilol, metoprolol succinate, metoprolol tartrate, nadolol, propranolol, and timolol.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.21 22 23 501 504 1200 However, diminished response to β-blockers is largely eliminated when administered concomitantly with a thiazide diuretic.500

Nebivolol Hydrochloride Dosage and Administration

General

  • Individualize dosage according to patient response.1

  • If long-term therapy is discontinued, reduce dosage gradually over a period of about 1–2 weeks.1 (See Abrupt Withdrawal of Therapy under Cautions.)

  • β1-Adrenergic blocking selectivity diminishes as dosage is increased beyond 10 mg.1

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 once daily without regard to meals.1

Frequent administration (i.e., daily divided doses) unlikely to be more beneficial than once-daily administration.1

Dosage

Available as nebivolol hydrochloride; dosage expressed in terms of nebivolol.1

Adults

Hypertension
Oral

Initially, 5 mg once daily, either alone or in combination with other antihypertensives.1 11 24 Increase at 2-week intervals (up to 40 mg daily) in patients whose BP is uncontrolled with the initial dosage.1 11 Some experts state usual dosage range is 5–40 mg once daily.1200

Prescribing Limits

Adults

Hypertension
Oral

Maximum 40 mg daily.1

Special Populations

Hepatic Impairment

Initially, 2.5 mg once daily in patients with moderate hepatic impairment (Child-Pugh class B).1 11 Increase dosage carefully, if necessary.1

Contraindicated in patients with severe hepatic impairment (Child-Pugh class C).1 6 (See Contraindications under Cautions.)

Renal Impairment

Initially, 2.5 mg once daily in patients with severe renal impairment (Clcr <30 mL/minute).1 11 Increase dosage carefully, if necessary.1

Geriatric Patients

Dosage adjustment not required.1

Poor CYP2D6 Metabolizers

No dosage adjustment required in poor metabolizers of CYP2D6 substrates.1 7

Cautions for Nebivolol Hydrochloride

Contraindications

  • Severe bradycardia.1

  • Heart block greater than first degree.1

  • Cardiogenic shock.1

  • Decompensated cardiac failure.1 (See Heart Failure under Cautions.)

  • Sick sinus syndrome (unless a functioning permanent pacemaker is present).1

  • Severe hepatic impairment (Child-Pugh class C).1

  • Known hypersensitivity to nebivolol or any ingredient in the formulation.1

Warnings/Precautions

Warnings

Abrupt Withdrawal of Therapy

Abrupt discontinuance of therapy is not recommended as it may exacerbate angina symptoms or precipitate MI and ventricular arrhythmias in patients with CAD.1 Gradually decrease dosage over a period of about 1–2 weeks; monitor patients carefully and advise patients to temporarily limit their physical activity during withdrawal of therapy.1 If exacerbation of angina occurs or acute coronary insufficiency develops, reinstitute therapy (at least temporarily).1

Heart Failure

Possible precipitation of heart failure.1

Avoid use in patients with overt heart failure; use cautiously in patients with inadequate cardiac function and, if necessary, in patients with well-compensated heart failure.1 If heart failure worsens, consider discontinuing therapy.1

Ischemic Heart Disease

Safety and efficacy in patients with angina pectoris or recent MI have not been established.1

Major Surgery

Possible increased risks associated with general anesthesia (e.g., severe hypotension, difficulty in restarting or maintaining a heart beat) have occurred in some patients who received β-blockers.1 Use with caution in patients undergoing major surgery involving general anesthesia, especially with myocardial-depressant anesthetics (e.g., cyclopropane, ether, trichloroethylene).1

Effects of β-blockers can be reversed by administration of β-agonists (e.g., dobutamine, isoproterenol).1

Bronchospastic Disease

Possible bronchospasm.1 Generally should not be used in patients with bronchospastic disease.1 2

Diabetes Mellitus and Hypoglycemia

Possible decreased signs and symptoms of hypoglycemia (e.g., tachycardia) and increased insulin-induced hypoglycemia.1

Use with caution in patients with history of spontaneous hypoglycemia and in patients with diabetes receiving hypoglycemic agents.1

Thyrotoxicosis

Signs of hyperthyroidism (e.g., tachycardia) may be masked.1 Possible exacerbation of hyperthyroidism or thyroid storm if therapy is abruptly withdrawn.1

Peripheral Vascular Disease

Possible precipitation or aggravation of arterial insufficiency.1 Use with caution.1

Interactions

Concomitant use with nondihydropyridine calcium-channel blocking agents (e.g. verapamil, diltiazem) requires caution.1 (See Specific Drugs under Interactions.)

General Precautions

Risk of Anaphylactic Reactions

Patients with a history of anaphylactic reactions to a variety of allergens may be more reactive to repeated accidental, diagnostic, or therapeutic challenges with allergens while taking β-blockers.1 Such patients may be unresponsive to usual doses of epinephrine.1

Pheochromocytoma

Use with caution in patients suspected of having pheochromocytoma; initiate therapy with α-adrenergic blocking agent before using any β-blocker.1

Specific Populations

Pregnancy

Category C.1

Lactation

Distributed into milk in rats; not known whether distributed into human milk.1 Discontinue nursing or drug.1

Pediatric Use

Safety and efficacy not established in children <18 years of age.1

Geriatric Use

No substantial differences in safety or efficacy relative to younger adults.1

Hepatic Impairment

Decreased clearance in patients with moderate hepatic impairment (Child-Pugh class B); use with caution.1 7 (See Hepatic Impairment under Dosage and Administration.)

Safety and efficacy not established in patients with severe hepatic impairment (Child-Pugh class C); use is contraindicated in these patients.1 (See Contraindications.)

Renal Impairment

Decreased clearance in patients with severe renal impairment (Clcr <30 mL/minute); use with caution.1 7 (See Renal Impairment under Dosage and Administration.)

Not specifically studied in patients undergoing dialysis; use with caution in these patients.1

Common Adverse Effects

Headache,1 2 3 4 5 13 fatigue,1 2 3 4 5 11 13 dizziness,1 2 3 4 5 11 13 diarrhea,1 3 4 nausea.1 3

Interactions for Nebivolol Hydrochloride

Metabolized by CYP2D6;1 7 11 does not inhibit CYP isoenzymes at clinically relevant concentrations.1

Drugs Affecting Hepatic Microsomal Enzymes

CYP2D6 inhibitors: Potential increased plasma nebivolol concentrations;1 11 monitor patients carefully and adjust dosage according to BP response.1

Specific Drugs

Drug

Interaction

Comments

Antiarrhythmic agents (e.g., amiodarone, disopyramide)

Possible conduction disturbances1 2

Use concomitantly with caution1 2 24

Antidiabetic agents (oral)

May mask symptoms of hypoglycemia (e.g., tachycardia)1

Use concomitantly with caution1

β-Blockers

Possible additive effects1

Concomitant use with other β-blockers not recommended1

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

Possible conduction disturbances1 2 27 28

Use concomitantly with caution;1 2 24 27 28 monitor BP and ECG with concomitant use1

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

Potential additive effects (e.g., hypotension, bradycardia)1 26

Monitor closely for symptoms (e.g., vertigo, syncope, postural hypotension)1 26

Charcoal (activated)

Pharmacokinetic interaction unlikely1

Cimetidine

Potential increased plasma nebivolol concentrations1 2 7 20 24

No apparent change in pharmacodynamics of nebivolol (e.g., BP, heart rate)2 7 20

Clonidine

Potential for increased rebound hypertension following discontinuance of clonidine25

If used concurrently, discontinue nebivolol therapy several days before clonidine therapy is to be gradually discontinued1 25

Digoxin

Possible additive negative effects on AV conduction and heart rate;1 increased risk of bradycardia1

Concomitant use did not affect pharmacokinetics of digoxin or nebivolol1 7 24

Use concomitantly with caution2

Diuretics (e.g., furosemide, hydrochlorothiazide, spironolactone)

Pharmacokinetic interactions unlikely1 7 24

Fluoxetine

Potential increased plasma nebivolol concentrations 1 11

Use concomitantly with caution1

Insulin

May mask symptoms of hypoglycemia (e.g., tachycardia)1

Use concomitantly with caution1

Losartan

Pharmacokinetic interaction unlikely1 7 24

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

Increased risk of hypotension and difficulty in restarting or maintaining heartbeat1

Closely monitor with concomitant use1

Paroxetine

Potential increased plasma nebivolol concentrations 1

Use concomitantly with caution1

Propafenone

Potential increased plasma nebivolol concentrations1

Use concomitantly with caution1

Quinidine

Potential increased plasma nebivolol concentrations1

Use concomitantly with caution1

Ramipril

Pharmacokinetic interaction unlikely1 7 24

Ranitidine

Pharmacokinetic interaction unlikely; no apparent change in pharmacodynamics of nebivolol (e.g., BP, heart rate) 1 7 20 24

Sildenafil

Additive effects on BP and pulse1

Potential decreased peak plasma concentrations of sildenafil; modest effect on peak plasma concentration and AUC of d-nebivolol1

Warfarin

No effect on PT or warfarin pharmacokinetics observed1 7 24

Nebivolol Hydrochloride Pharmacokinetics

Absorption

Bioavailability

Absolute bioavailability not determined.1

Following oral administration, mean peak plasma concentrations occur within approximately 1.5–4 hours.1

Food

Food does not alter pharmacokinetics; however, may slightly reduce nebivolol glucuronides.1

Distribution

Extent

Distributed into milk in rats; not known whether distributed into human milk.1

Plasma Protein Binding

Approximately 98% (mainly albumin).1

Elimination

Metabolism

Undergoes first-pass metabolism in the liver mainly via glucuronidation of the parent drug and, to a lesser extent, via N-dealkylation and oxidation by CYP2D6.1 2 7 11

Elimination Route

Excreted in urine (38%) and feces (44%), principally as metabolites;1 <0.5% eliminated in urine and feces as unchanged drug.7 11

Half-life

12 hours for d-nebivolol.1

Special Populations

Poor CYP2D6 metabolizers: Eliminated in urine (67%) and feces (13%), principally as metabolites.1 7 Half-life is 19 hours.1

Decreased clearance in patients with moderate hepatic impairment (Child-Pugh class B) or with severe renal impairment (Clcr <30 mL/minute).1 7

Stability

Storage

Oral

Tablets

Tight, light-resistant containers at 20–25° C.1

Actions

  • Inhibits response to adrenergic stimuli by competitively blocking β1-adrenergic receptors within the myocardium in extensive CYP2D6 metabolizers and at doses ≤10 mg.1 Blocks both β1- and β2-adrenergic receptors in poor CYP2D6 metabolizers and at doses >10 mg.1

  • Exhibits vasodilatory effects through stimulation of endothelial nitric oxide activity;2 7 8 9 10 24 precise mechanism of this effect not fully elucidated.7 9

  • Precise mechanism of hypotensive action not fully elucidated;1 may reduce BP by decreasing heart rate, myocardial contractility, and sympathetic outflow from the CNS; suppressing renin activity; and/or decreasing peripheral vascular resistance as a result of its vasodilating effects.1 11

  • Does not exhibit intrinsic sympathomimetic (β1-agonist) activity, membrane-stabilizing (local anesthetic) activity, or α1-adrenergic blocking activity at clinically relevant concentrations.1 7

  • Racemic mixture: d-isomer has substantial β-adrenergic blocking activity; l-isomer appears to be pharmacologically active, but precise contribution to pharmacologic effects not fully established.2 7

Advice to Patients

  • Importance of taking nebivolol exactly as prescribed.1

  • Importance of not interrupting or discontinuing therapy without consulting a clinician;1 patients should temporarily limit physical activity when discontinuing therapy.1

  • If a dose is missed, importance of patient taking only the next scheduled dose (i.e., the next dose should not be doubled).1

  • Importance of avoiding some activities (e.g., driving, operating machinery) until effects on the patient are known.1

  • Importance of warning patients receiving insulin or oral hypoglycemic agents and those subject to spontaneous hypoglycemia that β-blockers can mask some symptoms of hypoglycemia (e.g., tachycardia).1

  • Importance of immediately informing clinician at the first sign or symptom (e.g., weight gain, shortness of breath) of CHF.1

  • Importance of patients informing their anesthesiologist or dentist about nebivolol therapy before undergoing major surgery.1

  • Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as any concomitant illnesses.1

  • Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.1

  • Importance of informing patients of other important precautionary information.1 (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.

Nebivolol Hydrochloride

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Tablets

2.5 mg (of nebivolol)

Bystolic

Forest

5 mg (of nebivolol)

Bystolic

Forest

10 mg (of nebivolol)

Bystolic

Forest

20 mg (of nebivolol)

Bystolic

Forest

AHFS DI Essentials™. © Copyright 2019, Selected Revisions January 28, 2019. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, Maryland 20814.

References

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