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
Introduction
β-adrenergic blocking agent.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
One of several preferred initial therapies in hypertensive patients with heart failure, postmyocardial infarction, high CHD risk, and/or diabetes mellitus.12
Can be used as monotherapy for initial management of uncomplicated hypertension; however, thiazide diuretics are preferred by JNC 7.12
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
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.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
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
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 Cardiac 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
Cardiac Failure
Possible precipitation of CHF.1
Avoid use in patients with overt CHF; 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-adrenergic blocking agents.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-adrenergic blocking agents 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-adrenergic blocking agents.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-adrenergic blocking agent.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-Adrenergic blocking agents | Possible additive effects1 | Concomitant use with other β-adrenergic blocking agents 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
ActionsActions
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-adrenergic blocking agents 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.
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 |
Comparative Pricing
This pricing information is subject to change at the sole discretion of DS Pharmacy. This pricing information was updated 03/2011. Actual costs to patients will vary depending on the use of specific retail or mail-order locations and health insurance copays.
Bystolic 10MG Tablets (FOREST): 30/$69.99 or 90/$193.95
Bystolic 2.5MG Tablets (FOREST): 30/$67.77 or 90/$186.96
Bystolic 20MG Tablets (FOREST): 30/$68.98 or 90/$184.7
Bystolic 5MG Tablets (FOREST): 30/$67.77 or 90/$182.29
Disclaimer
This report on medications is for your information only, and is not considered individual patient advice. Because of the changing nature of drug information, please consult your physician or pharmacist about specific clinical use.
The American Society of Health-System Pharmacists, Inc. and Drugs.com represent that the information provided hereunder was formulated with a reasonable standard of care, and in conformity with professional standards in the field. The American Society of Health-System Pharmacists, Inc. and Drugs.com make no representations or warranties, express or implied, including, but not limited to, any implied warranty of merchantability and/or fitness for a particular purpose, with respect to such information and specifically disclaims all such warranties. Users are advised that decisions regarding drug therapy are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and the information is provided for informational purposes only. The entire monograph for a drug should be reviewed for a thorough understanding of the drug's actions, uses and side effects. The American Society of Health-System Pharmacists, Inc. and Drugs.com do not endorse or recommend the use of any drug. The information is not a substitute for medical care.
AHFS Drug Information. © Copyright, 1959-2011, Selected Revisions July 2009. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.
References
1. Forest Laboratories, Inc. Bystolic (nebivolol) tablets prescribing information. St. Louis, MO; 2008 Aug.
2. Veverka A, Nuzum DS, Jolly JL. Nebivolol: A third-generation β-adrenergic blocker. Ann Pharmacother. 2006; 40:1353-60. [PubMed 16822893]
3. Weiss RJ, Weber MA, Carr AA et al. A randomized, double-blind, placebo-controlled parallel-group study to assess the efficacy and safety of nebivolol, a novel β-blocker, in patients with mild to moderate hypertension. J Clin Hypertens. 2007; 9:667-76.
4. Saunders E, Smith WB, DeSalvo KB et al. The efficacy and tolerability of nebivolol in hypertensive African American patients. J Clin Hypertens. 2007; 9:866-75.
5. Gradman AH. Addition of the β-blocker nebivolol to ongoing therapy in the management of mild-moderate hypertension. Poster presentation from American Society of Hypertension 22nd Annual Meeting; Chicago, IL; May 19-22, 2007.
6. Forest Laboratories, Inc., St. Louis, MO: Personal communication.
7. Prisant LM. Nebivolol: pharmacologic profile of an ultraselective, vasodilatory β1-blocker. J Clin Pharmacol. 2008; 48:225-39. [PubMed 18083889]
8. Mason RP, Kalinowski L, Jacob RF et al. Nebivolol reduces nitroxidative stress and restores nitric oxide bioavailability in endothelium of black Americans. Circulation. 2005; 112:3795-801. [PubMed 16330685]
9. Dessy C, Saliez J, Ghisdal P et al. Endothelial B3-adrenoreceptors mediate nitric oxide-dependent vasorelaxation of coronary microvessels in response to the third-generation β-blocker nebivolol. Circulation. 2005; 112:1198-205. [PubMed 16116070]
10. Rosei EA, Rizzoni D. Metabolic profile of nebivolol, a β-adrenoceptor antagonist with unique characteristics. Drugs. 2007; 67:1097-107. [PubMed 17521213]
11. Anon. Nebivolol (Bystolic) for hypertension. Med Lett Drugs Ther. 2008; 50:17-9. [PubMed 18323772]
12. National Heart, Lung, and Blood Institute National High Blood Pressure Education Program. The seventh report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC VII) Express. Bethesda, MD: May 14 2003. From NIH website. (). (Also published in JAMA. 2003; 289.)
13. Van Nueten L, Taylor FR, Robertson JL.. Nebivolol vs. atenolol and placebo in essential hypertension: a double-blind randomised trial. J Hum Hypertens. 1998; 12:135-40. [PubMed 9504355]
14. Uhlir O, Feifusa M, Havanek K et al. Nebivolol versus metoprolol in the treatment of hypertension. Drug Invest. 1991; 3(Suppl):107.
15. Rosei EA, Rizzoni D, Comini S et al. Evaluation of the efficacy and tolerability of nebivolol versus lisinopril in the treatment of essential arterial hypertension: a randomized, multicentre, double-blind study. Blood Pressure 2003; (Suppl 1): 30-35. [PubMed 21067346]
16. Van Bortel LM, Bulpitt CJ, Fici F. Quality of life and antihypertensive effect with nebivolol and losartan. Am J Hypertens. 2005; 18:1060-6. [PubMed 16296572]
17. Van Nueten LM. , Schelling A, Verommen C et al. Nebivolol vs enalapril in the treatment of essential hypertension: a double-blind randomised trial. J Hum Hypertens. 1997; 11:813-9. [PubMed 9468009]
18. Van Nueten LM. , Lacouriere Y, Vyssoulis G et al. Nebivolol versus nifedipine in the treatment of essential hypertension: A double-blind, randomized, comparative trial. Am J Ther. 1998; 5:237-43. [PubMed 10099065]
19. Mazza A. , Gil-Extremera B, Maldonato A et al. Nebivolol vs amlodipine as first-line treatment of essential arterial hypertension in the elderly. Blood Press. 2002; 11:182-8. [PubMed 12126265]
20. Kamali F, Howes A, Thomas SH et al. A pharmacokinetic and pharmacodynamic interaction study between nebivolol and the H2-receptor antagonists cimetidine and ranitidine. Br J Clin Pharmacol. 1997; 43:201-4. [PubMed 9131955]
21. Douglas JG, Bakris GL, Epstein M et al. Management of high blood pressure in African Americans: Consensus statement of the Hypertension in African Americans Working Group of the International Society on Hypertension in Blacks. Arch Intern Med. 2003; 163:525-41. [IDIS 494836] [PubMed 12622600]
22. Wright JT, Dunn JK, Cutler JA et al. Outcomes in hypertensive black and nonblack patients treated with chlorthalidone, amlodipine, and lisinopril. JAMA. 2005; 293:595-607.
23. Neaton JD, Kuller LH. Diuretics are color blind. JAMA. 2005; 293:1663-6. [IDIS 531056] [PubMed 15811986]
24. Gray CL, Ndefo UA. Nebivolol: a new antihypertensive agent. Am J Health-Syst Pharm. 2008; 65:1125-33. [PubMed 18541682]
25. Boehringer Ingelheim. Catapres (clonidine hydrochloride) tablets prescribing information. Ridgefield, CT; 2007 Jan 5.
26. King Pharmaceuticals, Inc. Corgard (nadolol) tablets prescribing information. Bristol, TN; 2007 Jul.
27. Biovail Pharmaceuticals, Inc. Cardizem (diltiazem hydrochloride) capsules prescribing information. Bridgewater, NJ; 2001 Aug.
28. Pfizer. Calan (verapamil hydrochloride) tablets prescribing information. New York, NY; 2006 May.
More Nebivolol Hydrochloride resources
- Nebivolol Hydrochloride Side Effects (in more detail)
- Nebivolol Hydrochloride Dosage
- Nebivolol Hydrochloride Use in Pregnancy & Breastfeeding
- Nebivolol Hydrochloride Drug Interactions
- Nebivolol Hydrochloride Support Group
- 85 Reviews for Nebivolol Hydrochloride - Add your own review/rating
Compare Nebivolol Hydrochloride with other medications
- High Blood Pressure
- Mitral Valve Prolapse
No comments:
Post a Comment