(ne BIV oh lole)
Hypertension: Treatment of hypertension, alone or in combination with other agents
Guideline recommendations:
Hypertension: The 2014 guideline for the management of high blood pressure in adults (Eighth Joint National Committee [JNC 8]) recommends initiation of pharmacologic treatment to lower blood pressure for the following patients (JNC8 [James 2013]):
- Patients ≥60 years of age, with systolic blood pressure (SBP) ≥150 mm Hg or diastolic blood pressure (DBP) ≥90 mm Hg. Goal of therapy is SBP <150 mm Hg and DBP <90 mm Hg.
- Patients <60 years of age, with SBP ≥140 mm Hg or DBP ≥90 mm Hg. Goal of therapy is SBP <140 mm Hg and DBP <90 mm Hg.
- Patients ≥18 years of age with diabetes, with SBP ≥140 mm Hg or DBP ≥90 mm Hg. Goal of therapy is SBP <140 mm Hg and DBP <90 mm Hg.
- Patients ≥18 years of age with chronic kidney disease (CKD), with SBP ≥140 mm Hg or DBP ≥90 mm Hg. Goal of therapy is SBP <140 mm Hg and DBP <90 mm Hg.
Chronic kidney disease (CKD) and hypertension: Regardless of race or diabetes status, the use of an ACE inhibitor (ACEI) or angiotensin receptor blocker (ARB) as initial therapy is recommended to improve kidney outcomes. In the general nonblack population (without CKD) including those with diabetes, initial antihypertensive treatment should consist of a thiazide-type diuretic, calcium channel blocker, ACEI, or ARB. In the general black population (without CKD) including those with diabetes, initial antihypertensive treatment should consist of a thiazide-type diuretic or a calcium channel blocker instead of an ACEI or ARB.
Coronary artery disease (CAD) and hypertension: The American Heart Association, American College of Cardiology, and American Society of Hypertension (AHA/ACC/ASH) 2015 scientific statement for the treatment of hypertension in patients with CAD recommends the use of a beta blocker as part of a regimen in patients with hypertension and chronic stable angina with a history of prior MI. A BP target of <140/90 mm Hg is reasonable for the secondary prevention of cardiovascular events. A lower target BP (<130/80 mm Hg) may be appropriate in some individuals with CAD, previous MI, stroke or transient ischemic attack, or CAD risk equivalents (AHA/ACC/ASH [Rosendorff 2015]).
Hypersensitivity to nebivolol or any component of the formulation; severe bradycardia; heart block greater than first-degree (except in patients with a functioning artificial pacemaker); cardiogenic shock; decompensated heart failure; sick sinus syndrome (unless a permanent pacemaker is in place); severe hepatic impairment (Child-Pugh class C)
Canadian labeling: Additional contraindications (not in US labeling): Severe peripheral arterial circulatory disorders; sinoatrial block; rare hereditary conditions of Galactose intolerance, Lapp lactase deficiency or glucose-galactose malabsorption
Hypertension: Oral:
US labeling: Initial: 5 mg once daily; if initial response is inadequate, may be increased at 2-week intervals to a maximum dose of 40 mg once daily; usual dosage range (ASH/ISH [Weber, 2014]): 5 to 10 mg once daily
Canadian labeling: Initial: 5 mg once daily; if initial response is inadequate, may be increased at 2-week intervals to a maximum dose of 20 mg once daily; usual dosage range (ASH/ISH [Weber, 2014]): 5 to 10 mg once daily
Refer to adult dosing.
CrCl 50 to 80 mL/minute: There are no dosage adjustments provided in the manufacturer 's labeling; however, dose adjustment does not appear necessary. Following a single 5 mg dose in patients with CrCl 50 to 80 mL/minute, nebivolol clearance was unchanged.
CrCl 30 to 50 mL/minute: There are no dosage adjustments provided in the manufacturer 's labeling; however, dose adjustment is likely not necessary. Following a single 5 mg dose in patients with moderate impairment, reduction in nebivolol clearance was negligible (~17%) (Shaw 2005).
CrCl <30 mL/minute: Initial: 2.5 mg once daily; if initial response is inadequate, may increase cautiously.
Hemodialysis: There are no dosage adjustments provided in the manufacturer 's labeling (has not been studied). Due to lack of data, the Canadian labeling does not recommend use.
Mild impairment (Child-Pugh class A): There are no dosage adjustments provided in the manufacturer 's labeling; use caution.
Moderate impairment (Child-Pugh class B): Initial: 2.5 mg once daily; if initial response is inadequate, may increase cautiously
Severe impairment (Child-Pugh class C): Use is contraindicated.
May be administered with or without food.
Store at 20 ‚ °C to 25 ‚ °C (68 ‚ °F to 77 ‚ °F). Protect from light.
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Tablet, Oral:
Bystolic: 2.5 mg, 5 mg, 10 mg, 20 mg [contains fd&c blue #2 aluminum lake, fd&c yellow #6 aluminum lake, polysorbate 80]
Acetylcholinesterase Inhibitors: May enhance the bradycardic effect of Beta-Blockers. Monitor therapy
Alfuzosin: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy
Alpha-/Beta-Agonists (Direct-Acting): Beta-Blockers may enhance the vasopressor effect of Alpha-/Beta-Agonists (Direct-Acting). Epinephrine used as a local anesthetic for dental procedures will not likely cause clinically relevant problems. Some beta-adrenoceptor mediated effects of Alpha-/Beta-Agonists (Direct-Acting), including anti-anaphylactic effects of epinephrine, may be diminished by Beta-Blockers. Management: Cardioselective beta-blockers and lower doses of epinephrine may confer a more limited risk. Patients who may require acute subcutaneous epinephrine (e.g., bee sting kits) should probably avoid beta blockers. Exceptions: Dipivefrin. Consider therapy modification
Alpha1-Blockers: Beta-Blockers may enhance the orthostatic hypotensive effect of Alpha1-Blockers. The risk associated with ophthalmic products is probably less than systemic products. Monitor therapy
Alpha2-Agonists: May enhance the AV-blocking effect of Beta-Blockers. Sinus node dysfunction may also be enhanced. Beta-Blockers may enhance the rebound hypertensive effect of Alpha2-Agonists. This effect can occur when the Alpha2-Agonist is abruptly withdrawn. Management: Closely monitor heart rate during treatment with a beta blocker and clonidine. Withdraw beta blockers several days before clonidine withdrawal when possible, and monitor blood pressure closely. Recommendations for other alpha2-agonists are unavailable. Exceptions: Apraclonidine. Consider therapy modification
Amifostine: Blood Pressure Lowering Agents may enhance the hypotensive effect of Amifostine. Management: When amifostine is used at chemotherapy doses, blood pressure lowering medications should be withheld for 24 hours prior to amifostine administration. If blood pressure lowering therapy cannot be withheld, amifostine should not be administered. Consider therapy modification
Aminoquinolines (Antimalarial): May decrease the metabolism of Beta-Blockers. Monitor therapy
Amiodarone: May enhance the bradycardic effect of Beta-Blockers. Possibly to the point of cardiac arrest. Amiodarone may increase the serum concentration of Beta-Blockers. Monitor therapy
Amphetamines: May diminish the antihypertensive effect of Antihypertensive Agents. Monitor therapy
Anilidopiperidine Opioids: May enhance the bradycardic effect of Beta-Blockers. Anilidopiperidine Opioids may enhance the hypotensive effect of Beta-Blockers. Monitor therapy
Antipsychotic Agents (Phenothiazines): May enhance the hypotensive effect of Beta-Blockers. Beta-Blockers may decrease the metabolism of Antipsychotic Agents (Phenothiazines). Antipsychotic Agents (Phenothiazines) may decrease the metabolism of Beta-Blockers. Monitor therapy
Antipsychotic Agents (Second Generation [Atypical]): Blood Pressure Lowering Agents may enhance the hypotensive effect of Antipsychotic Agents (Second Generation [Atypical]). Monitor therapy
Barbiturates: May decrease the serum concentration of Beta-Blockers. Monitor therapy
Barbiturates: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy
Beta2-Agonists: Beta-Blockers (Beta1 Selective) may diminish the bronchodilatory effect of Beta2-Agonists. Of particular concern with nonselective beta-blockers or higher doses of the beta1 selective beta-blockers. Monitor therapy
Bradycardia-Causing Agents: May enhance the bradycardic effect of other Bradycardia-Causing Agents. Monitor therapy
Bretylium: May enhance the bradycardic effect of Bradycardia-Causing Agents. Bretylium may also enhance atrioventricular (AV) blockade in patients receiving AV blocking agents. Monitor therapy
Brimonidine (Topical): May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy
Bupivacaine: Beta-Blockers may increase the serum concentration of Bupivacaine. Monitor therapy
Calcium Channel Blockers (Nondihydropyridine): May enhance the hypotensive effect of Beta-Blockers. Bradycardia and signs of heart failure have also been reported. Calcium Channel Blockers (Nondihydropyridine) may increase the serum concentration of Beta-Blockers. Exceptions: Bepridil. Monitor therapy
Cardiac Glycosides: Beta-Blockers may enhance the bradycardic effect of Cardiac Glycosides. Monitor therapy
Ceritinib: Bradycardia-Causing Agents may enhance the bradycardic effect of Ceritinib. Management: If this combination cannot be avoided, monitor patients for evidence of symptomatic bradycardia, and closely monitor blood pressure and heart rate during therapy. Avoid combination
Cholinergic Agonists: Beta-Blockers may enhance the adverse/toxic effect of Cholinergic Agonists. Of particular concern are the potential for cardiac conduction abnormalities and bronchoconstriction. Management: Administer these agents in combination with caution, and monitor for conduction disturbances. Avoid methacholine with any beta blocker due to the potential for additive bronchoconstriction. Monitor therapy
CYP2D6 Inhibitors (Moderate): May increase the serum concentration of Nebivolol. Monitor therapy
CYP2D6 Inhibitors (Strong): May increase the serum concentration of Nebivolol. Monitor therapy
Diazoxide: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy
Dipyridamole: May enhance the bradycardic effect of Beta-Blockers. Monitor therapy
Disopyramide: May enhance the bradycardic effect of Beta-Blockers. Beta-Blockers may enhance the negative inotropic effect of Disopyramide. Monitor therapy
Dronedarone: May enhance the bradycardic effect of Beta-Blockers. Dronedarone may increase the serum concentration of Beta-Blockers. This likely applies only to those agents that are metabolized by CYP2D6. Management: Use lower initial beta-blocker doses; adequate tolerance of the combination, based on ECG findings, should be confirmed prior to any increase in beta-blocker dose. Consider therapy modification
DULoxetine: Blood Pressure Lowering Agents may enhance the hypotensive effect of DULoxetine. Monitor therapy
Ergot Derivatives: Beta-Blockers may enhance the vasoconstricting effect of Ergot Derivatives. Exceptions: Nicergoline. Consider therapy modification
Fingolimod: Beta-Blockers may enhance the bradycardic effect of Fingolimod. Management: Avoid the concomitant use of fingolimod and beta-blockers if possible. If coadministration is necessary, patients should have overnight continuous ECG monitoring conducted after the first dose of fingolimod. Monitor patients for bradycardia. Consider therapy modification
Floctafenine: May enhance the adverse/toxic effect of Beta-Blockers. Avoid combination
Grass Pollen Allergen Extract (5 Grass Extract): Beta-Blockers may enhance the adverse/toxic effect of Grass Pollen Allergen Extract (5 Grass Extract). More specifically, Beta-Blockers may inhibit the ability to effectively treat severe allergic reactions to Grass Pollen Allergen Extract (5 Grass Extract) with epinephrine. Some other effects of epinephrine may be unaffected or even enhanced (e.g., vasoconstriction) during treatment with Beta-Blockers. Consider therapy modification
Herbs (Hypertensive Properties): May diminish the antihypertensive effect of Antihypertensive Agents. Monitor therapy
Herbs (Hypotensive Properties): May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy
Hypotension-Associated Agents: Blood Pressure Lowering Agents may enhance the hypotensive effect of Hypotension-Associated Agents. Monitor therapy
Insulin: Beta-Blockers may enhance the hypoglycemic effect of Insulin. Monitor therapy
Ivabradine: Bradycardia-Causing Agents may enhance the bradycardic effect of Ivabradine. Monitor therapy
Lacosamide: Bradycardia-Causing Agents may enhance the AV-blocking effect of Lacosamide. Monitor therapy
Levodopa: Blood Pressure Lowering Agents may enhance the hypotensive effect of Levodopa. Monitor therapy
Lidocaine (Systemic): Beta-Blockers may increase the serum concentration of Lidocaine (Systemic). Monitor therapy
Lidocaine (Topical): Beta-Blockers may increase the serum concentration of Lidocaine (Topical). Monitor therapy
Mepivacaine: Beta-Blockers may increase the serum concentration of Mepivacaine. Monitor therapy
Methacholine: Beta-Blockers may enhance the adverse/toxic effect of Methacholine. Avoid combination
Methylphenidate: May diminish the antihypertensive effect of Antihypertensive Agents. Monitor therapy
Midodrine: Beta-Blockers may enhance the bradycardic effect of Midodrine. Monitor therapy
Molsidomine: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy
Naftopidil: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy
Nicergoline: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy
Nicorandil: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy
NIFEdipine: May enhance the hypotensive effect of Beta-Blockers. NIFEdipine may enhance the negative inotropic effect of Beta-Blockers. Monitor therapy
Nitroprusside: Blood Pressure Lowering Agents may enhance the hypotensive effect of Nitroprusside. Monitor therapy
Nonsteroidal Anti-Inflammatory Agents: May diminish the antihypertensive effect of Beta-Blockers. Monitor therapy
Obinutuzumab: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Management: Consider temporarily withholding blood pressure lowering medications beginning 12 hours prior to obinutuzumab infusion and continuing until 1 hour after the end of the infusion. Consider therapy modification
Pentoxifylline: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy
Phosphodiesterase 5 Inhibitors: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy
Propafenone: May increase the serum concentration of Beta-Blockers. Propafenone possesses some independent beta blocking activity. Monitor therapy
Prostacyclin Analogues: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy
Quinagolide: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy
Regorafenib: May enhance the bradycardic effect of Beta-Blockers. Monitor therapy
Reserpine: May enhance the hypotensive effect of Beta-Blockers. Monitor therapy
Rifamycin Derivatives: May decrease the serum concentration of Beta-Blockers. Exceptions: Rifabutin. Monitor therapy
Rivastigmine: May enhance the bradycardic effect of Beta-Blockers. Avoid combination
Ruxolitinib: May enhance the bradycardic effect of Bradycardia-Causing Agents. Management: Ruxolitinib Canadian product labeling recommends avoiding use with bradycardia-causing agents to the extent possible. Monitor therapy
Selective Serotonin Reuptake Inhibitors: May increase the serum concentration of Beta-Blockers. Exceptions: Citalopram; Escitalopram; FluvoxaMINE. Monitor therapy
Sulfonylureas: Beta-Blockers may enhance the hypoglycemic effect of Sulfonylureas. Cardioselective beta-blockers (eg, acebutolol, atenolol, metoprolol, and penbutolol) may be safer than nonselective beta-blockers. All beta-blockers appear to mask tachycardia as an initial symptom of hypoglycemia. Ophthalmic beta-blockers are probably associated with lower risk than systemic agents. Monitor therapy
Theophylline Derivatives: Beta-Blockers (Beta1 Selective) may diminish the bronchodilatory effect of Theophylline Derivatives. Management: Monitor for reduced theophylline efficacy during concomitant use with any beta-blocker. Beta-1 selective agents are less likely to antagonize theophylline than nonselective agents, but selectivity may be lost at higher doses. Monitor therapy
Tofacitinib: May enhance the bradycardic effect of Bradycardia-Causing Agents. Monitor therapy
Yohimbine: May diminish the antihypertensive effect of Antihypertensive Agents. Monitor therapy
Blood pressure, ECG; serum glucose (in diabetic patients)
1% to 10%:
Cardiovascular: Peripheral edema (1%), bradycardia ( ≤1%), chest pain ( ≤1%)
Central nervous system: Headache (6% to 9%), fatigue (dose related; 2% to 5%), dizziness (2% to 4%), insomnia (1%)
Dermatologic: Rash ( ≤1%)
Endocrine & metabolic: HDL levels decreased, hypercholesterolemia, triglyceride levels increased, uric acid levels increased
Gastrointestinal: Diarrhea (dose related; 2% to 3%), nausea (1% to 3%), abdominal pain
Hematologic: Platelet count decreased
Neuromuscular & skeletal: Paresthesia, weakness
Renal: BUN increased
Respiratory: Dyspnea ( ≤1%)
<1% (Limited to important or life-threatening): Acute pulmonary edema, acute renal failure, allergic vasculitis, angioedema, AST increased, ALT increased, AV block (second and third degree), bilirubin increased, bronchospasm, claudication, erectile dysfunction, hepatic function abnormal, hypersensitivity reaction, MI, peripheral ischemia, pruritus, psoriasis, Raynauds phenomenon, skin disorder, somnolence, syncope, thrombocytopenia, urticaria, vertigo, vomiting
Clearance was unchanged in patients with mild renal impairment and was reduced negligibly in patients with moderate renal impairment. However, clearance was reduced by 53% in patients with severe renal impairment.
Cmax increases 3-fold, AUC increases 10-fold, and apparent clearance decreases 86% in patients with moderate hepatic impairment.
Concerns related to adverse effects:
- Anaphylactic reactions: Use caution with history of severe anaphylaxis to a variety of allergens; patients taking beta-blockers may become more sensitive to repeated challenges. Treatment of anaphylaxis (eg, epinephrine) in patients taking beta-blockers may be ineffective or promote undesirable effects.
Disease-related concerns:
- Bronchospastic disease: In general, patients with bronchospastic disease should not receive beta-blockers; for patients with bronchospastic disease who do not respond to or cannot tolerate other therapies, initial low doses of beta1-selective nebivolol may be employed and used cautiously with close monitoring. Ensure patient has an inhaled beta2-agonist immediately available.
- Diabetes: Use with caution in patients with diabetes mellitus; may potentiate hypoglycemia and/or mask signs and symptoms.
- Heart failure (HF): Note: Nebivolol has not been shown to reduce morbidity or mortality in the general HF population; only beta-blockers proven to reduce mortality (ie, bisoprolol, carvedilol, or extended-release metoprolol succinate) should be used in the treatment of heart failure. Use with caution in patients with compensated HF and monitor for a worsening of the condition. If condition worsens, consider temporary discontinuation or dosage reduction of nebivolol. Patients should be stabilized on HF regimen prior to initiation of beta-blocker. Beta-blocker therapy should be initiated at very low doses with gradual and very careful titration. Adjustment of other medications (ACE inhibitors and/or diuretics) may be required.
- Hepatic impairment: Use with caution in patients with hepatic impairment; dosage adjustment required with moderate impairment (Child-Pugh class B). Use is contraindicated in patients with Child-Pugh class C hepatic impairment.
- Myasthenia gravis: Use with caution in patients with myasthenia gravis.
- Peripheral vascular disease (PVD) and Raynauds disease: Can precipitate or aggravate symptoms of arterial insufficiency in patients with PVD and Raynaud's disease. Use with caution and monitor for progression of arterial obstruction. Canadian labeling contraindicates use in severe peripheral vascular disease.
- Pheochromocytoma (untreated): Adequate alpha-blockade is required prior to use of any beta-blocker.
- Psoriasis: Beta-blocker use has been associated with induction or exacerbation of psoriasis, but cause and effect have not been firmly established.
- Psychiatric disease: Use with caution in patients with a history of psychiatric illness; may cause or exacerbate CNS depression.
- Renal impairment: Use with caution in patients with renal impairment; dosage adjustment required with severe renal impairment (CrCl <30 mL/minute). Nebivolol has not been evaluated in dialysis-dependent patients.
- Thyroid disease: May mask signs of hyperthyroidism (eg, tachycardia). If thyrotoxicosis is suspected, carefully manage and monitor; abrupt withdrawal may exacerbate symptoms of hyperthyroidism or precipitate thyroid storm.
Concurrent drug therapy issues:
- Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.
Special populations:
- Elderly: Bradycardia may be observed more frequently in elderly patients (>65 years of age); dosage reductions may be necessary.
Other warnings/precautions:
- Abrupt withdrawal: Beta-blocker therapy should not be withdrawn abruptly (particularly in patients with coronary artery disease), but gradually tapered over 1-2 weeks to avoid acute tachycardia, hypertension, and/or ischemia. Severe exacerbation of angina, ventricular arrhythmias, and myocardial infarction (MI) have been reported following abrupt withdrawal of beta-blocker therapy. Temporary but prompt resumption of beta-blocker therapy may be indicated with worsening of angina or acute coronary insufficiency.
- Major surgery: Chronic beta-blocker therapy should not be routinely withdrawn prior to major surgery.
C
Adverse events have been observed in some animal reproduction studies. Adverse events, such as fetal/neonatal bradycardia, hypoglycemia, reduced birth weight, have been observed following in utero exposure to beta-blockers as a class. Adequate facilities for monitoring infants at birth is generally recommended.
Untreated chronic maternal hypertension and preeclampsia are also associated with adverse events in the fetus, infant, and mother (ACOG 2015; Magee 2014). Although beta-blockers may be used when treatment of hypertension in pregnancy is indicated, agents other than nebivolol are preferred (ACOG 2013; Magee 2014; Regitz-Zagrosek 2011).
Highly-selective inhibitor of beta1-adrenergic receptors; at doses ≤10 mg nebivolol preferentially blocks beta1-receptors. Nebivolol, unlike other beta-blockers, also produces an endothelium-derived nitric oxide-dependent vasodilation resulting in a reduction of systemic vascular resistance.
Rapid
Vd: 8 to 12 L/kg
Hepatic; via glucuronidation and CYP2D6; extensive first-pass metabolism to multiple active metabolites with variable activity
Urine (extensive metabolizers: 38%; poor metabolizers: 67%; <0.5% of total dose as unchanged drug); feces (extensive metabolizers: 44%; poor metabolizers: 13%; <0.5% of total dose as unchanged drug)
1.5 to 4 hours
Terminal: 12 hours (extensive metabolizers) or 19 hours (poor metabolizers); up to 32 hours has been reported in poor metabolizers (Mangrella, 1998).
~98%, primarily to albumin
- Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)
- Patient may experience headache or loss of strength and energy. Have patient report immediately to prescriber signs of low blood sugar (dizziness, headache, fatigue, feeling weak, shaking, a fast heartbeat, confusion, hunger, or sweating), angina, severe dizziness, passing out, shortness of breath, excessive weight gain, swelling of arms or legs, arrhythmia, bradycardia, or burning or numbness feeling (HCAHPS).
- Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.
Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for healthcare professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience and judgment in diagnosing, treating and advising patients.