Nebivolol - a selective B-1 blocker for Hypertension

Nebivolol is a selective Beta-1 receptor blocker, especially when used in doses of less than 10 mg per day. It is indicated for the treatment of hypertension. Beta-blockers are not considered first-line drugs for the treatment of hypertension. However, patients with hypertension and cardiovascular disease are the best candidates for the use of beta-blockers.

Nebivolol Dose in Adults

Nebivolol is given in a starting dose of 5 mg once daily. The dose is titratedd at 2-weeks intervals to a maximum dose of 40 mg once daily.

Nebivolol Dose in Childrens

Nebivolol has not been studied in pediatric patients, however, because it does not have any negative effects on the metabolism, nebivolol may be considered in children with hypertension.

Pregnancy Risk Factor C

Beta-blockers have been linked to fetal hypoglycemia and bradycardia.
Rarely, there has been fatal bradycardia after utero exposure.
However, preeclampsia and maternal hypertension are associated with adverse maternal and fetal outcomes.
The ACOG recommends the use of beta-blockers in pregnancy when other options are not available.
Agents other than nebivolol should also be considered. (Download ACOG recommendations in pregnancy here)

Nebivolol during breastfeeding

It is unknown if nebivolol can be excreted into breastmilk.
The manufacturer doesn't recommend nebivolol during pregnancy due to its potentially dangerous adverse effects on the neonate, such as bradycardia.

Nebivolol Dose in Renal Disease:

eGFR of 30 ml/min/1.73m2 or more: No dose adjustment necessary
eGFR of 30 mL/minute/1.73m2: 2.5 mg once daily, may increase the dose cautiously.
Patients on Hemodialysis: No dose adjustment has been provided by the manufacturer.

Nebivolol Dose in Liver Disease:

Mild hepatic impairmeent (Child Class A): No dose adjustment required in mild hepatic impairment
Moderate hepatic impairment (Child Class B): 2.5 mg once daily. Increase the dose cautiously.
Severe impairment (Child class C): Contraindicated in severe hepatic impairment.

Side Effects of Nebivolol

Cardiovascular: Peripheral edema, bradycardia, and chest pain.
Central nervous system: Headache, fatigue, dizziness, insomnia, and paresthesia
Dermatologic: Skin rash
Endocrine & metabolic: Decreased HDL cholesterol levels, Increases total cholesterol, increased serum triglycerides, and increased uric acid levels
Gastrointestinal: Diarrhea, nausea, and abdominal pain
Hematologic & oncologic: Thrombocytopenia
Neuromuscular & skeletal: Weakness
Renal: Increased blood urea nitrogen
Respiratory: Dyspnea

Less common side effects:

Acute pulmonary edema, acute renal failure, angioedema, atrioventricular block (second and third degree), bronchospasm, claudication, erectile dysfunction, increased serum ALT, increased serum AST, increased serum bilirubin, pruritus, psoriasis, Raynaud's phenomenon, syncope, vertigo, and vomiting

Contraindication to Nebivolol

Allergy to the drug (nebivolol), or any component of its formulation
Bradycardia severe
Heart block other that first-degree
Cardiogenic shock
Heart failure that has been decompensated
Sick sinus syndrome
Severe decompensated hepatitis (Child-Pugh Class C)
Severe peripheral arterial disease
Galactose intolerance
Lactase deficiency in Lapp or glucose-galactose malabsorption

Warnings/Precautions

Asthma and Bronchospastic disease: Patients with Allergic airway disease (also known as Asthma) should not be advised to Beta Bockers.
Low dose selective beta blockers such as nebivolol, may be used if the benefits outweigh any risks.
Patients must be closely monitored and inhaled beta-agonists must be available immediately.
Use with caution in Diabetes: Nebivolol may potentiate hypoglycemia and mask signs and symptoms of hypoglycemia which may be serious.
Heart failure: Nebivolol may lead to worsening symptoms of heart failure. You should start slowly and increase the dose with careful monitoring.

Nebivolol is not effective in reducing mortality or morbidity in patients with Heart Failure. The only beta-blockers that have been proven to reduce mortality include bisoprolol, carvedilol, or extended-release metoprolol succinate. Before initiating beta-blockers, patients must be stable.

Severe liver disease (Child C) is a contraindication for Nebivolol. The dose should be decreased in moderate hepatic impairment.
Patients with myasthenia gravis should be treated with caution.
Patients with Raynaud disease or peripheral arterial disease may experience symptoms such as arterial insufficiency that can be exacerbated by Nebivolol.
Pheochromocytoma - Before using a beta-blocker in patients suffering from pheochromocytoma a patient must first be prescribed an alpha blocker.
Beta blockers may exacerbate the symptoms of Psoriasis.
Take care when treating thyroid disease and renal impairment. Thyroid crisis can be caused by abrupt withdrawal of beta-blockers in patients suffering from thyrotoxicosis.
Beta blockers should not be routinely withdrawn prior to surgery.

Caution! Abrupt withdrawal of a beta blocker, especially in patients with coronary artery disease may result in hypertension, tachycardia, angina, ventricular arrhythmias, and myocardial infarction. It should be tapered gradually over a period of 1-2 weeks. If a patient develops these symptoms, the beta blocker must be resumed temporarily.

Nebivolol: Drug Interaction

Risk Factor C (Monitor therapy)
Acetylcholinesterase Inhibitors	May enhance the bradycardic effect of Beta-Blockers.
Alfuzosin	May enhance the hypotensive effect of Blood Pressure Lowering Agents.
Alpha1-Blockers	Beta-Blockers may enhance the orthostatic hypotensive effect of Alpha1Blockers. The risk associated with ophthalmic products is probably less than systemic products.
Aminoquinolines (Antimalarial)	May decrease the metabolism of Beta-Blockers.
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.
Amphetamines	May diminish the antihypertensive effect of Antihypertensive Agents.
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.
Antipsychotic Agents (Second Generation [Atypical])	Blood Pressure Lowering Agents may enhance the hypotensive effect of Antipsychotic Agents (Second Generation [Atypical]).
Barbiturates	May decrease the serum concentration of Beta-Blockers.
Barbiturates	May enhance the hypotensive effect of Blood Pressure Lowering Agents.
Benperidol	May enhance the hypotensive effect of Blood Pressure Lowering Agents.
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.
Bradycardia-Causing Agents	May enhance the bradycardic effect of other Bradycardia-Causing Agents.
Bretylium	May enhance the bradycardic effect of Bradycardia-Causing Agents. Bretylium may also enhance atrioventricular (AV) blockade in patients receiving AV blocking agents.
Brigatinib	May diminish the antihypertensive effect of Antihypertensive Agents. Brigatinib may enhance the bradycardic effect of Antihypertensive Agents.
Brimonidine (Topical)	May enhance the hypotensive effect of Blood Pressure Lowering Agents.
Bupivacaine	Beta-Blockers may increase the serum concentration of Bupivacaine.
Calcium Channel Blockers (Nondihydropyridine)	May enhance the hypotensive effect of BetaBlockers. Bradycardia and signs of heart failure have also been reported. Calcium Channel Blockers (Nondihydropyridine) may increase the serum concentration of Beta-Blockers. Exceptions: Bepridil.
Cardiac Glycosides	Beta-Blockers may enhance the bradycardic effect of Cardiac Glycosides.
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.
CYP2D6 Inhibitors (Moderate)	May increase the serum concentration of Nebivolol.
CYP2D6 Inhibitors (Strong)	May increase the serum concentration of Nebivolol.
Dexmethylphenidate	May diminish the therapeutic effect of Antihypertensive Agents.
Diazoxide	May enhance the hypotensive effect of Blood Pressure Lowering Agents.
Dipyridamole	May enhance the bradycardic effect of Beta-Blockers.
Disopyramide	May enhance the bradycardic effect of Beta-Blockers. Beta-Blockers may enhance the negative inotropic effect of Disopyramide.
DULoxetine	Blood Pressure Lowering Agents may enhance the hypotensive effect of DULoxetine.
EPINEPHrine (Nasal)	Beta-Blockers (Beta1 Selective) may diminish the therapeutic effect of EPINEPHrine (Nasal).
EPINEPHrine (Oral Inhalation)	Beta-Blockers (Beta1 Selective) may diminish the therapeutic effect of EPINEPHrine (Oral Inhalation).
Epinephrine (Racemic)	Beta-Blockers (Beta1 Selective) may diminish the therapeutic effect of Epinephrine (Racemic).
EPINEPHrine (Systemic)	Beta-Blockers (Beta1 Selective) may diminish the therapeutic effect of EPINEPHrine (Systemic).
Herbs (Hypertensive Properties)	May diminish the antihypertensive effect of Antihypertensive Agents.
Herbs (Hypotensive Properties)	May enhance the hypotensive effect of Blood Pressure Lowering Agents.
Hypotension-Associated Agents	Blood Pressure Lowering Agents may enhance the hypotensive effect of Hypotension-Associated Agents.
Insulins	Beta-Blockers may enhance the hypoglycemic effect of Insulins.
Ivabradine	Bradycardia-Causing Agents may enhance the bradycardic effect of Ivabradine.
Lacosamide	Bradycardia-Causing Agents may enhance the AV-blocking effect of Lacosamide.
Levodopa-Containing Products	Blood Pressure Lowering Agents may enhance the hypotensive effect of Levodopa-Containing Products.
Lidocaine (Systemic)	Beta-Blockers may increase the serum concentration of Lidocaine (Systemic).
Lidocaine (Topical)	Beta-Blockers may increase the serum concentration of Lidocaine (Topical).
Lormetazepam	May enhance the hypotensive effect of Blood Pressure Lowering Agents.
Mepivacaine	Beta-Blockers may increase the serum concentration of Mepivacaine.
Methoxyﬂurane	May enhance the hypotensive effect of Beta-Blockers.
Methylphenidate	May diminish the antihypertensive effect of Antihypertensive Agents.
Midodrine	May enhance the bradycardic effect of Bradycardia-Causing Agents.
Molsidomine	May enhance the hypotensive effect of Blood Pressure Lowering Agents.
Naftopidil	May enhance the hypotensive effect of Blood Pressure Lowering Agents.
Nicergoline	May enhance the hypotensive effect of Blood Pressure Lowering Agents.
Nicorandil	May enhance the hypotensive effect of Blood Pressure Lowering Agents.
NIFEdipine	May enhance the hypotensive effect of Beta-Blockers. NIFEdipine may enhance the negative inotropic effect of Beta-Blockers.
Nitroprusside	Blood Pressure Lowering Agents may enhance the hypotensive effect of Nitroprusside.
Nonsteroidal Anti-Inﬂammatory Agents	May diminish the antihypertensive effect of BetaBlockers.
Opioids (Anilidopiperidine)	May enhance the bradycardic effect of Beta-Blockers. Opioids (Anilidopiperidine) may enhance the hypotensive effect of Beta-Blockers.
Pentoxifylline	May enhance the hypotensive effect of Blood Pressure Lowering Agents.
Pholcodine	Blood Pressure Lowering Agents may enhance the hypotensive effect of Pholcodine.
Phosphodiesterase 5 Inhibitors	May enhance the hypotensive effect of Blood Pressure Lowering Agents.
Propafenone	May increase the serum concentration of Beta-Blockers. Propafenone possesses some independent beta blocking activity.
Prostacyclin Analogues	May enhance the hypotensive effect of Blood Pressure Lowering Agents.
Quinagolide	May enhance the hypotensive effect of Blood Pressure Lowering Agents.
Regorafenib	May enhance the bradycardic effect of Beta-Blockers.
Reserpine	May enhance the hypotensive effect of Beta-Blockers.
Rifamycin Derivatives	May decrease the serum concentration of Beta-Blockers. Exceptions: Rifabutin.
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.
Selective Serotonin Reuptake Inhibitors	May increase the serum concentration of Beta-Blockers. Exceptions: Citalopram; Escitalopram; FluvoxaMINE.
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.
Terlipressin	May enhance the bradycardic effect of Bradycardia-Causing Agents.
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.
Tofacitinib	May enhance the bradycardic effect of Bradycardia-Causing Agents.
Yohimbine	May diminish the antihypertensive effect of Antihypertensive Agents.
Risk Factor D (Consider therapy modification)
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 Alpha2Agonists. 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.
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.
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. Exceptions are discussed in separate monographs.
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 betablocker dose.
Ergot Derivatives	Beta-Blockers may enhance the vasoconstricting effect of Ergot Derivatives. Exceptions: Nicergoline.
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.
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.
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.
Risk Factor X (Avoid combination)
Bromperidol	Blood Pressure Lowering Agents may enhance the hypotensive effect of Bromperidol. Bromperidol may diminish the hypotensive effect of Blood Pressure Lowering Agents.
Floctafenine	May enhance the adverse/toxic effect of Beta-Blockers.
Methacholine	Beta-Blockers may enhance the adverse/toxic effect of Methacholine.
Rivastigmine	May enhance the bradycardic effect of Beta-Blockers.

Monitoring Parameters:

Monitor blood pressure, ECG, and serum glucose in diabetic patients.

How to Administer Nebivolol?

Take the drug with or without food.

Mechanism of Action of Nebivolol:

Nebivolol, a beta-blocker that is highly selective, can be taken in doses as low as 10 mg.
Endothelium-derived Nitric Ox release also causes vasodilation.
It reduces blood pressure through two mechanisms: vasodilation, and reduction of systemic vascular resistance.

Absorption is Rapid. It is bound to albumin in the plasma (98%), and metabolism is via the liver ( glucoronidation)

Bioavailability varies from 12% in extensive metabolizers to 96% in poor metabolizers.

Half-life elimination of the terminal products is 12 to 19 hours

Time to peak plasma concentration is 1.5 to 4 hours

Excretion is via urine and feces.

International Brands of Nebivolol:

Bipinor
Hypoloc
Ivolol
Lobivon
Lovispes
Mavilor
Nabila
Nebasco
Nebican
Nebicar
Nebicard
Nebicard-5
Nebiem
Nebiem 5
Nebil
Nebilet
Nebilong
Nebilox
Nebimel
Nebinorm
Nebiphar
Nebistar
Nebistol
Nebita
Nebitlol
Nebitrend
Nebival
Nebivas
Nebivel
Neblock
Nebol
Nebyol
Nelet
Nepvol
Nerispes
Nevetrol
Neviolet
Nevodio
Nevol
Nevolmin
Nobiten
Nodon
Pertium
Silostar
Temerit
Toricard-5
Volone
Zinebi

Nebivolol Brands in Pakistan:

Nebil 2.5 mg, 5 mg (Getz Pharma)
Byscard 2.5 mg, 5 mg, 10 mg (Searle Pharma)
Nebix 5 mg, 10 mg (Highnoon Pharma)

Nebivolol (Hcl) [Tabs 2.5]
Nebil	Getz Pharma Pakistan (Pvt) Ltd.

Nebivolol (Hcl) [Tabs 5 Mg]
Byscard	Searle Pakistan (Pvt.) Ltd.
Byscard	Searle Pakistan (Pvt.) Ltd.
Nebil	Getz Pharma Pakistan (Pvt) Ltd.
Nebix	Highnoon Laboratories Ltd.