Each tablet contains Nebivolol hydrochloride 5.45 mg equivalent to Nebivolol 5 mg.
PHARMACOLOGY: Pharmacodynamics: Nebivolol is a cardioselective beta blocker. It has vasodilating activity, which appears to be due to a direct action on the endothelium, possibly involving nitric oxide release.
It is reported to lack intrinsic sympathomimetic and membrane-stabilising activity.
Pharmacokinetics: Nebivolol is rapidly absorbed after oral doses. It is extensively metabolised in the liver by alicyclic and aromatic hydroxylation, N-dealkylation, and glucuronidation; the hydroxy metabolites are reported to be active. The rate of aromatic hydroxylation by cytochrome P450 isoenzyme CYP2D6 is subject to genetic polymorphism, and bioavailability and half-life vary widely. In fast metabolisers the elimination half-life of nebivolol is about 10 hours and that of the hydroxy metabolites is about 24 hours. Peak plasma concentrations of unchanged drug plus active metabolites are 1.3 to 1.4 times higher in slow metabolisers and the half-lives of nebivolol and its hydroxy metabolites are prolonged.
Nebivolol is about 98% bound to plasma proteins. It has high lipid solubility. It is excreted in the urine and faeces, almost entirely as metabolites. Nebivolol is distributed into breast milk in animals.
Hypertension: Treatment of essential hypertension.
Chronic heart failure (CHF): Treatment of stable mild and moderate chronic heart failure in addition to standard therapies in elderly patients ≥ 70 years.
Hypertension: Adults: The dose is one tablet (5 mg) daily, preferably at the same time of the day.
The blood pressure lowering effect becomes evident after 1-2 weeks of treatment.
Occasionally, the optimal effect is reached only after 4 weeks.
Combination with other antihypertensive agents: Beta-blockers can be used alone or concomitantly with other antihypertensive agents. To date, an additional antihypertensive effect has been observed only when Nebivolol is combined with hydrochlorothiazide 12.5-25 mg.
Patients with renal insufficiency: In patients with renal insufficiency, the recommended starting dose is 2.5 mg daily. If needed, the daily dose may be increased to 5 mg.
Patients with hepatic insufficiency: Data in patients with hepatic insufficiency or impaired liver function are limited. Therefore the use of Nebivolol in these patients is contra-indicated.
Older people: In patients over 65 years, the recommended starting dose is 2.5 mg daily. If needed, the daily dose may be increased to 5 mg. However, in view of the limited experience in patients above 75 years, caution must be exercised and these patients monitored closely.
Paediatric population: The efficacy and safety of Nebivolol in children and adolescents aged below 18 years has not been established. No data are available. Therefore, use in children and adolescents is not recommended.
Chronic heart failure (CHF): The treatment of stable chronic heart failure has to be initiated with a gradual uptitration of dosage until the optimal individual maintenance dose is reached.
Patients should have stable chronic heart failure without acute failure during the past six weeks. It is recommended that the treating physician should be experienced in the management of chronic heart failure.
For those patients receiving cardiovascular drug therapy including diuretics and/or digoxin and/or ACE inhibitors and/or angiotensin II antagonists, dosing of these drugs should be stabilized during the past two weeks prior to initiation of Nebivolol treatment.
The initial uptitration should be done according to the following steps at 1-2 weekly intervals based on patient tolerability: 1.25 mg nebivolol, to be increased to 2.5 mg nebivolol once daily, then to 5 mg once daily and then to 10 mg once daily.
The maximum recommended dose is 10 mg nebivolol once daily.
Initiation of therapy and every dose increase should be done under the supervision of an experienced physician over a period of at least 2 hours to ensure that the clinical status (especially as regards blood pressure, heart rate, conduction disturbances, signs of worsening of heart failure) remains stable.
Occurrence of adverse events may prevent all patients being treated with the maximum recommended dose. If necessary, the dose reached can also be decreased step by step and reintroduced as appropriate.
During the titration phase, in case of worsening of the heart failure or intolerance, it is recommended first to reduce the dose of nebivolol, or to stop it immediately if necessary (in case of severe hypotension, worsening of heart failure with acute pulmonary oedema, cardiogenic shock, symptomatic bradycardia or AV block).
Treatment of stable chronic heart failure with nebivolol is generally a long-term treatment.
The treatment with nebivolol is not recommended to be stopped abruptly since this might lead to a transitory worsening of heart failure. If discontinuation is necessary, the dose should be gradually decreased divided into halves weekly.
Patients with renal insufficiency: No dose adjustment is required in mild to moderate renal insufficiency since uptitration to the maximum tolerated dose is individually adjusted. There is no experience in patients with severe renal insufficiency (serum creatinine ≥ 250 μmol/L). Therefore, the use of nebivolol in these patients is not recommended.
Patients with hepatic insufficiency: Data in patients with hepatic insufficiency are limited. Therefore the use of Nebivolol in these patients is contra-indicated.
Older people: No dose adjustment is required since uptitration to the maximum tolerated dose is individually adjusted.
Paediatric population: The efficacy and safety of Nebivolol in children and adolescents aged below 18 years has not been established. Therefore, use in children and adolescents is not recommended. No data are available.
Symptoms: Bradycardia, hypotension, low-output cardiac failure, and cardiogenic shock are the most common effects of beta-blocker intoxication.
Cardiovascular: Asystole, tachycardia (partial agonist), prolonged QT interval (sotalol), prolonged QRS complex (membrane-stabilizing agents), ventricular dysrhythmias (membrane-stabilizing agents, sotalol), hypotension, hypertension (partial agonist); bradycardia, AV block.
Central nervous system: Seizures; coma; depressed level of consciousness.
Gastrointestinal: Mesenteric ischemia; esophageal spasms.
Metabolic: Hyperkalemia; hypoglycemia.
Respiratory: Apnea; cyanosis; respiratory depression; bronchospasm.
Miscellaneous: Renal failure.
Treatment: Perform evaluation of the "ABCs" (airway, breathing, and circulation) as well as rapid assessment of serum glucose levels with correction of hypoglycemia using IV glucagon. Early ventilatory control is essential in addition to chest radiography, serum electrolytes, and arterial blood gases. Administer activated charcoal to all patients and perform gastric lavage in patients who present within 1 to 2 hours after ingestion.
Hypersensitivity to nebivolol or any ingredient in the formulation.
Liver insufficiency or liver function impairment.
Acute heart failure, cardiogenic shock or episodes of heart failure decompensation requiring i.v. inotropic therapy.
In addition, as with other beta-blocking agents, Nebivolol is contra-indicated in: Sick sinus syndrome, including sino-atrial block; Second and third degree heart block (without a pacemaker); History of bronchospasm and bronchial asthma; Untreated pheochromocytoma; Metabolic acidosis; Bradycardia (heart rate < 60 bpm prior to start therapy); Hypotension (systolic blood pressure < 90 mmHg); Severe peripheral circulatory disturbances.
Abrupt Withdrawal of Therapy: Abrupt withdrawal of β-adrenergic blocking agents (β-blockers) may exacerbate angina symptoms and/or precipitate myocardial infarction and ventricular arrhythmias in patients with coronary artery disease. Therefore, patients receiving nebivolol (especially those with ischemic heart disease) should be warned not to interrupt or abruptly discontinue therapy without consulting their clinician. When discontinuance of nebivolol therapy is planned, dosage of the drug should be reduced gradually over a period of 1-2 weeks. Patients should be carefully monitored and advised to temporarily limit their physical activity. If exacerbation of angina occurs or acute coronary insufficiency develops after nebivolol therapy is interrupted or discontinued, treatment with the drug should be reinstituted, at least temporarily.
Heart Failure: In patients with heart failure, sympathetic stimulation is vital for support of circulatory function. Nebivolol should be used with caution in patients with inadequate cardiac function, since further depression of myocardial contractility and cardiac failure may be precipitated.
Although β-blockers should be avoided in patients with overt heart failure, nebivolol may be administered cautiously, if necessary, to patients with well-compensated heart failure. If heart failure worsens, discontinuance of nebivolol should be considered.
Ischemic Heart Disease: Safety and efficacy of nebivolol in patients with angina pectoris or recent myocardial infarction have not been established to date.
Anesthesia and Major Surgery: Nebivolol should be used with caution in patients undergoing major surgery involving general anesthesia. Particular caution should be employed if anesthetics that depress the myocardium are used. Severe, protracted hypotension and difficulty in restarting or maintaining a heart beat have occurred during surgery in some patients who have received β-blockers. The β-adrenergic blocking effects of nebivolol can be reversed by administration of β-agonists (e.g., dobutamine, isoproterenol).
Bronchospastic Diseases: Patients with bronchospastic disease generally should not receive β-blockers.
Diabetes Mellitus and Hypoglycemia: β-Blockers may mask signs and symptoms of hypoglycemia (e.g., tachycardia). Nonselective β-blockers may potentiate insulin-induced hypoglycemia and delay recovery of serum glucose concentrations.
Nebivolol should be used with caution in patients subject to spontaneous hypoglycemia and in diabetic patients receiving insulin or oral hypoglycemic agents.
Thyrotoxicosis: β-Blockers may mask signs of hyperthyroidism (e.g., tachycardia). Abrupt withdrawal of β-adrenergic blockade may exacerbate manifestations of hyperthyroidism or precipitate thyroid storm.
Peripheral Vascular Disease: β-Blockers may precipitate or aggravate symptoms of arterial insufficiency in patients with peripheral vascular disease, nebivolol should be used with caution in these patients.
Nondihydropyridine Calcium-channel Blocking Agents: Because of their negative inotropic and chronotropic effects, nebivolol and nondihydropyridine calcium-channel blocking agents (e.g. verapamil, diltiazem) should be used concomitantly with caution.
Risk of Anaphylactic Reactions: Patients who have a history of anaphylactic reactions to a variety of allergens reportedly may be more reactive to repeated accidental, diagnostic, or therapeutic challenges with such allergens while taking β-blockers and may be unresponsive to usual doses of epinephrine used to treat such reactions.
Pheochromocytoma: In patients with known or suspected pheochromocytoma, treatment with an α-adrenergic blocking agent should be instituted prior to use of a β-blocker (e.g., nebivolol).
Pregnancy: Insufficient data exist on the use of nebivolol in human pregnancy to determine its potential harmfulness. Animal studies have not shown any indication of harmful effects, other than on the basis of its pharmacological properties, Beta-blockers reduce placental perfusion, which may result in intrauterine fetal death and in immature and premature delivery. In addition, adverse effects (hypoglycemia and bradycardia) may occur in the fetus and the neonate. There is an increased risk of cardiac and pulmonary complications in the neonate in the postnatal period. Therefore, nebivolol should not be used during pregnancy.
Lactation: Most Beta-blockers, particularly lipophilic compounds like nebivolol and its active metabolites, pass into breast milk although to a variable extent. Since it is not known whether nebivolol is excreted into human milk, the use of nebivolol when breast feeding is contra-indicated. Animal studies have shown that nebivolol is excreted in breast milk.
Very common (1-10%): 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%), paresthesia.
Dermatologic: Skin rash (≤ 1%).
Endocrine & metabolic: Decreased HDL cholesterol, hypercholesterolemia, increased serum triglycerides, increased uric acid.
Gastrointestinal: Diarrhea (dose-related; 2% to 3%), nausea (1% to 3%), abdominal pain.
Hematologic & oncologic: Decreased platelet count.
Neuromuscular & skeletal: Weakness.
Renal: Increased blood urea nitrogen.
Respiratory: Dyspnea (≤ 1%).
≤ 1%, postmarketing, and/or case reports: Acute pulmonary edema, acute renal failure, angioedema, atrioventricular block (second and third degree), bronchospasm, claudication, dermatological disease, drowsiness, erectile dysfunction, hepatic insufficiency, hypersensitivity angiitis, hypersensitivity reaction, increased serum ALT, increased serum AST, increased serum bilirubin, myocardial infarction, peripheral ischemia, pruritus, psoriasis, Raynaud's phenomenon, syncope, thrombocytopenia, urticarial, vertigo, vomiting.
Drugs Affecting Hepatic Microsomal Enzymes: Nebivolol is metabolized by cytochrome P-450 (CYP) isoenzyme 2D6 but does not inhibit CYP isoenzymes at clinically relevant concentrations.
Potent inhibitors of CYP2D6 (e.g., quinidine, propafenone, fluoxetine, paroxetine): Potential pharmacokinetic interaction (increased plasma concentrations of nebivolol). Monitor patient carefully; adjust nebivolol dosage according to blood pressure response.
Drugs Affecting Cardiac Conduction: Antiarrhythmic Agents: Possible conduction disturbance when nebivolol is used concomitantly with antiarrhythmic agents (e.g., amiodarone, disopyramide). Use concomitantly with caution.
β-Adrenergic Blocking Agents: Possible additive negative effects on AV conduction and heart rate. Concomitant use of nebivolol with other β-adrenergic blocking agents (β-blockers) is not recommended.
Calcium-channel Blocking Agents: Possible conduction disturbance when nebivolol is used concomitantly with nondihydropyridine calcium-channel blocking agents (e.g., diltiazem, verapamil). Use concomitantly with caution; monitor blood pressure and ECG with concomitant use.
Digoxin: Possible additive negative effects on AV conduction and heart rate; increased risk of bradycardia. Use concomitantly with caution. Concomitant use of digoxin (0.25 mg once daily) and nebivolol (10 mg once daily) for 10 days in healthy adults did not affect the pharmacokinetics of either drug.
Catecholamine-depleting Agents: Potential additive effects (e.g., hypotension, bradycardia) with catecholamine-depleting agents (e.g., reserpine, guanethidine). Monitor closely for symptoms (e.g., vertigo, syncope, postural hypotension).
Other Cardiovascular Drugs: Clonidine: Potential pharmacologic interaction (increased rebound hypertension following discontinuance of clonidine). When clonidine is to be discontinued in patients receiving clonidine and nebivolol concurrently, nebivolol should be discontinued several days before gradual withdrawal of clonidine.
Diuretics: No pharmacokinetic interactions observed in healthy individuals receiving nebivolol (10 mg daily for 10 days) and a diuretic (single 40-mg dose of furosemide, hydrochlorothiazide 25 mg once daily for 10 days, or spironolactone 25 mg once daily for 10 days).
Losartan: No pharmacokinetic interaction observed following single-dose administration of nebivolol (10 mg) and losartan potassium (50 mg).
Propafenone: Potential pharmacokinetic interaction (increased plasma concentrations of nebivolol). Use concomitantly with caution.
Quinidine: Potential pharmacokinetic interaction (increased plasma concentrations of nebivolol). Use concomitantly with caution.
Ramipril: No pharmacokinetic interaction observed following concomitant administration of nebivolol (10 mg once daily) and ramipril (5 mg once daily) for 10 days.
Sildenafil: Potential pharmacokinetic interaction (modest [21-23%] decrease in peak plasma concentration and area under the plasma concentration-time curve [AUC] of sildenafil, modest [less than 20%] effect on peak plasma concentration and AUC of d-nebivolol). Nebivolol and sildenafil have additive effects on blood pressure and pulse.
GI Drugs: Activated Charcoal: No effect on nebivolol pharmacokinetics following single-dose administration of nebivolol (10 mg) and repeated-dose administration of activated charcoal over 48 hours.
Cimetidine: Potential pharmacokinetic interaction (modest [21-23%] increase in plasma nebivolol concentrations) observed following concomitant administration of nebivolol (single 5-mg dose) and cimetidine (400 mg twice daily for 3 days). No apparent change in pharmacodynamics of nebivolol (e.g., blood pressure, heart rate).
Ranitidine: No effect on nebivolol pharmacokinetics or pharmacodynamics (e.g., blood pressure, heart rate) observed following concomitant administration of nebivolol (single 5-mg dose) and ranitidine (150 mg twice daily for 3 days).
Psychotherapeutic Agents: Fluoxetine: Potential pharmacokinetic interaction (increased plasma concentrations of nebivolol). Eightfold increase in AUC and threefold increase in peak plasma concentration of d-nebivolol observed in healthy individuals receiving a single 10-mg dose of nebivolol following administration of fluoxetine 20 mg daily for 21 days. Use concomitantly with caution.
Paroxetine: Potential pharmacokinetic interaction (increased plasma concentrations of nebivolol). Use concomitantly with caution.
Warfarin: No effect on warfarin or nebivolol pharmacokinetics observed in individuals receiving warfarin (single 10-mg dose) and nebivolol (10 mg once daily for 10 days); no effect on prothrombin times after a single warfarin dose.
C07AB12 - nebivolol ; Belongs to the class of selective beta-blocking agents. Used in the treatment of cardiovascular diseases.
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