Bivolol

White, round, biconvex, uncoated tablets plain on both sides.
Each uncoated tablet contains: Nebivolol (as Nebivolol Hydrochloride) 5 mg.

Pharmacotherapeutic group: Beta blocking agent, selective. ATC code: C07AB12.
Pharmacology: Pharmacodynamics: Nebivolol is a racemate of two enantiomers, SRRR-nebivolol (or d-nebivolol) and RSSS-nebivolol (or l-nebivolol). It combines two pharmacological activities: It is a competitive and selective beta-receptor antagonist: this effect is attributed to the SRRR-enantiomer (d-enantiomer).
It has mild vasodilating properties due to an interaction with the L-arginine/nitric oxide pathway.
Single and repeated doses of nebivolol reduce heart rate and blood pressure at rest and during exercise, both in normotensive and in hypertensive patients. The antihypertensive effect is maintained during chronic treatment. At therapeutic doses, Nebivolol is devoid of alpha-adrenergic antagonism.
During acute and chronic treatment with nebivolol in hypertensive patients systemic vascular resistance is decreased. Despite heart rate reduction, reduction in cardiac output during rest and exercise may be limited due to an increase in stroke volume. In hypertensive patients, nebivolol increases the NO-mediated vascular response to acetylcholine (ACh) which is reduced in patients with endothelial dysfunction.
Pharmacokinetics: Both nebivolol enantiomers are rapidly absorbed after oral administration. The absorption of nebivolol is not affected by food; nebivolol can be given with or without meals. Nebivolol is extensively metabolized, partly to active hydroxy-metabolites. Nebivolol is metabolized via alicyclic and aromatic hydroxylation, N-dealkylation and glucuronidation; in addition, glucuronides of the hydroxy-metabolites are formed. The metabolism of nebivolol by aromatic hydroxylation is subject to the CYP2D6 dependent genetic oxidative polymorphism. The oral bioavailability of nebivolol averages 12% in fast metabolizers and is virtually complete in slow metabolizers. At steady state and at the same dose level, the peak plasma concentration of unchanged nebivolol is about 23 times higher in poor metabolizers than in extensive metabolizers. When unchanged drug plus active metabolites are considered, the difference in peak plasma concentrations is 1.3 to 1.4 fold. Because of the variation in rates of metabolism, the dose of nebivolol should always be adjusted to the individual requirements of the patient: poor metabolizers therefore may require lower doses.
In fast metabolizers, elimination half-lives of the nebivolol enantiomers average 10 hours. In slow metabolizers, they are 3-5 times longer. In fast metabolizers, plasma levels of the RSSS-enantiomer are slightly higher than for the SRRR-enantiomer. In slow metabolizers, this difference is larger. In fast metabolizers, elimination half-lives of the hydroxy-metabolites of both enantiomers average 24 hours, and are about twice as long in slow metabolizers.
Steady-state plasma levels (fast metabolizers) are reached within 24 hours for nebivolol and within a few days for the hydroxy-metabolites.
Plasma concentrations are dose-proportional between 1 and 30 mg. The pharmacokinetics of nebivolol are not affected by age.
In plasma, both nebivolol enantiomers are predominantly bound to albumin. Plasma protein binding is 98.1% for SRRR-nebivolol and 97.9% for RSSS-nebivolol. One week after administration, 38% of the dose is excreted in the urine and 48% in the feces. Urinary excretion of unchanged nebivolol is less than 0.5% of the dose.

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.

Posology: Hypertension: Adults: The dose is 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 5 mg is combined with hydrochlorothiazide 12.5-25 mg.
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: The use of Nebivolol in these patients is contraindicated.
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: 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: The use of nebivolol in these patients is not recommended.
Patients with hepatic insufficiency: The use of nebivolol in these patients is contraindicated.
Older people: No dose adjustment is required since uptitration to the maximum tolerated dose is individually adjusted.
Paediatric population: The use of nebivolol in children and adolescents is not recommended. No data are available.
Mode of Administration: Oral use.
Tablets may be taken with meals.

No data are available on overdosage with nebivolol.
Symptoms: Symptoms of overdosage with beta-blockers are: bradycardia, hypotension, bronchospasm and acute cardiac insufficiency.
Treatment: In case of overdosage or hypersensitivity, the patient should be kept under close supervision and be treated in an intensive care ward. Blood glucose levels should be checked. Absorption of any drug residues still present in the gastro-intestinal tract can be prevented by gastric lavage and the administration of activated charcoal and a laxative. Artificial respiration may be required. Bradycardia or extensive vagal reactions should be treated by administering atropine or methylatropine. Hypotension and shock should be treated with plasma/plasma substitutes and, if necessary, catecholamines. The beta-blocking effect can be counteracted by slow intravenous administration of isoprenaline hydrochloride, starting with a dose of approximately 5 μg/minute, or dobutamine, starting with a dose of 2.5 μg/minute, until the required effect has been obtained. In refractory cases isoprenaline can be combined with dopamine. If this does not produce the desired effect either, intravenous administration of glucagon 50-100 μg/kg i.v. may be considered. If required, the injection should be repeated within one hour, to be followed -if required- by an i.v. infusion of glucagon 70 μg/kg/h. In extreme cases of treatment-resistant bradycardia, a pacemaker may be inserted.

Hypersensitivity to the active substance or to any of the excipients of 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 contraindicated in: sick sinus syndrome, including sino-atrial block.
Second and third degree heart block (without a pacemaker).
History of bronchospasm and bronchial asthma.
Untreated phaeochromocytoma.
Metabolic acidosis.
Bradycardia (heart rate <60 bpm prior to start therapy).
Hypotension (systolic blood pressure <90 mmHg).
Severe peripheral circulatory disturbances.

Anaesthesia: Caution should be observed with certain anaesthetics that cause myocardial depression. The patient can be protected against vagal reactions by intravenous administration of atropine.
Cardiovascular: In general, beta-blockers should not be used in patients with untreated congestive heart failure (CHF), unless their condition has been stabilized.
In patients with ischemic heart disease, treatment with beta-blockers should be discontinued gradually, i.e. over 1-2 weeks. If necessary, replacement therapy should be initiated at the same time to prevent exacerbation of angina pectoris.
Beta-blockers may induce bradycardia: if the pulse rate drops below 50-55 bpm at rest and/or the patient experiences symptoms that are suggestive of bradycardia, the dosage should be reduced.
Beta-blockers should be used with caution: in patients with peripheral circulatory disorders (Raynaud's disease or syndrome, intermittent claudication), as aggravation of these disorders may occur; in patients with first degree heart block, because of the negative effect of beta-blockers on conduction time; in patients with Prinzmetal's angina due to unopposed alpha-receptor mediated coronary artery vasoconstriction: beta-blockers may increase the number and duration of anginal attacks.
Combination of nebivolol with calcium channel antagonists of the verapamil and diltiazem type, with Class I antiarrhythmic drugs, and with centrally acting antihypertensive drugs is generally not recommended.
Metabolic/Endocrinological: Nebivolol does not affect glucose levels in diabetic patients. Care should be taken in diabetic patients, however, as nebivolol may mask certain symptoms of hypoglycemia (tachycardia, palpitations).
Beta-blockers may mask tachycardic symptoms in hyperthyroidism. Abrupt withdrawal may intensify symptoms.
Respiratory: In patients with chronic obstructive pulmonary disorders, beta-blockers should be used with caution as airway constriction may be aggravated.
Other: Patients with a history of psoriasis should take beta-blockers only after careful consideration.
Beta-blockers may increase the sensitivity to allergens and the severity of anaphylactic reactions.
The initiation of Chronic Heart Failure treatment with nebivolol necessitates regular monitoring. Treatment discontinuation should not be done abruptly unless clearly indicated.

Pregnancy: Nebivolol has pharmacological effects that may cause harmful effects on pregnancy and/or the fetus/newborn. Nebivolol should not be used during pregnancy unless clearly necessary. If treatment with nebivolol is considered necessary, the uteroplacental blood flow and the fetal growth should be monitored. In case of harmful effects on pregnancy or the fetus alternative treatment should be considered. The newborn infant must be closely monitored. Symptoms of hypoglycemia and bradycardia are generally to be expected within the first 3 days.
Breastfeeding: Breastfeeding is not recommended during administration of nebivolol.

The frequency grouping is defined using the following convention: Common (≥1/100 to <1/10), Uncommon (≥1/1,000 to <1/100), Very Rare (<1/10,000) and Not Known.
Common: headache, dizziness, paraesthesia, dyspnoea, constipation, nausea, diarrhoea, tiredness, oedema.
Uncommon: nightmares, depression, impaired vision, bradycardia, heart failure, slowed AV conduction/AV-block, hypotension, (increase of) intermittent claudication, bronchospasm, dyspepsia, flatulence, vomiting, pruritus, rash erythematous, impotence.
Very Rare: syncope, psoriasis aggravated.
Not known: angioneurotic oedema, hypersensitivity, urticaria.

Pharmacodynamic interactions: The following interactions apply to beta-blockers in general: Combinations not recommended: Class I antiarrhythmics (quinidine, hydroquinidine, cibenzoline, flecainide, disopyramide, lidocaine, mexiletine, propafenone): effect on atrio-ventricular conduction time may be potentiated and negative inotropic effect increased.
Calcium channel antagonists of verapamil/diltiazem type: negative influence on contractility and atrio-ventricular conduction. Intravenous administration of verapamil in patients with β-blocker treatment may lead to profound hypotension and atrio-ventricular block.
Centrally-acting antihypertensives (clonidine, guanfacin, moxonidine, methyldopa, rilmenidine): concomitant use of centrally acting antihypertensive drugs may worsen heart failure by a decrease in the central sympathetic tonus (reduction of heart rate and cardiac output, vasodilation). Abrupt withdrawal, particularly if prior to beta-blocker discontinuation, may increase risk of "rebound hypertension".
Combinations to be used with caution: Class III antiarrhythmic drugs (Amiodarone): effect on atrio-ventricular conduction time may be potentiated.
Anaesthetics - volatile halogenated: concomitant use of beta-adrenergic antagonists and anaesthetics may attenuate reflex tachycardia and increase the risk of hypotension. As a general rule, avoid sudden withdrawal of beta-blocker treatment. The anaesthesiologist should be informed when the patient is receiving nebivolol.
Insulin and oral antidiabetic drugs: although nebivolol does not affect glucose level, concomitant use may mask certain symptoms of hypoglycemia (palpitations, tachycardia).
Baclofen (antispastic agent), amifostine (antineoplastic adjunct): concomitant use with antihypertensives is likely to increase the fall in blood pressure, therefore the dosage of the antihypertensive medication should be adjusted accordingly.
Combinations to be considered: The following concomitant use with Nebivolol should be considered.
Digitalis glycosides, Calcium antagonists of the dihydropyridine type (amlodipine, felodipine, lacidipine, nifedipine, nicardipine, nimodipine, nitrendipine), Antipsychotics, antidepressants (tricyclics, barbiturates and phenothiazines), Non steroidal anti-inflammatory drugs (NSAID), Sympathicomimetic agents.
Pharmacokinetic interactions: Co-administration of Nebivolol with bupropion, paroxetine, fluoxetine, thioridazine, quinidine, chloroquine, levomepromazin, terbinafine and cimetidine may lead to increased plasma levels of nebivolol.
Co-administration of ranitidine, alcohol, furosemide or hydrochlorothiazide did not affect the pharmacokinetics of nebivolol.
Combining Nebivolol with Nicardipine slightly increased the plasma levels of both drugs.
Nebivolol does not affect the pharmacokinetics and pharmacodynamics of warfarin.

Store at temperatures not exceeding 30°C. Protect from light and moisture.

Beta-Blockers

C07AB12 - nebivolol ; Belongs to the class of selective beta-blocking agents. Used in the treatment of cardiovascular diseases.

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