Nebilet

Nebilet

nebivolol

Manufacturer:

A. Menarini

Distributor:

Zuellig
Full Prescribing Info
Contents
Nebivolol HCl.
Description
Each scored tablet contains nebivolol HCl 5.45 mg equivalent to nebivolol 5 mg. It also contains lactose as an excipient.
Action
Pharmacotherapeutic Group: Beta-blocking agent, selective.
Pharmacology: Pharmacodynamics: Nebivolol is a racemate of 2 enantiomers, SRRR-Nebivolol (or d-Nebivolol) and RSSS-Nebivolol (or l-Nebivolol). It combines 2 pharmacological activities: It is a competitive and selective β-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 subjects and in hypertensive patients. The antihypertensive effect is maintained during chronic treatment. At therapeutic doses, nebivolol is devoid of α-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. The clinical relevance of these hemodynamic differences as compared to other β1-receptor antagonists has not been fully established.
In hypertensive patients, nebivolol increases the nitric oxide-mediated vascular response to acetylcholine (ACh) which is reduced in patients with endothelial dysfunction.
In a mortality-morbidity, placebo-controlled trial performed in 2128 patients ≥70 years (median age 75.2 years) with stable chronic heart failure with or without impaired left ventricular ejection fraction (LVEF) (Mean LVEF: 36 ≥12.3%, with the following distribution: LVEF <35% in 56% of patients, LVEF between 35% and 45% in 25% of patients and LVEF >45% in 19% of patients) followed for a mean time of 20 months, nebivolol, on top of standard therapy, significantly prolonged the time to occurrence of deaths or hospitalizations for cardiovascular reasons (primary endpoint for efficacy) with a relative risk reduction of 14% (Absolute Reduction: 4.2%). This risk reduction developed after 6 months of treatment and was maintained for all treatment duration (Median Duration: 18 months). The effect of nebivolol was independent from age, gender or LVEF of the population on study. The benefit on all cause mortality did not reach statistical significance in comparison to placebo (Absolute Reduction: 2.3%). A decrease in sudden death was observed in nebivolol treated patients (4.1% vs 6.6%, relative reduction of 38%).
In vitro and in vivo experiments in animals showed that nebivolol has no intrinsic sympathicomimetic activity.
In vitro and in vivo experiments in animals showed that at pharmacological doses, nebivolol has no membrane stabilizing action.
In healthy volunteers, nebivolol has no significant effect on maximal exercise capacity or endurance.
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 hydroxymetabolites. It 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 Nebilet should always be adjusted to the individual requirements of the patient. Poor metabolizers therefore may require lower doses.
In fast metabolizers, elimination t½ of the nebivolol enantiomers average 10 hrs. 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 t½ of the hydroxymetabolites of both enantiomers average 24 hrs, and are about twice as long in slow metabolizers. Steady-state plasma levels in most subjects (fast metabolizers) are reached within 24 hrs 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 <0.5% of the dose.
Toxicology: Preclinical Safety Data: Preclinical data reveal no special hazard for humans based on conventional studies of genotoxicity and carcinogenic potential.
Indications/Uses
Treatment of essential hypertension and stable mild and moderate chronic heart failure (CHF) in addition to standard therapies in elderly patients.
Dosage/Direction for Use
Hypertension: Adults: One tablet (5 mg) daily, preferably at the same time of the day. Tablets may be taken with meals.
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 Nebilet 5 mg is combined with hydrochlorothiazide 12.5-25 mg.
Renal Insufficiency: Recommended Starting Dose: 2.5 mg daily. If needed, the daily dose may be increased to 5 mg. No dose adjustment is required in mild to moderate renal insufficiency since up-titration to the maximum tolerated dose is individually adjusted.
Elderly >65 years: Recommended Starting Dose: 2.5 mg daily. If needed, the daily dose may be increased to 5 mg.
Chronic Heart Failure: The treatment of stable chronic heart failure has to be initiated with a gradual up-titration of dosage until the optimal individual maintenance dose is reached.
Patients should have stable chronic heart failure without acute failure during the past 6 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 2 weeks prior to initiation of Nebilet treatment.
The initial up-titration should be done according to the following steps at 1-2 weekly intervals based on the patient's tolerability: Nebivolol 1.25 mg, to be increased to 2.5 mg once daily, then to 5 mg once daily and then to 10 mg once daily. The maximum recommended dose is nebivolol 10 mg 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 hrs 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 edema, cardiogenic shock, symptomatic bradycardia or atrioventricular 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 ½ weekly.
Administration: Tablets may be taken with meals.
If physician prescribed to take ¼ or ½ tablet daily, follow the given instructions on how to break Nebilet 5 mg cross-scored tablets: Place the tablets onto a flat, hard surface (eg, a table or worktop), with the cross score facing up; break the tablet by pushing it with the index fingers of both hands placed along 1 breakmark. Tablet quarters are obtained by breaking the halves in the same way.
Overdosage
No data are available on overdosage with Nebilet.
Symptoms: Symptoms of overdosage with β-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 GIT 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 β-blocking effect can be counteracted by slow IV administration of isoprenaline HCl, starting with a dose of approximately 5 mcg/min, or dobutamine, starting with a dose of 2.5 mcg/min, 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, IV administration of glucagon 50-100 mcg/kg IV may be considered. If required, the injection should be repeated within 1 hr, to be followed (if required) by an IV infusion of glucagon 70 mcg/kg/hr. In extreme cases of treatment-resistant bradycardia, a pacemaker may be inserted.
Contraindications
Hypersensitivity to nebivolol or to any of the excipients of Nebilet. Liver insufficiency or liver function impairment. Acute heart failure, cardiogenic shock or episodes of heart failure decompensation requiring IV inotropic therapy.
In addition, as with other β-blocking agents, Nebilet is contraindicated in sick sinus syndrome, including sino-atrial block; 2nd- and 3rd-degree heart block (without a pacemaker); history of bronchospasm and bronchial asthma; untreated pheochromocytoma; metabolic acidosis; bradycardia (heart rate <60 bpm prior to therapy); hypotension (systolic blood pressure <90 mmHg); severe peripheral circulatory disturbances.
Hepatic Insufficiency: Data in patients with hepatic insufficiency or impaired liver function are limited. Therefore the use of Nebilet in these patients is contraindicated.
Special Precautions
Anesthesia: Continuation of β-blockade reduces the risk of arrhythmias during induction and intubation. If β-blockade is interrupted in preparation for surgery, the β-adrenergic antagonist should be discontinued at least 24 hrs beforehand. Caution should be observed with certain anesthetics that cause myocardial depression. The patient can be protected against vagal reactions by IV administration of atropine.
Cardiovascular: In general, β-adrenergic antagonists should not be used in patients with untreated congestive heart failure, unless their condition has been stabilized.
In patients with ischemic heart disease, treatment with a β-adrenergic antagonist should be discontinued gradually, ie, over 1-2 weeks. If necessary replacement therapy should be initiated at the same time, to prevent exacerbation of angina pectoris.
Beta-adrenergic antagonists 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-adrenergic antagonists 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; 1st-degree heart block, because of the negative effect of β-blockers on conduction time; Prinzmetal's angina due to unopposed α-receptor mediated coronary artery vasoconstriction (β-adrenergic antagonists may increase the number and duration of anginal attacks).
Combination of nebivolol with calcium channel antagonist of the verapamil and diltiazem type, with class I antiarrhythmic drugs, and with centrally-acting antihypertensive drugs is generally not recommended.
Metabolic/Endocrinological: Nebilet 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-adrenergic blocking agents may mask tachycardic symptoms in hyperthyroidism. Abrupt withdrawal may intensify symptoms.
Respiratory: In patients with chronic obstructive pulmonary disorders, β-adrenergic antagonists should be used with caution as airway constriction may be aggravated.
Other: Patients with a history of psoriasis should take β-adrenergic antagonists only after careful consideration.
Beta-adrenergic antagonists 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.
Nebilet contains lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take Nebilet.
Renal Insufficiency: There is no experience in patients with severe renal insufficiency (serum creatinine ≥250 micromol/L). Therefore, the use of nebivolol in these patients is not recommended.
Effects on the Ability to Drive or Operate Machinery: No studies on the effects on the ability to drive and use machines have been performed. Pharmacodynamic studies have shown that Nebilet 5 mg does not affect psychomotor function. When driving vehicles or operating machines, it should be taken into account that dizziness and fatigue may occasionally occur.
Use in pregnancy: Nebivolol has pharmacological effects that may cause harmful effects on pregnancy and/or the fetus/newborn. In general, β-adrenoceptor blockers reduce placental perfusion, which has been associated with growth retardation, intrauterine death, abortion or early labor. Adverse reactions (eg, hypoglycemia and bradycardia) may occur in the fetus and newborn infant. If treatment with β-adrenoceptor blockers is necessary, β1-selective adrenoceptor blockers are preferable.
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.
Use in lactation: Animal studies have shown that nebivolol is excreted in breast milk. It is not known whether this drug is excreted in human milk. Most β-blockers, particularly lipophilic compounds like nebivolol and its active metabolites, pass into breast milk although to a variable extent. Therefore, breastfeeding is not recommended during administration of nebivolol.
Use in children: No studies have been conducted in children and adolescents. Therefore, use in children and adolescents is not recommended.
Use in the elderly: In view of the limited experience in patients >75 years, caution must be exercised and these patients monitored closely.
Use In Pregnancy & Lactation
Use in pregnancy: Nebivolol has pharmacological effects that may cause harmful effects on pregnancy and/or the fetus/newborn. In general, β-adrenoceptor blockers reduce placental perfusion, which has been associated with growth retardation, intrauterine death, abortion or early labor. Adverse reactions (eg, hypoglycemia and bradycardia) may occur in the fetus and newborn infant. If treatment with β-adrenoceptor blockers is necessary, β1-selective adrenoceptor blockers are preferable.
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.
Use in lactation: Animal studies have shown that nebivolol is excreted in breast milk. It is not known whether this drug is excreted in human milk. Most β-blockers, particularly lipophilic compounds like nebivolol and its active metabolites, pass into breast milk although to a variable extent. Therefore, breastfeeding is not recommended during administration of nebivolol.
Adverse Reactions
Adverse events are listed separately for hypertension and chronic heart failure because of differences in the background diseases.
Hypertension: The adverse reactions reported, which are in most of the cases of mild to moderate intensity, are tabulated (see table), classified by system organ class and ordered by frequency. The following adverse reactions have also been reported with some β-adrenergic antagonists: Hallucinations, psychoses, confusion, cold/cyanotic extremities, Raynaud's phenomenon, dry eyes and oculo-mucocutaneous toxicity of the practolol type. (See table.)

Click on icon to see table/diagram/image

Chronic Heart Failure: Data on adverse reactions in chronic heart failure patients are available from 1 placebo-controlled clinical trial involving 1067 patients taking nebivolol and 1061 patients taking placebo. In this study, a total of 449 nebivolol patients (42.1%) reported at least possibly casually related adverse reactions compared to 334 placebo patients (31.5%). The most commonly reported adverse reactions in nebivolol patients were bradycardia and dizziness, both occurring in approximately 11% of patients. The corresponding frequencies among placebo patients were approximately 2% and 7%, respectively.
The following incidences were reported for adverse reactions (at least possibly drug-related) which are considered specifically relevant in the treatment of chronic heart failure: Aggravation of cardiac failure occurred in 5.8% of nebivolol patients compared to 5.2% of placebo patients; postural hypotension was reported in 2.1% of nebivolol patients compared to 1% of placebo patients; drug intolerance occurred in 1.6% of nebivolol patients compared to 0.8% of placebo patients; 1st-degree atrioventricular block occurred in 1.4% of nebivolol patients compared to 0.9% of placebo patients; edema of the lower limb were reported by 1% of nebivolol patients compared to 0.2% of placebo patients.
Drug Interactions
Pharmacodynamic Interactions: The following interactions apply to β-adrenergic antagonists in general.
Combinations Not Recommended: Class I Antiarrhythmics (Quinidine, Hydroquinidine, Cibenzoline, Flecainide, Disopyramide, Lidocaine, Mexiletine, Propafenone): Effect on atrioventricular conduction time may be potentiated and negative inotropic effect increased.
Calcium Channel Antagonists of Verapamil/Diltiazem Type: Negative influence on contractility and atrioventricular conduction. Intravenous administration of verapamil in patients with β-blocker treatment may lead to profound hypotension and atrioventricular block.
Centrally-Acting Antihypertensives (Clonidine, Guanfacine, 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 β-blocker discontinuation, may increase risk of rebound hypertension.
Combinations to be Used with Caution: Class III Antiarrhythmic Drugs (Amiodarone): Effect on atrioventricular conduction time may be potentiated.
Anesthetics - Volatile Halogenated: Concomitant use of β-adrenergic antagonists and anesthetics may attenuate reflex tachycardia and increase the risk of hypotension. As a general rule, avoid sudden withdrawal of β-blocker treatment. The anesthesiologist should be informed when the patient is receiving Nebilet.
Insulin and Oral Antidiabetic Drugs: Although Nebivolol does not affect glucose level, concomitant use may mask certain symptoms of hypoglycemia (palpitations, tachycardia).
Combinations to be Considered: Digitalis Glycosides: Concomitant use may increase atrioventricular conduction time. Clinical trials with nebivolol have not shown any clinical evidence of an interaction. Nebivolol does not influence the kinetics of digoxin.
Calcium Antagonists of the Dihydropyridine Type (Amlodipine, Felodipine, Lacidipine, Nifedipine, Nicardipine, Nimodipine, Nitrendipine): Concomitant use may increase the risk of hypotension, and an increase in the risk of a further deterioration of the ventricular pump function in patients with heart failure cannot be excluded.
Antipsychotics, Antidepressants (Tricyclics, Barbiturates and Phenothiazines): Concomitant use may enhance the hypotensive effect of the β-blockers (additive effect).
Nonsteroidal Anti-Inflammatory Drugs (NSAIDs): No effect on the blood pressure lowering effect of nebivolol.
Sympathicomimetic Agents: Concomitant use may counteract the effect of β-adrenergic antagonists. Beta-adrenergic agents may lead to unopposed α-adrenergic activity of sympathicomimetic agents with both α- and β-adrenergic effects (risk of hypertension, severe bradycardia and heart block).
Pharmacokinetic Interactions: As nebivolol metabolism involves the CYP2D6 isoenzyme, co-administration with substances inhibiting this enzyme, especially paroxetine, fluoxetine, thioridazine and quinidine may lead to increased plasma levels of nebivolol associated with an increased risk of excessive bradycardia and adverse events.
Co-administration of cimetidine increased the plasma levels of nebivolol, without changing the clinical effect. Co-administration of ranitidine did not affect the pharmacokinetics of nebivolol. Provided, Nebilet is taken with meal and an antacid between meals, the 2 treatments can be prescribed.
Combining Nebivolol with nicardipine slightly inceased the plasma levels of both drugs, without changing the clinical effect. Co-administration of alcohol, furosemide or hydrochlorothiazide did not affect the pharmacokinetics of nebivolol.
Nebivolol does not affect the pharmacokinetics and pharmacodynamics of warfarin.
Storage
Store at temperatures not exceeding 30°C.
MIMS Class
ATC Classification
C07AB12 - nebivolol ; Belongs to the class of selective beta-blocking agents. Used in the treatment of cardiovascular diseases.
Presentation/Packing
Tab 5 mg x 30's.
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