HypertensionTreatment 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.
AdultsThe 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 agentsBeta-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.
Patients with renal insufficiencyIn 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 insufficiencyData in patients with hepatic insufficiency or impaired liver function are limited. Therefore the use of Nebilet in these patients is contra-indicated.
Older peopleIn 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 populationThe efficacy and safety of Nebilet 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 stabilised during the past two weeks prior to initiation of Nebilet 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 insufficiencyNo 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 ≥ 250μmol/L). Therefore, the use of nebivolol in these patients is not recommended.
Patients with hepatic insufficiencyData in patients with hepatic insufficiency are limited. Therefore the use of Nebilet in these patients is contra-indicated.
Older peopleNo dose adjustment is required since uptitration to the maximum tolerated dose is individually adjusted.
Paediatric populationThe efficacy and safety of Nebilet 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.
Method of administrationOral use.Tablets may be taken with meals.
AnaesthesiaContinuation of beta-blockade reduces the risk of arrhythmias during induction and intubation. If beta-blockade is interrupted in preparation for surgery, the beta-adrenergic antagonist should be discontinued at least 24 hours beforehand. Caution should be observed with certain anaesthetics that cause myocardial depression. The patient can be protected against vagal reactions by intravenous administration of atropine.
CardiovascularIn general, beta-adrenergic antagonists should not be used in patients with untreated congestive heart failure (CHF), unless their condition has been stabilised.In patients with ischaemic heart disease, treatment with a beta-adrenergic antagonist 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-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;• 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 alphareceptor mediated coronary artery vasoconstriction: beta-adrenergic antagonists 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, for details please refer to section 4.5.
Metabolic/EndocrinologicalNebilet does not affect glucose levels in diabetic patients. Care should be taken in diabetic patients however, as nebivolol may mask certain symptoms of hypoglycaemia (tachycardia, palpitations).Beta-adrenergic blocking agents may mask tachycardic symptoms in hyperthyroidism. Abrupt withdrawal may intensify symptoms.
RespiratoryIn patients with chronic obstructive pulmonary disorders, beta-adrenergic antagonists should be used with caution as airway constriction may be aggravated.
OtherPatients with a history of psoriasis should take beta-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. For the posology and method of administration please refer to section 4.2. Treatment discontinuation should not be done abruptly unless clearly indicated. For further information please refer to section 4.2.This medicinal product contains lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp-lactase deficiency or glucose-galactose malapsorption should not take this medicinal product.
Pharmacodynamic interactions:The following interactions apply to beta-adrenergic antagonists 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 (see section 4.4).Calcium channel antagonists of verapamil/diltiazem type: negative influence on contractility and atrio-ventricular conduction. Intravenous administration of verapamil in patients with ß-blocker treatment may lead to profound hypotension and atrio-ventricular block (see section 4.4).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) (see section 4.4). Abrupt withdrawal, particularly if prior to beta-blocker discontinuation, may increase risk of rebound hypertension.
Combinations to be used with cautionClass 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 (see section 4.4). As a general rule, avoid sudden withdrawal of beta-blocker treatment. The anaesthesiologist 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 hypoglycaemia (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 consideredDigitalis glycosides: concomitant use may increase atrio-ventricular 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 hypothensive effect of the beta-blockers (additive effect).Non steroidal anti-inflammatory drugs (NSAID): no effect on the blood pressure lowering effect of nebivolol.Sympathicomimetic agents: concomitant use may counteract the effect of beta-adrenergic antagonists. Beta-adrenergic agents may lead to unopposed alpha-adrenergic activity of sympathicomimetic agents with both alpha- and beta-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 the meal, and an antacid between meals, the two treatments can be co-prescribed. Combining nebivolol with nicardipine slightly increased 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.
PregnancyNebivolol has pharmacological effects that may cause harmful effects on pregnancy and/or the foetus/newborn. In general, beta-adrenoceptor blockers reduce placental perfusion, which has been associated with growth retardation, intrauterine death, abortion or early labour. Adverse effects (e.g. hypoglycaemia and bradycardia) may occur in the foetus and newborn infant. If treatment with beta-adrenoceptor blockers is necessary, beta1-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 foetal growth should be monitored. In case of harmful effects on pregnancy or the foetus alternative treatment should be considered. The newborn infant must be closely monitored. Symptoms of hypoglycaemia and bradycardia are generally to be expected within the first 3 days.
Breast-feedingAnimal studies have shown that nebivolol is excreted in breast milk. It is not known whether this drug is excreted in human milk. Most beta-blockers, particularly lipophilic compounds like nebivolol and its active metabolites, pass into breast milk although to a variable extent. A risk to the newborns/infants cannot be excluded. Therefore, mothers receiving Nebivolol should not breast feed.
Nebivolol had no effect on rat fertility except at doses several fold higher than the human maximum recommended dose when adverse effects on male and female reproductive organs in rats and mice were observed. The effect of nebivolol on human fertility is unknown.
HypertensionThe adverse reactions reported, which are in most of the cases of mild to moderate intensity, are tabulated below, classified by system organ class and ordered by frequency:
|SYSTEM ORGAN CLASS||Common (≥1/100 to < 1/10)||Uncommon (≥1/1,000 to ≤1/100)||Very Rare (≤1/10,000)||Not Known|
|Immune system disorders||angioneurotic oedema, hypersensitivity|
|Psychiatric disorders||nightmares; depression|
|Nervous system disorders||headache, dizziness, paraesthesia||syncope|
|Eye disorders||impaired vision|
|Cardiac disorders||bradycardia, heart failure, slowed AV conduction/AV-block|
|Vascular disorders||hypotension, (increase of) intermittent claudication|
|Respiratory, thoracic and mediastinal disorders||dyspnoea||bronchospasm|
|Gastrointestinal disorders||constipation, nausea, diarrhoea||dyspepsia, flatulence, vomiting|
|Skin and subcutaneous tissue disorders||pruritus, rash erythematous||psoriasis aggravated||urticaria|
|Reproductive system and breast disorders||impotence|
|General disorders and administration site conditions||tiredness, oedema|
Chronic heart failureData on adverse reactions in CHF patients are available from one 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 causally 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 1.0% of placebo patients. - Drug intolerance occurred in 1.6% of nebivolol patients compared to 0.8% of placebo patients. - First degree atrio-ventricular block occurred in 1.4% of nebivolol patients compared to 0.9% of placebo patients.- Oedema of the lower limb were reported by 1.0% of nebivolol patients compared to 0.2% of placebo patients.
Reporting of suspected adverse reactions:
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme. Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.
SymptomsSymptoms of overdosage with beta-blockers are: bradycardia, hypotension, bronchospasm and acute cardiac insufficiency.
TreatmentIn 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.
Available preclinical and clinical evidence in hypertensive patients has not shown that nebivolol has a detrimental effect on erectile function.
Polysorbate 80 (E433)
Croscarmellose sodium (E468)
Microcrystalline cellulose (E460)
Silica, colloidal anhydrous (E551)
Magnesium stearate (E572)