Summary of Product Characteristics
1. NAME OF THE MEDICINAL PRODUCT
/…/ 5 mg tablets
2. QUALITATIVE AND QUANTITATIVE COMPOSITION
Each tablet contains 5 mg of nebivolol equivalent to 5.45 mg of nebivolol hydrochloride. Excipients: 192.4 mg of lactose monohydrate/tablet For a full list of excipients, see section 6.1.
3. PHARMACEUTICAL FROM
Tablet.
Round, white, convex, 9 mm cross-scored tablets, marked with ‘N 5’ on the other side.
The tablet can be divided into equal halves and quarters.
4. CLINICAL PARTICULARS
4.1 Therapeutic indications
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.
4.2 Posology and method of administration
Method of administration: The tablet should be swallowed with a sufficient amount of liquid (e.g. one glass of water). The tablets can be taken with or without meals.
Hypertension Adults The dose is one tablet (5 mg) daily, preferably at the same time of the day. Tablets may be taken with meals. 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 /…/ in these patients is contra-indicated.
Elderly 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.
Children and adolescents No studies have been conducted in children and adolescents. Therefore, use in children and adolescents below 18 years 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 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 / / in these patients is contra-indicated.
Elderly No dose adjustment is required since uptitration to the maximum tolerated dose is individually adjusted.
Children and adolescents No studies have been conducted in children and adolescents. Therefore, use in children and adolescents below 18 years is not recommended.
4.3 Contraindications
- Hypersensitivity to the active substance or to any of the excipients. - 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, /.../ is contra-indicated in: - sick sinus syndrome, including sino-atrial block. - second and third degree atrioventricular 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.
4.4 Special warnings and precautions for use
See also section 4.8.
Anaesthesia Continuation 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.
Cardiovascular In 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 atrioventricular 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/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 hypoglycaemia (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, beta-adrenergic antagonists should be used with caution as airway constriction may be aggravated.
Other Patients 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. Beta blockers may cause decreased lacrimation (for information of the wearers of contact lenses). 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 malabsorption should not take this medicinal product.
4.5 Interactions with other medicinal products and other forms of interaction
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 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 (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 nebivolol.
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 considered Digitalis 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), organic nitrates and other antihypertensives: concomitant use may enhance the hypotensive effect of the beta-blockers (additive effect).
Non steroidal anti-inflammatory drugs (NSAID): no effect on the blood pressure lowering effect of nebivolol.
Sympathomimetic agents: concomitant use may counteract the effect of beta-adrenergic antagonists. Beta-adrenergic agents may lead to unopposed alpha-adrenergic activity of sympathomimetic 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 bupropion, paroxetine, fluoxetine, thioridazine, quinidine, chloroquine, levomepromazin and terbinafine 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 /…/ 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.
4.6 Pregnancy and lactation
Use in pregnancy Nebivolol 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-selcetive 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.
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 beta-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.
4.7 Effects on the ability to drive and use machines
No studies on the effects on the ability to drive and use machine have been performed. Pharmacodynamic studies have shown that nebivolol does not affect psychomotor function. When driving vehicles or operating machines it should be taken into account that dizziness and fatigue may occasionally occur (see section 4.8).
4.8 Undesirable effects
Adverse events are listed separately for hypertension and CHF because of differences in the background disease.
Hypertension: The adverse reactions reported, are tabulated below, classified by system organ class and ordered by frequency:
Organ class Common Uncommon Very rare Not known (>1/100 to <1/10) (>1/1,000 to (<1/10,000) (cannot be <1/100) estimated from the available data) Immune system Angioneurotic disorders oedema, hypersensitivity
Psychiatric Nightmares; disorders depression Nervous system Headache, Syncope disorders dizziness, paraesthesia Eye disorders Impaired vision Cardiac disorders Bradycardia, heart failure, slowed AV conduction/AV- block Vascular disorders Hypotension, (increase of) intermittent claudication Respiratory, Dyspnoea Bronchospasm thoracic and mediastinal disorders Gastrointestinal Constipation, Dyspepsia, disorders nausea, diarrhoea flatulence, vomiting Skin and Pruritus, Aggrevated subcutaneous tissue erythematous rash psoriasis disorders Reproductive Impotence system and breast disorders General disorders Tiredness, and administration oedema site conditions
The following adverse reactions have also been reported with some beta-adrenergic antagonists: hallucinations, psychoses, confusion, cold/cyanotic extremities, Raynaud phenomenon, dry eyes, and oculo-mucocutaneous toxicity of the practolol-type.
Chronic heart failure Data 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 was reported by 1.0% of nebivolol patients compared to 0.2% of placebo patients.
4.9 Overdose
No data are available on overdose with nebivolol.
Symptoms Symptoms of overdose with beta-blockers are: bradycardia, hypotension, bronchospasm and acute cardiac insufficiency.
Treatment In case of overdose 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.
5. PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Beta blocking agents, selective. ATC code: C07 AB 12
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- enatiomer (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 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. The clinical relevance of these haemodynamic differences as compared to other beta1 receptor antagonists has not been fully established. In hypertensive patients, nebivolol increases the NO-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 (mean LVEF: 36 ± 12.3%, with the following distribution: LVEF less than 35% in 56% of patients, LVEF between 35% and 45% in 25% of patients and LVEF greater than 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 hospitalisations for cardiovascular reasons (primary end-point 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 left ventricular ejection fraction 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 sympathomimetic activity. In vitro and in vivo experiments in animals showed that at pharmacological doses nebivolol has no membrane stabilising action. In healthy volunteers, nebivolol has no significant effect on maximal exercise capacity or endurance.
5.2 Pharmacokinetic properties
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 metabolised, partly to active hydroxy-metabolites. Nebivol is metabolised 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 metabolisers and is virtually complete in slow metabolisers. At steady state and at the same dose level, the peak plasma concentration of unchanged nebivolol is about 23 times higher in poor metabolisers than in extensive metabolisers. 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 metabolisers therefore may require lower doses. In fast metabolisers, elimination half-lives of the nebivolol enantiomers average 10 hours. In slow metabolisers, they are 3-5 times longer. In fast metabolisers, plasma levels of the RSSS-enantiomer are slightly higher than for the SRRR-enantiomer. In slow metabolisers, this difference is larger. In fast metabolisers, elimination half-lives of the hydroxymetabolites of both enantiomers average 24 hours, and are about twice as long in slow metabolisers. Steady-state plasma levels in most subjects (fast metabolisers) 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 faeces. Urinary excretion of unchanged nebivolol is less than 0.5% of the dose.
5.3 Preclinical safety data
Preclinical data reveal no special hazard for humans based on conventional studies of genotoxicity and carcinogenic potential.
6. PHARMACEUTICAL PARTICULARS
6.1 List of excipients
Silica colloidal anhydrous Magnesium stearate Croscarmellose sodium Macrogol 6000 Lactose monohydrate
6.2 Incompatibilities
Not applicable.
6.3 Shelf life
3 years
6.4 Special precautions for storage
This medicinal product does not require special storage precautions.
6.5 Nature and contents of container
Aluminium (lacquered)-PVC/PE/PVDC-blister of 7, 10 or 15 tablets and HDPE container with sealed LDPE cap.
Pack sizes: Carton with blister: 7, 10, 14, 20, 28, 30, 50, 56, 60, 90, 100, 500 and hospital pack with 500 (10x50) tablets
HDPE tablet container: 7, 14, 20, 28, 30, 50, 56, 60, 90, 100, 500 and hospital pack with 500 (10x50) tablets
Not all pack sizes may be marketed.
6.6 Special precautions for disposal
No special requirements.
7. MARKETING AUTHORISATION HOLDER
<[To be completed nationally]>
8. MARKETING AUTHORISATION NUMBERS(S)
<[To be completed nationally]>
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
<[To be completed nationally]>
10. DATE OF REVISION OF THE TEXT
<[To be completed nationally]>
Package Leaflet
PACKAGE LEAFLET: INFORMATION FOR THE USER
/…/ 5 mg tablets Nebivolol
Read all of this leaflet carefully before you start taking this medicine. - Keep this leaflet. You may need to read it again. - If you have any further questions, ask your doctor or pharmacist. - This medicine has been prescribed for you. Do not pass it on to others. It may harm them, even if their symptoms are the same as yours. - If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet, please tell your doctor or pharmacist.
In this leaflet: 1. What /…/ is and what it is used for 2. Before you take /…/ 3. How to take/…/ 4. Possible side effects 5. How to store /…/ 6. Further information
1. WHAT /…/ IS AND WHAT IT IS USED FOR
/…/ is a medicinal product that mainly acts on the function of your heart (beta-blocker). It decreases the blood pressure and improves the heart power.
/…/ is used for the treatment of high blood pressure (essential hypertension) in addition to standard therapy (e.g. with diuretics, digoxin, ACE inhibitors, angiotensin II antagonists) for the treatment of stable mild or moderate chronic heart failure in patients aged 70 years or over.
2. BEFORE YOU TAKE /…/
Do not take /…/ - if you are allergic (hypersensitive) to the active substance nebivolol hydrochloride or any of the other ingredients of /…/, - if you have liver function disorders or impaired liver function (hepatic insufficiency), - if you are pregnant or breast-feeding, - if you suffer from acute heart failure, cardiogenic shock or episodes of worsening heart failure (decompensation), which requires intravenous treatment with inotropic active substances, - if you suffer from sinus syndrome (a certain type of disturbance in heart rhythm) including sino- arterial block (SA block), - if you suffer from certain heart conduction disorders (2nd and 3rd degree heart block – AV block [without pacemaker]), - if you have a history of bronchial spasm and bronchial asthma, - if you suffer from untreated adrenal gland tumours (phaeochromocytoma), - if you suffer from hyperacidity of the blood (metabolic acidosis), - if you have a heart rate (pulse rate) at rest before treatment of less than 60 beats per minute lying down (bradycardia), - if you have a pathologically low blood pressure (systolic blood pressure < 90 mmHg), - if you have seriously poor circulation in the limbs.
If you are unsure, contact your doctor.
Take special care with /…/ - if the pulse is unusually low (less than 50 – 55 beats per minute at rest and/or symptoms such as dizziness, weakness and unsteady gait) during treatment with nebivolol, - if you are suffering from heart disease (e.g. angina pectoris, ischaemic heart disease, heart rhythm disorders); in patients with ischaemic heart disease, treatment should be stopped gradually, i.e. over the course of 1 – 2 weeks, and if necessary alternative treatment should be started at the same time, - if you have circulatory problems in your arms or legs, - if you suffer from constant respiratory problems, especially chronic obstructive airway disease, - if you have diabetes. /…/ does not affect the blood sugar level but it may mask signs of low blood sugar (nervousness, shaking, fast pulse). Sweating as symptom is however not masked by /…/. - if you have an overactive thyroid gland: possible masking of an increased pulse (tachycardia) as a sign of disease; abruptly stopping medication with /…/ can lead to an increased heart rate, - if you have an allergy. /…/ may intensify the reaction against pollen or other items that you are allergic to. - if you suffer from psoriasis: patients with existing psoriasis or a known history of the disorder should only take /…/ after the benefits and risks have been carefully weighed, - /…/ can reduce the flow of tears (for information if you are wearer of contact lenses).
Children and adolescents No studies have been conducted in children and adolescents. Therefore, the use in children and adolescents below 18 years is not recommended.
Elderly people In patients over 65 years of age a lower starting dose is recommended (see section “How to take /…/”). In patients over 75 years of age, special care should be taken and treatment should be closely monitored by the doctor.
Taking other medicines Please tell your doctor or pharmacist if you are taking or have recently taken any other medicines, including medicines obtained without a prescription.
This applies particularly for: - some medicines for the treatment of heart rhythm disorders (class I anti-arrhythmics such as quinidine, hydroquinidine, cibenzoline, flecainide, disopyramide, mexiletine, propafenone and lidocain as well as amiodarone) can increase the depressant effects of nebivolol on cardiac activity when taken at the same time as nebivolol. - certain medicines against high blood pressure and cramps of the blood vessels of the heart (so- called calcium antagonists) which may increase the effect of /…/ (e.g. verapamil and diltiazem, or amlodipine, felodipine, lacidipine, nifedipine, nicardipine, nimodipine and nitrendipine). - other centrally acting medicines against high blood pressure (clonidine, guanfacin, moxonidine, methyldopa, rilmenidine) may increase the risk of a strong rise in blood pressure (“rebound hypertension”) – especially after abrupt withdrawal of these medicines when taken for a long time. They may only be withdrawn if the beta-blocker (e.g. nebivolol) has been stopped a few days before. - if beta-receptor blockers and digitalis glycosides are used at the same time, a certain disturbance of cardiac activity may occur (prolonged conduction time). However, clinical studies with nebivolol have not shown any evidence of this interaction. Nebivolol did not influence the blood concentration of digoxin. - certain medicines against asthma, stuffed nose or certain eye diseases (so-called sympathomimetics) which may reduce the effect of /…/ (e.g. dopamine, ephedrine). - medicines against diabetes (insulin and medicines for oral use). See also “Take special care with /…/”. - baclofen (used to treat muscle spasm) and amifostine (used during cancer chemotherapy): may increase the fall in blood pressure. Your doctor might adjust your dose of /…/. - anaesthetics: always inform the anaesthetist that you take /…/ before narcosis. - certain antipsychotics may increase the effect of /…/. Simultaneous treatment with agents for treating depression (tricyclic antidepressants, paroxetine), barbiturates (e.g. for the treatment of epilepsy), sedatives (phenothiazines, e.g. thioridazin), organic nitrates (treatment of angina and heart failure) and other medicinal products against high blood pressure may lead to a sharp drop in blood pressure. - if serotonin-reuptake inhibitors (certain agents for depression, e.g. paroxetine and fluoxetine) are administered at the same time as /…/ the doctor may need to adjust the dose. - certain medicines, that are metabolised in a similar way as nebivolol, may lead to increased blood levels of nebivolol, associated with increased adverse events. Some of these are e.g. bupropion (antidepressant), chloroquin (used for the prevention of malaria and for the treatment of autoimmune diseases like rheumatoid arthritis), levomepromazin (neuroleptic agent) and terbinafine (antifungal).
If you in addition to /…/ also take an antacid against excess of acid in the stomach, you should take /…/ with food and the antacid between the meals.
Taking /…/ with food and drink You can take /…/ with food and drink.
Pregnancy and breast-feeding Ask your doctor or pharmacist for advice before taking any medicine.
Pregnancy There is a risk that the foetus is affected. Therefore, do not use /…/ during pregnancy.
Breast-feeding It is not known whether /…/ is excreted in breast milk. Therefore, do not use /…/ during breast- feeding.
Driving and using machines No studies on the effects on the ability to drive and use machines have been performed. Dizziness or fatigue may occasionally occur as an adverse reaction of /…/. Take this into consideration when you drive a car or use machines (see section 4 “Possible side effects”).
Important information about some of the ingredients of /…/ /…/ contains lactose monohydrate. If you have been told by your doctor that you have an intolerance to some sugars, contact your doctor before taking this medicine.
3. HOW TO TAKE /…/
Always take /…/ exactly as your doctor has told you. You should check with your doctor or pharmacist if you are not sure.
Hypertension Adults: The usual dose is 1 tablet per day (5 mg nebivolol). It usually takes 1 to 2 weeks before the maximum effect of /…/ is achieved.
Combination with other antihypertensive medicines: Beta-receptor blockers can be used alone or in combination with other antihypertensive medicines. To date, an added antihypertensive effect has only been observed in the combination of 5 mg nebivolol with 12.5 – 25 mg of the active substance hydrochlorothiazide.
Patients with impaired kidney function (renal insufficiency): In patients with renal insufficiency, the recommended starting dose is ½ a tablet (2.5 mg nebivolol) daily. If necessary, the daily dose can be increased to 1 tablet (5 mg nebivolol).
Patients with impaired liver function (hepatic insufficiency): Not enough experience has been gained in the use of /…/ in patients with impaired liver function or disorders of liver function. For this reason, /…/ must not be used in these patients (see “Do not take /…/”).
Elderly patients: In patients aged 65 or more, the recommended starting dose is ½ a tablet (2.5 mg nebivolol) daily. If necessary, the daily dose can be increased to 1 tablet (5 mg nebivolol). In all cases, special care should be taken and treatment should be closely monitored in view of the limited experience in patients over 75 years of age.
Children and adolescents: No studies have been conducted in children and adolescents. Therefore, the use in children and adolescents below 18 years is not recommended.
Chronic heart failure The treatment of stable chronic heart failure must be started with a slow increase in dose, until the optimum individual maintenance dose has been reached. In patients taking other cardiovascular medicines such as diuretics, digoxin, ACE inhibitors or angiotensin II antagonists, the dosage of these medicines must be stabilized before treatment with /…/ is started.
The initial dose titration should be as follows with adjustments every one or two weeks, depending on how the dose is tolerated by the patient: - ¼ tablet (1.25 mg nebivolol) once daily, - increased to ½ tablet (2.5 mg nebivolol) once daily, - then to 1 tablet (5 mg nebivolol) once daily and - then to 2 tablets (10 mg nebivolol) once daily. The recommended maximum dose is 2 tablets (10 mg nebivolol) once a day.
The patient should be monitored during the first 2 hours after taking the first dose and during the first 2 hours after each dose increase to make sure the clinical condition has remained stable.
Patients with impaired kidney function (renal insufficiency): Since the dose is increased individually up to the maximum tolerated dose, no adjustment is necessary in patients with mild to moderate renal insufficiency. There is no experience in patients with severe renal insufficiency, therefore the use of nebivolol in these patients is not recommended.
Patients with impaired liver function (hepatic insufficiency): Not enough experience has been gained in patients with impaired liver function. /…/ must therefore not be used in these patients (see “Do not take /…/”).
Elderly patients: Since the dose is increased individually up to the maximum tolerated dose, no adjustment is necessary.
Children and adolescents: No studies have been conducted in children and adolescents. Therefore, the use in children and adolescents below 18 years is not recommended.
Mode of administration: The prescribed daily dose should preferably always be taken at the same time of day. The tablets should be swallowed with a sufficient amount of liquid (e.g. one glass of water) with or without meals.
If you feel that the effect of /…/ is too strong or too weak, contact your doctor or pharmacist.
If you take more /…/ than you should The symptoms of an overdose are: slow heartbeat, low blood pressure, breathing difficulties and sudden (acute) heart problems.
Contact you doctor if you have taken more /…/ than you should. You should lie down with your legs higher than the heart.
If you forget to take /…/ If you have forgotten to take your medicine one day, then continue the medication next day at the usual time. Do not take a double dose to make up for a forgotten dose.
If you stop taking /…/ Do not stop taking your tablets even if you are feeling well, unless your doctor tells you.
When treatment is interrupted or ended early the blood pressure can rise or the heart problems will increase.
If you have any further questions on the use of this product, ask your doctor or pharmacist.
4. POSSIBLE SIDE EFFECTS
Like all medicines, /…/ can cause side effects, although not everybody gets them.
The side effects observed are listed below, arranged according to frequencies. The following side effects may occur:
In patients with high blood pressure
Common (affects 1 to 10 users in 100) Headache, dizziness, tingling skin, difficulty breathing, constipation, nausea, diarrhoea, tiredness, swelling with water retention (oedema)
Uncommon (affects 1 to 10 users in 1,000) Nightmares, depression, visual disturbances, unusually low heart rate (slow pulse), weak cardiac performance, conduction defects in the heart, low blood pressure (hypotension), occurrence of or increase in pain occurring in the feet when walking due to narrowed arteries and insufficient blood circulation (intermittent claudication), wheezing or shortness of breath (bronchospasm), indigestion, flatulence, vomiting, itching, skin rash, impotence
Very rare (affects less than 1 user in 10,000) Fainting (syncope), worsening of psoriasis
Not known (frequency cannot be estimated from the available data) Swelling of face, lips, throat or tongue (angioneurotic oedema), allergy (hypersensitivity)
The following side effects have also been reported with similar medicines: hallucinations, psychotic reactions (psychoses), confusion, cold/bluish-red discoloration of the arms and legs, pain in fingers and toes which first turn bluish, then whitish, and finally reddish (Raynaud’s syndrome), dry eyes and also formation of new connective tissue in the eyes and the diaphragm (practolol-type oculo- mucocutaneous toxicity).
In patients with chronic heart failure
Very common (affects more than 1 user in 10) Dizziness, unusually low heart rate (slow pulse)
Common (affects 1 to 10 users in 100) Headache, worsening of heart failure, heart rhythm disorder (called first degree AV-block), fall in blood pressure on standing up (postural hypotension), tiredness/weakness1, drug intolerance, water retention (oedema) in the legs, reduction of pulse, fall in blood pressure
If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet, please tell your doctor or pharmacist.
5. HOW TO STORE /…/
Keep out of the reach and sight of children.
Do not use /…/ after the expiry date which is stated on the carton after EXP. The expiry date refers to the last day of that month.
This medicinal product does not require any special storage conditions.
Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how to dispose of medicines no longer required. These measures will help to protect the environment.
6. FURTHER INFORMATION
What /…/ contains - The active substance is nebivolol. Each tablet contains 5 mg of nebivolol equivalent to 5.45 mg of nebivolol hydrochloride. - The other ingredients are silica colloidal anhydrous, magnesium stearate, croscarmellose sodium, macrogol 6000 and lactose monohydrate
What /…/ looks like and contents of the pack Round, white, convex, 9 mm cross-scored tablets, marked with ‘N 5’ on the other side. The tablets can be divided into equal halves and quarters.
Blister (of 7, 10 or 15 tablets) and HDPE container with sealed LDPE cap
Pack sizes: Blister: 7, 10, 14, 20, 28, 30, 50, 56, 60, 90, 100, 500 and hospital pack with 500 (10x50) tablets HDPE tablet container: 7, 14, 20, 28, 30, 50, 56, 60, 90, 100, 500 and hospital pack with 500 (10x50) tablets
Not all pack sizes may be marketed.
Marketing Authorisation Holder and Manufacturer <[To be completed nationally]>
This medicinal product is authorised in the Member States under the following names: Germany Nebivolol-Actavis 5mg Tabletten Austria Nebivolol Actavis 5 mg Tabletten Belgium Tyskten Czech Republic Nebivolol +pharma 5 mg Estonia Nebivolol Actavis Finland Nebivolol Actavis Iceland Nebivolol Actavis Latvia Nebivolol Actavis Malta Nebivolol Actavis Hungary Nevotens Poland Ebivol Italy Nebivololo Actavis Lithuania Nebivolol Actavis 5 mg tabletés Netherlands Nebivolol Actavis 5mg Slovak Republic Nebivolol Actavis 5mg
This leaflet was approved in <[To be completed nationally]>
Labelling
OUTER PACKAGING Carton for blisters / tablet container (HDPE container with sealed LPDE cap)
1. NAME OF THE MEDICINAL PRODUCT /…/ Nebivolol
2. STATEMENT OF ACTIVE SUBSTANCE(S) Each tablet contains 5 mg of nebivolol equivalent to 5.45 mg of nebivolol hydrochloride.
3. LIST OF EXCIPIENTS Contains lactose monohydrate. Refer to the package leaflet before use
4. PHARMACEUTICAL FORM AND CONTENTS Tablet 7 tablets 10 tablets (only for blister) 14 tablets 20 tablets 28 tablets 30 tablets 50 tablets 56 tablets 60 tablets 90 tablets 100 tablets 500 (10 x 50) tablets Not all pack sizes may be marketed.
5. METHOD AND ROUTE(S) OF ADMINISTRATION Oral use Read the package leaflet before use.
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF THE REACH AND SIGHT OF CHILDREN Keep out of the reach and sight of children.
7. OTHER SPECIAL WARNING(S), IF NECESSARY
8. EXPIRY DATE EXP
9. SPECIAL STORAGE CONDITIONS
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR WAST MATERIALS SERIVED FORM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER <[To be completed nationally]>
12. MARKETING AUTHORISATION NUMBERS(S) <[To be completed nationally]>
13. BATCH NUMBER Batch
14. GENERAL CLASSIFICATIONS FOR SUPPLY <[To be completed nationally]>
15. INSTRUCTIONS ON USE
16. INFORMATION IN BRAILLE <[To be completed nationally]>
INNER PACKAGING PVDC-Aluminium-Blister
1. NAME OF THE MEDICINAL PRODUCT /…/ Nebivolol
2. NAME OF THE MARKETING AUTHORISATION HOLDER <[To be completed nationally]>
3. EXPIRY DATE EXP
4. BATCH NUMBER Batch
5. OTHER