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 of ≥70 years.

4.2. Posology and method of administration

Posology

Hypertension

Adults

2.5mg: The dose is 5 mg (two tablets) daily, preferably at the same time of the day.

5mg: The dose is 5 mg (one tablet) daily, preferably at the same time of the day.

The blood pressure lowering effect becomes evident after 1-2 weeks of treatment. Occasionally, the optimal effect is reached only after 4 weeks.

Combination with other antihypertensive agents

Beta –Blockers can be used alone or concomitantly with other antihypertensive agents. To date, an additional antihypertensive effect has been observed only when nebivolol is combined with hydrochlorothiazide 12.5-25 mg.

Patients with renal insufficiency

In patients with renal insufficiency, the recommended starting dose is 2.5 mg daily. If needed, the daily dose may be increased to 5 mg.

Patients with hepatic insufficiency

Data in patients with hepatic insufficiency or impaired liver function are limited. Therefore the use of Nebivolol 2.5mg or Nebivolol 5mg tablets 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.

Paediatric population

The efficacy and safety of Nebivolol 2.5mg or Nebivolol 5mg Tablets 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 Nebivolol 2.5mg or Nebivolol 5mg Tablets 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 ≥250μmol/L). Therefore, the use of nebivolol in these patients is not recommended.

Patients with hepatic insufficiency

Data in patients with hepatic insufficiency are limited. Therefore the use of Nebivolol 2.5mg or Nebivolol 5mg Tablets in these patients is contra-indicated.

Elderly

No dose adjustment is required since up-titration to the maximum tolerated dose is individually adjusted.

Paediatric population

The efficacy and safety of Nebivolol 2.5mg or Nebivolol 5mg Tablets 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 administration

Oral use.

The tablet should be swallowed with a sufficient amount of fluid (e.g one glass of water). The tablet can be taken with or without food.

4.3. Contraindications

- Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

- Liver insufficiency or liver function impairment.

- Acute heart failure, cardiogenic shock or episodes of heart failure decompensation requiring i.v. inotropic therapy.

- sick sinus syndrome, including sino-atrial block.

- second and third degree AV-block (without a pacemaker).

- history of bronchial asthma or chronic obstructive pulmonary disease.

- 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.

The following warnings and precautions apply to beta-adrenergic antagonists, such as nebivolol, in general.

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 coronary 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/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-blockers could further increase the risk of severe hypoglycaemia when used concurrently with sulfonylureas. Diabetic patients should be advised to carefully monitor blood glucose levels. (see Section 4.5).

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 rarely cause decreased lacrimation.

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, total lactase deficiency or glucose-galactose malabsorption should not take this medicinal product.

4.5. Interaction with other medicinal products and other forms of interaction

Pharmacodynamic interactions

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 2.5mg or Nebivolol 5mg Tablets

Insulin and oral antidiabetic drugs: although nebivolol does not affect glucose level, concomitant use may mask certain symptoms of hypoglycaemia (palpitations, tachycardia). The concomitant use of beta-blockers with sulfonylureas could increase the risk of severe hypoglycaemia. (see Section 4.4).

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.

Mefloquine (antimalarian drug): Theoretically co-administration with β-adrenergic blocking agents might contribute to a prolongation of the QTc interval.

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 and sedatives (tricyclics, barbiturates and phenothiazines), organic nitrates as well as other antihypertensive agents: 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. 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 Nebivolol 2.5mg or Nebivolol 5mg 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. Fertility, pregnancy and lactation

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 -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 hypoglycaemia and bradycardia are generally to be expected within the first 3 days.

Breast-feeding

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. A risk to the newborns/infants cannot be excluded. Therefore, mothers receiving nebivolol should not breastfeed.

Fertility

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.

4.7. Effects on ability to drive and use machines

No studies on the effects on the ability to drive and use machines have been performed. Pharmacodynamic studies have shown that nebivolol does not affect psychomotor function. Some patients may experience adverse effects (see. section 4.8) which are mostly due to the reduction in blood pressure, such as dizziness or fainting. Should these occur, one should refrain from driving and other activities requiring alertness. These effects are more likely to occur after initiation of the treatment or after dose increases.

4.8. Undesirable effects

The following terminologies have been used in order to classify the occurrence of undesirable effects:

<Very common (≥1/10)>

<Common (≥1/100 to <1/10)>

<Uncommon (≥1/1,000 to <1/100)>

<Rare (≥1/10,000 to <1/1,000)>

<Very rare (≤1/10,000)>

<Not known (cannot be estimated from the available data)>

Adverse events are listed separately for hypertension and CHF because of differences in the background diseases.

Hypertension

The adverse reactions reported, which are in most cases of mild to moderate intensity, are tabulated below, classified by system organ class and ordered by frequency:

SYSTEM ORGAN CLASS

Common

Uncommon

Very rare

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

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.

Beta-blockers may cause decreased lacrimation.

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.

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 at: www.mhra.gov.uk/yellowcard.

4.9. Overdose

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 intravenous may be considered. If required, the injection should be repeated within one hour, to be followed -if required- by an intravenous infusion of glucagon 70 μg/kg/h. In extreme cases of treatment-resistant bradycardia, a pacemaker may be inserted.