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NEBIVOLOL 2.5 MG TABLETS

Active substance(s): NEBIVOLOL HYDROCHLORIDE

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SUMMARY OF PRODUCT CHARACTERISTICS
1

NAME OF THE MEDICINAL PRODUCT
Nebivolol 2.5 mg tablets

2

QUALITATIVE AND QUANTITATIVE COMPOSITION
Each tablet contains 2.5 mg of nebivolol (as nebivolol hydrochloride).
Excipient(s) with known effect:
Each tablet contains 70.775 mg of lactose monohydrate.
For the full list of excipients, see section 6.1.

3

PHARMACEUTICAL FORM
Tablet
White to off white, round, plain biconvex tablets with score line on one side.
The tablet can be divided into equal doses.

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
For oral administration
Posology

Hypertension
Adults
The dose is 5 mg (one 5 mg tablet or two 2.5 mg tablets) 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 in these patients is contraindicated.
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
No data are available. Nebivolol should therefore not be used in children and
adolescents.
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 medicinal therapy including
diuretics and/or digoxin and/or ACE inhibitors and/or angiotensin II
antagonists, dosing of these medicines should be stabilised during the past two
weeks prior to initiation of nebivolol 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 longterm 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 tablets 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 is not recommended.
Method of administration
The tablets should be taken with some water. They may be taken with meals.

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 intravenous inotropic therapy.
In addition, as with other beta-blocking agents, nebivolol are contra-indicated in:
• sick sinus syndrome, including sino-atrial block,
• second and third degree heart block (without a pacemaker),
• history of bronchospasm and bronchial asthma,
• untreated phaeochromocytoma,
• metabolic acidosis,
• bradycardia (heart rate < 60 bpm prior to start therapy),
• hypotension (systolic blood pressure < 90 mmHg),
• severe peripheral circulatory disturbances.

4.4

Special warnings and precautions for use
See also 4.8 Undesirable effects.
The following warnings and precautions apply to beta-adrenergic antagonists
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 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 or 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 active substances, and with
centrally acting antihypertensive active substances is generally not
recommended, for details see 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.
The initiation of Chronic Heart Failure treatment with nebivolol necessitates
regular monitoring. For the posology and method of administration see section
4.2. Treatment discontinuation should not be done abruptly unless clearly
indicated. For further information see section 4.2.
This medicinal product contains lactose. Patients with rare hereditary
problems of galactose intolerance, the Lapp-lactase deficiency or glucosegalactose malabsorption should not take this medicinal product.

4.5

Interaction 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 medicinal products 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 betablocker discontinuation, may increase risk of “rebound hypertension”.
Combinations to be used with caution
Class III antiarrhythmic substances (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 tablets.
Insulin and oral antidiabetic substances:
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 medicinal products
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):
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 nebivolol tablets are taken
with the meal, and an antacid between meals, the two treatments can be coprescribed.
Combining nebivolol with nicardipine slightly increased the plasma levels of
both active substances, 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 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-feeding
Animal studies have shown that nebivolol is excreted in breast milk. It is not
known whether this medicine 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 ability to drive and use machines
Nebivolol has minor influence on the ability to drive and use machines.
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.

4.8

Undesirable effects
Adverse reactions are listed separately for hypertension and CHF 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 below, classified by system organ class and
ordered by frequency:
System organ
class

Common

Uncommon

(≥1/100 to < (≥1/1,000 to
1/10)
≤1/100)

Very rare
(≤1/10,000)

Immune system
disorders
Psychiatric
disorders

Not known

angioneurotic
oedema,
hypersensitivity
nightmares;
depression

Nervous system headache,
dizziness,
disorders
paraesthesia

syncope

Eye disorders

impaired
vision

Cardiac
disorders

bradycardia,
heart failure,
slowed AV
conduction/A
V-block

Vascular
disorders

hypotension,
(increase of)
intermittent
claudication

System organ
class

Common

Uncommon

(≥1/100 to < (≥1/1,000 to
1/10)
≤1/100)
Respiratory,
thoracic and
mediastinal
disorders

dyspnoea

Very rare

Not known

(≤1/10,000)

bronchospasm

Gastrointestinal constipation, dyspepsia,
nausea,
flatulence,
disorders
diarrhoea
vomiting
Skin and
subcutaneous
tissue disorders

pruritus, rash
erythematous

Reproductive
system and
breast disorders

impotence

General
disorders and
administration
site conditions

psoriasis
aggravated

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.
Chronic heart failure
Data on adverse reactions in CHF patients are available from one placebocontrolled 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
substance-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.
- Intolerance to the substance 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 mportant. It allows continued monitoring of the benefit/risk balance
of the medicinal product. Healthcare professionals are asked to report any
suspected adverse reactions via 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 active substance 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.

5

PHARMACOLOGICAL PROPERTIES

5.1

Pharmacodynamic properties
Pharmacotherapeutic group: Beta blocking agents, selective; ATC code:
C07AB12
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 Larginine/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 sympathicomimetic 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, Ndealkylation and glucuronidation; in addition, glucuronides of the hydroxymetabolites 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 active substance 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 tablets
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 hydroxymetabolites.
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 RSSSnebivolol.
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
Non-clinical data reveal no special hazard for humans based on conventional
studies of genotoxicity and carcinogenic potential.

6

PHARMACEUTICAL PARTICULARS

6.1

List of excipients
Lactose monohydrate
Microcrystalline cellulose
Crospovidone (Type-B)
Copovidone
Magnesium stearate

6.2

Incompatibilities
Not applicable.

6.3

Shelf life
Alu-Alu blister packs: 3 years.
PVC/PE/PVdC-Alu blister packs: 12 months

6.4

Special precautions for storage
This medicinal product does not require any special storage precautions.

6.5

Nature and contents of container
Alu-Alu blister or clear PVC/PE/PVdC-Alu blister. Pack size: 28 tablets

6.6

Special precautions for disposal
No special requirements.

7

MARKETING AUTHORISATION HOLDER
Mercury Pharmaceuticals Ltd
Capital House
85 King William Street,
London EC4N 7BL
United Kingdom

8

MARKETING AUTHORISATION NUMBER(S)
PL 12762/0498

9

DATE OF FIRST AUTHORISATION/RENEWAL OF THE
AUTHORISATION
27/08/2014

10

DATE OF REVISION OF THE TEXT
27/08/2014

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Source: Medicines and Healthcare Products Regulatory Agency

Disclaimer: Every effort has been made to ensure that the information provided here is accurate, up-to-date and complete, but no guarantee is made to that effect. Drug information contained herein may be time sensitive. This information has been compiled for use by healthcare practitioners and consumers in the United States. The absence of a warning for a given drug or combination thereof in no way should be construed to indicate that the drug or combination is safe, effective or appropriate for any given patient. If you have questions about the substances you are taking, check with your doctor, nurse or pharmacist.

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