Nebilet 5mg tablets

United Kingdom - English - eMC (Electronic Medicines Compendium)

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Active ingredient:
Nebivolol hydrochloride
Available from:
CST Pharma Ltd
ATC code:
C07AB12
INN (International Name):
Nebivolol hydrochloride
Dosage:
5mg
Pharmaceutical form:
Tablet
Administration route:
Oral
Class:
No Controlled Drug Status
Prescription type:
Valid as a prescribable product
Product summary:
BNF: 02040000; GTIN: 5055946800981

Patient Information Leaflet

Nebilet® 5mg Tablets

(Nebivolol hydrochloride)

The name of your medicine is Nebilet 5mg Tablets, but will be referred to

as Nebilet throughout the remainder of the leaflet.

Read all this leaflet carefully before you start using 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 Nebilet is and what it is used for

2. Before you take Nebilet

3. How to take Nebilet

4. Possible side effects

5. How to store Nebilet

6. Further information

1. What Nebilet is and what it is used for

Nebilet contains nebivolol, a cardiovascular drug belonging to the group

of selective beta-blocking agents (i.e. with a selective action on the

cardiovascular system). It prevents increased heart rate, controls heart

pumping strength. It also exerts a dilating action on blood vessels, which

contributes as well to lower blood pressure.

It is used to treat raised blood pressure (hypertension).

Nebilet is also used to treat mild and moderate chronic heart failure in

patients aged 70 or over, in addition to other therapies.

2. Before you take Nebilet

Do not take Nebilet

if you are allergic (hypersensitive) to nebivolol or any of the other

ingredients of Nebilet

if you have one or more of the following disorders:

low blood pressure

serious circulation problems in the arms or legs

very slow heartbeat (less than 60 beats per minute)

certain other serious heart rhythm problems (e.g. 2nd and 3rd

degree atrioventricular block, heart conduction disorders).

heart failure, which has just occurred or which has recently

become worse, or you are receiving treatment for circulatory

shock due to acute heart failure by intravenous drip feed to help

your heart work

asthma or wheezing (now or in the past)

untreated phaeochromocytoma, a tumour located on top of the

kidneys (in the adrenal glands)

liver function disorder

a metabolic disorder (metabolic acidosis), for example, diabetic

ketoacidosis.

Take special care with Nebilet

Inform your doctor if you have or develop one of the following problems:

abnormally slow heartbeat

a type of chest pain due to spontaneously occurring heart cramp

called Prinzmetal angina

untreated chronic heart failure

1st degree heart block (a kind of light heart conduction disorder

that affects heart rhythm)

poor circulation in the arms or legs, e.g. Raynaud’s disease or

syndrome, cramp-like pains when walking

prolonged breathing problems

diabetes: This medicine has no effect on blood sugar, but it could

conceal the warning signs of a low sugar level (e.g. palpitations,

fast heartbeat).

overactive thyroid gland: This medicine may mask the signs of an

abnormally fast heart rate due to this condition

allergy: This medicine may intensify your reaction to pollen or

other substances you are allergic to

psoriasis (a skin disease - scaly pink patches) or if you have ever

had psoriasis

if you have to have surgery, always inform your anaesthetist that

you are on Nebilet before being anaesthetised.

If you have serious kidney problems do not take Nebilet for heart failure

and tell your doctor.

You will be regularly monitored at the beginning of your treatment for

chronic heart failure by an experienced physician (see section 3).

This treatment should not be stopped abruptly unless clearly indicated

and evaluated by your doctor (see section 3).

Children and adolescents

Because of the lack of data on the use of the product in children and

adolescents, Nebilet is not recommended for use in them.

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. Certain medicines cannot be used at the same time, while

other drugs require specific changes (in the dose, for example).

Always tell your doctor if you are using or receiving any of the following

medicines in addition to Nebilet:

Medicines for controlling the blood pressure or medicines for heart

problems (such as amiodarone, amlodipine, cibenzoline, clonidine,

digoxin, diltiazem, disopyramide, felodipine, flecainide, guanfacin,

hydroquinidine, lacidipine, lidocaine, methyldopa, mexiletine,

moxonidine, nicardipine, nifedipine, nimodipine, nitrendipine,

propafenone, quinidine, rilmenidine, verapamil).

Sedatives and therapies for psychosis (a mental illness) e.g.

barbiturates (also used for epilepsy), phenothiazine (also used for

vomiting and nausea) and thioridazine.

Medicines for depression e.g. amitriptyline, paroxetine, fluoxetine.

Medicines used for anaesthesia during an operation.

Medicines for asthma, blocked nose or certain eye disorders such

as glaucoma (increased pressure in the eye) or dilation (widening)

of the pupil.

Baclofen (an antispasmodic drug); Amifostine (a protective

medicine used during cancer treatment)

All these drugs as well as nebivolol may influence the blood pressure

and/or heart function.

Medicines for treating excessive stomach acid or ulcers (antacid

drug), e.g. cimetidine: you should take Nebilet during a meal and

the antacid drug between meals.

Taking Nebilet with food and drink

Nebilet can be taken with food or on an empty stomach, but the tablet is

best taken with some water.

Pregnancy and breast-feeding

Nebilet should not be used during pregnancy, unless clearly necessary. It

is not recommended for use while breast-feeding. Ask your doctor or

pharmacist for advice before taking any medicine.

Driving or operating machinery

This medicine may cause dizziness or fatigue. If affected, do not drive or

operate machinery.

Important information about some of the ingredients of Nebilet

This product contains lactose. 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 Nebilet

Always take Nebilet exactly as your doctor has told you. You should

check with your doctor if you are not sure. Nebilet may be taken before,

during or after the meal, but, alternatively, you can take it independently

of meals. The tablet is best taken with some water.

Treatment of raised blood pressure (hypertension)

The usual dose is 1 tablet per day. The dose should be taken

preferably at the same time of the day.

Elderly patients and patients with a kidney disorder will usually start

with ½ (half) tablet daily.

The therapeutic effect on blood pressure becomes evident after 1-2

weeks of treatment. Occasionally, the optimal effect is reached only

after 4 weeks.

Treatment of chronic heart failure

Your treatment will be started and closely supervised by an

experienced physician.

Your doctor will start your treatment with ¼ (quarter) tablet per day.

This may be increased after 1-2 weeks to ½ (half) tablet per day,

then to 1 tablet per day and then to 2 tablets per day until the

correct dose is reached for you. Your doctor will prescribe the dose

that is right for you at each step and you should closely follow

his/her instructions.

The maximum recommended dose is 2 tablets (10mg) a day.

You will need to be under the close supervision for 2 hours by an

experienced physician when you start treatment and every time

your dose is increased

Your doctor may reduce your dose if necessary

You should not stop treatment abruptly as this can make your

heart failure worse.

Patients with serious kidney problems should not take this

medicine.

Take your medicine once daily, preferably at about the same time

of day.

If you have been told by your doctor to take ¼ (quarter) or ½ (half) tablet

daily, please refer to the instructions below on how to break Nebilet 5 mg

cross-scored tablets.

Place the tablets onto a flat, hard surface (e.g. a table or worktop),

with the cross score facing up.

Break the tablet by pushing it with the index fingers of both hands

placed along one breakmark (Diagrams 1 and 2).

Tablet quarters are obtained by breaking the halves in the same

way (Diagrams 3 and 4).

Diagrams 1 and 2: Easy breaking of the Nebivolol 5 mg cross-scored

tablet in half.

PP2/1268/V1

Diagrams 3 and 4: Easy breaking of half of the Nebivolol 5 mg cross-

scored tablet into quarters.

Your doctor may decide to combine Nebilet tablets with other

medicines to treat your condition.

Do not use in children or adolescents.

If you take more Nebilet than you should

If you accidentally take an overdose of this medicine, tell your doctor of

pharmacist immediately. The most frequent symptoms and signs of a

Nebilet overdose are very slow heart beat (bradycardia), low blood

pressure with possible fainting (hypotension), breathlessness such as in

asthma (bronchospasm), and acute heart failure.

You can take activated charcoal (which is available at your pharmacy)

while you wait for the arrival of the doctor.

If you forget to take Nebilet

If you forget a dose of Nebilet, but remember a little later on that you

should have taken it, take that day’s dose as usual. However, if a long

delay has occurred (e.g. several hours), so that the next due dose is

near, skip the forgotten dose and take the next, scheduled, normal dose

at the usual time. Do not take a double dose. Repeated skipping,

however, should be avoided.

If you stop taking Nebilet

You should always consult with your doctor before stopping Nebilet

treatment, whether you are taking it for high blood pressure or chronic

heart failure.

You should not stop Nebilet treatment abruptly as this can temporarily

make your heart failure worse.

If it is necessary to stop Nebilet treatment for chronic heart failure, the

daily dose should be decreased gradually, by halving the dose, at weekly

intervals.

If you have any further questions on the use of this product, ask your

doctor or pharmacist.

4. Possible side effects

Like all medicines, Nebilet can cause side effects, although not

everybody gets them.

When Nebilet is used for the treatment of raised blood pressure, the

possible side effects are:

Common side effects (more than 1 person in every 100 treated but fewer

than 1 person in every 10 treated):

headache

dizziness

tiredness

an unusual itching or tingling feeling

diarrhoea

constipation

nausea

shortness of breath

swollen hands or feet.

Uncommon side effects (more than 1 person in every 1,000 treated, but

fewer than 1 person in every 100 treated):

slow heartbeat or other heart complaints

low blood pressure

cramp-like leg pains on walking

abnormal vision

impotence

feelings of depression

digestive difficulties (dyspepsia), gas in stomach or bowel, vomiting

skin rash, itchiness

breathlessness such as in asthma, due to sudden cramps in the

muscles around the airways (bronchospasm)

nightmares.

Very rare side effects (fewer than 1 person in every 10,000 treated):

fainting

worsening of psoriasis (a skin disease - scaly pink patches).

The following side effects have been reported only in some isolated

cases during Nebilet treatment:

whole-body allergic reactions, with generalised skin eruption

(hypersensitivity reactions);

rapid-onset swelling, especially around the lips, eyes, or of the

tongue with possible sudden difficulty breathing (angioedema).

In a clinical study for chronic heart failure, the following side effects

were seen:

Very common side effects (more than 1 person in every 10 treated):

slow heart beat

dizziness

Common side effects (more than 1 person in every 100 but less than 1

person in every 10 treated):

worsening of heart failure

low blood pressure (such as feeling faint when getting up quickly)

inability to tolerate this medicine

a kind of light heart conduction disorder that affects heart rhythm

(1st degree AV-block)

swelling of the lower limbs (such as swollen ankles).

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.

Reporting Side Effects

If you get any side effects, talk to your doctor or pharmacist or nurse.

This includes any possible side effects not listed in this leaflet. You can

also report side effects directly via the Yellow Card Scheme at:

www.mhra.gov.uk/yellowcard

By reporting side effects you can help provide more information on the

safety of this medicine.

5. How to store Nebilet

Keep out of the sight and reach of children.

This medicinal product does not require any special storage conditions.

Do not take Nebilet after the expiry date which is stated on the carton

label and blister foil after EXP. The expiry date refers to the last day of

that month.

Nebilet 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

Nebilet 5mg Tablets are white, round tablets, cross-scored on one side

and plain on reverse. Tablets are provided in blister packs

(PVC/aluminium blister).

The active substance is nebivolol. Each tablet contains 5 mg nebivolol

(as nebivolol hydrochloride): 2.5 mg of d-nebivolol and 2.5 mg of

l-nebivolol.

Also contains: lactose monohydrate, polysorbate 80 (E433),

hypromellose (E464), maize starch, croscarmellose sodium (E468),

microcrystalline cellulose (E460), silica colloidal anhydrous (E551),

magnesium stearate (E572).

Nebilet are available in blister packs of 28 tablets.

Manufactured by Berlin Chemie AG, Glienicker Weg 125, 12489 Berlin,

Germany or Menarini – Von Heyden GmbH, Leipziger Strasse 7-13,

01097 – Dresden, Germany or Qualiphar N.V. Rijksweg 9, 2880 Bornem,

Belgium. Procured from within the EU. Product Licence Holder: Quadrant

Pharmaceuticals Ltd, Lynstock House, Lynstock Way, Lostock, Bolton

BL6 4SA. Repackaged by Maxearn Ltd, Bolton BL6 4SA.

Nebilet 5mg Tablets PL 20774/1268

Nebilet is a registered trademark of Janssen-Cilag Ltd

Date of preparation 26

November 2013

PP2/1268/V1

POM

SUMMARY OF PRODUCT CHARACTERISTICS

1

NAME OF THE MEDICINAL PRODUCT

NEBILET 5 mg tablets

2

QUALITATIVE AND QUANTITATIVE COMPOSITION

Each Nebilet tablet contains 5 mg of nebivolol (as nebivolol hydrochloride):

2.5 mg of SRRR-nebivolol (or d-nebivolol) and 2.5 mg of RSSS-nebivolol (or l-

nebivolol).

Excipients: each tablet contains 141.75 mg of lactose monohydrate (see section 4.4

and 6.1).

For a full list of excipients, see section 6.1.

3

PHARMACEUTICAL FORM

Tablet.

White, round, cross-scored tablet.

The tablet can be divided in equal 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

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 Nebilet 5

mg 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 Nebilet 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 is not recommended.

Chronic heart failure (CHF)

The treatment of stable chronic heart failure has to be initiated with a gradual

uptitration of dosage until the optimal individual maintenance dose is reached.

Patients should have stable chronic heart failure without acute failure during the past

six weeks. It is recommended that the treating physician should be experienced in the

management of chronic heart failure.

For those patients receiving cardiovascular drug therapy including diuretics and/or

digoxin and/or ACE inhibitors and/or angiotensin II antagonists, dosing of these

drugs should be stabilised during the past two weeks prior to initiation of Nebilet

treatment.

The initial uptitration should be done according to the following steps at 1-2 weekly

intervals based on patient tolerability:

1.25 mg nebivolol, to be increased to 2.5 mg nebivolol once daily, then to 5 mg once

daily and then to 10 mg once daily.

The maximum recommended dose is 10 mg nebivolol once daily.

Initiation of therapy and every dose increase should be done under the supervision of

an experienced physician over a period of at least 2 hours to ensure that the clinical

status (especially as regards blood pressure, heart rate, conduction disturbances, signs

of worsening of heart failure) remains stable.

Occurrence of adverse events may prevent all patients being treated with the

maximum recommended dose. If necessary, the dose reached can also be decreased

step by step and reintroduced as appropriate.

During the titration phase, in case of worsening of the heart failure or intolerance, it is

recommended first to reduce the dose of nebivolol, or to stop it immediately if

necessary (in case of severe hypotension, worsening of heart failure with acute

pulmonary oedema, cardiogenic shock, symptomatic bradycardia or AV block).

Treatment of stable chronic heart failure with nebivolol is generally a long-term

treatment.

The treatment with nebivolol is not recommended to be stopped abruptly since this

might lead to a transitory worsening of heart failure. If discontinuation is necessary,

the dose should be gradually decreased divided into halves weekly.

Tablets may be taken with meals.

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

mol/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 Nebilet 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.

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

episodes

heart

failure

decompensation requiring i.v. inotropic therapy.

In addition, as with other betablocking agents, Nebilet is contraindicated in:

sick sinus syndrome, including sinoatrial block.

second and third degree heart block (without a pacemaker).

history of bronchospasm and bronchial asthma.

untreated phaeochromocytoma.

metabolic acidosis.

bradycardia (heart rate <60bpm prior to start therapy).

hypotension (systolic blood pressure <90mmHg).

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,

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

Nebilet 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 please refer to section

4.2. Treatment discontinuation should not be done abruptly unless clearly indicated.

For further information please refer to section 4.2.

This medicinal product contains lactose. Patients with rare hereditary problems of

galactose intolerance, the Lapp-lactase deficiency or glucose-galactose malapsorption

should not take this medicinal product.

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 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

Nebilet.

Insulin and oral antidiabetic drugs: although nebivolol does not affect glucose level,

concomitant use may mask certain symptoms of hypoglycaemia (palpitations,

tachycardia).

Baclofen (antispastic agent), amifostine (antineoplastic adjunct): concomitant use

with antihypertensives is likely to increase the fall in blood pressure, therefore the

dosage of the antihypertensive medication should be adjusted accordingly.

Combinations to be 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 Nebilet is taken with the meal, and an

antacid between meals, the two treatments can be co-prescribed.

Combining nebivolol with nicardipine slightly increased the plasma levels of both

drugs, without changing the clinical effect. Co-administration of alcohol, furosemide

or hydrochlorothiazide did not affect the pharmacokinetics of nebivolol. Nebivolol

does not affect the pharmacokinetics and pharmacodynamics of warfarin.

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,

beta

-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.

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

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

No studies on the effects on the ability to drive and use machines have been

performed. Pharmacodynamic studies have shown that Nebilet 5 mg does not affect

psychomotor function. When driving vehicles or operating machines it should be

taken into account that dizziness and fatigue may occasionally occur.

4.8

Undesirable effects

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 of the cases of

mild to moderate intensity, are tabulated below, classified by system organ

class and ordered by frequency: The following adverse reactions have also

been

reported

with

some

beta

adrenergic

antagonists:

hallucinations,

psychoses, confusion, cold/cyanotic extremities, Raynaud phenomenon, dry

eyes, and oculomucocutaneous toxicity of the practololtype.

SYSTEM

ORGAN

CLASS

Common

1/100 to <

1/10)

Uncommon

1/1,000 to

1/100)

Very Rare

1/10,000)

Not Known

angioneurotic

Immune system

oedema,

disorders

hypersensitivity

Psychiatric

disorders

nightmares;

depression

Nervous system

disorders

headache,

dizziness,

paraesthesia

syncope

Eye disorders

impaired vision

bradycardia,

heart failure,

Cardiac

disorders

slowed AV

conduction/AV-

block

hypotension,

Vascular

disorders

(increase of)

intermittent

claudication

Respiratory,

thoracic and

mediastinal

dyspnoea

bronchospasm

disorders

Gastrointestinal

constipation,

dyspepsia,

disorders

nausea,

flatulence,

diarrhoea

vomiting

Skin and

subcutaneous

tissue disorders

pruritus, rash

erythematous

psoriasis

aggravated

Reproductive

system and

breast disorders

impotence

General

disorders and

administration

site conditions

tiredness,

oedema

Chronic heart failure Data on adverse reactions in CHF patients are available

from

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

nebivolol

patients

were

bradycardia

dizziness, both occurring in approximately 11% of patients. The corresponding

frequencies

among

placebo

patients

were

approximately

respectively. The following incidences were reported for adverse reactions (at

least possibly drug related) which are considered specifically relevant in the

treatment of chronic heart failure: Aggravation of cardiac failure occurred in

5.8 % of nebivolol patients compared to 5.2% of placebo patients. Postural

hypotension was reported in 2.1% of nebivolol patients compared to 1.0% of

placebo patients. Drug intolerance occurred in 1.6% of nebivolol patients

compared to 0.8% of placebo patients. First degree atrio-ventricular block

occurred in 1.4% of nebivolol patients compared to 0.9% of placebo patients.

Oedema of the lower limb were reported by 1.0% of nebivolol patients

compared to 0.2% of placebo patients.

4.9

Overdose

No data are available on overdosage with Nebilet.

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

prevented

gastric

lavage

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

g/minute,

or dobutamine, starting with a dose of 2.5

g/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

g/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

g/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 agent, 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 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

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.

Available preclinical and clinical evidence in hypertensive patients has shown that

nebivolol has no detrimental effect on erectile function.

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

metabolised

alicyclic

aromatic

hydroxylation,

dealkylation and glucuronidation; in addition, glucuronides of the hydroxy-

metabolites

formed.

metabolism

nebivolol

aromatic

hydroxylation

subject

CYP2D6

dependent

genetic

oxidative

polymorphism. The oral bioavailability of nebivolol averages 12% in fast

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