Hypoloc 5mg tablets

United Kingdom - English - MHRA (Medicines & Healthcare Products Regulatory Agency)

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Active ingredient:
Nebivolol hydrochloride
Available from:
A. Menarini Farmaceutica Internazionale SRL
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: 5038227000263
Authorization number:
PL 16239/0019

Package leaflet: Information for the user

HYPOLOC

5 mg tablets

Nebivolol

Read all of this leaflet carefully before you start using this medicine

because it contains

important information for you.

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 only. Do not pass it on to others. It may harm

them, even if their signs of illness are the same as yours.

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. See section 4.

What is in this leaflet:

What Hypoloc is and what it is used for

What you need to know before you take Hypoloc

How to take Hypoloc

Possible side effects

How to store Hypoloc

Contents of the pack and other information

1.

What Hypoloc is and what it is used for

Hypoloc 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).

Hypoloc is also used to treat mild and moderate chronic heart failure in patients aged 70 or over,

in addition to other therapies.

2.

What you need to know before you take Hypoloc

Do not take Hypoloc

if you are allergic to nebivolol or any of the other ingredients of this medicine (listed in

section 6).

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. 2

and 3

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.

Warnings and precautions

Talk to your doctor or pharmacist before taking Hypoloc.

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

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 Hypoloc before

being anaesthetised.

If you have serious kidney problems do not take Hypoloc 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, Hypoloc is

not

recommended for use in them.

Other medicines and Hypoloc

Tell your doctor or pharmacist if you are taking, have recently taken or might take any other

medicines.

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

to Hypoloc:

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): you should take

Hypoloc during a meal and the antacid drug between meals.

Hypoloc with food and drink

Please refer to section 3.

Pregnancy and breast-feeding

Hypoloc should not be used during pregnancy, unless clearly necessary.

It is not recommended for use while breast-feeding.

If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby,

ask your doctor or pharmacist for advice before taking this medicine.

Driving and using machines

This medicine may cause dizziness or fatigue. If affected,

do not

drive or operate machinery.

Hypoloc contains lactose

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.

This medicine contains less than 1 mmol sodium (23 mg) per tablet, that is to say essentially ‘sodium-

free’.

3.

How to take Hypoloc

Always take this medicine exactly as your doctor has told you. Check with your doctor or

pharmacist if you are not sure.

Hypoloc 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 Hypoloc 5 mg cross-scored tablets.

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

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.

Diagrams 3 and 4: Easy breaking of half of the Nebivolol 5 mg cross-scored tablet into quarters.

Your doctor may decide to combine Hypoloc tablets with other medicines to treat your

condition.

Do not use in children or adolescents.

If you take more Hypoloc than you should

accidentally

take

overdose

this

medicine,

tell

your

doctor

pharmacist

immediately

. The most frequent symptoms and signs of a Hypoloc 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 Hypoloc

If you forget a dose of Hypoloc, 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 Hypoloc

You should always consult with your doctor before stopping Hypoloc treatment, whether you are

taking it for high blood pressure or chronic heart failure.

You should not stop Hypoloc treatment abruptly as this can temporarily make your heart failure

worse.

If it is necessary to stop Hypoloc 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, this medicine can cause side effects, although not everybody gets them.

When Hypoloc is

used for the treatment of raised blood pressure

, the possible side effects are:

Common side effects (may affect up to 1 in 10 people):

headache

dizziness

tiredness

an unusual itching or tingling feeling

diarrhoea

constipation

nausea

shortness of breath

swollen hands or feet.

Uncommon side effects (may affect up to 1 in 100 people):

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

(may affect up to 1 in 10,000 people):

fainting

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

The following side effects have been reported only in some isolated cases during Hypoloc

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);

kind of skin rash notable for pale red, raised, itchy bumps of allergic or non allergic causes

(urticaria).

In a clinical study for

chronic heart failure,

the following side effects were seen

:

Very common side effects (may affect more than 1 in 10 people):

slow heart beat

dizziness

Common side effects (may affect up to 1 in 10 people):

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 (1

degree AV-block)

swelling of the lower limbs

(such as swollen ankles).

Reporting of side effects

If you get any side effects, talk to your doctor, 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. Website: 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 Hypoloc

Keep this medicine out of the sight and reach of children.

This medicinal product does not require any special storage conditions. Do not use this medicine

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.

Do not throw any medicine via wastewater or household waste. Ask your pharmacist how to

throw away medicines you no longer use. These measures will help to protect the environment.

6.

Contents of the pack and other information

What Hypoloc contains

active

substance

nebivolol.

Each

tablet

contains

nebivolol

nebivolol

hydrochloride):

2.5 mg of d-nebivolol and 2.5 mg of l-nebivolol.

The other ingredients are: lactose monohydrate, polysorbate 80 (E433), hypromellose (E464),

maize

starch,

croscarmellose

sodium

(E468),

microcrystalline

cellulose

(E460),

silica

colloidal anhydrous (E551), magnesium stearate (E572).

What Hypoloc looks like and contents of the pack

Hypoloc is available as white, round, cross-scored tablets in packs of 7, 14, 28, 30, 50, 56, 90,

100, 500 tablets. Tablets are provided in blister packs (PVC/aluminium blister).

(Not all pack sizes may be marketed)

Marketing Authorisation Holder and Manufacturer

Marketing Authorisation Holder

Menarini International Operations Luxembourg S.A.

1, Avenue de la Gare L-1611 Luxembourg

Luxembourg

Manufacturer

Berlin-Chemie AG

Glienicker Weg 125, 12489 Berlin, Germany

Menarini - von Heyden GmbH

Leipziger Strasse 7-13, 01097 – Dresden, Germany

Qualiphar N.V.

Rijksweg 9, 2880 Bornem, Belgium

Marketed by

A. Menarini Farmaceutica Internazionale SRL

This medicinal product is authorised in the Member States of the EEA under the following

names:

Austria: Hypoloc

Belgium: Nobiten

Cyprus: Lobivon

Denmark: Hypoloc

Finland: Hypoloc

France: Temerit

Germany: Nebilet

Greece: Lobivon

Ireland: Hypoloc

Italy: Nebilox

Iceland: Hypoloc

Luxembourg: Nobiten

Norway: Hypoloc

Portugal: Nebilet

Spain: Lobivon

Sweden: Hypoloc

The Netherlands: Nebilet

United Kingdom: Hypoloc

This leaflet was last revised in 06/2018.

SUMMARY OF PRODUCT CHARACTERISTICS

1

NAME OF THE MEDICINAL PRODUCT

HYPOLOC 5 mg tablets

2

QUALITATIVE AND QUANTITATIVE COMPOSITION

Each Hypoloc 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).

Excipient with known effect: each tablet contains 141.75 mg of lactose monohydrate

(see section 4.4 and 6.1).

For the 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

Posology

Hypertension

Adults

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

The blood pressure lowering effect becomes evident after 1-2 weeks of treatment.

Occasionally, the optimal effect is reached only after 4 weeks.

Combination with other antihypertensive agents

Beta-blockers can be used alone or concomitantly with other antihypertensive agents.

To date, an additional antihypertensive effect has been observed only when Hypoloc

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 Hypoloc in these patients is contra-indicated.

Older people

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 Hypoloc 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 Hypoloc

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

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 Hypoloc

in these patients is contra-indicated.

Older people

No dose adjustment is required since uptitration to the maximum tolerated dose is

individually adjusted.

Paediatric population

The efficacy and safety of Hypoloc 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.

Tablets may be taken with meals.

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.

In addition, as with other beta-blocking agents, Hypoloc is 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,

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

Hypoloc 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

Hypoloc.

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 Hypoloc 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, 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.

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. 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 Hypoloc 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:

SYSTEM ORGAN

CLASS

Common

1/100 to <

1/10)

Uncommon

1/1,000 to

1/100)

Very Rare

1/10,000)

Not Known

Immune system

disorders

angioneurotic

oedema,

hypersensitivity

Psychiatric

disorders

nightmares;

depression

Nervous system

disorders

headache,

dizziness,

paraesthesia

syncope

Eye disorders

impaired

vision

Cardiac disorders

bradycardia,

heart failure,

slowed AV

conduction/A

V-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.

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 were reported by 1.0% of nebivolol patients compared

to 0.2% of placebo patients.

Reporting of suspected adverse reactions:

Reporting suspected adverse reactions after authorisation of the medicinal product is

important. It allows continued monitoring of the benefit/risk balance of the medicinal

product. Healthcare professionals are asked to report any suspected adverse reactions

via the Yellow Card Scheme. Website: www.mhra.gov.uk/yellowcard.

4.9.

Overdose

No data are available on overdosage with Hypoloc.

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

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.

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