CONCOR 10 MG

DOR-10150-1216-13

Patient leaflet in accordance with the

Pharmacists’ Regulations )Preparations( 1986

The dispensing of this medicine requires

a doctor’s prescription

Concor 5 mg

Concor 10 mg

Film-coated

tablets

Film-coated

tablets

Active ingredients:

Each film-coated tablet Concor 5 mg contains:

bisoprolol fumarate 5 mg

Each film-coated tablet Concor 10 mg contains:

bisoprolol fumarate 10 mg

Inactive ingredients and allergens: See

Section 6 “Additional Information”.

Read the entire leaflet carefully before

using this medicine. This leaflet contains

concise information about this medicine. If you

have further questions, refer to your doctor

or pharmacist.

This medicine has been prescribed for you.

Do not pass it on to others. It may harm them,

even if it seems to you that their medical

condition is similar to yours.

This medicine is not intended for children.

1. What is this medicine intended for?

This medicine is intended for treating high blood

pressure (hypertension) and angina pectoris.

This medicine is also intended for treating chronic

conditions of medium to severe stable heart

failure, in combination with other medicines.

Therapeutic group:

Selective beta blockers agents.

2. Before using this medicine

Do not use this medicine:

If you are sensitive to bisoprolol or to any

of the other ingredients that this medicine

contains (see section 6 “Additional

Information”)

In patients suffering from acute heart failure

In patients suffering from worsening heart

failure that requires injection into the vein

of medicines that increase the force of

the heart’s contraction

In case of cardiogenic shock, which is a

serious heart condition causing low blood

pressure and circulatory failure

In case of severely impaired impulse

conduction in the heart (second or third

degree AV block); in patients who have

a slower heart rate

In patients suffering from low blood

pressure

In patients suffering from severe asthma

In case of certain heart conditions which

cause a very slow heart rate or irregular

heartbeat (sick sinus syndrome) and

blockage of the the electrical signal in

the heart’s pacemaker (sinatorial block)

In patients suffering from a severe blood

circulation problem in the limbs (such as

severe cases of Raynaud’s syndrome), a

syndrome which may cause your fingers

and toes to tingle or turn pale or blue

If you are suffering from an untreated

phaeochromocytoma (a rare benign

tumor of the adrenal gland medulla)

In case of metabolic acidosis, a condition

in which there is too much acid in the blood

Special warnings about using this

medicine

Before starting treatment with “Concor”,

tell your doctor if:

You are pregnant or breast-feeding

You are suffering from certain heart diseases

such as disturbances in heart rhythm, or

severe chest pain at rest (Prinzmetal’s angina)

You are suffering from kidney or liver problems

You are suffering from chronic lung disease

or asthma

You are suffering from disorders of the thyroid

You are suffering from diabetes

You have a blood circulation problem in

your limbs

You are suffering from a tumor in your

adrenal gland (phaeochromocytoma)

You are suffering or have sufferd from a

scaly skin rash (psoriasis)

You are on a strict fast

You are about to have desensitization

therapy (for example to prevent hay fever),

because Concor may make it more likely that

you experience an allergic reaction, or else

the reaction may be more severe

You are going to be anesthetized (for

example for surgery), because Concor

may influence how your body responds to

the anesthesia.

If you are suffering from a chronic lung disease

or less severe asthma please inform your doctor

immediately if you start to experience new

difficulties in breathing, coughing, wheezing after

exercise or similar effects when using Concor.

If you are taking or have recently taken any

other medicines, including non-prescription

medicines and nutrition supplements,

please tell your doctor or pharmacist as

this can prevent risks or inefficacy that are

caused by drug interactions.

In particular tell the doctor or pharmacist if

you are taking:

medicines to treat high blood pressure,

angina pectoris or irregular heartbeat

(calcium channels blockers such as

verapamil and diltiazem).

medicines to treat high blood pressure such

as clonidine, methyldopa, moxonidine,

rilmenidine. However, do not stop taking

these medicines without checking with your

doctor first.

certain medicines used to treat heartbeat

disorders (class I antiarrhythmic medicines

such as quinidine, disopyramide, lidocaine,

phenytoin, flecainide, propafenone).

medicines to treat high blood pressure or

angina pectoris (dihydropyridine-type calcium

blockers such as felodipine and amlodipine).

certain medicines used to treat heartbeat

disorders (Class III antiarrhythmic medicines

such as amiodarone).

anaesthetic agents - (for example during

surgery).

heart glycosides (digitalis), used to treat

heart failure.

antidiabetic medicines including insulin.

beta blockers for topical use (such as in eye

drops for treating glaucoma), non-steroidal

anti-inflammatory drugs (NSAIDs) used

to treat arthritis, pain or inflammation (for

example ibuprofen or diclofenac).

any medicine which can lower blood

pressure intentially or unintentially, such

as antihypertensives, certain medicines for

depression (tricyclic antidepressants such as

imipramine or amitriptyline), certain medicines

used to treat epilepsy or during anaesthesia

(barbiturates such as phenobarbital), or

certain medicines to treat mental illness

characterized by a loss of contact with reality

(phenothiazines such as levomepromazine).

medicines to treat Alzheimer’s disease

or glaucoma (parasympathomimetics

medicines such as: tacrine or carbachol) or

medicines that are used to treat acute heart

problems (sympathomimetics medicines

such as: dobutamine and isoprenaline).

mefloquine, a medicine used for treatment

or prevention of malaria.

antidepressants medicines (MAO inhibitors

except for MAO-B) such as moclobemide.

Using the medicine and food

Take the tablet in the morning, with or without

food.

Using the medicine and alcohol consumption

Due to individual differences between people,

alcohol consumption may have an impact

on your function. Therefore, be careful when

drinking alcoholic beverages.

Pregnancy and breastfeeding

If you are pregnant or breast-feeding, consult

your doctor or pharmacist before taking

medicines.

There is a risk that use of Concor during

pregnancy may harm the baby. If you are

pregnant or planning to become pregnant,

tell your doctor. He or she will decide whether

you can take Concor during the pregnancy.

It is not known whether bisoprolol is excreted

into breast milk. Therefore, breastfeeding

not recommended during therapy with Concor.

Driving and using machines

Your ability to drive or use machinery may be

affected by taking Concor depending on how

well you tolerate the medicine. Be especially

cautious when you start treatment, when the

dose is increased or your medication is changed

or as a result of consuming alcohol.

3. How to use this medicine?

Always use according to the doctor’s

instructions. Check with your doctor or

pharmacist if you are not sure. Your doctor

will determine your dosage and how you should

take the medicine.

Treatment with Concor must be started at a low

dosage and increased gradually.

Your doctor will decide how to increase the

dosage.

In chronic cases of stable heart failure

The dosage must be increased as follows:

1.25 mg bisoprolol once daily for one week

2.5 mg bisoprolol once daily for one week

3.75 mg bisoprolol once daily for one week

5 mg bisoprolol once daily for four weeks

7.5 mg bisoprolol once daily for four weeks

10 mg bisoprolol once daily for maintenance

(ongoing) dosage.

The maximum recommended daily dosage is

10 mg bisoprolol.

Depending on how well you tolerate the

medicine, your doctor may also decide to

lengthen the time between dosage increases.

If your condition gets worse or you can

no longer tolerate the medicine, it may be

necessary to reduce your dosage again or to

temporarily stop treatment.

In some patients a maintenance dose lower

than 10 mg bisoprolol may be sufficient.

Your doctor will tell you what to do.

If you have to stop treatment entirely, your doctor

will usually advise you to reduce the dosage

gradually, as otherwise your condition worsen.

Hypertension treatment

The recommended dosage is 5 mg once daily.

In mild cases of hypertension your doctor may

decide that a dosage of 2.5 mg once daily is

sufficient.

If necessary, your doctor may tell you to

increase your dosage to 10 mg, once daily.

The highest recommended dosage is 20 mg,

once daily.

Angina pectoris

The recommended dosage is 5 mg once daily.

If necessary, your doctor may tell you to

increase your dosage to 10 mg, once daily.

The highest recommended dose is 20 mg,

once daily.

Do not exceed the recommended dose.

The tablet may be grinded to make swallowing

easier or for use in enteral feeding. The tablet

may be divided and a half of a dose taken

as required.

Treatment with Concor is usually long-term.

Tests and follow-up

Treatment with Concor requires regular

monitoring of several signs (heart rate, blood

pressure, symptoms of worsening heart

function) by your doctor: This is particularly

necessary when you start treatment, during

dose increase, and when you stop treatment.

If you have accidentally taken a higher dose,

or if a child has accidentally swallowed

some medicine, go immediately to a hospital

emergency room and bring the medicine

package with you.

Symptoms of an overdose with Concor may

include slowed heart rate, severe difficulty in

breathing, feeling dizzy, or trembling (due to

decreased blood sugar).

If you forget to take the medicine at the

scheduled time, do not take a double dose to

make up for a forgotten dose. Take your usual

dose the next morning.

Persist with the treatment as recommended

by the doctor.

Do not change or stop your treatment with

Concor without consulting your doctor.

Otherwise your condition could get worse.

Do not take medicines in the dark! Check the

label and dose each time you take the medicine.

Wear glasses if you need them.

If you have any further questions about using

this medicine, consult your doctor or the

pharmacist.

4. Side effects

Like all medicines, taking “Concor” may

cause side effects in some people. Do not be

alarmed by this list of side effects. You may

not experience any of them.

The most serious side effects are related to

heart function:

slowing of heart rate (may affect more than

1 in 10 patients)

worsening of heart failure (may affect up to

1 in 10 patients)

slow or irregular heartbeat (may affect up

to 1 in 100 patients)

If you feel dizzy, weak or have breathing difficulties

- contact your doctor as soon as possible.

Additional side effects:

Common side effects – may affect 1-10 in

100 users:

tiredness, feeling weak, dizziness, headache

low blood pressure

stomach or intestinal problems such as

nausea, diarrhea, vomiting, constipation

feeling of coldness and numbness in hands

or feet

Uncommon side effects – may affect 1-10

in 1,000 users:

breathing problems in patients with asthma

or chronic lung diseases

muscle weakness or muscle cramps

sleep disturbances

depression

dizziness when standing up

Rare side effects – may affect 1-10 in 10,000

users:

blood test results for liver enzymes or fat

levels differing from normal

inflammation of the liver which can cause

yellowing of the skin or whites of the eyes

fainting

reduced tear flow (this might be a problem

if you wear contact lenses)

hearing disturbances

allergic runny nose

allergy-like reactions such as itching,

flushing, rash

erection problems, nightmares

hallucinations.

Very rare side effects – may affect less than

one in 10,000 users:

irritation and redness of the eye (conjunctivitis)

hair loss

appearance or worsening of scaly skin rash

(psoriasis), psoriasis-like rash.

If you experience any side effect, if any side

effect gets worse, or if you experience a side

effect not mentioned in this leaflet, or if you feel

a change in your general well-being consult

your doctor immediately.

Side effects can be reported to the Ministry

of Health by clicking on the link “Report Side

Effects of Drug Treatment” that appears on the

homepage of the Ministry of Health’s website

)www.health.gov.il) which links to an online form

for reporting side effects, or by the following link:

h t t p s : / / f o r m s . g o v . i l / g l o b a l d a t a /

g e t s e q u e n c e / g e t s e q u e n c e .

aspx?formType=AdversEffectMedic@moh.gov.il

and by emailing the Registration Holder's

Patient Safety Unit at:

drugsafety@neopharmgroup.com

5. How to store the medicine?

Prevent poisoning! To prevent poisoning,

keep this, and all other medicines, in a

closed place out of reach of children and/

or infants. Do not induce vomiting unless

explicitly instructed to do so by a doctor.

Do not use the medicine after the expiry

date (exp. date) appearing on the package.

The expiry date refers to the last day of

that month.

Do not store above 30°C.

Do not store different medicines in the same

package.

Do not throw away any medicines via

wastewater or household waste. Ask your

pharmacist how to throw away of medical

products you no longer use. These measures

will help protect the environment.

6. Additional information

In addition to the active ingredients this

medicine also contains:

Tablet:

Silica colloidal anhydrous, Magnesium stearate,

Crospovidone, Microcrystalline cellulose, Maize

starch, Calcium hydrogen phosphate anhydrous.

Coating:

Iron oxide yellow (E172), Dimethicone 100,

Macrogol 400, Titanium dioxide (E171),

Hypromellose (2910/15).

Concor 10 mg also contains: Iron oxide red (E172).

What the medicine looks like and what are

the contents of the package:

Concor 5 mg film-coated tablets are yellowish-

white and heart-shaped with a break-line on

both sides.

The tablets are packed in a blister tray made

of aluminum coated with rigid PVC, and stored

in a cardboard box.

The product is packaged in the following

quantities of tablets: 30, 50, 100, and 300 tablets.

Concor 10 mg film-coated tablets are pale

orange to light orange and heart-shaped with

a break-line on both sides.

The tablets are packed in a blister tray made

of aluminum foil coated with rigid PVC and

stored in a cardboard box.

The product is packaged in the following

quantities of tablets: 30, 50, 100, and 300 tablets.

Not all pack sizes may be marketed.

Registration holder: Neopharm (Israel)

1996 Ltd. P.O.Box 063, Petah Tiqva 49170.

Manufacturer: Merck KGaA, Darmstadt,

Germany.

This leaflet was reviewed and approved by

the Ministry of Health in: July 2016

Registration number of the medicine in

the National Drug Registry of the Ministry

of Health:

Concor 5 mg 057-79-25169-01

Concor 10 mg 057-78-25170-01

.جلاعلا فاقيإ ءانثأو ،ة

يئاودلا تاعرجلا ةدايز علاتباب لفط ماق اذإ وأ ىلعأ ةعرج ،أطخلا قيرط نع تلوانت اذإ ئراوطلا ةفرغ ىلإ ،ا

روف ،ه

جوتف أطخلا قيرط نع ءاودلا نم ةي

مك .كعم ءاودلا ةبلع رضحأو ،ىفشتسملا يف ضبن ؤطابت لمشت نأ نكمم ةطرفم ةعرج لوانتل تاملاعلا ضافخنا ببسب) فاجترا وأ راود ،ةريطخ سفنت تابوعص ،بلقلا .(مدلا ركس ةعرج ا

دبأ لوانتت لا ،د

دح

ملا تقولا يف ءاودلا اذه لوانت تيسن اذإ تيسن يتلا ةديحولا ةعرجلا نع "ضيوعتلا" لجأ نم ةفعاضم .يلاتلا مويلا حابص يف ةيداعلا ةعرجلا لوانت .اهلوانت .بيبطلا ةيصوت ب

سح ءاودلا لوانت يف رارمتسلاا بجي لاإو .كبيبط ةراشتسا نود روكنوكب جلاعلا فاقيإ وأ رييغت عنم

.كتلاح مقافتت نأ نكمملا نم ءاودلا ة

وبع ىلع قصلملا نم ق

قحت !ملاظلا يف ةيودلأا لوانت عنم

تارا

ظنلا عض .ءاود اهيف لوانتت ة

رم

لك يف ة

يئاودلا ةعرجلا نمو .اهيلإ ةجاحب تنك اذإ ةي

بطلا

شتساف ءاودلا لامعتسا ىلإ ةبسنلاب ة

يفاضإ ةلئسأ كيدل تناك اذإ

يلديصلا وأ بيبطلا

4

.

ة

ّ

يبناجلا ضارعلأا

يبناج ا

ضارعأ "روكنوك" لامعتسا ب

بسي دق ،ةيودلأا عيمجك ضارعلأا ةمئاق ةءارق دنع مدصت لا .نيمدختسملا نم مسق ىدل .اهنم

ٍّ

يأ نم يناعت

لاأ لمتحملا نم .ة

يبناجلا :بلقلا لمعب قلعتت ةروطخ رثكلأا ة

يبناجلا ضارعلأا

(نيجلاعتم ١٠ نم ١ نم رثكأ ىلع رثؤي نأ نكمم) بلقلا ضبن ؤطابت

١٠ نم ١ ىتح ىلع رثؤي نأ نكمم) بلقلا روصق مقافت (نيجلاعتم

ىتح ىلع رثؤي نأ نكمم) ميلس ريغ ضبن وأ ضبنلا ؤطابت (نيجلاعتم ١٠٠ نم ١ ىلإ هجوت – سفنتلا يف تابوعص وأ فعض ،راودب ترعش اذإ .نكمم تقو عرسأ يف بيبطلا

يفاضإ ة

يبناج ضارعأ نيمدختسم ١٠-١ ىدل رهظت نأ نكمي – ةعئاش ة

ّ

يبناج ضارعأ :١٠٠ نيب نم

عاد

ص ،راود ،فعض ،قاهرإ

ضفخنم مد طغض

كاسمإ ،تاؤيقت ،لاهسإ ،نايثغ لثم ءاعملأا وأ نطبلا يف لكاشم

نيمدقلاو نيديلاب ساسحلإا نادقفو دربلاب روعش ١٠-١ ىدل رهظت نأ نكمي – ةعئاش ريغ ة

ّ

يبناج ضارعأ :١٠٠٠ نيب نم نيمدختسم

ةنمز

م ة

يوئر ضارمأ وأ وبرلا ىضرم ىدل سفنتلا يف لكاشم

تلاضعلا يف (تاصلقت) تاجنشت وأ تلاضعلا يف فعض

مونلا يف تابارطضا

بائتكا

فوقولا ءانثأ راود نيمدختسم ١٠-١ ىدل رهظت نأ نكمي – ةردان ة

ّ

يبناج ضارعأ :١٠٫٠٠٠ نيب نم

ةفلتخم تايوتسم تاذ تاينهد وأ دبكلا تاميزنلإ مد تاصوحف يعيبطلا نع

دلجلا رارفصإ ىلإ ب

بس

ي نأ نكمم يذلا دبكلا يف باهتلا نينيعلا ضايب وأ

يعولا نادقف

لاح يف ةلكشم اذه نوكي نأ نكمم) عمدلا زارفإ يف ضافخنا (ةقصلا تاسدع مدختست تنك

عمسلا يف تابارطضا

ةيساسح ةيفلخ ىلع ةلزن

يدلج حفط ،رارمحإ ،ة

كح لثم ةيساسحلاب ةهيبش لعف دودر

سيباوك ،باصتنا لكاشم

.تاسوله مدختسم نم لقأ ىدل رهظت نأ نكمي – ا

ً

دج ةردان ة

ّ

يبناج ضارعأ :١٠٫٠٠٠ نيب نم دحاو

(ةمحتلملا باهتلا) نيعلا رارمحإو ج

يهت

رعشلا طقاست

يدلج حفط ،(فاد

يرشقت يدلج حفط مقافت وأ روهظ .فاد

صلاب هيبش اذإ وأ ة

يبناجلا ضارعلأا دحأ مقافت اذإ ،يبناج ضرع رهظ اذإ لصح اذإ وأ ،ةرشنلا يف ةروكذم ريغ ة

يبناج ضارعأ نم تيناع

.ا

ً

روف بيبطلا ةراشتسا كيلع ،ماعلا كروعش يف ر

يغت ةطساوب ةحصلا ةرازول ةيبناج ضارعأ نع غيلبتلا نكمي جلاع بقع ةيبناج ضارعأ نع غيلبتلا' طبارلا ىلع طغضلا ةحصلا ةرازو عقومب ةيسيئرلا ةحفصلا يف دوجوملا 'يئاود

نع غيلبتلل ةيتنرتنلإا ةرامتسلال هجوملا (www.health.gov.il) :طبارلل لوخدلا قيرط نع وأ ،ةيبناج ضارعأ

h t t p s : / / f o r m s . g o v . i l / g l o b a l d a t a /

g e t

s e q u e n c e /

g e t

s e q u e n c e .

aspx?formType=AdversEffectMedic@moh.gov.il

بحاصل نيج

لاع

ملا ةملاس ةدحول ينورتكللإا ديربلا ةطساوبو drugsafety@neopharmgroup.com :ليجستلا

٥

.

؟ءاودلا نزخي فيك

،قلغم ناكم يف ،رخآ ءاود

لكو ،ءاودلا اذه ظفح بجي !م

مستلا ب

نجت اذكهو ،لافطلأا وأ/و دلاولأا يديأ لوانتمو ةيؤر لاجم نع ا

ديعب .ﺐﻴﺒﻄلا ﻦم ةﺤيﺮص تاﻤﻴلعت نوﺪب ؤ

يقتلا ﺐّﺒﺴت لا .م

مستلا ب

نجتت

(exp. date) ة

يحلاصلا ءاهتنا خيرات دعب ءاودلا لوانت عنم

وبعلا ىلع رهاظلا

.رهشلا يف ريخلأا مويلا ىلإ بسني ة

يحلاصلا ءاهتنا خيرات

.٣٠˚C نع ديزت ةرارح ةجردب نزخلا عنمي

وبعلا سفن يف ةفلتخم ةيودأ نزخ عنم

مق .تيبلا يف تلامهملا ة

لس يف يئاودلا جتنملا اذه ءاقلإ عنم

يبطلا تاجتنملا نم ص

لختلا ةيفيك ىلإ ةبسنلاب ك

يلديص ةراشتساب . ةئيبلا ىلع ظافحلا يف دعاسيس كلذ

نإ .اهل ةجاحب دعت مل يتلا

٦

.

ة

ّ

يفاضإ تامولعم

ضيأ ،ءاودلا يوتحي ،ةلا

عفلا

داوملا ىلإ ةفاضلإاب :صرقلا

Silica colloidal anhydrous, Magnesium stearate,

Crospovidone, Microcrystalline cellulose,

Maize starch, Calcium hydrogen phosphate

anhydrous.

:ءلاطلا

Iron oxide yellow (E172), Dimethicone 100,

Macrogol 400, Titanium dioxide (E171),

Hypromellose (2910/15).

.Iron oxide red (E172) :ىلع ا

ضيأ غلم ١٠ روكنوك يوتحي

وبعلا يوحت اذامو ءاودلا ودبي فيك رفصلأا ىلإ ليمي نولب ة

يلطم صارقأ يه غلم ٥ روكنوك صارقأ يتهج نم اهلوط ىلع رطشلل طخ عم ،بلق لكش تاذ ،ضيبأ ىتح موينمولأ ةحيفص نم عونصم طيرشب ةمزورم صارقلأا .صرقلا .نوترك بلع يف ةنوزخمو بلص PVC ـب ةف

لغم .٣٠٠ ،١٠٠ ،٥٠ ،٣٠ :ةيلاتلا صارقلأا تايمكل مزر رضحتسملل دجوي تهاب يلاقترب نولب ة

يلطم صارقأ يه غلم١٠ روكنوك صارقأ .اهلوط ىلع رطشلل طخ عم ،بلق لكش تاذ ،حتاف يلاقترب ىتح ـب ةف

لغم موينمولأ ةحيفص نم عونصم طيرشب ةمزورم صارقلأا .نوترك بلع يف ةنوزخمو بلص PVC .٣٠٠ ،١٠٠ ،٥٠ ،٣٠ :ةيلاتلا صارقلأا تايمكل مزر رضحتسملل دجوي .تا

وبعلا ماجحأ عيمج قيوست متي لا

.ب.ص ،.ض.م ١٩٩٦ (ليئارسإ) مرافوئين :ليجستلا بحاص .٤٩١٧٠ اڨكت حتيپ ،٧٠٦٣

.ايناملأ ،تاتشمراد ،يا.يا.يج.يك كريم :جتنملا يف ة

حصلا ةرازو لب

ق نم اهيلع قيدصتلاو ةرشنلا هذه صحف

مت ٢٠١٦ زومت :خيرات

حصلا ةرازو يف

يمسرلا ةيودلأا

لجس يف ءاودلا ليجست مقر

٠٥٧-٧٩-٢٥١٦٩-٠١ غلم ٥ روكنوك

٠٥٧-٧٨-٢٥١٧٠-٠١ غلم ١٠ روكنوك

كذملا ةغيصب

صنلا درو اهليهستو ةرشنلا هذه ةءارق طيسبتل

.نيسنجلا لاكل

دعم ءاودلاف اذه عم

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Summary of Product Characteristics

1.

Name of the medicinal product

Concor 5 mg, film-coated tablets

Concor 10 mg, film-coated tablets

2.

Qualitative and quantitative composition

Concor 5 mg:

Each tablet contains 5 mg bisoprolol fumarate.

Concor 10 mg:

Each tablet contains 10 mg bisoprolol fumarate.

For the full list of excipients see section 6.1.

3.

Dosage form

Film-coated tablets

Concor 5 mg are yellowish white, heart-shaped, scored and film-coated tablets

Concor 10 mg are pale orange - light orange, heart-shaped, scored and film-coated tablets

The scored tablets can be divided into two equal doses.

4.

Clinical data

4.1

Therapeutic indications

Treatment of stable chronic, moderate to severe heart failure with impaired systolic

ventricular function (ejection fraction < 35 %, determined by echocardiography) in addition

to ACE inhibitors and diuretics, and optionally cardiac glycosides.

Hypertension

Coronary heart disease (angina pectoris)

4.2

Posology

Heart Failure

Standard treatment of CHF consists of an ACE inhibitor (or an angiotensin receptor blocker

in case of intolerance to ACE inhibitors), a beta-blocker, diuretics, and when appropriate

cardiac glycosides. Patients should be stable (without acute failure) when Concor treatment

is initiated.

It is recommended that the treating physician should be experienced in the management of

chronic heart failure.

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Transient worsening of heart failure, hypotension, or bradycardia may occur during the

titration period and thereafter.

Titration phase

The treatment of stable chronic heart failure with Concor requires a titration phase.

The treatment with Concor is to be started with a gradual up titration according to the

following steps:

1.25 mg once daily for 1 week, if well tolerated increase to

2.5 mg once daily for a further week, if well tolerated increase to

3.75 mg once daily for a further week, if well tolerated increase to

5 mg once daily for the 4 following weeks, if well tolerated increase to

7.5 mg once daily for the 4 following weeks, if well tolerated increase to

10 mg once daily for the maintenance therapy.

The maximum recommended dose is 10 mg once daily.

Close monitoring of vital signs (heart rate, blood pressure) and symptoms of worsening heart

failure is recommended during the titration phase. Symptoms may already occur within the

first day after initiating the therapy.

Treatment modification

If the maximum recommended dose is not well tolerated, gradual dose reduction may be

considered.

In case of transient worsening of heart failure, hypotension, or bradycardia reconsideration of

the dosage of the concomitant medication is recommended. It may also be necessary to

temporarily lower the dose of Concor or to consider discontinuation.

The reintroduction and/or uptitration of Concor should always be considered when the

patient becomes stable again.

If discontinuation is considered, gradual dose decrease is recommended, since abrupt

withdrawal may lead to acute deterioration of the patient's condition.

Treatment of stable chronic heart failure with Concor is generally a long-term treatment.

Patients with hepatic or renal impairment

There is no information regarding pharmacokinetics of Concor in patients with chronic heart

failure and with impaired hepatic or renal function. Uptitration of the dose in these

populations should therefore be made with additional caution.

Hypertension and Coronary heart disease (angina pectoris).

Treatment should principally be initiated gradually with low doses, which are then increased

slowly. In all cases the dosage should be adjusted individually, in particular according to the

pulse rate and therapeutic success.

Hypertension

The recommended dosage is 5 mg bisoprolol fumarate once daily.

3/12

In milder forms of hypertension (diastolic blood pressure up to 105 mmHg) therapy with

2.5 mg once daily may be adequate.

If necessary, the dosage may be increased to 10 mg once daily. Any further increase of

dosage is justified only in exceptional cases.

The maximum recommended dosage is 20 mg once daily.

Coronary heart disease (angina pectoris)

The recommended dosage is 5 mg bisoprolol fumarate once daily.

If necessary, the dosage may be increased to 10 mg once daily. Any further increase of

dosage is justified only in exceptional cases.

The maximum recommended dosage is 20 mg once daily.

Dosage in hepatic and/or renal insufficiency

In patients with liver or kidney function disorders of mild to moderate severity no dosage

adjustment

normally

required.

patients

with

severe

kidney

function

disorders

(creatinine clearance < 20 ml/min) and in patients with severely impaired liver function a

daily dose of 10 mg bisoprolol fumarate should not be exceeded.

There is only limited experience with the use of Concor in dialysis patients. There are no

indications of the necessity to alter the dose regimen.

Older people

No dose adjustment is required.

Paediatric population

There is no paediatric experience with Concor. Therefore, its use cannot be recommended in

paediatric patients.

Method of administration

Concor tablets should be taken in the morning and can be taken with food. They should be

swallowed with liquid and should not be chewed.

4.3.

Contraindications

Concor

is contraindicated in chronic heart failure patients with:

acute heart failure or during episodes of heart-failure decompensation requiring i.v.

inotropic therapy

cardiogenic shock

second or third degree AV block

sick sinus syndrome

sinoatrial block

symptomatic bradycardia

symptomatic hypotension

severe bronchial asthma

severe forms of peripheral arterial occlusive disease or severe forms of Raynaud's

syndrome

untreated phaeochromocytoma (see section 4.4)

metabolic acidosis

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hypersensitivity to Concor or to any of the excipients listed in section 6.1

4.4

Special warnings and special precautions for use

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

titration phase.

Especially in patients with ischaemic heart disease the cessation of therapy with Concor must

not be done abruptly unless clearly indicated, because this may lead to transitional worsening

of heart condition.

The initiation and cessation of treatment of stable chronic heart failure with Concor

necessitates regular monitoring.

There is no therapeutic experience of Concor treatment of heart failure in patients with the

following diseases and conditions:

insulin dependent diabetes mellitus (type I)

severely impaired renal function

severely impaired hepatic function

restrictive cardiomyopathy

congenital heart disease

hemodynamically significant organic valvular disease

myocardial infarction within 3 months

Concor must be used with caution in:

bronchospasm (bronchial asthma, obstructive airways diseases)

diabetes mellitus with large fluctuations in blood glucose values; Symptoms of

hypoglycaemia can be masked

strict fasting

ongoing desensitization therapy. As with other beta-blockers, Concor may increase both

the sensitivity towards allergens and the severity of anaphylactic reactions. Epinephrine

treatment does not always yield the expected therapeutic effect

first degree AV block

Prinzmetal’s angina: Cases of coronary vasospasm have been observed. Despite its

high beta1-selectivity, angina attacks cannot be completely excluded when Concor

is administered to patients with Prinzmetal's angina.

peripheral arterial occlusive disease. Aggravation of symptoms may occur especially

when starting therapy.

general anaesthesia

In patients undergoing general anaesthesia beta-blockade reduces the incidence of

arrhythmias and myocardial ischemia during induction and intubation, and the

postoperative period. It is currently recommended that maintenance beta-blockade be

continued peri-operatively. The anaesthetist must be aware of beta-blockade because of

the potential for interactions with other drugs, resulting in bradyarrhythmias, attenuation

5/12

of the reflex tachycardia and the decreased reflex ability to compensate for blood loss. If

it is thought necessary to withdraw beta-blocker therapy before surgery, this should be

done gradually and completed about 48 hours before anaesthesia.

Combination of Concor with calcium antagonists of the verapamil or 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.

Although cardioselective (beta1) beta-blockers may have less effect on lung function than

non-selective beta-blockers, as with all beta-blockers, these should be avoided in patients

with obstructive airways diseases, unless there are compelling clinical reasons for their use.

Where such reasons exist, Concor may be used with caution. In patients with obstructive

airways diseases, the treatment with Concor should be started at the lowest possible dose and

patients should be carefully monitored for new symptoms (e.g. dyspnea, exercise intolerance,

cough). In bronchial asthma or other chronic obstructive lung diseases, which may cause

symptoms, bronchodilating therapy should be given concomitantly. Occasionally an increase

of the airway resistance may occur in patients with asthma, therefore the dose of beta2-

stimulants may have to be increased.

Patients with psoriasis or with a history of psoriasis should only be given beta-blockers (e.g.

Concor) after carefully balancing the benefits against the risks.

In patients with phaeochromocytoma Concor must not be administered until after alpha-

receptor blockade.

Under treatment with Concor the symptoms of a thyreotoxicosis may be masked.

4.5

Interaction with other medicinal products and other forms of interaction

Combinations

not recommended:

Calcium antagonists of the verapamil type and to a lesser extent of the diltiazem type:

Negative influence on contractility and atrio-ventricular conduction. Intravenous

administration of verapamil in patients on β-blocker treatment may lead to

profound hypotension and atrioventricular block.

Class I antiarrhythmic drugs (e.g. quinidine, disopyramide; lidocaine, phenytoin; flecainide,

propafenone): Effect on atrio-ventricular conduction time may be potentiated and negative

inotropic effect increased.

Centrally acting antihypertensive drugs such as clonidine and others (e.g. methyldopa,

moxonodine,

rilmenidine

Concomitant use of

centrally acting a antihypertensive drugs may

worsen heart failure by a decrease in the

central sympathetic

tonus

(reduction of heart rate and

cardiac

output

vasodilation).

Abrupt

withdrawal

particularly

prior

beta-blocker

discontinuation,

may increase the risk of "rebound hypertension".

6/12

Combinations to be used with caution:

Calcium antagonists of the dihydropyridine type such as felodipine and amlodipine:

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.

Class III antiarrhythmic

drugs

(e.g. amiodarone): Effect on atrio-ventricular conduction time

may be potentiated.

Topical beta-blockers (e.g. eye drops for glaucoma treatment) may add to the systemic

effects of Concor.

Parasympathomimetic drugs: Concomitant use may increase atrio-ventricular conduction

time and the risk of bradycardia.

Insulin and oral antidiabetic drugs: Increase of blood sugar lowering effect. Blockade of beta-

adrenoreceptors may mask symptoms of hypoglycaemia.

Anaesthetic

agents:

Attenuation

reflex

tachycardia

increase

risk

hypotension (for further information on general anaesthesia see also section 4.4)

Digitalis glycosides: Reduction of heart rate, increase of atrio-ventricular conduction time.

Non-steroidal anti-inflammatory drugs (NSAIDs): NSAIDs may reduce the hypotensive

effect of Concor.

Beta-sympathomimetics agents (e.g. isoprenaline, dobutamine): Combination with Concor

may reduce the effect of both agents.

Sympathomimetics that activate both β- and α-adrenoceptors (e.g. noradrenaline, adrenaline):

Combination with Concor may unmask the α-adrenoceptor-mediated vasoconstrictor effects

of these agents leading to blood pressure increase and exacerbated intermittent claudication.

Such interactions are considered to be more likely with nonselective β -blockers.

Concomitant use with antihypertensive agents as well as with other drugs with blood

pressure lowering potential (e.g. tricyclic antidepressants, barbiturates, phenothiazines) may

increase the risk of hypotension.

Combinations to be considered

Mefloquine: increased risk of bradycardia

Monoamine oxidase inhibitors (except MAO-B inhibitors): Enhanced hypotensive effect

of the beta-blockers but also risk for hypertensive crisis.

4.6

Fertility, pregnancy and lactation:

Concor has pharmacological effects that may cause harmful effects on pregnancy and/or

the fetus/newborn.

general,

beta-adrenoceptor

blockers

reduce

placental

perfusion,

which

been

associated with growth retardation, intrauterine death, abortion or early labour. Adverse

effects (e.g. hypoglycaemia and bradycardia) may occur in the fetus and newborn infant. If

7/12

treatment

with

beta-adrenoceptor

blockers

necessary,

beta

-selective

adrenoceptor

blockers are preferable.

Concor should not be used during pregnancy unless clearly necessary. If treatment with

Concor is considered necessary, the uteroplacental blood flow and the fetal growth should

be monitored. In case of harmful effects on pregnancy or the fetus, alternative treatment

should be considered. The newborn infant must be closely monitored. Symptoms of

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

Breast-feeding

It is not known whether this drug is excreted in human milk. Therefore, breastfeeding is

not recommended during administration of Concor.

4.7

Effects on ability to drive and use machines

In a study with coronary heart disease patients Concor did not impair driving performance.

However, due to individual variations in reactions to the drug, the ability to drive a vehicle or

to operate machinery may be impaired. This should be considered particularly at start of

treatment and upon change of medication as well as in conjunction with alcohol.

4.8

Undesirable effects

The following definitions apply to the frequency terminology used hereafter:

Very common (≥ 1/10)

Common (≥1/100 to <1/10)

Uncommon (≥1/1,000 to <1/100)

Rare (≥1/10,000 to <1/1,000)

Very rare (<1/10,000)

Frequency not known (cannot be estimated from available data)

Cardiac disorders

Very common

bradycardia.

Common

worsening of heart failure.

Uncommon

AV-conduction disturbances

Investigations

Rare:

Increased triglycerides, increased liver enzymes (ALAT, ASAT)

Nervous system disorders

Common

Dizziness, headache

Rare

Syncope

Eye disorders

Rare

Reduced tear flow (to be considered if the patient uses lenses)

Very rare

Conjunctivitis

Ear and labyrinth disorders

Rare

Hearing disorders

8/12

Respiratory, thoracic and mediastinal disorders

Uncommon

Bronchospasm in patients with bronchial asthma or a history of

obstructive airways disease

Rare

Allergic rhinitis

Gastrointestinal disorders

Common

Gastrointestinal complaints such as nausea, vomiting, diarrhoea,

constipation

Skin and subcutaneous tissue disorders

Rare

Hypersensitivity reactions (pruritus, flush, rash)

Very rare

alopecia. Beta-blockers may provoke or worsen psoriasis or induce

psoriasis-like rash

Musculoskeletal and connective tissue disorders

Uncommon

Muscular weakness and cramps

Vascular disorders

Common

feeling of coldness or numbness in the extremities, hypotension

Uncommon:

orthostatic hypotension

General disorders

Common

asthenia, fatigue

Hepatobiliary disorders

Rare

Hepatitis

Reproductive system and breast disorders

Rare

erectile dysfunction

Psychiatric disorders

Uncommon

sleep disorders, depression

Rare

nightmares, hallucinations

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.

Any suspected adverse events should be reported to the Ministry of Health according to

the National Regulation by using an online form https://sideeffects.health.gov.il/

and emailed to the Registration Holder’s Patient Safety Unit at:

drugsafety@neopharmgroup.com

4.9

Overdose

Symptoms

With overdose (e.g. daily dose of 15 mg instead of 7.5 mg) third degree AV-block,

bradycardia, and dizziness have been reported. In general the most common signs expected

with overdosage of a beta-blocker are bradycardia, hypotension, bronchospasm, acute cardiac

9/12

insufficiency and hypoglycaemia. To date a few cases of overdose (maximum: 2000 mg)

with Concor have been reported in patients suffering from hypertension and/or coronary

heart disease showing bradycardia and/or hypotension; all patients recovered. There is a wide

interindividual variation in sensitivity to one single high dose of Concor and patients with

heart failure are probably very sensitive. Therefore it is mandatory to initiate the treatment of

these patients with a gradual uptitration according to the scheme given in section 4.2.

Management

If overdose occurs, Concor treatment should be stopped and supportive and symptomatic

treatment should be provided. Limited data suggest that Concor is hardly dialysable. Based

on the expected pharmacologic actions and recommendations for other beta-blockers, the

following general measures should be considered when clinically warranted.

Bradycardia: Administer intravenous atropine. If the response is inadequate, isoprenaline or

another agent with positive chronotropic properties may be given cautiously. Under some

circumstances, transvenous pacemaker insertion may be necessary.

Hypotension:

Intravenous

fluids

vasopressors

should

administered.

Intravenous

glucagon may be useful.

AV block (second or third degree): Patients should be carefully monitored and treated with

isoprenaline infusion or transvenous cardiac pacemaker insertion.

Acute worsening of heart failure: Administer i.v. diuretics, inotropic agents, vasodilating

agents.

Bronchospasm:

Administer

bronchodilator

therapy

such

isoprenaline,

beta

sympathomimetic drugs and/or aminophylline.

Hypoglycaemia: Administer i.v. glucose.

5.

Pharmacological properties

5.1

Pharmacodynamic properties

Pharmacotherapeutic group: Beta blocking agents, selective

ATC Code: C07AB07

Mechanism of action

Concor

highly

beta

-selective-adrenoceptor

blocking

agent,

lacking

intrinsic

stimulating and relevant membrane-stabilising activity. It only shows low affinity to the

beta

-receptor of the smooth muscles of bronchi and vessels as well as to the beta

receptors concerned with metabolic regulation. Therefore, Concor is generally not to be

expected to influence the airway resistance and beta

-mediated metabolic effects. Its

beta

-selectivity extends beyond the therapeutic dose range.

Clinical efficacy and safety

In total 2647 patients were included in the CIBIS II trial. 83% (n = 2202) were in NYHA

class III and 17% (n = 445) were in NYHA class IV. They had stable symptomatic systolic

heart failure (ejection fraction <35%, based on echocardiography). Total mortality was

reduced from 17.3% to 11.8% (relative reduction 34%). A decrease in sudden death (3.6%

10/12

vs 6.3%, relative reduction 44%) and a reduced number of heart failure episodes requiring

hospital admission (12% vs 17.6%, relative reduction 36%) was observed. Finally, a

significant improvement of the functional status according to NYHA classification has

been shown. During the initiation and titration of Concor hospital admission due to

bradycardia (0.53%), hypotension (0.23%), and acute decompensation (4.97%) were

observed, but they were not more frequent than in the placebo-group (0%, 0.3% and

6.74%). The numbers of fatal and disabling strokes during the total study period were 20

in the Concor group and 15 in the placebo group.

The CIBIS III trial investigated 1010 patients aged ≥65 years with mild to moderate

chronic heart failure (CHF; NYHA class II or III) and left ventricular ejection fraction

≤35%, who had not been treated previously with ACE inhibitors, beta-blockers, or

angiotensin receptor blockers. Patients were treated with a combination of Concor and

enalapril for 6 to 24 months after an initial 6 months treatment with either Concor or

enalapril.

There was a trend toward higher frequency of chronic heart failure worsening when

Concor was used as the initial 6 months treatment. Non inferiority of bisoprolol-first

versus enalapril-first treatment was not proven in the per-protocol analysis, although the

two strategies for initiation of CHF treatment showed a similar rate of the primary

combined endpoint death and hospitalization at study end (32.4% in the bisoprolol-first

group vs. 33.1 % in the enalapril-first group, per-protocol population). The study shows

that Concor can also be used in elderly chronic heart failure patients with mild to

moderate disease.

Concor is also used for the treatment of hypertension and angina.

In acute administration in patients with coronary heart disease without chronic heart

failure Concor reduces the heart rate and stroke volume and thus the cardiac output and

oxygen consumption. In chronic administration the initially elevated peripheral resistance

decreases.

5.2

Pharmacokinetic properties

Absorption

Concor is absorbed and has a biological availability of about 90% after oral administration.

Distribution

The distribution volume is 3.5 l/kg. The plasma protein binding of Concor is about 30%.

Biotransformation and Elimination

Concor is excreted from the body by two routes. 50% is metabolised by the liver to

inactive metabolites which are then excreted by the kidneys. The remaining 50% is

excreted by the kidneys in an unmetabolised form. Total clearance is approximately 15

l/h. The half-life in plasma of 10-12 hours gives a 24 hour effect after dosing once daily.

Linearity

The kinetics of Concor are linear and independent of age.

11/12

Special population

Since the elimination takes place in the kidneys and the liver to the same extent a dosage

adjustment is not required for patients with impaired liver function or renal insufficiency.

The pharmacokinetics in patients with stable chronic heart failure and with impaired liver

or renal function has not been studied. In patients with chronic heart failure (NYHA stage

III) the plasma levels of Concor are higher and the halflife is prolonged compared to

healthy volunteers. Maximum plasma concentration at steady state is 64+21 ng/ml at a

daily dose of 10 mg and the half-life is 17+5 hours.

5.3

Preclinical safety data

Preclinical data reveal no special hazard for humans based on conventional studies of safety

pharmacology, repeated dose toxicity, genotoxicity or carcinogenicity .

Like other beta-blockers, Concor caused maternal (decreased food intake and decreased body

weight) and embryo/fetal toxicity (increased incidence of resorptions, reduced birth weight

of the offspring, retarded physical development) at high doses but was not teratogenic.

6.

Pharmaceutical particulars

6.1

List of excipients

Concor 5 mg / 10 mg

Tablet

core:

Silica,

colloidal

anhydrous;

magnesium

stearate,

crospovidone,

microcrystalline cellulose, maize starch; calcium hydrogen phosphate, anhydrous.

Film-coating: Iron oxide yellow (E172), dimethicone 100, macrogol 400, titanium

dioxide (E171), hypromellose 2910/15.

In Concor 10 mg additionally: Iron oxide red (E172)

6.2

Incompatibilities

Not applicable.

6.3

Shelf life

Concor 5 mg and 10 mg

5 years.

6.4

Special precautions for storage

Do not store above 30°C.

6.5

Nature and contents of container

The container is a blister, which is made of a polyvinylchloride base film and an

aluminium cover foil.

Concor 5 mg

Pack sizes: 30, 50 and 100 tablets.

12/12

Hospital pack with 300 (10 x 30) film-coated tablets

Concor 10 mg

Pack sizes: 30, 50 and 100 tablets.

Hospital pack with 300 (10 x 30) film-coated tablets

6.6

Special precautions for disposal

No special requirements.

7.

Registration holder

Neopharm (Israel) 1996 Ltd., P.O.Box 7063, Petach Tiqva 49170

8.

Marketing authorization numbers

Concor 5 mg

057-79-25169-01

Concor 10 mg

057-78-25170-01

Approved in July 2016, updated in March

2020.