CARDILOC 1.25

1012C

118188010

1986 - ו"משתה )םירישכת( םיחקורה תונקת יפל ןכרצל ןולע .דבלב אפור םשרמ יפ לע תקוושמ הפורתה 1.25/2.5/5/10 קולידרק תוילבט :הליכמ 1.25 קולידרק לש הילבט לכ :בכרה

Bisoprolol

Fumarate

1.25

:הליכמ 2.5 קולידרק לש הילבט לכ

Bisoprolol

Fumarate

:הליכמ 5 קולידרק לש הילבט לכ

Bisoprolol

Fumarate

:הליכמ 10 קולידרק לש הילבט לכ

Bisoprolol

Fumarate

."ףסונ עדימ" :6 ףיעס האר - םיליעפ יתלב םירמוחל .הפורתב שמתשת םרטב ופוס דע ןולעה תא ןויעב ארק ,תופסונ תולאש ךל שי םא .הפורתה לע יתיצמת עדימ ליכמ הז ןולע .חקורה לא וא אפורה לא הנפ איה .םירחאל התוא ריבעת לא .ךתלחמב לופיטל המשרנ וז הפורת .המוד יאופרה םבצמ יכ ךל הארנ םא וליפא קיזהל הלולע .םידליל תדעוימ הניא הפורתה ?הפורתה תדעוימ המל .1 .בל תקיפס-יאב לופיטל :2.5 קולידרק/1.25 קולידרק ץחל רתיב לופיטל .בל תקיפס-יאב לופיטל :10 קולידרק/5 קולידרק .הזח תקועתב לופיטל .םד .אטיב ימסוח תצובקל תכייש הפורתה :תיטיופרת הצובק :הפורתב שומישה ינפל .2 :םא הפורתב שמתשהל ןיא םיפסונה םיביכרמהמ דחא לכל וא ליעפה רמוחל )יגרלא( שיגר התא .הפורתה הליכמ רשא תלחתה ינפל אפורב ץעוויהל ילבמ הפורתב שמתשהל ןיא :לופיטה .הקינמ וא ןוירהב ךניה םא המישנה תכרעמ :דוקפתב יוקילמ רבעב תלבס וא לבוס ךנה םא לש תוליעפ רתי ,ןתשה תכרעמ/הילכה ,דבכה ,בלה ,)המתסא ןוגכ( םיינייפואה םימוטפמיס ךסמל לולע הפורתב שומישה( סירתה תטולב ינמיס ךסמל לולע הפורתב שומישה( תרכוס ,)תוליעפ רתיב הטולבל .)הימקילגופיה :הפורתב שומישל תועגונה תודחוימ תורהזא .םד ץחל תוקידב ךורעל שי וז הפורתב לופיטה תפוקתב תרודצורפ וא )םייניש חותינ ללוכ( חותינ רובעל דמוע ךנה םא אפורל רפס .וז הפורת לטונ התאש יהשלכ םוריח האצותכ ,לופיטה תליחתב תונרעב םוגפל לולע וז הפורתב שומישה שי ךא ,לופיטה ךשמהב ףולחל היושע העפותה .םד ץחל תדירימ .בל הילא םישל ללוכ תורחא תופורת ,הנורחאל תחקל םא וא ,חקול התא םא .חקורל וא אפורל ךכ לע רפס ,הנוזת יפסותו םשרמ אלל תופורת :חקול התא םא חקורה וא אפורה תא עדייל שי דחוימב ץחל תדרוה תא ריבגהל תולולע - םד ץחל תדרוהל תורחא תופורת .םדה

הפורתה תוליעפ תא שילחהל תולולע - המתסא דגנ תופורת .תרכוסב לופיטל תופורת עיפשהל תולולע - ןיסקוגיד :ןוגכ ,בל בצקב תוערפהב לופיטל תופורת .הפורתה תוליעפ לע .ןוזמ םע הפורתה תא תחקל ןתינ - ןוזמו הפורתב שומיש הפורתב שמתשהל ןיא ,הקינמ וא ןוירהב ךניה םא - הקנהו ןוירה .אפורב ץעוויהל ילבמ תונכוסמ תונוכמ ליעפהל וא גוהנל ןיא - תונוכמב שומישו הגיהנ .תונרעב העיגפ בקע הפורתב לופיטה תלחתה תעב ?הפורתב שמתשת דציכ .3 חקורה וא אפורה םע קודבל ךילע .אפורה תוארוה יפל שמתשהל שי דימת .דבלב אפורה ידי לע ועבקי לופיטה ןפואו ןונימה .חוטב ךניא םא םע ,רקובב הפורתה תא עולבל שי .תצלמומה הנמה לע רובעל ןיא תסיעל יבגל עדימ ןיא .הילבטה תא שותכל ןתינ ךרוצה תדימב .םימ 2.5/5/10 קולידרק לש תוילבט תוצחל ןתינ ךרוצה תדימב .הילבטה .1.25 קולידרק תילבט לש היצח יבגל עדימ ןיא .ידיימ שומיש ךרוצל ןיבל הפורתה תליטנ ןיב תוחפל םייתעש לש ןמז קרפ ןיתמהל שי .הצמוח ירתוס םירישכת תליטנ תוקידב ךורעל שי וז הפורתב לופיטה תפוקתב :בקעמו תוקידב .םד ץחל דימ הנפ ,הפורתה ןמ דלי עלב תועטב םא וא רתי תנמ תלטנ םא .ךתיא הפורתה תזירא אבהו םילוח תיב לש ןוימ רדחל וא אפורל ,תרכזנשכ דימ הנמ לוטיל שי בוצק ןמזב וז הפורת לוטיל תחכש םא יפכ לופיטב דימתהל שי !דחיב תונמ יתש לוטיל ןיא ןפוא םושב ךא קיספהל ןיא ,ךתואירב בצמב רופיש לח םא םג .אפורה ידי לע ץלמוהש .חקורה וא אפורה םע תוצעייתה אלל הפורתב לופיטה .ךבצמב הרמחה תויהל הלולע הפורתה תליטנ תא קיספמ התא םא .תויתגרדהבו אפורב תוצעוויהב תושעיהל הכירצ הפורתב שומישה תקספה לטונ ךנהש םעפ לכב הנמהו תיוותה קודב !ךשוחב תופורת לוטיל ןיא תולאש ךל שי םא .םהל קוקז ךנה םא םייפקשמ בכרה .הפורתה תא .חקורב וא אפורב ץעוויה ,הפורתב שומישל עגונב תופסונ :יאוול תועפות .4 קלחב יאוול תועפותל םורגל לולע קולידרקב שומישה ,הפורת לכב ומכ אלו ןכתי .יאוולה תועפות תמישר ארקמל להבית לא .םישמתשמהמ .ןהמ תחא ףאמ לובסת בצק םא אפורל דימ תונפלו הפורתב שומישה תא קיספהל שי לש הרקמב וא ,הקדל תומיעפ 50 -ל תחתמ דרוי בלה תומיעפ .יתמסא ףקתה :תופסונ יאוול תועפות ,הליחב ,לושלש ,הנישב תוערפה ,שאר באכ :תובורק םיתיעל תועיפומ רתי תושיגרל םורגל הלולע הפורתהש ןוויכ .תווצקב רוק לש השגרה .רוקב תכשוממ הייהשב דחוימב ,ליגרהמ םח דוגיבל גואדל שי רוקל .תופייע תשוחת ,תרוחרחס :תוקוחר םיתיעל תועיפומ תעפותמ לבוס התא רשאכ וא ,הרימחמ יאוולה תועפותמ תחא םא .אפורה םע ץעייתהל ךילע ,ןולעב הרכזוה אלש יאוול ?הפורתה תא ןסחאל ךיא .5 רוגס םוקמב רומשל שי תרחא הפורת לכו וז הפורת !הלערה ענמ .הלערה ענמת ךכ ידי לעו תוקונית וא/ו םידלי לש םדי גשיהל ץוחמ .אפורהמ תשרופמ הארוה אלל האקהל םורגת לא לע עיפומה )

Date

( הגופתה ךיראת ירחא הפורתב שמתשהל ןיא .שדוח ותוא לש ןורחאה םויל סחייתמ הגופתה ךיראת .הזיראה יבג .רואמ ןגומ םוקמבו 25º

-ל תחתמ ןסחאל שי :ףסונ עדימ .6 :םג הליכמ הפורתה ליעפה רמוחה לע ףסונ

Dicalcium Phosphate, Microcrystalline Cellulose, Crospovidone,

Colloidal Silicon Dioxide, Magnesium Stearate, Opadry

לש תוזיראב קוושמ קולידרקה :הזיראה ןכות המו הפורתה תיארנ דציכ .)רטסילב( תישגמ תזיראב זוראו תוילבט 30 .הלוגעו המותכ הניה 1.25 קולידרק לש הילבט .תולוגעו תונבל ןניה 2.5/5/10 קולידרק לש תוילבט .א"ת 21429 .ד.ת ,מ"עב םראפינוא :םושירה לעב םש .תורבעמ ץוביק ,מ"עב המירת :ותבותכו ןרציה םש .09/12 :ךיראתב תואירבה דרשמ י"ע רשואו קדבנ הז ןולע :תואירבה דרשמ לש יתכלממה תופורתה סקנפב הפורתה לש םושירה רפסמ

128073065400 :2.5 קולידרק 148633351300 :1.25 קולידרק 119622998900 :10 קולידרק 119612998800 :5 קולידרק ףא לע .רכז ןושלב חסונ הז ןולע ,האירקה תלקהלו תוטשפה םשל .םינימה ינשל תדעוימ הפורתה ,תאז

118188010

1012C

PATIENT PACKAGE INSERT IN ACCORDANCE WITH THE

PHARMACISTS' REGULATIONS (PREPARATIONS) - 1986

The dispensing of this medicine requires a doctor’s prescription

CARDILOC 1.25/2.5/5/10

Tablets

COMPOSITION:

Each tablet of Cardiloc 1.25 contains:

Bisoprolol Fumarate 1.25 mg

Each tablet of Cardiloc 2.5 contains:

Bisoprolol Fumarate 2.5 mg

Each tablet of Cardiloc 5 contains:

Bisoprolol Fumarate 5 mg

Each tablet of Cardiloc 10 contains:

Bisoprolol Fumarate 10 mg

For inactive ingredients – see section 6: “Additional information”.

Read this package insert carefully in its entirety before using

this medicine.

This leaflet contains concise information about the medicine. If you

have further questions refer to your doctor or pharmacist.

This medicine has been prescribed for treatment of your ailment.

Do not pass it on to others. It may harm them even if it seems to

you that their medical condition is similar.

The medicine is not intended for children.

1. WHAT IS THE MEDICINE INTENDED FOR?

Cardiloc 1.25/Cardiloc 2.5: For the treatment of heart failure.

Cardiloc 5/Cardiloc 10: For the treatment of heart failure. For the

treatment of hypertension. For the treatment of angina pectoris.

Therapeutic group: The medicine belongs to the beta blockers

group.

2. BEFORE USING THE MEDICINE:

Do not use the medicine if:

you are sensitive (allergic) to the active ingredient or to any

other ingredient that the medicine contains.

Do not take this medicine without consulting a doctor before

starting treatment:

if you are pregnant or breastfeeding.

you are suffering, or have suffered in the past, from impaired

function of: the respiratory system (e.g. asthma), the heart, the

liver, the kidney/urinary tract, from an overactive thyroid (use of

the medicine may mask symptoms characteristic of an overactive

thyroid), diabetes (use of the medicine may mask signs of

hypoglycemia).

Special warnings regarding use of the medicine:

During treatment with this medicine, blood pressure should be

checked. If you about to undergo surgery (including dental surgery)

or any emergency procedure tell the doctor that you are taking this

medicine. Use of this medicine may impair alertness at the beginning

of treatment, due to decreased blood pressure. This symptom may

disappear during treatment but one should pay attention to it.

If you are taking or have recently taken other medicines, including

non-prescription medicines and nutritional supplements, inform

the doctor or pharmacist. You must especially tell the doctor or

pharmacist if you are taking:

other antihypertensives – may increase lowering of blood

pressure.

antiasthma preparations – may weaken the action of the

medicine.

antidiabetic agents.

antiarrhythmic agents, e.g.: digoxin – may affect the action of the

medicine.

Use of the medicine and food – the medicine can be taken with

food.

Pregnancy and breastfeeding – if you are pregnant or breastfeeding,

do not use the medicine without consulting the doctor.

Driving and use of machines – do not drive or operate dangerous

machines at the beginning of treatment with this medicine because

of impaired alertness.

3. HOW SHOULD YOU USE THE MEDICINE?

Always use according to the doctor’s instructions. Check with the

doctor or pharmacist if you are not sure. The dosage and the treatment

regimen will be determined by the doctor only. Do not exceed the

recommended dose. Swallow the medicine with water in the morning.

If necessary, the tablet can be crushed. There is no information

regarding chewing of the tablet. If necessary the Cardiloc 2.5/5/10

tablets can be halved for immediate use. There is no information

regarding halving of the Cardiloc 1.25 tablet. Allow a lapse of at least

two hours between taking the medicine and taking antacids.

Tests and follow-up: During treatment with this medicine blood

pressure should be checked.

If you have taken an overdose or if a child has accidentally swallowed

the medicine, refer immediately to the doctor or to a hospital

emergency room and bring the package of the medicine with you. If

you forget to take this medicine at the specified time, take the dose

as soon as you remember, but never take a double dose! Always

adhere to the treatment as recommended by the doctor. Even if there

is an improvement in your health, do not discontinue treatment with

the medicine without consulting the doctor or pharmacist. If you stop

taking the medicine your condition may worsen. Stopping treatment

with the medicine must be done gradually in consultation with the

doctor. Do not take medicines in the dark! Check the label and the

dose each time you take your medicines. Wear glasses if you need

them. If you have further questions regarding use of the medicine,

consult the doctor or pharmacist.

4. SIDE EFFECTS:

As with any medicine, use of Cardiloc may cause side effects in

some users. Do not be alarmed when reading the list of side effects.

You may not experience any of them.

Stop using the medicine and refer to the doctor immediately if

your heart rate decreases to below 50 beats per minute, or in case

of an asthma attack.

Other side effects:

Occurring frequently: headache, sleep disturbances, diarrhea,

nausea, feeling of coldness in the extremities. Because the medicine

may cause hypersensitivity to cold temperature, dress more warmly

than usual, especially during prolonged exposure to cold.

Occurring infrequently: dizziness, feeling tired.

If any of the side effects worsens, or if you suffer from a side effect

not mentioned in the leaflet, consult with the doctor.

5. HOW SHOULD THE MEDICINE BE STORED?

Avoid poisoning! This medicine and any other medicine must be kept

in a closed place out of the reach of children and/or infants to avoid

poisoning. Do not induce vomiting unless clearly indicated by the 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.

Store at a temperature below 25°C in a place protected from light.

6. ADDITIONAL INFORMATION:

In addition to the active ingredient, the medicine also contains:

Dicalcium Phosphate, Microcrystalline Cellulose, Crospovidone,

Colloidal Silicon Dioxide, Magnesium Stearate, Opadry.

How does the medicine look and what are the contents of the

package: Cardiloc is provided in packages of 30 tablets packed

in a blister tray. The Cardiloc 1.25 tablet is orange and round.

Cardiloc 2.5/5/10 tablets are white and round.

Name of License holder: Unipharm Ltd., P.O.Box 21429, Tel Aviv.

Name and address of Manufacturer: Trima Ltd., Kibbutz Maabarot.

This leaflet was checked and approved by the Ministry of Health

in: 09/12.

Registration number of the medicine in the National Drug Registry

of the Ministry of Health:

Cardiloc 1.25: 148633351300

Cardiloc 2.5: 128073065400

Cardiloc 5: 119612998800

Cardiloc 10: 119622998900

0912A

ע עבקנ הז ולע טמרופ ע עבקנ הז ולע טמרופ ע עבקנ הז ולע טמרופ ע עבקנ הז ולע טמרופ

"

""

"

ודי לע רשואו קדבנ ונכותו תואירבה דרשמ י ודי לע רשואו קדבנ ונכותו תואירבה דרשמ י ודי לע רשואו קדבנ ונכותו תואירבה דרשמ י ודי לע רשואו קדבנ ונכותו תואירבה דרשמ י

Summary of Product Characteristics

1. Name of the medicinal product

Cardiloc 1.25, film-coated tablet

Cardiloc 2.5, film-coated tablet

Cardiloc 5, film-coated tablet

Cardiloc 10, film-coated tablet

2. Qualitative and quantitative composition

Active substance: Bisoprolol fumarate

Cardiloc 1.25

One film-coated tablet contains 1.25 mg bisoprolol fumarate.

Cardiloc 2.5

One film-coated tablet contains 2.5 mg bisoprolol fumarate.

Cardiloc 5

One film-coated tablet contains 5 mg bisoprolol fumarate.

Cardiloc 10

One film-coated tablet contains 10 mg bisoprolol fumarate.

For a full list of excipients see section 6.1.

3. Dosage form

Film-coated tablets

Cardiloc 1.25 are orange, circular, biconvex, film-coated tablets.

Cardiloc 2.5 are white, circular, biconvex, film-coated tablets with breakline on one side.

Cardiloc 5 are white, circular, biconvex, film-coated tablets with breakline on one side.

Cardiloc 10 are white, circular, biconvex, film-coated tablets with breakline on one side.

Tablets with a breakline can be divided in halves.

4. Clinical data

4.1 Therapeutic indications

Cardiloc 1.25, 2.5, 5, 10:

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 (for

additional information see section 5.1).

Cardiloc 5, 10:

Management of angina pectoris, hypertention.

0912A

4.2 Posology and method of administration

Hypertension, 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.

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.

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

bisoprolol treatment is initiated.

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

of chronic heart failure.

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

titration period and thereafter.

Posology:

Titration phase

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

The treatment with bisoprolol is to be started with a gradual uptitration 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.

0912A

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 bisoprolol or to consider discontinuation.

The reintroduction and/or uptitration of bisoprolol 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 patients condition.

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

treatment.

Renal or hepatic impairment

There is no information regarding pharmacokinetics of bisoprolol 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.

Elderly

No dosage adjustment is required.

Paediatric population

There is no paediatric experience with bisoprolol, therefore its use cannot be

recommended in paediatric patients.

Method of administration:

Bisoprolol 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

Bisoprolol 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 or severe chronic obstructive pulmonary disease

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

syndrome

untreated phaeochromocytoma (see section 4.4)

metabolic acidosis

hypersensitivity to bisoprolol 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 bisoprolol has to be initiated with

special titration phase.

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

bisoprolol must not be done abruptly unless clearly indicated, because this may lead to

transitional worsening of heart condition.

The initiation and cessation of treatment with bisoprolol necessitates regular monitoring.

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

the following diseases and conditions:

insulin dependent diabetes mellitus (type I)

severely impaired renal function

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severely impaired hepatic function

restrictive cardiomyopathy

congenital heart disease

haemodynamically significant organic valvular disease

myocardial infarction within 3 months

Bisoprolol 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 desensitisation therapy. As with other beta-blockers, bisoprolol 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

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 post-

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

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

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

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 bisoprolol 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.

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

beta

-stimulants may have to be increased.

Patients with psoriasis or with a history of psoriasis should only be given beta-blockers

(e.g. bisoprolol) after carefully balancing the benefits against the risks.

In patients with phaeochromocytoma bisoprolol must not be administered until after

alpha-receptor blockade.

Under treatment with bisoprolol 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

-blocker treatment may lead to profound

hypotension and atrioventricular block.

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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 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 if prior to

beta-blocker discontinuation, may increase risk of “rebound hypertension”.

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 bisoprolol.

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 of the reflex tachycardia and increase of the risk of

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 bisoprolol.

-Sympathomimetic agents (e.g. isoprenaline, dobutamine): Combination with bisoprolol

may reduce the effect of both agents.

Sympathomimetics that activate both

- and

-adrenoceptors (e.g. noradrenaline,

adrenaline): Combination with bisoprolol may unmask the

-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

-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.

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4.6 Pregnancy and lactation:

Pregnancy

Bisoprolol has pharmacological effects that may cause harmful effects on pregnancy

and/or the fetus/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

fetus and newborn infant. If treatment with beta-adrenoceptor blockers is necessary,

beta1-selective adrenoceptor blockers are preferable.

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

with bisoprolol 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 bisoprolol.

4.7 Effects on ability to drive and use machines

In a study with coronary heart disease patients bisoprolol 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, < 1/10)

Uncommon ( 1/1,000, < 1/100)

Rare ( 1/10,000, < 1/1,000)

Very rare (< 1/10,000)

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.

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Ear and labyrinth disorders:

Rare: hearing disorders.

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 (itching, 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: potency disorders.

Psychiatric disorders:

Uncommon: sleep disorders, depression.

Rare: nightmares, hallucinations.

4.9 Overdose

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 insufficiency and hypoglycaemia. To date a few cases of overdose

(maximum: 2000 mg) with bisoprolol 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 bisoprolol 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.

If overdose occurs, bisoprolol treatment should be stopped and supportive and

symptomatic treatment should be provided. Limited data suggest that bisoprolol is hardly

dialysable. Based on the expected pharmacologic actions and recommendations for other

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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 and vasopressors should be 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 as isoprenaline, beta2-

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

Bisoprolol is a highly beta1-selective-adrenoceptor blocking agent, lacking intrinsic

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

beta2-receptor of the smooth muscles of bronchi and vessels as well as to the beta2-

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

be expected to influence the airway resistance and beta2-mediated metabolic effects. Its

beta1-selectivity extends beyond the therapeutic dose range.

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% 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 bisoprolol 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 bisoprolol 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 bisoprolol and

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

enalapril.

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

bisoprolol 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

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

moderate disease.

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

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

failure bisoprolol 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

Bisoprolol 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 bisoprolol is about

30%.

Biotransformation and Elimination

Bisoprolol 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 bisoprolol are linear and independent of age.

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 bisoprolol are higher and the half-life 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, bisoprolol 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

Cardiloc 1.25

Anhydrous Dicalcium Phosphate; Microcrystalline Cellulose; Crospovidone; Colloidal

Silicon Dioxide; Magnesium Stearate; Opadry OY-8704.

Cardiloc 2.5, 5 and 10

Anhydrous Dicalcium Phosphate; Microcrystalline Cellulose; Crospovidone 1.5 mg;

Colloidal Silicon Dioxide; Magnesium Stearate; Opadry Y-1-7000.

6.2 Incompatibilities

Not applicable.

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6.3 Shelf life

Cardiloc 1.25

2 years

Cardiloc 2.5, 5 and 10

3 years

5.4 Special precautions for storage

Store below 25°C. Protect from light.

6.5 Nature and contents of container

Cardiloc 1.25: The container is an ALU/ALU blister.

Cardiloc 2.5, 5 and 10: The container is a blister, which is made of a polyvinylchloride

base film and an aluminium cover foil.

Cardiloc 1.25 and 2.5

Pack sizes:

,15,20,30 tablets.

Cardiloc 5 and 10

Pack sizes: 7;10;14;20, 28, 30 tablets.

Not all pack sizes may be marketed.

6.6 Special precautions for disposal

No special requirements.

7. Registration holder

Unipharm Ltd.,

, P.o.b 21429, Tel-Aviv.