Reasons for adding or updating:

• Change to section 4.2 - Posology and method of administration
• Change to section 4.3 - Contraindications
• Change to section 4.4 - Special warnings and precautions for use
• Change to section 4.8 - Undesirable effects
• Change to section 4.9 - Overdose
• Change to section 5.1 - Pharmacodynamic properties

Date of revision of text on the SPC: 11-Sep-2015

Legal Category:POM

Black Triangle (CHM): NO

Free-text change information supplied by the pharmaceutical company:

Section 4.3 - Contraindications
"or severe chronic obstructive pulmonary disease" has been deleted.

Section 4.4 - Special warnings and precautions for use.

New text:

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, Cardicor may be used with caution. In patients with obstructive airways diseases, the treatment with bisoprolol should be started at the lowest possible dose and patients should be carefully monitored for new symptoms (e.g. dyspnea, exercise intolerance, cough).

The main change is the deletion of the contra-indication in severe chronic obstructive pulmonary disease which is moved to the Warnings section.  There are also editorial changes in Sections 4.2, 4.8, 4.9 and 5.1 including QRD version 9 updates, such as how to report side effects in section 4.8.

Our Ref: TW 778824

Reasons for adding or updating:

• Change to section 6.3 - Shelf life
• Change to section 6.4 - Special precautions for storage
• Change to section 6.5 - Nature and contents of container

Date of revision of text on the SPC: 06-Mar-2015

Legal Category:POM

Black Triangle (CHM): NO

Free-text change information supplied by the pharmaceutical company:



6.3 Shelf Life

 

Shelf life for PVC/Alu blister

Cardicor 1.25 mg, 2.5 mg and 3.75 mg

3 years.

Cardicor 5 mg, 7.5 mg and 10 mg:

5 years

 

Shelf life for Alu/Alu blister

Cardicor 1.25 mg, 2.5 mg, 3.75 mg, 5 mg, 7.5 mg and 10 mg

3 years.

 

6.4 Special precautions for storage

 

Storage conditions for PVC/Alu blister

 

Cardicor 1.25 mg, 2.5 mg and 3.75 mg

Do not store above 25 ^oC.

 

Cardicor 5 mg, 7.5 mg and 10 mg:

Do not store above 30 ^oC.

 

Storage conditions for Alu/Alu blister

 

Cardicor 1.25 mg, 2.5 mg, 3.75 mg, 5 mg, 7.5 mg and 10 mg

This medicinal product does not require any special storage conditions.

 

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.

The container is a blister, which is made of an aluminium forming foil and an aluminium sealing foil.

 

Pack sizes: 20, 28, 30, 50, 56, 60, 90 and 100 tablets.

 

Not all pack sizes may be marketed.

Reasons for adding or updating:

• Change to section 2 - Qualitative and quantitative composition
• Change to section 3 - Pharmaceutical form
• Change to section 4.2 - Posology and method of administration
• Change to section 4.3 - Contraindications
• Change to section 4.4 - Special warnings and precautions for Use
• Change to section 4.5 - Interaction with other medicinal products and other forms of interaction
• Change to section 4.6 - Pregnancy and Lactation
• Change to section 4.8 - Undesirable Effects
• Change to section 5.2 - Pharmacokinetic Properties
• Change to section 9 - Date of first Authorisation/renewal of the Authorisation
• Change to section 10 date of revision of the text

Date of revision of text on the SPC: 19-Jul-2012

Legal Category:POM

Black Triangle (CHM): NO

Free-text change information supplied by the pharmaceutical company:



1. NAME OF THE MEDICINAL PRODUCT

Cardicor 1.25 mg film-coated tablets

Cardicor 2.5 mg film-coated tablets

Cardicor 3.75 mg film-coated tablets

Cardicor 5 mg film-coated tablets

Cardicor 7.5 mg film-coated tablets

Cardicor 10 mg film-coated tablets

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Cardicor 1.25 mg: Each tablet contains 1.25 mg bisoprolol

 

hemifumarate

 

Cardicor 2.5 mg: Each tablet contains 2.5 mg bisoprolol

 

hemifumarate

 

Cardicor 3.75 mg: Each tablet contains 3.75 mg bisoprolol

 

hemifumarate

 

Cardicor 5 mg: Each tablet contains 5 mg bisoprolol

 

hemifumarate

 

Cardicor 7.5 mg: Each tablet contains 7.5 mg bisoprolol

 

hemifumarate

 

Cardicor 10 mg: Each tablet contains 10 mg bisoprolol

 

hemifumarate

 

For

 

thea full list of excipients, see section 6.1.

 

3. PHARMACEUTICAL FORM

Film-coated tablet.

Cardicor 1.25 mg white, round film-coated tablets

Cardicor 2.5 mg white, heart-shaped, scored and film-coated tablets

Cardicor 3.75 mg off-white, heart-shaped, scored and film-coated tablets

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

Cardicor 7.5 mg pale yellow, heart-shaped, scored and film-coated tablets

Cardicor 10 mg pale orange - light orange, heart-shaped, scored and film-coated

tablets

The scored tablets can be divided into

 

two equal halvesdoses.

 

4. CLINICAL PARTICULARS

4.1 Therapeutic indications

Treatment of stable chronic heart failure with reduced systolic left ventricular function in addition to

ACE inhibitors, and diuretics, and optionally cardiac glycosides (for additional information see section

5.1).

4.2 Posology and method of administration

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.

4

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.

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.

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.

Special population

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.

Children

 

 

Paediatric population

 

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

 

for in

 

children

 

 

paediatric patients.

 

5

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 (without a pacemaker)

 

•

 

sick sinus syndrome

 

•

 

sinoatrial block

 

•

 

symptomatic bradycardia with less than 60 beats/min before the start of therapy

 

•

 

symptomatic hypotension (systolic blood pressure less than 100 mm Hg)

 

•

 

severe bronchial asthma or severe chronic obstructive pulmonary disease

 

•

 

late stagessevere forms of peripheral arterial occlusive disease and 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 a 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

 

•

 

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; sSymptoms 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

 

6

•

 

Prinzmetal’s angina

 

•

 

peripheral arterial occlusive disease. Aggravation(intensification of symptomscomplaints

 

m

 

ayight occurhappen especially whenduring the starting of 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.

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

 

•

 

 

severely impaired hepatic function

 

•

 

 

restrictive cardiomyopathy

 

•

 

 

congenital heart disease

 

•

 

 

haemodynamically significant organic valvular disease

 

•

 

 

myocardial infarction within 3 months

 

Combination of bisoprolol with calcium antagonists of the verapamil or diltiazem type, with Class I

antiarrhytmic 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

 

2-stimulants may have to be

 

increased.

As with other beta-blockers, bisoprolol may increase both the sensitivity towards allergens and the

severity of anaphylactic reactions. Adrenaline treatment does not always give the expected therapeutic

effect.

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.

The initiation of treatment with bisoprolol necessitates regular monitoring. For the posology and

method of administration please refer to section 4.2.

The cessation of therapy with bisoprolol should not be done abruptly unless clearly indicated. For

further information please refer to section 4.2.

7

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 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:

 

Intensification 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.

β

 

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

 

the effect of both agents.

Sympathomimetics that activate both

 

β- and α-adrenoceptors (e.g. noradrenaline, adrenaline):

 

Combination with bisoprolol 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 betablockers

but also risk for hypertensive crisis.

4.6

 

Fertility, pPregnancy 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.

8

hypoglycaemia and bradycardia) may occur in the fetus and newborn infant. If treatment with betaadrenoceptor

blockers is necessary, beta

 

1-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.

Lactation

 

 

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.

Ear and labyrinth disorders:

Rare: hearing

 

impairmentdisorders.

 

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.

9

Skin and subcutaneous tissue disorders:

Rare: hypersensitivity reactions (itching, flush, rash).

Very rare:

 

alopecia. bBeta-blockers may provoke or worsen psoriasis or induce psoriasis-like

 

rash

 

, alopecia.

 

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 betablocker

 

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 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, beta

 

2-sympathomimetic drugs

 

and/or aminophylline.

10

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 beta

 

1-selective-adrenoceptor blocking agent, lacking intrinsic stimulating and

 

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

 

2-receptor of the smooth

 

muscles of bronchi and vessels as well as to the beta

 

2-receptors concerned with metabolic regulation.

 

Therefore, bisoprolol is generally not to be expected to influence the airway resistance and beta

 

2-

 

mediated metabolic effects. Its beta

 

1-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 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.

 

The

 

plasma protein binding of bisoprolol is about 30%.

11

Distribution

The distribution volume is 3.5 l/kg.

 

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.

 

 

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.

 

 

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.

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

Cardicor 1.25 mg

Tablet core: Silica, colloidal anhydrous; magnesium stearate, crospovidone, pregelatinised maize

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

Film coating: Dimethicone, talc, macrogol 400, titanium dioxide (E171), hypromellose.

Cardicor 2.5 mg

Tablet core: Silica, colloidal anhydrous; magnesium stearate, crospovidone, microcrystalline cellulose,

maize starch, calcium hydrogen phosphate, anhydrous.

Film coating: Dimethicone, macrogol 400, titanium dioxide (E171), hypromellose.

Cardicor 3.75 mg

Tablet core: Silica, colloidal anhydrous; magnesium stearate, crospovidone, microcrystalline cellulose,

maize starch, calcium hydrogen phosphate, anhydrous.

Film coating: Iron oxide yellow (E172), dimethicone, macrogol 400, titanium dioxide (E171),

hypromellose.

12

Cardicor 5 mg

Tablet core: Silica, colloidal anhydrous; magnesium stearate, crospovidone, microcrystalline cellulose,

maize starch, calcium hydrogen phosphate, anhydrous.

Film coating: Iron oxide yellow (E172), dimethicone, macrogol 400, titanium dioxide (E171),

hypromellose.

Cardicor 7.5 mg

Tablet core: Silica, colloidal anhydrous, magnesium stearate, crospovidone, microcrystalline cellulose,

maize starch, calcium hydrogen phosphate, anhydrous.

Film coating: Iron oxide yellow (E172), dimethicone, macrogol 400, titanium dioxide (E171),

hypromellose.

Cardicor 10 mg

Tablet core: Silica, colloidal anhydrous; magnesium stearate, crospovidone, microcrystalline cellulose,

maize starch, calcium hydrogen phosphate, anhydrous.

Film coating: Iron oxide red (E172), iron oxide yellow (E172), dimethicone, macrogol 400, titanium

dioxide (E171), hypromellose.

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

Cardicor 1.25 mg, 2.5 mg and 3.75 mg

3 years.

Cardicor 5 mg, 7.5 mg and 10 mg

5 years.

6.4 Special precautions for storage

Cardicor 1.25 mg, 2.5 mg and 3.75 mg

Do not store above 25

 

oC.

 

Cardicor 5 mg, 7.5 mg and 10 mg

Do not store above 30

 

oC.

 

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.

Pack sizes: 10, 20, 28, 30, 50, 56, 60, 90 and 100 tablets.

Not all pack sizes may be marketed.

6.6 Special precautions for disposal

No special requirements.

7. MARKETING AUTHORISATION HOLDER

Merck KGaA, Frankfurter Strasse 250, 64293 Darmstadt, Germany

13

8. MARKETING AUTHORISATION NUMBERS

Cardicor 1.25 mg 15374

Cardicor 2.5 mg 15232

Cardicor 3.75 mg 15375

Cardicor 5 mg 15376

Cardicor 7.5 mg 15233

Cardicor 10 mg 15234

[To be completed nationally]

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: 4 June 1999

Date of la

 

test renewal: 4 June 200922 December 2009

 

[To be completed nationally]

10. DATE OF REVISION OF THE TEXT

22 December 2009

Reasons for adding or updating:

• Change to section 4.1 - Therapeutic indications
• Change to section 4.8 - Undesirable Effects
• Change to section 4.4 - Special warnings and precautions for Use
• Change to section 4.2 - Posology and method of administration
• Change to section 4.3 - Contraindications
• Change to section 5.1 - Pharmacodynamic Properties

Date of revision of text on the SPC: 15-Sep-2010

Legal Category:POM

Black Triangle (CHM): NO

Free-text change information supplied by the pharmaceutical company:

New Sections updated as follows:

Reasons for adding or updating:

• Change to section 7 - Marketing Authorisation Holder
• Change to section 8 - MARKETING AUTHORISATION NUMBER(S)
• Change to section 10 date of revision of the text

Date of revision of text on the SPC: 01-Feb-2010

Legal Category:POM

Black Triangle (CHM): NO

Free-text change information supplied by the pharmaceutical company:



New Details:

Marketing Authorisation Holder

Merck Serono Ltd

Bedfont Cross

Stanwell Road

Feltham

Middlesex

TW14 8NX

UK

Marketing authorisation numbers

PL 11648/0071 - 76

Date of Revision of the Text

01^st February 2010

Reasons for adding or updating:

• Correction of spelling/typing errors

Date of revision of text on the SPC: 23-Jun-2009

Legal Category:POM

Black Triangle (CHM): NO

Reasons for adding or updating:

• Change to section 4.8 - Undesirable Effects

Date of revision of text on the SPC: 01-Jul-2009

Legal Category:POM

Black Triangle (CHM): NO

Free-text change information supplied by the pharmaceutical company:

Section 4.8 - Undesirable Effects updated to include the following:

Syncope

Reasons for adding or updating:

• Change to section 7 - Marketing Authorisation Holder

Date of revision of text on the SPC: 20-Oct-2008

Legal Category:POM

Black Triangle (CHM): NO

Free-text change information supplied by the pharmaceutical company:

Change in address of MA Holder from

E Merck Ltd

Harrier House

High Street

West Drayton

Middlesex

UB7 7QG

UK

to

E Merck Ltd

Bedfont Cross

Stanwell Road

Feltham

Middlesex

TW14 8NX

UK

Reasons for adding or updating:

• Change to section 2 - Qualitative and quantitative composition
• Change to section 3 - Pharmaceutical form
• Change to section 10 date of revision of the text

Date of revision of text on the SPC: 01-Jun-2007

Legal Category:POM

Black Triangle (CHM): NO

Free-text change information supplied by the pharmaceutical company:

Reasons for adding or updating:

• Correction of spelling/typing errors

Reasons for adding or updating:

• Removal of Black Triangle

Date of revision of text on the SPC: 01-May-2005

Legal Category:POM

Black Triangle (CHM): NO

Free-text change information supplied by the pharmaceutical company:

Removal of black triangle.

Reasons for adding or updating:

• Correction of spelling/typing errors

Reasons for adding or updating:

• Correction of spelling/typing errors

Reasons for adding or updating:

• Correction of spelling/typing errors

Reasons for adding or updating:

• Change to section 4.4 - Special Warnings and Precautions for Use
• Change to section 4.5 - Interactions with other Medicaments and other forms of Interaction

Reasons for adding or updating:

• Transferred from eMC version 1

Reasons for adding or updating:

• No reasons supplied

Reasons for adding or updating:

• No reasons supplied