Cardicor 1.25mg, 2.5mg, 3.75mg, 5mg, 7.5mg, 10mg film-coated tablets

Minor amendments to section 4 & 6
TW 2965329

Angioedema added in section 4.8

(Our ref: TW 2351891)

(Our ref: TW 2351891)

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

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.

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.

two equal halvesdoses.

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.

for in

paediatric patients.

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

untreated phaeochromocytoma (see section 4.4)

metabolic acidosis

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

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

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

first degree AV block

Prinzmetal’s angina

peripheral arterial occlusive disease. Aggravation(intensification of symptomscomplaints

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.

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

2-stimulants may have to be

increased.

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.

-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.

:

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.

Breast-feeding:

≥ 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.

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.

. 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.

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.

The

plasma protein binding of bisoprolol is about 30%.

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

Total clearance is approximately 15 l/h. The half-life in plasma of 10-12

oC.

Cardicor 5 mg, 7.5 mg and 10 mg

Do not store above 30

oC.

test renewal: 4 June 200922 December 2009

Date of first authorisation: 4 June 1999

Date of last renewal: 04 June 2009

 
Date of Revision of the Text

March 2010

Common: dizziness, headache.

Rare: syncope