Concor PI CCDS 11 All Strengths
Concor PI CCDS 11 All Strengths
Bisoprolol fumarate
Selective beta blocking agents
2. PHARMACEUTICAL FORM
Film-coated tablet.
3. CLINICAL PARTICULARS
3.1 Indications
Concor 1.25 mg, Concor 2.5 mg, Concor 5 mg, and Concor 10 mg
Treatment of stable chronic heart failure with reduced systolic left ventricular function in addition to ACE
inhibitors, and diuretics, and optionally cardiac glycosides.
In all cases the dosage is adjusted individually, in particular according to the pulse rate and therapeutic
success.
Titration phase
The treatment of stable chronic heart failure with bisoprolol is initiated according to the following titration
scheme, individual adaptation may be necessary depending on how well the patient tolerates each dose,
i.e. the dose is to be increased only, if the previous dose is well tolerated.
Close monitoring of vital signs (blood pressure, heart rate) 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: There is no information regarding pharmacokinetics of Bisoprolol
in patients with chronic heart failure and with impaired liver or renal function. Uptitration of the dose in these
populations should therefore be made with additional caution.
Elderly
No dosage adjustment is required.
Children
There is no experience with bisoprolol in children, therefore its use cannot be recommended for children.
Administration
Tablets are taken in the morning with or without food. They are swallowed with some liquid and not to be
chewed.
3.3 Contraindications
Bisoprolol is contraindicated in patients with:
• acute heart failure or during episodes of heart failure decompensation requiring i.v. inotropic therapy
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• 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 Raynaud's syndrome
• untreated phaeochromocytoma (see section 3.4 Special Warnings and Special Precautions for Use)
• metabolic acidosis
• hypersensitivity to Bisoprolol or to any of the excipients (see section 5.1 List of Excipients)
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.
Bisoprolol must be used with caution in patients with hypertension or angina pectoris and accompanying
heart failure.
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 liver function,
• restrictive cardiomyopathy,
• congenital heart diseases
• haemodynamically significant organic valvular disease.
• myocardial infarction within 3 months.
Combination of Bisoprolol with calcium antagonist 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 3.5 Interaction with other medicinal products and other forms of interaction.
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, Bisoprolol
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). 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 Bisoprolol) after
carefully balancing the benefits against the risks.
In patients with phaeochromocytoma Bisoprolol must not be administered until after alpha-receptor
blockade.
3.5 Interaction with Other Medicinal Products and Other Forms of Interaction
Combinations not recommended
Treatment of stable chronic heart failure
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.
All indications
Calcium antagonists of the Verapamil type and to a lesser extent of the Diltiazem type: Negative influence
on contractility, atrio-ventricular conduction and blood pressure. Intravenous administration of Verapamil in
patients on beta-blocker treatment may lead to profound hypotension and atrioventricular block.
All indications
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Calcium antagonists of the dihydropyridine type (e.g. Nifedipine, Felodipine, Amlodipine): Concomitant use
may increase the risk of hypotension, and an increased risk of a further deterioration of the ventricular pump
function in patients with heart failure cannot be excluded.
Class-III antiarrhythmic medicines (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: Intensification 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.
Non-steroidal anti-inflammatory drugs (NSAIDs): may reduce the hypotensive effect of bisoprolol.
Beta-Sympathomimetics (e.g. Isoprenaline, Dobutamine): combination with bisoprolol may reduce the
effect of both agents.
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.
Monoamineoxidase inhibitors (except MAO-B inhibitors): Enhanced hypotensive effect of beta-blockers but
also risk of hypertensive crisis.
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.
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Breast-feeding
It is not known whether this drug is excreted in human milk. Therefore, breastfeeding is not recommended
during administration of Bisoprolol.
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.
Cardiac disorders
Very common: bradycardia (in patients with chronic heart failure)
Common: worsening of heart failure (in patients with chronic heart failure)
Uncommon: AV-conduction disturbances; worsening of pre-existing heart failure (in patients with
hypertension or angina pectoris); bradycardia (in patients with hypertension or angina
pectoris)
Investigations
Rare: increased triglycerides, increased liver enzymes (ALAT, ASAT)
Eye disorders
Rare: reduced tear flow (to be considered if the patient uses contact lenses)
Very rare: conjunctivitis
Gastrointestinal disorders
Common: gastrointestinal complaints such as nausea, vomiting, diarrhoea, constipation
Vascular disorders
Common: feeling of coldness or numbness in the extremities, hypotension, especially in patients with
hearth failure
General disorders
Common: asthenia (in patients with chronic heart failure), fatigue*
Uncommon: asthenia (in patients with hypertention of angina pectoris)
Hepatobilary disorders
Rare: hepatitis
Psychiatric disorders
Uncommon: depression, sleep disorder
Rare: nightmare, hallucination
3.9 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 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 3.2 Posology and Method
of Administration.
Management
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-bockers, the following general measures
should be considered when clinically warranted.
Bradycardia: Administer intravenous atropine. If 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.
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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.
4. PHARMACOLOGICAL PROPERTIES
4.1 Pharmacodynamic Properties
Pharmacotherapeutic group : Beta blocking agents, selective. ATC Code : C07AB07
Mechanism of action
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 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 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.
Distribution
The plasma protein binding of bisoprolol is about 30%. 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.
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 mild to moderate 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 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. PHARMACEUTICAL PARTICULARS
5.1 List of Excipients
Concor 1.25 mg: Calcium hydrogen phosphate anhydrous, Corn starch, Pregelatinized maize starch,
Colloidal silicon dioxide, Microcrystalline cellulose pH 101, Crosspovidone, Magnesium stearate,
Hydroxypropyl methyl cellulose 2910, Polyethylene Glycol 400, Dimeticon 100, Titanium Dioxide, Talc fine
powder, Purified water.
Concor 2.5 mg: Calcium hydrogen phosphate anhydrous, Corn starch, Colloidal silicon dioxide,
Microcrystalline cellulose pH 101, Crospovidone, Magnesium stearate, Hydroxypropyl methyl cellulose 615,
Polyethylene Glycol 400, Titanium dioxide, Dimeticon 100, Purified water.
Concor 5 mg: Calcium hydrogen phosphate anhydrous, Corn starch, Colloidal silicon dioxide,
Microcrystalline cellulose pH 101, Crospovidone, Magnesium stearate, Hydroxyproyl methyl cellulose 615,
Polyethylene Glycol 400, Titanium dioxide, Dimeticon 100, Iron Oxide Yellow (Cl No. 77492), Purified water.
5.2 Shelf-life
The expiry date is indicated on the packaging.
Manufactured by
PT Merck Tbk,
Jakarta, Indonesia