: bisoprolol hemifumarate
Each film-coated tablet contains
5mg bisoprolol hemifumarate as active ingredient.
Excipients : Tablet core :
Silica, colloidal anhydrous; magnesium stearate, crospovidone,
microcrystalline cellulose, maize starch, calcium hydrogen phosphate,
Film coating : Iron oxide
yellow, dimethicone, macrogol 400, titanium dioxide, hypromellose.
Yellowish white, heart-shaped,
biconvex film-coated tablets, scored on both sides.
Bisoprolol, the active ingredient
of Concor is a beta1-selective-adrenoceptor blocking agent, lacking
intrinsic stimulating and relevant membrane stabilising activity. It only
shows very 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.
Absorption. Bisoprolol is
almost completely ( >90% ) absorbed from the gastrointestinal tract and,
because of its small first pass metabolism of approximately 10%, has an
bioavailability of approximately 90% after oral administration. The
bioavailability is not affected by food intake. Bisoprolol shows linear
kinetics and the plasma concentrations are proportional to the administered
dose over the dose range 5 to 20mg. Peak plasma concentrations occur within
is extensively distributed. The volume of distribution is 3.5 l/kg. Binding
to plasma proteins is approximately 30%.
Metabolism. Bisoprolol is
metabolised via oxidative pathways with no subsequent conjugation. All
metabolites, being very polar, are renally eliminated. The major metabolites
in human plasma and urine were found to be without pharmacological activity.
In vitro data from studies in human liver microsomes show that bioprolol is
primarily metabolised via CYP3A4 ( ~95% ) with CYP2D6 having only a minor
Elimination. The clearance of bisoprolol is 'balanced' between renal elimination of the unchanged molecule
( ~50% ) and hepatic metabolism ( ~50% ) to metabolites which are also
renally excreted. The total clearnace of bisoprolol is approximately 15 l/h.
Bisoprolol has an elimination half-life of 10-12 hours.
* Treatment of high blood
pressure ( hypertension )
* Treatment of coronary heart
disease ( angina pectoris )
* Treatment of stable chronic
moderate to severe heart failure with reduced systolic ventricular function
( ejection fraction ≤ 35%, based on echocardiography ) in addition to ACE
inhibitors, and diuretics, and optionally cardiac glycosides.
Concor must not be used in
patients with :
* acute heart failure or during
episodes of heart failure decompensation requiring intravenous therapy with
substances increasing the contractility of the heart,
* shock induced by disorders of
cardiac function ( cardiogenic shock ),
* severe disturbances of
atrioventricular conduction ( second or third degree AV block ) without a
* sick sinus syndrome,
* sinoatrial block,
* slowed heart rate, causing
* decreased blood pressure,
* severe forms of peripheral
arterial occlusive disease or Raynaud's syndrome,
* untreated tumors of the adrenal
gland ( phaeochromocytoma ),
* metabolic acidosis,
* hypersensitivity to bisoprolol
or to any of the excipients ( see composition ).
Special warnings and
The following section describes
when Concor must be used with special caution :
* diabetes mellitus with
extremely fluctuating blood glucose levels : symptoms of markedly reduced
blood glucose ( hypoglycaemia ) such as tachycardia, palpitations or
sweating can be masked.
* strict fasting,
* ongoing desensitisation
* mild disturbances of
atrioventricular conduction ( first degree AV block ),
* disturbed blood flow in the
coronary vessels due to vasospasms ( Prinzmetal's angina ),
* peripheral arterial occlusive
disease ( intensification of complaints may occur especially when starting
* patients with a personal or
family history of psoriasis.
Respiratory system : In
bronchial asthma or other symptomatic chronic obstructive pulmonary disease
concomitant bronchodilator therapy is indicated. An increase in airway
resistance may occasionally occur in patients with asthma, requiring a
higher dose of beta2-sympathomimetics.
Allergic reactions :
Beta-blockers, including Concor, may increase the sensitivity to allergens
and the severity of anaphylactic reactions because the adrenergic
counter-regulation under beta-blockade may be alleviated. Treatment with
adrenaline may not always give the expected therapeutic effect.
General anaesthesia : In
patient undergoing general anaesthesia the anaesthetist must be aware of
beta-blockage. If it is thought necessary to withdraw Concor before surgery,
this should be done gradually and completed about 48 hours prior to
Phaeochromocytoma : In
patients with a tumour of the adrenal gland ( phaeochromocytoma ) Concor may
only be administered after previous alpha-receptor blockade.
Thyrotoxicosis : Under
treatment with Concor the symptoms of a thyroid hyperfunction (
thyrotoxicosis ) may be masked.
So far no sufficient therapeutic
experience is available for Concor in patients with heart failure and
concomitant insulin dependent type I diabetes mellitus, impaired kidney
function ( serum creatinine ≥ 3.4 mg/dl ), impaired liver function,
restrictive cardiomyopathy, congenital heart diseases or haemodynamically
relevant organic valvular heart disease. No sufficient therapeutic
experience is available either in patients with mild heart failure ( NYHA II
) as well as heart failure and myocardial infarction within the last 3
There is insufficient experience
with bisoprolol in children, therefore the use of Concor cannot be
recommended for children.
Effects on the ability to
drive and use machines
In a study with patients
suffering from coronary heart disease bisoprolol did not affect the driving
performance of the patients. However, due to individually different
reactions, the ability to drive a vehicle or to operate machinery may be
impaired. This needs to be considered particularly at the start of
treatment, after change of dose, as well as in conjunction with alcohol.
Pregnancy and lactation
During pregnancy Concor should
only recommended following careful assessment of benefit-to-risk ratio by
the doctor. In general, beta-blockers reduce placental blood flow and may
affect the development of the unborn child. Placental and uterine blood flow
as well as the growth of the unborn child must be monitored and, in case of
harmful effects on pregnancy or the foetus, alternative therapeutic measures
The new born infant must be
monitored closely after delivery. Symptoms of reduced blood glucose and
slowed pulse rate generally may occur within the first 3 days of life.
There are no data on the
excretion of bisoprolol in human breast milk or the safety of bisoprolol
exposure in infants. Therefore administration of Concor is not recommended