Summary of Product Characteristics Updated 06-May-2015 | Merck
|Congescor 1.25 mg:||Each tablet contains 1.25 mg bisoprolol fumarate|
|Congescor 2.5 mg:||Each tablet contains 2.5 mg bisoprolol fumarate|
|Congescor 1.25 mg||white, round film-coated tablets|
|Congescor 2.5 mg||white, heart-shaped, scored and film-coated tablets|
Titration phaseThe 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 modificationIf 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.
Patients with hepatic or renal impairmentThere 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.
Older peopleNo dosage adjustment is required.
Paediatric populationThere is no paediatric experience with bisoprolol, therefore its use cannot be recommended in paediatric patients.
Method of administrationBisoprolol tablets should be taken in the morning and can be taken with food. They should be swallowed with liquid and should not be chewed.
Combinations not recommendedCalcium 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 cautionCalcium 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.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 consideredMefloquine: increased risk of bradycardiaMonoamine oxidase inhibitors (except MAO-B inhibitors): Enhanced hypotensive effect of the beta-blockers but also risk for hypertensive crisis.
PregnancyBisoprolol 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-feedingIt is not known whether this drug is excreted in human milk. Therefore, breastfeeding is not recommended during administration of bisoprolol.
|Uncommon:||sleep disorders, depression.|
|Nervous system disorders:|
|Rare:||reduced tear flow (to be considered if the patient uses lenses).|
|Ear and labyrinth disorders:|
|Common:||worsening of heart failure.|
|Common:||feeling of coldness or numbness in the extremities, hypotension.|
|Respiratory, thoracic and mediastinal disorders:|
|Uncommon:||bronchospasm in patients with bronchial asthma or a history of obstructive airways disease.|
|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.|
|Reproductive system and breast disorders:|
|Rare:||increased triglycerides, increased liver enzymes (ALAT, ASAT).|
SymptomsWith 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.
ManagementIf 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, beta2-sympathomimetic drugs and/or aminophylline.Hypoglycaemia: Administer i.v. glucose.
Mechanism of actionBisoprolol 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.
Clinical efficacy and safetyIn 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.
AbsorptionBisoprolol is absorbed and has a biological availability of about 90% after oral administration.
DistributionThe distribution volume is 3.5 l/kg. The plasma protein binding of bisoprolol is about 30%.
Biotransformation and EliminationBisoprolol 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.
LinearityThe kinetics of bisoprolol are linear and independent of age.
Special populationSince 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.
Congescor 1.25 mgTablet 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.
Congescor 2.5 mgTablet core: Silica, colloidal anhydrous; magnesium stearate, crospovidone, microcrystalline cellulose, maize starch, calcium hydrogen phosphate, anhydrous.Film coating: Dimethicone, macrogol 400, titanium dioxide (E171), hypromellose.
|Congescor 1.25 mg||PL 11648/0035|
|Congescor 2.5 mg||PL 11648/0036|
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