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    / Unipharm


    Active Ingredient
    Bisoprolol Fumarate 1.25, 2.5, 5, 10 mg

    Status in Israel
    RX

    Presentation and Status in Health Basket

    Presentation Basket Yarpa Pharmasoft

    Film Coated Tablets

    30 X 1.25 mg

    not in the basket chart 38162 9602

    Film Coated Tablets

    30 X 2.5 mg

    not in the basket chart 56392 3275

    Film Coated Tablets

    30 X 5 mg

    not in the basket chart 24788 3687

    Film Coated Tablets

    30 X 10 mg

    not in the basket chart 24787 3686

    Related information


    Dosage

    Hypertension, Angina pectorisTreatment should principally be initiated gradually with low doses, which are then increased slowly. In all cases the dosage should be adjusted individually, in particular according to the pulse rate and therapeutic success.
    Hypertension: The recommended dosage is 5 mg bisoprolol fumarate once daily. In milder forms of hypertension (diastolic blood pressure up to 105 mmHg) therapy with 2.5 mg once daily may be adequate. If necessary, the dosage may be increased to 10 mg once daily. Any further increase of dosage is justified only in exceptional cases. The maximum recommended dosage is 20 mg once daily.
    Coronary heart disease (angina pectoris): The recommended dosage is 5 mg bisoprolol fumarate once daily. If necessary, the dosage may be increased to 10 mg once daily. Any further increase of dosage is justified only in exceptional cases. The maximum recommended dosage is 20 mg once daily.
    CHF: 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.
    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.
    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.
    Paediatric population: There is no paediatric experience with bisoprolol, therefore its use cannot be recommended in paediatric patients.


    Indications

    Management of hypertension, angina pectoris.


    Contra-Indications

    2nd or 3rd degree AV block, sinus bradycardia, sick sinus syndrome, severe peripheral arterial disease, Printzmetal’s angina, uncompensated cardiac failure (except carvedilol), cardiogenic shock, hypotension, right ventricular failure secondary to pulmonary hypertension, significant cardiomegaly, untreated phaeochromocytoma, metabolic acidosis. Non-cardioselective β-blockers (nadolol, oxprenolol, penbutolol, pindolol, propranolol, timolol) are also generally contraindicated in patients with obstructive airways disease or a history of bronchospasm.
    For full details see prescribing information.


    Special Precautions

    The treatment of stable chronic heart failure with bisoprolol has to be initiated with 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; Symptoms 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
    – Prinzmetal’s angina
    – peripheral arterial occlusive disease. Aggravation of symptoms may occur especially when starting therapy.
    – general anaesthesia In patients undergoing general anaesthesia beta-blockade reduces the incidence of arrhythmias and myocardial ischemia during induction and intubation, and the postoperative 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. Combination of bisoprolol with calcium antagonists of the verapamil or diltiazem type, with Class I antiarrhythmic drugs and with centrally acting antihypertensive drugs is generally not recommended. 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. Under treatment with bisoprolol the symptoms of a thyreotoxicosis may be masked.
    For full details see prescribing information.


    Side Effects

    Cold extremities, CNS and sleep disturbances (particularly with the more lipophilic drugs), bradycardia (less with carvedilol, pindolol), exertional tiredness, bronchospasm, heart failure, hypotension, GI upset, alopecia, thrombocytopenia. Withdraw gradually in unexplained dry eyes or skin rash.
    For full details see prescribing information.


    Drug interactions

    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: 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. 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 beta-blockers but also risk for hypertensive crisis.


    Pregnancy 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. 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-feeding: It is not known whether this drug is excreted in human milk. Therefore, breastfeeding is not recommended during administration of bisoprolol.


    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 overdose 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 posology and method of administration . 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, beta2- sympathomimetic drugs and/or aminophylline.
    Hypoglycaemia: Administer i.v. glucose.


    Manufacturer
    Trima Israel Pharmaceutical Products Maabarot Ltd. Israel
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