Bisocor

Bisoprolol fumarate.

Each tablet contains: Bisoprolol Fumarate 5 mg.
Excipients/Inactive Ingredients: Silicified Microcrystalline Cellulose, Croscarmellose Sodium, Sodium Starch Glycolate, Iron Oxide Yellow, Magnesium Stearate.

Pharmacotherapeutic group: Beta blocking agents, selective. ATC Code: C07AB07.
Pharmacology: Pharmacodynamics: Mechanism of action: Bisoprolol is a potent highly beta₁-selective-adrenoceptor blocking agent, lacking intrinsic stimulating and without 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.
Hypertension or angina pectoris: Bisoprolol is used for the treatment of hypertension and angina pectoris. As with other beta₁-blocking agents, the method of acting in hypertension is unclear. However, it is known that bisoprolol reduces plasma renin activity markedly.
Antianginal mechanism: Bisoprolol by inhibiting the cardiac beta receptors inhibits the response given to sympathetic activation. That results in the decrease of heart rate and contractility this way decreasing the oxygen demand of the cardiac muscle. 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.
Pharmacokinetics: Bisoprolol is absorbed almost completely from the gastrointestinal tract. Together with the very small first pass effect in the liver, this results in a high bioavailability of approximately 90%. The plasma protein binding of bisoprolol is about 30%. The distribution volume is 3.5 l/kg. The total clearance is approximately 15 l/h.
The plasma elimination half-life (10-12 hours) provides 24 hours efficacy following a once daily dosage.
Bisoprolol 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. Since 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.

Treatment of hypertension.
Treatment of stable chronic angina.
Treatment of stable chronic heart failure with reduced systolic left ventricular function in addition to ACE inhibitors, and diuretics, and optionally cardiac glycosides.

Bisoprolol fumarate tablet should be taken in morning and can be taken with food in morning. They should be swallowed in liquid and should not be chewed.
The tablet is subdivisible into two equal doses. For doses not a multiple of 2.5 mg, consider using other strengths available in the market.
Treatment of hypertension and chronic stable angina pectoris: Adults: The dosage should be individually adjusted. It is recommended to start with 5 mg per day. The usual dose is 10 mg once daily with a maximum recommended dose of 20 mg per day.
Patients with renal impairment: In patients with severe renal impairment (creatinine clearance <20 ml/min), the dose should not exceed 10 mg once daily. This dosage may eventually be divided into halves.
Patients with severe liver impairment: No dosage adjustment is required, however careful monitoring is advised.
Discontinuation of treatment: Treatment should not be stopped abruptly. The dosage should be diminished slowly by a weekly halving of the dose.
Treatment of stable chronic heart failure: Adults: Standard treatment of chronic heart failure 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.
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.
Special populations: 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 normally required.
Paediatric population: There is no paediatric experience with bisoprolol, therefore its use cannot be recommended for children.
Method of administration: To be taken orally.

Symptoms: The most common signs expected with overdose of a beta-blocker are bradycardia, hypotension, bronchospasm, acute cardiac insufficiency and hypoglycaemia. There is limited experience with overdose of bisoprolol; only a few cases of overdose with bisoprolol have been reported. Bradycardia and/or hypotension were noted. All patients recovered. There is a wide inter-individual variation in sensitivity to one single high dose of bisoprolol, and patients with heart failure are probably very sensitive.
Treatment: In general, if overdose occurs, bisoprolol treatment is stopped and supportive and symptomatic treatment is provided.

Bisoprolol is contraindicated in chronic heart failure patients with: 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; Symptomatic hypotension; Severe bronchial asthma or severe chronic obstructive pulmonary disease; Late stages of peripheral arterial occlusive disease and Raynaud's syndrome; Untreated phaeochromocytoma; Metabolic acidosis; Hypersensitivity to the active substance or to any of the excipients.

Applies only to chronic heart failure: The treatment of stable chronic heart failure with bisoprolol has to be initiated with special titration phase.
Applies to all indications: Especially in patients with ischemic heart disease, the cessation of therapy with bisoprolol must not be done abruptly unless clearly indicated, because this may lead to transition worsening of heart condition.

Applies only to hypertension or angina pectoris: Bisoprolol must be used with caution in patients with hypertension or angina pectoris and accompanying heart failure.
Applies only to chronic heart failure: The initiation 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.
Applies to all indications: 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 (e.g. tachycardia, palpitations or sweating) can be masked); strict fasting; ongoing desensitisation therapy; first degree AV block; Prinzmetal's angina; peripheral arterial occlusive disease (intensification of complaints might happen especially during the start of therapy); general anaesthesia.
In bronchial asthma or other chronic obstructive lung diseases, which may cause symptoms, bronchodilating therapy is recommended to 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.
As with other beta-blockers, bisoprolol may increase both the sensitivity towards allergens and the severity of anaphylactic reactions.
Adrenaline treatment does not always give the expected therapeutic effect.
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 anaesthetist 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.
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 thyrotoxicosis may be masked.
Effects on ability to drive and use machines: In a study with coronary heart disease patients, bisoprolol did not impair driving performance. 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.

Pregnancy: Bisoprolol has pharmacological effects that may cause harmful effects on pregnancy and/or the foetus/newborn. In general, β-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 foetus and newborn infant. If treatment with β-adrenoceptor blockers is necessary, β₁-selective adrenoceptor blockers are preferable.
Bisoprolol is not recommended during pregnancy unless clearly necessary. If treatment with bisoprolol is considered necessary, the uteroplacental blood flow and the foetal growth should be monitored. In case of harmful effects on pregnancy or the foetus, 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.
Lactation: There are no data on the excretion of bisoprolol excreted in human milk. Therefore, breastfeeding is not recommended during administration of bisoprolol.

The following definitions apply to the frequency terminology used hereafter: Very common (≥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).
Psychiatric disorders: Uncommon: sleep disorders, depression.
Rare: nightmares, hallucinations.
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 disorders.
Cardiac disorders: Very common: bradycardia (in patients with chronic heart failure).
Common: worsening of pre-existing 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).
Vascular disorders: Common: feeling of coldness or numbness in the extremities, hypotension especially in patient with heart failure.
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.
Hepatobiliary disorders: Rare: hepatitis.
Skin and subcutaneous tissue disorders: Rare: hypersensitivity reactions (such as itching, flush, rash).
Very rare: beta-blockers may provoke or worsen psoriasis or induce psoriasis-like rash, alopecia.
Musculoskeletal and connective tissue disorders: Uncommon: muscular weakness and cramps.
Reproductive system and breast disorders: Rare: potency disorder.
General disorders: Common: asthenia (in patients with chronic heart failure), fatigue*.
Uncommon: asthenia (in patients with hypertension or angina pectoris).
Investigations: Rare: increased triglycerides, increased liver enzymes (ALAT, ASAT).
Applies only to hypertension or angina pectoris: * These symptoms especially occur at the beginning of the therapy. They are generally mild and usually disappear within 1-2 weeks.

Combinations not recommended: Applies only to chronic heart failure: Class I antiarrhythmic drugs (e.g. quinidine, disopyramide; lidocaine, phenytoin; flecainide, propafenone): Effect on atrioventricular conduction time may be potentiated and negative inotropic effect increased.
Applies to all indications: Calcium antagonists of the verapamil type and to a lesser extent of the diltiazem type: Negative influence on contractility and atrioventricular conduction. Intravenous administration of verapamil in patients on beta-blocker treatment may lead to profound hypotension and atrioventricular block.
Centrally acting antihypertensive drugs such as clonidine and others (e.g. methyldopa, moxonidine, 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: Applies only to hypertension or angina pectoris: Class I antiarrhythmic drugs (e.g. quinidine, disopyramide; lidocaine, phenytoin; flecainide, propafenone): Effect on atrioventricular conduction time may be potentiated and negative inotropic effect increased.
Applies to all indications: 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 atrioventricular 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 atrioventricular 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 atrioventricular conduction time.
Non-steroidal anti-inflammatory drugs (NSAIDs): NSAIDs may reduce the hypotensive effect of bisoprolol.
Beta-sympathomimetic agents (e.g. isoprenaline, dobutamine): Combination with bisoprolol may reduce the effect of both agents.
Sympathomimetics that activate both beta- and alpha-adrenoceptors (e.g. noradrenaline, adrenaline): Combination with bisoprolol may unmask the alpha-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 beta-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.
Rifampicin: Slight reduction of the half-life of bisoprolol due to the induction of hepatic drug metabolising enzymes. Normally no dosage adjustment is necessary.
Ergotamine derivatives: Exacerbation of peripheral circulatory disturbances.

Store below 30°C. Protect from light and moisture.
Shelf-Life: 3 years from the date of manufacture.

Beta-Blockers

C07AB07 - bisoprolol ; Belongs to the class of selective beta-blocking agents. Used in the treatment of cardiovascular diseases.

P₁S₁S₃