Bistapro

Film-coated tablets: 5 mg: Yellow coloured, round, scored film-coated tablets, divisible in four parts, with a one-sided embossment "BIS 5".
Each 5 mg film-coated tablet contains 5 mg of Bisoprolol fumarate.
10 mg: Apricot coloured, round, snap tab film-coated tablets, divisible in four parts, with a one-sided embossment "BIS 10".
Each 10 mg film-coated tablet contains 10 mg of Bisoprolol fumarate.
These tablets can be divided into equal halves.

Pharmacotherapeutic group: Beta blocking agents, selective. ATC code: C07AB07.
Pharmacology: Pharmacodynamics: Mechanism of action: Bisoprolol is a highly beta1-selective adrenoreceptor blocking agent, lacking intrinsic sympathomimetic 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.
Bisoprolol is used for the treatment of hypertension, angina pectoris and heart failure. As with other beta-1-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.
The indication heart failure was investigated in the CIBIS II trial. In total 2647 patients were included, 83% (N = 2,202) 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 1,010 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-blocking agents, 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.
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: Absorption and distribution: Bisoprolol is absorbed and has a biological availability of about 90% after oral administration. 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.
Biotransformation and elimination: 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 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 have not been studied.
Linearity/non-linearity: The kinetics of bisoprolol are linear and independent of age.
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.
Toxicology: Preclinical Safety Data: Preclinical data reveals no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity or carcinogenicity. Like other beta-blocking agents, bisoprolol caused maternal (decreased food intake and decreased body weight) and embryo/foetal toxicity (increased incidence of resorptions, reduced birth weight of the offspring, retarded physical development) at high doses, but was not teratogenic.

The safety information presented in this document refers to the following indications: Treatment of hypertension.
Treatment of coronary heart disease (angina pectoris).
Treatment of stable chronic heart failure with reduced systolic left ventricular function in addition to ACE inhibitors and diuretics, and optionally cardiac glycosides (for additional information, see Pharmacology: Pharmacodynamics under Actions).

Treatment of hypertension or angina pectoris: Adults: For both indications the dosage is 5 mg bisoprolol fumarate once daily. If necessary, the dose may be increased to 10 mg bisoprolol fumarate once daily. The maximum recommended dose is 20 mg once daily.
In all cases the dose is adjusted individually, in particular according to the pulse rate and therapeutic success.
Treatment of stable chronic heart failure: 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.
Titration phase: The treatment of stable chronic heart failure with bisoprolol requires a titration phase.
The recommended starting dose is 1.25 mg bisoprolol fumarate once daily. Depending on individual tolerance the dose is increased to 2.5 mg, 3.75 mg, 5 mg, 7.5 mg, and 10 mg once daily in intervals of two weeks or longer.
If a dose increase is not well tolerated treatment may be maintained at a lower dose.
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.
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.
Duration of therapy for all indications: Treatment with bisoprolol is generally a long-term therapy.
The treatment with bisoprolol must not be stopped abruptly since this might lead to a transitory worsening of condition. Especially in patients with ischaemic heart disease, treatment must not be discontinued suddenly. Gradual reduction of the daily dose is recommended.
Special populations: Renal or hepatic impairment: Applies only to hypertension or angina pectoris: In patients with hepatic or renal impairment of mild to moderate severity, no dose adjustment is normally required. In patients with severe renal impairment (creatinine clearance <20 mL/min) and in patients with severe hepatic impairment it is recommended that a daily dose of 10 mg bisoprolol is not exceeded. Experience with the use of bisoprolol in renal dialysis patients is limited; however, there is no evidence that the dose regimen needs to be altered.
Applies only to CHF: There is no information regarding pharmacokinetics of bisoprolol in patients with chronic heart failure and with impaired liver or renal function. Titration of the dose in these populations should therefore, be made with particular 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: Bisoprolol should be taken in the morning with or without food. The tablets should be swallowed with some liquid and should not be chewed.

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 overdose of a beta-blocker are bradycardia, hypotension, bronchospasm, acute cardiac insufficiency and hypoglycaemia.
To date a few cases of overdose (maximum: 2,000 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 Dosage & Administration.
Management: In general, if overdose occurs, discontinuation of bisoprolol treatment and supportive and symptomatic treatment is recommended.
Limited data suggest that bisoprolol is hardly dialysable.
Based on the expected pharmacologic actions and recommendations for other beta-blockers, the following general measures may 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 temporary pacing.
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.

Bisoprolol is contraindicated in 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, sick sinus syndrome, sinoatrial block, symptomatic bradycardia, symptomatic hypotension, severe bronchial asthma or severe chronic obstructive pulmonary disease, severe forms of peripheral arterial occlusive disease or severe forms of Raynaud's syndrome, untreated phaeochromocytoma (see Precautions), metabolic acidosis.
Bisoprolol is contraindicated in patients with hypersensitivity to bisoprolol or to any of the excipients.

Applies only to CHF: The treatment of stable chronic heart failure with bisoprolol has to be initiated with a special titration phase.
Applies to all indications: 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.
Applies only to CHF: The initiation and cessation of treatment of stable chronic heart failure with bisoprolol necessitates regular monitoring.
There is no therapeutic experience of bisoprolol treatment in 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 showing 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 may 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.
Patients with psoriasis or with a history of psoriasis should only be given beta-blockers (e.g. bisoprolol) after a careful balancing of benefits against risks.
The symptoms of thyrotoxicosis may be masked under treatment with bisoprolol.
In patients with phaeochromocytoma bisoprolol must not be administered until after alpha-receptor blockade.
In patients undergoing general anaesthesia, the anaesthetist must be aware of beta-blockade. If it is thought necessary to withdraw beta-blocker therapy before surgery, this should be done gradually and completed about 48 hours before anaesthesia.
In bronchial asthma or other chronic obstructive pulmonary diseases, which may cause symptoms, concomitant bronchodilating therapy is recommended. Occasionally an increase of the airway resistance may occur in patients with asthma, therefore the dose of beta2-stimulants may have to be increased.
Athletes must be aware that this medicine may cause a positive reaction to 'anti-doping' tests.
Effects on ability to drive and use machines: Depending on the individual patients' response to treatment the ability to drive a vehicle or to use machines may be impaired. This needs to be considered particularly at start of treatment, upon change of medication, or in conjunction with alcohol.

Pregnancy: Bisoprolol has pharmacological effects that may cause harmful effects on pregnancy and/or the foetus/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 foetus and newborn infant. If treatment with beta-adrenoceptor blockers is necessary, beta1-selective adrenoceptor blockers are preferable.
Bisoprolol is not recommended during pregnancy unless clearly necessary. If treatment is considered necessary, monitoring of the uteroplacental blood flow and foetal growth is recommended. In case of harmful effects on pregnancy or the foetus consideration of alternative treatment is recommended. The newborn infant must be closely monitored. Symptoms of hypoglycaemia and bradycardia are generally to be expected within the first 3 days.
Lactation: Breastfeeding is not recommended during administration of bisoprolol.

Very common (≥ 1/10), common (≥ 1/100 to <1/10), uncommon (≥ 1/1,000 to <1/100), rare (≥ 1/10,000 to <1/1,000), very rare (<1/10,000).
Psychiatric disorders: Uncommon: Depression, sleep disorders.
Rare: Nightmares, hallucinations.
Nervous system disorders: Common: Dizziness*, headache*.
Rare: Syncope.
Eye disorders: Rare: Reduced tear flow.
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.
Uncommon: Orthostatic hypotension.
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: Alopecia. Beta-blockers may provoke or worsen psoriasis or induce psoriasis-like rash.
Musculoskeletal and connective tissue disorders: Uncommon: Muscular weakness, muscle cramps.
Reproductive system and breast disorders: Rare: Potency disorders.
General disorders and administration site conditions: 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 CHF: Class-I antiarrhythmic agents: Effect on atrio-ventricular 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 atrio-ventricular conduction. Intravenous administration of verapamil in patients on beta-blocker treatment may lead to profound hypotension and atrioventricular block.
Centrally acting antihypertensive agents: Concomitant use of centrally acting antihypertensive agents may lead to reduction of heart rate and cardiac output and to vasodilatation. Abrupt withdrawal may increase risk of 'rebound hypertension'.
Combinations to be used with caution: Applies only to hypertension or angina pectoris: Class-I antiarrhythmic agents: Effect on atrio-ventricular conduction time may be potentiated and negative inotropic effect increased.
Applies to all indications: Calcium antagonists of the dihydropyridine type: 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 agents: Effect on atrio-ventricular conduction time may be potentiated.
Parasympathomimetic agents: Concomitant use may increase atrio-ventricular conduction time and the risk of bradycardia.
Topical beta-blockers (e.g. eye drops for glaucoma treatment): May add to the systemic effects of bisoprolol.
Insulin and oral antidiabetic agents: 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: Increase of atrio-ventricular conduction time, reduction in heart rate.
Non-steroidal anti-inflammatory drugs (NSAIDs): NSAIDs may reduce the hypotensive effect of bisoprolol.
Beta-sympathomimetics: Combination with bisoprolol may reduce the effect of both agents.
Sympathomimetics that activate both beta- and alpha-adrenoceptors: Combination with bisoprolol may lead to blood pressure increase.
Concomitant use with antihypertensive agents as well as with other medicinal products with blood pressure lowering potential 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.

Incompatibilities: Not applicable.

Store at temperatures not exceeding 30°C.

Beta-Blockers

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

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