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Therapeutic Category
- CARDIOVASCULAR DRUGS
- BETA-ADRENOCEPTOR BLOCKING AGENTS
- Pharmaceutical Form : Film coated tablets
- Composition : Bisoprolol Fumarate 10 mg
- Active Substance : Bisoprolol Fumarate
PROPERTIES:
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 beta 2-receptor of the smooth muscles of bronchi and vessels as well as to the beta 2-receptors concerned with metabolic regulation. Therefore, bisoprolol is generally not to be expected to influence the airway resistance and beta 2-mediated metabolic effects. Its beta1-selectivity extends beyond the therapeutic dose range.
PHARMACOLOGICAL CLASSIFICATIONS:
Cardiovascular drugs- beta adrenoceptor blocking agents
PHARMACOKINETIC PROPERTIES:
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 metabolized 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.
INDICATIONS:
-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
CONTRAINDICATIONS:
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 bisoprolol or to any of the excipients.
WARNINGS:
Special warnings:
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.
SIDE EFFECTS:
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, diarrhea, 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 disorders
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.
PRECAUTIONS:
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)
In bronchial asthma or other chronic obstructive lung diseases, which may cause symptoms, broncho dilating therapy is recommended to be given concomitantly. Occasionally an increase of the airway resistance may occur in patients with asthma; therefore the dose of beta 2-stimulants may have to be increased.
– Diabetes mellitus with large fluctuations in blood glucose values; symptoms of hypoglycaemia (e.g. Tachycardia, palpitations or sweating) can be masked.
– Strict fasting
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.
– First degree AV block – Prinzmetal’s angina
– Peripheral arterial occlusive disease – General anaesthesia
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 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 anesthesia.
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.
DRUG INTERACTIONS:
Combinations not recommended
Applies only to chronic heart failure:
- Class I antiarrhythmic drugs (e.g. Quinidine, disopyramide; lidocaine, phenytoin; flecainide, propafenone (
Applies to all indications:
- Calcium antagonists of the verapamil type and to a lesser extent of the diltiazem type
- Centrally acting antihypertensive drugs such as clonidine and others (e.g. Methyldopa, moxonodine, rilmenidine (
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 (
Applies to all indications:
- Calcium antagonists of the dihydropyridine type such as felodipine and amlodipine
- Class-III antiarrhythmic drugs (e.g. amiodarone.(
- Topical beta-blockers (e.g. Eye drops for glaucoma treatment)
- Parasympathomimetic drugs • Insulin and oral antidiabetic drugs
- Anaesthetic agents. • Digitalis glycosides.
- Non-steroidal anti-inflammatory drugs (NSAIDs).
- β-Sympathomimetic agents (e.g. Isoprenaline, dobutamine (
- Sympathomimetic that activate both β- and α -adrenoceptors (e.g. Noradrenaline, adrenaline. (
- 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
- Monoamine oxidase inhibitors (except MAO-B inhibitors(
- Rifampicin • Ergotamine derivatives
Pregnancy: Bisoprolol is not recommended during pregnancy unless clearly necessary.
Lactation: There are no data on the excretion of bisoprolol in human milk. Therefore, breastfeeding is not recommended during administration of bisoprolol.
DOSES\INDICATIONS
Administration: For oral use.
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.
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.
Elderly: No dosage adjustment is normally required. It is recommended to start with the lowest possible dose.
Children: There is no experience with bisoprolol in children, therefore its use cannot be recommended for children.
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 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.
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 up titration 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 normally required.
Children: There is no pediatric experience with bisoprolol, therefore its use cannot be recommended for children.
OVERDOSAGE:
The most common signs expected with overdose of a beta-blocker are bradycardia, hypotension, bronchospasm, acute cardiac insufficiency and hypoglycemia.
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.
In general, if overdose occurs, discontinuation of bisoprolol treatment and supportive and symptomatic treatment is recommended.
STORAGE CONDITIONS
Don’t Store above 30°C.
PACKAGING:
CONO – FACT 2.5: Pack contains 20 film coated tablets.
CONO – FACT 5: Pack contains 20 film coated tablets.
CONO – FACT 10: Pack contains 20 film coated tablets.