Bisoprolol hemifumarate
Selective β1-adrenoceptor blocker
Compositions
| Concor® 2.5 | : | Each film-coated tablet contains Bisoprolol Hemifumarate 2.5 mg |
| Concor® 5 | : | Each film-coated tablet contains Bisoprolol Hemifumarate 5 mg |
Mode of action
Bisoprolol is a highly β1-selective-adrenoceptor blocking agent, lacking intrinsic stimulating and relevant membrane stabilizing activity. It only shows low affinity to the β2-receptor of the smooth muscles of bronchi and vessels as well as to the (β2-receptors concerned with metabolic regulation. Therefore, bisoprolol is generally not to be expected to influence the airway resistance and β2-mediated metabolic effects. Its β1,-selectivity extends beyond the therapeutic dose range.
In 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 admissions 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 stroke during the total study period were 20 in the bisoprolol group and 15 in the placebo group.
Bisoprolol is already 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.
Indications
Treatment of stable chronic moderate to severe heart failure with reduced systolic ventricular function (ejection fraction ≤ 35%, based on echocardiography) in addition to ACE inhibitors, and diuretics, and optionally cardiac glycosides.
Bisoprolol is already used for the treatment of hypertension and angina (Concor*5)
Pharmacokinetics
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-life in plasma of 10-12 hours gives a 24 hour effect after dosing once daily.
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 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 studies.
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 ± 2 ng/ml at a daily dose of 10 mg and the shelf-life is 17 ± 5 hours.
Dosage and administrations
1 tablet (Concor 5) daily in the morning before or after breakfast. In milder from of diseases Concor 5 daily may be sufficient, most patients will be controlled by 10 mg daily, only in few cases a dosage of 20 mg daily is required. For patients with final stages of renal impairment or severe disturbances in liver function, the maximum dosage is 10 mg daily.
The patients should have stable chronic heart failure without acute failure during the past six weeks and a mainly unchanged basic therapy during the past two weeks. They should be treated at optimal dose with an optimal dose with an ACE inhibitor (or other vasodilator in case of intolerance to ACE inhibitors) and a diuretic, and optionally cardiac glycosides, prior to the administration of bisoprolol.
It is recommended that the treating physician should be experienced in the management of chronic heart failure.
Warning: The treatment of stable chronic heart failure with bisoprolol has to be initiated with a titration phase as given in the description below
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 fora 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.
After initiation of treatment with 1.25 mg, the patients should be observed over a period of approximately 4 hours (especially as regards blood pressure, heart rate, conduction disturbances, signs of worsening of heart failure).
No abrupt withdrawal of Concor.
The maximum recommended dose is 10 mg once daily.
Occurrence of adverse events may prevent all patients being treated with the maximum recommended dose. If necessary, the dose reached can also be decreased step by step. The treatment may be interrupted if necessary and reintroduced as appropriate. During the titration phase, in case of worsening of the heart failure or intolerance, it is recommended first to reduce the dose of bisoprolol, or to stop immediately if necessary (in case of severe hypotension, worsening of heart failure with acute pulmonary oedema, cardiogenic shock, symptomatic bradycardia or AV block).
Treatment of stable chronic heart failure with bisoprolol is generally a long-term treatment.
The treatment with bisoprolol is not recommended to be stopped abruptly since this might lead to a transitory worsening of heart failure. If discontinuation is necessary, the dose should be gradually decreased divided into halves weekly.
Bisoprolol tablets should be taken in the morning and can be taken with food. They should be swallowed with liquid and should not be chewed.
Renal or liver insufficiency
There is no information regarding pharmacokinetics of bisoprolol in patients with chronic heart failure and with impaired fiver or renal function. Uptitration of the dose m these populations should therefore be made with additional caution.
Elderly
No dosage adjustment is required.
Children
There is no pediatric experience with bisoprolol, therefore its use can not be recommended for children.
Precautions
Bisoprolol must be used with caution in:
- Bronchospasm (bronchial asthma, obstructive airways diseases)
- Concomitant treatment with inhalation anesthetics
- Diabetes mellitus with large fluctuations in blood glucose values; symptoms of hypoglycaemia can be masked
- Strict fasting
- Ongoing desensitization therapy
- AV block of first degree
- Prinzmetal's angina
- Peripheral arterial occlusive disease (intensification of complaints might happen especially during the start of therapy)
There is no therapeutic experience of bisoprolol treatment in heart failure in patients with the following diseases and conditions:
- NYHA class II heart failure
- Insulin dependent diabetes mellitus (type I)
- Impaired renal function (serum creatinine ≥ 300 micromol/l)
- Impaired liver function
- Patients older than 80 years
- Restrictive cardiomyopathy
- Congenital heart disease
- Haemodynamically significant organic valvular disease
- Myocardial infarction within 3 months
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 β2-stimulants may have to be increased.
As with other β-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.
Patients with psoriasis or with a history of psoriasis should only be given β-blockers (e.g. bisoprolol) after carefully balancing the benefits against the risks.
In patients with phaeochromocytoma bisoprolol must not be administered until after α-receptor blockade.
Under treatment with bisoprolol the symptoms of a thyreotoxicosis may be masked.
The initiation of treatment with bisoprolol necessitates regular monitoring. For the posology and method of administration please refer to dosage and administration.
The cessation of therapy with bisoprolol should not be done abruptly unless clearly indicated.
Use during pregnancy and lactation
Pregnancy: Bisoprolol has pharmacological effects that may cause harmful effects on pregnancy and/or the fetus/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 fetus and newborn infant. If treatment with β-adrenoceptor blockers is necessary β1-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 arc generally to be expected within the first 3 days.
Lactation: It is not known whether this drug is excreted in human milk. Therefore, breastfeeding is not recommended during administration of bisoprolol.
Effects on ability to drive and use machines
In 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.
Side effects
The table below shows incidences of adverse events reported from both the placebo and the bisoprolol cohort of the CIBIS II trial. Regardless of causal relationship all adverse events are included. Each patient is only counted once for each adverse event occurring in at least 5 of the study population.
Preferred Term WHO
|
Placebo
(n-1321)
|
Bisoprolol
(n-1328)
| ||
Pat. With AE
|
% Pat. With AE
|
Pat With AE
|
% Pat. With AE
| |
Cardiac failure
|
301
|
22.8
|
244
| 18.4 |
Dyspnoea
|
224
|
17.0
|
183
| 13.8 |
Dizziness
|
126
|
9.5
|
177
| 13.3 |
Cardiomyopathy
|
132
|
10.0
|
141
| 10.6 |
Bradycardia
|
60
|
4.5
|
202
| 15.2 |
Hypotension
|
96
|
7.3
|
152
| 11.4 |
Tachycardia
|
144
|
10.9
|
79
| 5.9 |
Fatigue
|
94
|
7.1
|
123
| 9.3 |
Viral infection
|
75
|
5.7
|
86
| 6.5 |
| Pneumonia | 69 | 5.2 | 65 | 4.9 |
Post-marketing data
There are no post-marketing data available for bisoprolol in the indication stable chronic heart failure. The following data result from post-marketing experience with bisoprolol in the indications hypertension and coronary heart disease.
| Common (≥ 1% and ‹ 10%) | Circ: | Feeling of coldness or numbness in the extremities |
| CNS: | Tiredness*, exhaustion*, dizziness*, headache* | |
| GI: | Nausea, vomiting, diarrhea, constipation | |
| Uncommon (≥ 0.1% and ‹ 10%) | General: | Muscular weakness and cramps |
| Circ: | Bradycardia, AV-stimulus disturbances, worsening of heart failure, orthostatic hypotension | |
| CNS: | Sleep disturbances, depression | |
| Airways: | Bronchospasm in patients with bronchial asthma or a history of obstructive airways disease. | |
| Rare (≥ 0.01% and ‹ 0.1%) | CNS | Nightmares, hallucinations |
| Skin: | Hypersensitivity reactions (itching, flush, rash) | |
| Liver: | Increased liver enzymes (ALAT, ASAT), hepatitis | |
| Metabolism: | Increased triglycerides | |
| Urogenital: | Potency disorders | |
| Ear-nose-throat: | Hearing impairment, allergic rhinitis | |
| Eyes: | Reduced tear flow (to be considered if the patient uses lenses) | |
| Single cases (‹ 0.01%) | Eyes: | Conjunctivitis |
| Skin: | b-blockers may provoke or worsen psoriasis or induce psoriasis-like rash, alopeci |
Overdose
There is no experience yet regarding overdosage of bisoprolol in patients with stable chronic heart failure. The most common signs expected with overdosage of a β-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 dosage and administration.
In general, 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 β-blockers, the following general measures should be considered when clinically warranted.
Bradycardia: Administer intravenous atropine. If 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, β2-sympathomimetic drugs and/or aminophylline.
Hypoglycaemia: administer i.v. glucose.
Contraindications
Bisoprolol is contra-indicated in chronic heart failure patients with:
- Acute heart failure or during episodes of heart failure decompensation requiring i.v. inotropic therapy
- Cardiogenic shock
- AV block of second or third degree (without a pacemaker)
- Sick sinus syndrome
- Sinoatrial block
- Bradycardia with less than 60 beats/min before the start of therapy
- Hypotension (systolic blood pressure less than 100 mm Hg)
- Severe bronchial asthma or severe chronic obstructive pulmonary disease
- Latest ages of peripheral arterial occlusive disease and Raynaud's syndrome
- Untreated phaeochromocytoma
- Metabolic acidosis
- Hypersensitivity to bisoprolol
Interactions
Combinations not recommended
Calcium antagonists: Negative influence on contractility, atrio-ventricular conduction and blood pressure.
Clonidine: Increased risk of "rebound hypertension" as well as exaggerated decrease in heart rate and cardiac conduction.
Monoamineoxidase inhibitors (except MAO-B inhibitors): Enhanced hypotensive effect of β-blockers but also risk of hypertensive crisis.
Combinations to be used with caution
Class-I antiarrhythmic drugs (e.g. disopyramide, quinidine): Effect on atrial conduction time may be;
potentiated and negative inotropic effect may be increased.
Class-III antiarrhythmic drugs (e.g. amiodarone): Effect on atrial conduction time maybe potentiated.
Parasympathomimetic drugs (including tacrine): Atrio-ventricular conduction time may be increased.
Other &beta-blockers, including eye drops, have additive effects.
Insulin and oral antidiabetic drugs: Intensification of blood sugar lowering effect. Blockade of β-adrenoreceptors may mask symptoms of hypoglycaemia.
Anaesthetic agents: Attenuation of the reflex tachycardia and increase of the risk of hypotension.
Continuation of β-blockade reduces the risk of arrhythmia during induction and intubation. The
anaesthesiologist should be informed when the patient is receiving bisoprolol.
Digitalis glycosides: Reduction of heart rate, increase of atrio-ventricular conduction time. Prostaglandin synthetase inhibiting drugs: Decreased hypotensive effect.
Ergotamine derivatives: Exacerbation of peripheral circulatory disturbances.
Sympathomimetic agents: Combination with bisoprolol may reduce the effect of both agents. Higher doses of epinephrine may be necessary for treatment of allergic reactions.
Tricyclic antidepressants, barbiturates, phenothiazines as well as other antihypertensive agents: Increased blood pressure lowering effect.
Rifampicin: Slight reduction of the half-life of bisoprolol possible due to the induction of hepatic drug-metabolising enzymes. Normally no dosage adjustment is necessary.
Presentation
| Concor 2.5 | : | Box of 3 x 10 film-coated tablets in blister |
| Concor 5 | : | Box of 10 x 10 film-coated tablets in blister Bottle of 75 film-coated tablets (ASKES) |
Storage
Store in a dry place, below 30°C
"On medical prescription only"
"Harus dengan resep dokter"
Manufactured by
PT.Merck Tbk., Jakarta
under licence from
Merck KGaA, Germany
Reg. Nos.
| Concor 2.5 | : | DKL0215803817B1 |
| Concor 5 | : | DKL9115803817A1 (in blister) DKX9615803817A2 (ASKES) |
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