Bisoprolol 10mg Tablets
SUMMARY OF PRODUCT CHARACTERISTICS
1 NAME OF THE MEDICINAL PRODUCT
BISOPROLOL 10 mg TABLETS
2 QUALITATIVE AND QUANTITATIVE COMPOSITION
Each tablet contains 10mg of Bisoprolol fumarate.
For excipients see 6.1.
3 PHARMACEUTICAL FORM
Film coated tablets.
Description: Round, biconvex, light brown coloured, film-coated tablets with a breakline on one face.
4. CLINICAL PARTICULARS
4.1 Therapeutic Indications
Management of hypertension.
Management of angina pectoris.
4.2 Posology and method of administration
Route of administration Oral
Posology
Adults: The usual dose is 10mg once daily with a maximum recommended dose of 20mg per day. In some patients 5mg per day may be adequate. In patients with final stage impairment of renal (creatinine clearance < 20ml/min) or liver dysfunction, the dose should not exceed 10mg Bisoprolol once daily.
Elderly: No dosage adjustment is normally required but 5mg per day may be adequate in some patients; as for other adults, dosage may have to be reduced in cases of severe renal or hepatic dysfunction.
Children: Not recommended as there is no experience.
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.
4.3 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
• 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 section 4.4)
• metabolic acidosis
• hypersensitivity to bisoprolol or to any of the excipients listed in section 6.1
4.4 Special warnings and precautions for use
The treatment of stable chronic heart failure with bisoprolol has to be initiated with a 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:
- heart failure (the treatment of stable chronic heart failure with bisoprolol has to be
initiated with a special titration phase [for details, see SPC for bisoprolol indicated for the treatment of stable chronic heart failure])
- 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 give the expected therapeutic effect.
- AV block of first degree
- Prinzmetal's angina
- peripheral arterial occlusive disease. Aggravation of symptoms may occur especially when starting therapy
- general anaesthesia
In patients undergoing 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 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 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 and diltiazem type, with Class I antiarrhythmic drugs and with centrally acting antihypertensive drugs is to be used with caution, for details please refer to section 4.5.
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 betablockers
(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 thyrotoxicosis may be masked.
4.5 Interaction with other medicinal products and other forms of interaction
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 beta-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, 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-blockade 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-adrenoceptors may mask symptoms of hypoglycaemia.
Anaesthetic agents: Attenuation of the reflex tachycardia and increase of the risk of hypotension (for further information on general anaesthesia see also section 4.4) 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.
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 alphaadrenoceptormediated 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.
4.6 Fertility, pregnancy and lactation
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 should not be used 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
It is not known whether this drug is excreted in human milk. Therefore, breastfeeding is not recommended during administration of bisoprolol.
4.7 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.
4.8 Undesirable effects
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)
Cardiac disorders:
Very common: bradycardia.
Common: worsening of heart failure. Uncommon: AV-conduction disturbances.
Investigations:
Rare: increased triglycerides, increased liver enzymes (ALAT, ASAT).
Nervous system disorders:
Common: dizziness, headache.
Eye disorders:
Rare: reduced tear flow (to be considered if the patient uses lenses).
Very rare: conjunctivitis.
Ear and labyrinth disorders:
Rare: hearing disorders.
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.
Skin and subcutaneous tissue disorders:
Rare: hypersensitivity reactions (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 and cramps.
Vascular disorders:
Common: feeling of coldness or numbness in the extremities, hypotension. Uncommon: orthostatic hypotension.
General disorders:
Common: asthenia, fatigue.
Hepatobiliary disorders:
Rare: hepatitis.
Reproductive system and breast disorders:
Rare: potency disorders.
Psychiatric disorders:
Uncommon: sleep disorders, depression. Rare: nightmares, hallucinations.
4.9 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 overdosage 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 sensitive. Therefore it is mandatory to initiate treatment of these patients with a gradual uptitration according to the scheme given in section 4.2.
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 pharmacological 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, B2-sympathomimetic drugs and/or aminophylline.
Hypoglycaemia: Administer i.v. glucose.
5 PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Beta blocking agents, selective ATC Code: C07AB07
Bisoprolol is a highly betai-selective-adrenoceptor blocking agent, lacking intrinsic stimulating 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.
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 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 1010 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-blockers, or angiotensin receptor blockers. The trial compared the efficacy and safety of an initial
six-month monotherapy with bisoprolol (target dose 10 mg once daily), to which the
ACE inhibitor enalapril (target dose 10 mg twice daily) was added for further 6 to 24
months, with the opposite sequence of treatment initiation. Each group comprised 505
patients.
The two strategies were blindly compared with regard to the combined primary endpoint of all-cause mortality or hospitalisation, and each of these components
individually. In the intention-to-treat population the primary endpoint occurred in 178
patients (35.2%) in the bisoprolol-first group vs. 186 (36.8%) in the enalapril-first
group, showing bisoprolol-first treatment to be comparably effective (non-inferior) as
enalapril-first treatment. With bisoprolol-first, 65 patients died vs. 73 with enalaprilfirst
(between-group difference p=0.44), and 151 vs. 157 patients were hospitalisised (p=0.66). The number of serious and total adverse events was similar in the two groups. Analysis of data from the first year showed a non-significant trend of the bisoprolol-first strategy to reduce all-cause mortality by 31% compared with the enalapril-first strategy. Mainly the statistically significant risk-reduction of sudden death by 46% (p=0.049) during the first year contributed to the better survival in the bisoprolol-first group.
The two strategies for initiation of CHF treatment showed a similar rate of combined death and hospitalization, and a trend towards prolonged survival, particularly by reduction of sudden death, was observed in the bisoprolol-first group. The results indicate that it is as safe and efficacious to initiate treatment for CHF with bisoprolol as with enalapril.
Bisoprolol is also 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.
5.2 Pharmacokinetic properties
Absorption
Bisoprolol is absorbed and has a biological availability of about 90% after oral administration.
Distribution
The distribution volume is 3.5 l/kg. The plasma protein binding of bisoprolol is about 30%.
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. 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.
Linearity
The kinetics of bisoprolol are linear and independent of age.
Special population
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 studied. In patients with chronic heart failure (NYHA stage III) the plasma levels of bisoprolol are higher and the halflife 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.
5.3 Preclinical safety data
Preclinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity or carcinogenicity. Like other betablockers, bisoprolol caused maternal (decreased food intake and decreased body weight) and embryo/fetal toxicity (increased incidence of resorptions, reduced birth weight of the offspring, retarded physical development) at high doses but was not teratogenic.
6. PHARMACEUTICAL PARTICULARS
6.1 List of Excipients
The tablet also contains: maize starch
microcrystalline cellulose crospovidone
calcium hydrogen phosphate magnesium stearate colloidal silica
The coating contains:
hypromellose
titanium dioxide (E171)
macrogol
dimethicone
iron oxide red (E172)
iron oxide yellow (E172).
Incompatibilities
6.2
None known.
6.3 Shelf-Life
36 months.
6.4 Special Precautions for Storage
Do not store above 30°C. Store in the original package.
6.5 Nature and Contents of Container
Blister packs composed of PVC / PVdC that are covered by an aluminium lidding foil. The packs contain 28 tablets.
6.6 Special precautions for disposal
Not applicable.
7 MARKETING AUTHORISATION HOLDER
Relonchem Limited
27 Old Gloucester Street
London
WC1 3XX
United Kingdom
8 MARKETING AUTHORISATION NUMBER(S)
PL 20395/0026
9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 17/07/2008
10 DATE OF REVISION OF THE TEXT
04/09/2015