Bisoprolol 5mg Tablets
SUMMARY OF PRODUCT CHARACTERISTICS
1 NAME OF THE MEDICINAL PRODUCT
Bisoprolol 5mg Tablets
2 QUALITATIVE AND QUANTITATIVE COMPOSITION
Each tablet contains 5mg bisoprolol fumarate (2:1)
For a full list of excipients, see section 6.1.
3 PHARMACEUTICAL FORM
Film-coated tablets
Ivory coloured, scored, film-coated tablets.
4 CLINICAL PARTICULARS
4.1 Therapeutic indications
1. Management of hypertension
2. Management of angina pectoris
4.2 Posology and method of administration
Adults: The usual dose is 10 mg once daily with a maximum recommended dose of 20 mg per day. In some patients 5 mg per day may be adequate. In patients with final stage impairment of renal function (creatinine clearance < 20 ml/min) or liver function, the dose should not exceed 10 mg bisoprolol once daily.
Elderly: No dosage adjustment is normally required, but 5 mg 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 and adolescents under 18: There is no paediatric experience with bisoprolol, therefore its use cannot be recommended for children.
Route of administration: Oral
4.3 Contraindications
Bisoprolol is contra-indicated 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 (without a pacemaker)
• sick sinus syndrome
• sinoatrial block
• bradycardia (heart rate less than 60 beats/min prior to start of therapy)
• hypotension (systolic blood pressure < 100mmHg)
• severe bronchial asthma or severe chronic obstructive pulmonary disease
• late stages of peripheral arterial occlusive disease and Raynaud's syndrome
• untreated phaeochromocytoma (see Special Warnings and Precautions)
• metabolic acidosis
• hypersensitivity to bisoprolol or to any of the excipients
4.4 Special warnings and precautions for use
Bisoprolol must be used with caution in:
• bronchospasm (bronchial asthma, obstructive airways diseases)
• concomitant treatment with inhalation anaesthetics (see Interactions section)
• diabetes mellitus with large fluctuations in blood glucose values; symptoms of hypoglycaemia can be masked
• strict fasting
• ongoing desensitisation therapy
• AV block of first degree
• Prinzmetal's angina
• peripheral arterial occlusive disease (intensification of complaints may occur particularly 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 pmol/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 B2-stimulants may have to be increased.
As with other B-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 B-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 a thyrotoxicosis may be masked.
In patients with ischaemic heart disease, treatment should not be withdrawn abruptly.
Combination with calcium antagonists, clonidine or monoamine oxidase inhibitors (except MAO-B inhibitors) is not recommended. See 'Interactions' section.
4.5 Interaction with other medicinal products and other forms of interaction
Combinations not recommended
Calcium antagonists such as verapamil and to a lesser extent diltiazem: Negative influence on contractility, atrio-ventricular conduction and blood pressure. Intravenous administration of verapamil in patients on beta-blocker treatment may lead to profound hypotension and atrioventricular block.
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 B-blockers but also risk of hypertensive crisis.
Combinations to be used with caution
Calcium antagonists such as dihydropyridine derivatives (eg, nifedipine): increased risk of hypotension. In patients with latent cardiac insufficiency, concomitant treatment with beta-blocking agents may lead to cardiac failure.
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 may be potentiated.
Parasympathomimetic drugs (including tacrine): Atrio-ventricular conduction time may be increased.
Other B-blockers, including eye drops, have additive effects.
Insulin and oral antidiabetic drugs: Intensification of blood sugar lowering effect. Blockade of B-adrenoceptors may mask symptoms of hypoglycaemia.
Anaesthetic agents: Attenuation of the reflex tachycardia and increase of the risk of hypotension. Continuation of B-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 effects.
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.
Moxisylyte: Possibly causes severe postural hypertension.
Combinations to be considered
Mefloquine: increased risk of bradycardia
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, P-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 P-adrenoceptor blockers is necessary, p1-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 of 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 the start of treatment and upon change of medication as well as in conjunction with alcohol.
4.8 Undesirable effects Clinical trial data
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 |
|
Dysponea |
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 |
AE = Adverse Events Post-marketing data
The following data result from post-marketing experience with bisoprolol in the indications hypertension and coronary heart disease. There are no post-marketing data available for bisoprolol in the indication stable chronic heart failure.
|
Common (> 1% and <10%) |
Circ: Feeling of coldness or numbness in the extremities CNS: Tiredness*, exhaustion*, dizziness*, headache* GI: Nausea, vomiting, diarrhoea, constipation |
|
Uncommon |
General: Muscular weakness and cramps |
|
(> 0.1% and <1%) |
Circ: Bradycardia, disturbance of AV conduction, 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 |
CNS : Nightmares, hallucinations |
|
(> 0.01% and <0.1%) |
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) | |
|
Very rare |
Eyes: conjunctivitis, visual disturbances |
|
(< 0.01%) |
Skin : P-blockers may provoke or worsen psoriasis or |
|
induce psoriasis-like rash, alopecia | |
|
Circ : chest pain |
* These symptoms especially occur at the beginning of the therapy. They are generally mild and often disappear within 1-2 weeks.
Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme, website www.mhra.gov.uk/yellowcard.
4.9 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 B-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.
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 pharmacological actions and recommendations for other B-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 (initial dose 1 - 10 mg i.v., then 2 - 2.5 mg per hour as continuous infusion) 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
ATC Code: C07AB07
Bisoprolol is a highly B1-selective-adrenoceptor blocking agent, lacking intrinsic stimulation and relevant membrane stabilizing activity. It only shows low affinity to the B2-receptor of the smooth muscles of bronchi and vessels as well as to the B2-receptors concerned with metabolic regulation. Therefore, bisoprolol is generally not to be expected to influence the airway resistance and B2-mediated metabolic effects. Its B1-selectivity extends beyond the therapeutic dose range.
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.
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 strokes during the total study period were 20 in the bisoprolol group and 15 in the placebo group.
5.2 Pharmacokinetic properties
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 hours 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 studied.
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.
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 ^-blockers, 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.
List of excipients
6.1
Tablet core:
Maize starch
Microcrystalline cellulose Crospovidone
Anhydrous calcium hydrogen phosphate Magnesium stearate Colloidal anhydrous silica.
Film-coating:
Hypromellose Titanium dioxide (E171)
Macrogol 6000
Dimeticone 350
Iron oxide yellow (E172).
6.2 Incompatibilities
Not applicable.
6.3 Shelf life
The shelf life for this product is 3 years.
6.4 Special precautions for storage
Do not store above 30°C
6.5 Nature and contents of container
Blister packs of aluminium foil and PVC/PVDC in cartons.
Pack size: 28 tablets.
6.6 Special precautions for disposal
No special requirements.
7 MARKETING AUTHORISATION HOLDER
Medley Pharma Limited Unit 2A,
Olympic Way Sefton Business Park Liverpool L30 1RD UK
8 MARKETING AUTHORISATION NUMBER(S)
PL 43870/0028
9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
24/08/2006
10 DATE OF REVISION OF THE TEXT
20/07/2015