Bisoprolol Fumarate 3.75mg Tablets
SUMMARY OF PRODUCT CHARACTERISTICS
1 NAME OF THE MEDICINAL PRODUCT
Bisoprolol Fumarate 3.75mg Tablets
2. QUALITATIVE AND QUANTITATIVE COMPOSITION
Bisoprolol Fumarate 3.75 mg: Each tablet contains 3.75 mg of bisoprolol fumarate
For the full list of excipients, see section 6.1.
3 PHARMACEUTICAL FORM
Tablet
Bisoprolol Fumarate 3.75 mg Tablet is a white to off white round biconvex tablet
4. CLINICAL PARTICULARS
4.1 Therapeutic indications
Treatment of stable chronic heart failure with reduced systolic left ventricular function in addition to ACE inhibitors, and diuretics, and optionally cardiac glycosides (see section 5.1).
4.2 Posology and method of administration
Standard treatment of CHF consists of an ACE inhibitor (or an angiotensin receptor blocker in case of intolerance to ACE inhibitors), a P-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 up-titration 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 patient’s condition.
Treatment of stable chronic heart failure with bisoprolol is generally a longterm treatment.
Administration
Bisoprolol Fumarate 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 fumarate in patients with chronic heart failure and with impaired liver or renal function. Up-titration of the dose in these populations should therefore be made with additional caution.
Elderly:
No dosage adjustment is required.
Children
Bisoprolol fumarate is not recommended for use in children due to a lack of experience in children.
4.3 Contraindications
Bisoprolol fumarate is contraindicated in chronic heart failure patients with:
- hypersensitivity to the active substance or to any of the excipients listed in section 6.1,
- 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,
- severe forms of peripheral arterial occlusive disease or Raynaud's syndrome,
- untreated phaeochromocytoma (see section 4.4),
- metabolic acidosis.
4.4 Special warnings and precautions for use
Bisoprolol fumarate must be used with caution in:
- 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 P-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.
- AV block of first degree,
- Prinzmetal's angina,
- peripheral arterial occlusive disease (intensification of complaints might happen especially during the start of therapy),
- general anaesthesia.
In patients undergoing general anaesthesia P-blockade reduces the incidence of arrhythmias and myocardial ischemia during induction and intubation, and the post-operative period. It is currently recommended that maintenance P-blockade be continued peri-operatively. The anaesthetist must be aware of P-blockade because of the potential for interactions with other medicinal products, 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 P-blocker therapy before surgery, this should be done gradually and completed about 48 hours before anaesthesia.
There is no therapeutic experience of bisoprolol fumarate treatment of heart failure in patients with the following diseases and conditions:
- insulin dependent diabetes mellitus (type I),
- severely impaired renal function,
- severely impaired liver function,
- restrictive cardiomyopathy,
- congenital heart disease,
- haemodynamically significant organic valvular disease,
- myocardial infarction within 3 months.
Combination of bisoprolol fumarate with calcium antagonists of the verapamil and diltiazem type, with Class I antiarrhythmic medicinal products and with centrally acting antihypertensive medicinal products is generally not recommended (see 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 p2-stimulants may have to be increased.
Patients with psoriasis or with a history of psoriasis should only be given P-blocking agents (e.g. bisoprolol fumarate) after carefully balancing the benefits against the risks.
In patients with phaeochromocytoma bisoprolol must not be administered until after a-receptor blockade.
Under treatment with bisoprolol fumarate the symptoms of a thyrotoxicosis may be masked.
The treatment of stable chronic heart failure with bisoprolol has to be initiated with a special titration phase (see section 4.2).
The initiation and cessation of treatment with bisoprolol fumarate necessitates regular monitoring (see section 4.2).
The cessation of therapy with bisoprolol fumarate must not be done abruptly unless clearly indicated, because this may lead to a transitional worsening of the heart condition (see section 4.2).
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 P-blocker treatment may lead to profound hypotension and atrioventricular block.
Class I antiarrhythmic medicinal products (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 medicinal products such as clonidine and others (e.g. methyldopa, moxonodine, rilmenidine): Concomitant use of centrally acting antihypertensive medicinal products 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 P-blocker 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 medicinal products (e.g. amiodarone): Effect on atrioventricular conduction time may be potentiated.
Topical P-blocking agents (e.g. eye drops for glaucoma treatment) may add to the systemic effects of bisoprolol.
Parasympathomimetic medicinal products: Concomitant use may increase atrio-ventricular conduction time and the risk of bradycardia.
Insulin and oral antidiabetic medicinal products: Intensification of blood sugar lowering effect. Blockade of P-adrenoreceptors may mask symptoms of hypoglycaemia.
Anaesthetic agents: Attenuation of the reflex tachycardia and increase of the risk of hypotension (see 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.
P-sympathomimetic agents (e.g. isoprenaline, dobutamine): Combination with bisoprolol may reduce the effect of both agents.
Sympathomimetics that activate both P- and a-adrenoceptors (e.g. noradrenaline, adrenaline): Combination with bisoprolol may unmask the a-adrenoceptor-mediated vasoconstrictor effects of these agents leading to blood pressure increase and exacerbated intermittent claudication. Such interactions are considered to be more likely with nonselective P-blockers.
Concomitant use with antihypertensive agents as well as with other medicinal products 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 P-blocking agents but also risk for hypertensive crisis.
4.6 Fertility, pregnancy and lactation
Pregnancy:
Bisoprolol fumarate 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 reactions (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 is not recommended 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.
Breast-feeding:
It is not known whether this drug is excreted in human milk. Therefore, breastfeeding is not recommended during administration of bisoprolol fumarate.
4.7 Effects on ability to drive and use machines
Bisoprolol fumarate has negligible influence on the ability to drive and use machines. In a study with coronary heart disease patients bisoprolol fumarate 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 terminologies have been used in order to classify the occurrence of undesirable effects:
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)
Not known (cannot be estimated from the available data)
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.
Common: worsening of heart failure.
Uncommon: AV-conduction disturbances.
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 (itching, flush, rash).
Very rare: P-blocking agents 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, fatigue.
Investigations:
Rare: increased triglycerides, increased liver enzymes (ALAT, ASAT). 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
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 P-blocking agent 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 inter-individual 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 up-titration according to the scheme given in section 4.2.
If overdose occurs, bisoprolol fumarate 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 P-blocking agents, the following general measures should be considered when clinically warranted.
Bradycardia: Atropine should be administered intravenously. 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: Bronchodilator therapy such as isoprenaline, p2-sympathomimetic medicinal products and/or aminophylline should be administered.
Hypoglycaemia: I.V. glucose should be administered.
5. PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: p-blocking agents, selective ATC Code: C07AB07
Bisoprolol fumarate is a highly p1-selective-adrenoceptor blocking agent, lacking intrinsic stimulating and relevant membrane stabilising activity. It only shows low affinity to the p2-receptor of the smooth muscles of bronchi and vessels as well as to the p2-receptors concerned with metabolic regulation. Therefore, bisoprolol fumarate is generally not to be expected to influence the airway resistance and p2-mediated metabolic effects. Its p1-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, P-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.
Bisoprolol fumarate is already used for the treatment of hypertension and angina.
In acute administration in patients with coronary heart disease without chronic heart failure bisoprolol fumarate 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 fumarate is absorbed and has a biological availability of about 90% after oral administration. The half-life in plasma of 10-12 hours gives a 24 hour effect after dosing once daily.
Distribution
The plasma protein binding of bisoprolol fumarate is about 30%. The distribution volume is 3.5 l/kg.
Elimination
Bisoprolol fumarate 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. Total clearance is approximately 15 l/h.
Special populations
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.
Hepatic/renal Insufficiency:
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.
Elderly:
The kinetics of bisoprolol fumarate are linear and independent of age.
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 P-blocking agents, bisoprolol fumarate 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
Microcrystalline Cellulose Colloidal Silicon Dioxide Croscarmellose sodium Sodium Starch glycolate (Type A)
Magnesium Stearate
6.2 Incompatibilities
Not applicable.
Shelf life
6.3
3 years.
6.4 Special precautions for storage
This medicinal product does not require any special storage conditions.
6.5 Nature and contents of container
PVC/PVDC/Aluminium blister: 10, 20, 28, 30, 50, 56, 60, 90 and 100 Not all pack sizes should be marketed).
6.6 Special precautions for disposal
No special requirements.
7 MARKETING AUTHORISATION HOLDER
STADA Arzneimittel AG StadastraBe 2-18, D-61118 Bad Vilbel Germany
8 MARKETING AUTHORISATION NUMBER(S)
PL 11204/0208
9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE
AUTHORISATION
23/02/2010
10
DATE OF REVISION OF THE TEXT
09/03/2014