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Bisoprolol Orifarm

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1. NAME OF THE MEDICINAL PRODUCT

Bisoprolol Orifarm 1.25 mg Tablets

Bisoprolol Orifarm 2.5 mg Tablets


2. QUALITATIVE AND QUANTITATIVE COMPOSITION


Each tablet contains 1.25 mg of bisoprolol fumarate

Each tablet contains 2.5 mg of bisoprolol fumarate


For the full list of excipients, see section 6.1.


3. PHARMACEUTICAL FORM


Tablet


1.25 mg: Diameter 5 mm, white to off white round biconvex tablet

2.5 mg: Diameter 6,5 mm, white to off white round biconvex tablet with a break line on one side


Bisoprolol Orifarm 2.5 mg only: The tablet can be divided into equal doses.


4. CLINICAL PARTICULARS


4.1 Therapeutic indications


Posology and method of administration


Posology

Bisoprolol OrifarmTablets should be taken in the morning and can be taken with food. They should be swallowed with liquid and should not be chewed.


Treatment with bisoprolol is generally a long-term treatment.


Stable chronic heart failure

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 fumarate requires a titration phase.

The treatment with bisoprolol fumarate 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.

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. It is recommended to start with the lowest possible Dose.


Hypertension and Angina pectoris

Adults

The usual dose is 10 mg once daily with a maximum recommended dose of 20 mg per day. In patients with ischemic heart disease, it is recommended that withdrawal of treatment should be gradually over 1-2 weeks. 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 failure, 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.


Paediatric use

Children under 12 years and adolescents: There is no paediatric experience with bisoprolol, therefore its use cannot be recommended for children.


Method of Administration

Oral use


4.3 Contraindications


4.4 Special warnings and precautions for use


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 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 is thought necessary to withdraw beta-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:



Combination of bisoprolol fumarate with calcium antagonists of the verapamil and diltiazem type, with Class I antiarrhythmic drugs and with centrally acting antihypertensive drugs is generally not recommended, 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.


As with other beta-blockers, bisoprolol fumarate 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 beta-blockers (e.g. bisoprolol fumarate ) after carefully balancing the benefits against the risks.


Under treatment with bisoprolol fumarate the symptoms of a thyrotoxicosis may be masked.


In patients with phaeochromocytoma bisoprolol must not be administered until after alpha-receptor blockade.


The initiation of treatment with bisoprolol fumarate necessitates regular monitoring. For the posology and method of administration please refer to section 4.2.

The cessation of therapy with bisoprolol fumarate should not be done abruptly unless clearly indicated. For further information please refer to 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 and blood pressure. 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, moxonodine, 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-blocker discontinuation, may increase risk of “rebound hypertension”.

Combinations to be used with caution

Calcium antagonists such as dihydropyridine derivatives with negative inotropic effect (eg, nifedipine). Nifedipine decrease myocardial contractility by affecting the amount of calcium. Its concomitant use in patients on beta-blocker treatment may increase the risk of hypotension and reduction of the ventricular pump function with possible development of heart failure in patients with latent cardiac insufficiency. The negative inotropism of nifedipine may precipitate or exacerbate heart failure.


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 atrial 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: Intensification of blood sugar lowering effect. Blockade of beta-adrenoreceptors 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.


Prostaglandin synthetase inhibiting drugs: Decreased hypotensive effect.


Ergotamine derivatives: Exacerbation of peripheral circulatory disturbances.


Non-steroidal anti-inflammatory drugs (NSAIDs): NSAIDs may reduce the hypotensive effect of bisoprolol.


β-Sympathomimetic agents (e.g. isoprenaline, dobutamine): Combination with bisoprolol may reduce the effect of both agents.


Sympathomimetics that activate both β- and α-adrenoceptors (e.g. noradrenaline, adrenaline): Combination with bisoprolol may unmask the α-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 β-blockers. Higher doses of ephedrine may be necessary for treatment of allergic reactions.


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.


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.


Moxisylate: Possibly causes severe postural hypotension.


Combinations to be considered

Mefloquine: increased risk of bradycardia


Monoamineoxidase inhibitors (except MAO-B inhibitors): Enhanced hypotensive effect of -blockers but also risk of hypertensive crisis.


4.6 Pregnancy and lactation

Pregnancy:

Bisoprolol fumarate has pharmacological effects that may cause harmful effects on pregnancy and/or the fetus/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 fetus 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 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 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 fumarate.


4.7 Effects on 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 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.

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 impairment.


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: beta-blockers may provoke or worsen psoriasis or induce psoriasis-

like rash, alopecia.


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.”


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 national

reporting system [to be completed nationally].


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 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 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, beta2-sympathomimetic drugs and/or aminophylline.


Hypoglycaemia: Administer i.v. glucose.


PHARMACOLOGICAL PROPERTIES


Pharmacodynamic properties

Pharmacotherapeutic group: Beta blocking agents, selective


ATC Code: C07AB07


Bisoprolol fumarate is a highly beta1-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 fumarate 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. 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 is already used for the treatment of hypertension and angina. As with other 1-blocking agents, the mode of action in hypertension is not clear but it is known that bisoprolol markedly depresses plasma rennin levels.


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. Hence bisoprolol is effective in eliminating or reducing the symptoms.


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 beta-blockers, 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

Silica, Colloidal Anhydrous

Croscarmellose sodium

Sodium Starch glycolate (Type A)

Magnesium Stearate


6.2 Incompatibilities

Not applicable.


6.3 Shelf life

3 years.


Special precautions for storage

This medicinal product does not require any special storage conditions.


6.5 Nature and contents of container

Blister of white PVC/PVDC/Aluminium.

1.25 mg: 7, 10, 20, 21, 28, 30, 98, 100

2.5 mg: 7, 10, 28, 30, 98, 100

Not all pack sizes may be marketed.


6.6 Special precautions for disposal and other handling

No special requirements.

Any unused product or waste material should be disposed of in accordance with local requirements.


7. MARKETING AUTHORISATION HOLDER

Orifarm Generics A/S

Energivej 15, 5260 Odense S

Denmark


8. MARKETING AUTHORISATION NUMBER

[To be completed nationally]


9. DATE OF FIRST AUTHORISATION/RENEWAL OF AUTHORISATION

2010-04-29/2015/04-29

[To be completed nationally]


DATE OF REVISION OF THE TEXT


2015-05-06

[To be completed nationally]