Bisoprolol Fumarate 5 mg Film-coated Tablets

The management of hypertension.

The management of angina pectoris.

Treatment of stable chronic heart failure with reduced systolic left ventricular function in addition to ACE inhibitors, and diuretics, and optionally cardiac glycosides (for additional information see section 5.1).

Posology

Hypertension/Angina pectoris

Adults

The usual adult dose is 10mg once daily with a maximum recommended dose of 20mg per day. In some patients, 5mg per day may be adequate.

Renal or hepatic impairment:

In patients with final stage impairment of renal function (creatinine clearance less than 20ml/min) or in patients with severe hepatic dysfunction, the dosage should not exceed 10mg bisoprolol once daily.

Experience of use of bisoprolol in renal dialysis patients is limited, however, it is thought that bisoprolol fumarate cannot be dialysed.

Special populations

Elderly

No dosage adjustment is normally required but 5mg per day may be adequate in some elderly patients; as for other adults, the dosage may have to be reduced in cases of severe renal or hepatic dysfunction.

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 requires a titration phase. 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 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 patient's condition.

Treatment of stable chronic heart failure with bisoprolol is generally a long- term treatment.

Patients with hepatic or renal impairment

There is no information regarding pharmacokinetics of bisoprolol in patients with chronic heart failure and with impaired hepatic or renal function. Uptitration of the dose in these populations should therefore be made with additional caution.

Older people

No dosage adjustment is required.

Paediatric population

There is no paediatric experience with bisoprolol, therefore its use cannot be recommended for children.

Method of administration

For oral administration.

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

Bisoprolol is contraindicated in patients with:

☐ acute heart failure or during episodes of heart failure decompensation requiring i.v. inotropic therapy

☐ cardiogenic shock.

☐ sinoatrial block.

☐ second or third degree AV block (without pacemaker).

☐ symptomatic bradycardia (heart rate less than 60 beats/min prior to start of therapy).

☐ severe bronchial asthma or severe chronic obstructive pulmonary disease.

☐ sick sinus syndrome.

☐ symptomatic hypotension (systolic blood pressure <100mmHg).

☐ severe forms of peripheral arterial occlusive disease and Raynaud's syndrome.

☐ untreated phaeochromocytoma (see section 4.4).

☐ metabolic acidosis.

☐ hypersensitivity to the active substance(s) or to any of the excipients listed in section 6.1

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:

• bronchospasm (bronchial asthma, obstructive airways diseases).

• diabetes mellitus with large fluctuations in blood glucose values; symptoms of hypoglycaemia can be masked. Beta-blockers could further increase the risk of severe hypoglycaemia when used concurrently with sulfonylureas. Diabetic patients should be advised to carefully monitor blood glucose levels (see Section 4.5).

• 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 yield the expected therapeutic effect.

• first degree AV block.

• prinzmetal's angina: Cases of coronary vasospasm have been observed. Despite its high beta1-selectivity, angina attacks cannot be completely excluded when bisoprolol is administered to patients with 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 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 of beta- blockade be continued perioperatively. The anaesthesist 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.

Combination of bisoprolol with calcium antagonists of the verapamil or 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.

Although cardioselective (beta1) beta-blockers may have less effect on lung function than non-selective beta-blockers, as with all beta-blockers, these should be avoided in patients with obstructive airways diseases, unless there are compelling clinical reasons for their use. Where such reasons exist, bisoprolol may be used with caution. In patients with obstructive airways diseases, the treatment with bisoprolol should be started at the lowest possible dose and patients should be carefully monitored for new symptoms (e.g. dyspnea, exercise intolerance, cough). 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 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) 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.

Combinations not recommended

Calcium antagonists: Bisoprolol should be used with care with myocardial depressants or inhibitors of AV conduction such as verapamil and diltiazem, because of their negative inotropic effects on contractility and atrioventricular conduction.

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 further decrease 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 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 antidysrhythmic agents, such as amiodarone, may potentiate the effect of beta- blockers on atrial conduction time.

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 anti-diabetic drugs: The use of beta-blockers may intensify the blood sugar lowering effects of these drugs. Beta-blockers may also mask signs of hypoglycaemia. The concomitant use of beta-blockers with sulfonylureas could increase the risk of severe hypoglycaemia (see Section 4.4).

Anaesthetic drugs: 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 alpha-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 beta-blockers.

Concomitant use with antihypertensive agents as well as with other drugs with blood pressure, lowering potential (e.g. tricyclic anti-depressants, 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.

Rifampicin can reduce the elimination half-life of bisoprolol, although an increase in the dose of bisoprolol is, generally, not necessary.

Pregnancy

Bisoprolol 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 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 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 expected within the first 3 days.

Breast-feeding

It is not known whether this drug is excreted in human milk. Therefore, breast-feeding is not recommended during administration of bisoprolol.

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.

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)

Frequency not known (cannot be estimated from available data)

Cardiac disorders:

Very common: bradycardia in patients with chronic heart failure.

Common: worsening of heart failure in patients with chronic heart failure.

Uncommon: AV-conduction disturbances, worsening of pre-existing heart failure (in patients with hypertension or angina pectoris), bradycardia (in patients with hypertension or angina pectoris).

Investigations:

Rare: increased triglycerides, increased liver enzymes (ALAT, ASAT).

Vascular disorders:

Common: feeling of coldness or numbness in the extremities, hypotension.

Uncommon: Orthostatic hypotension.

Metabolism and nutrition disorders:

Rare: Increased triglycerides.

Beta-blockers may mask the symptoms of thyrotoxicosis or hypoglycaemia.

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.

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 (pruritus, flush, rash and angioedema)

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.

Reproductive system and breast disorders:

Rare: erectile dysfunction.

General disorders:

Common: fatigue*, asthenia (patients with chronic heart failure)

Uncommon: asthenia (in patients with hypertension or angina pectoris)

*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 or search for MHRA Yellow Card in the Google Play or Apple App Store.

Symptoms

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 ß-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 section 4.2.

Management

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 ß-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, ß2- sympathomimetic drugs and/or aminophylline.

Hypoglycaemia: Administer i.v. glucose.

Pharmacotherapeutic group: Beta blocking agents, selective

ATC code: C07A B07

Mechanism of action

Bisoprolol is a highly selective β1-adrenoreceptor blocking agent devoid of 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 patients with hypertension, the mode of action of bisoprolol is not quite clear but it is known to have a negative inotropic effect, to reduce cardiac output and to depress plasma renin activity.

In patients with angina, the blockade of 1-receptors reduces heart action and thus reduces oxygen demand. Hence bisoprolol is effective in eliminating or reducing the symptoms of angina pectoris.

Clinical efficacy and safety

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 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.

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.

Preclinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity, carcinogenicity. Like other beta-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.

Mannitol (E421)

Microcrystalline cellulose (E460)

Magnesium stearate (E572)

Croscarmellose sodium

Coating ingredients:

Hypromellose(E464)

Titanium dioxide (E171)

Macrogol 6000

Not applicable

24 months

Blister: Do not store above 25^LJC. Keep blister in the outer carton.

The tablets are packaged in thermoformed PVC/PVdC colourless foils laminated with aluminium foils.

The blister strips are packed into cardboard cartons. Pack sizes: 20, 28, 30, 50, 56, 98, 100 and 105 tablets. Not all pack sizes may be marketed.

Not applicable.