Pentocor 5 Mg/10 Mg Tablets

PENTOCOR is indicated for the treatment of stable chronic moderate to severe heart failure with reduced systolic ventricular function (ejection fraction < 35 %, based on echocardiography), in addition to ACE inhibitors, and diuretics, and optionally digoxin, prior to the administration of PENTOCOR. The patients should have stable chronic heart failure without acute failure during the previous six weeks and an unchanged basic therapy during the previous two weeks. They should be treated at optimal dose with an ACE inhibitor (or other vasodilator in case of intolerance to ACE inhibitors) and a diuretic, and optionally digoxin, prior to the administration of PENTOCOR. It is recommended that the treating medical practitioner should be experienced in the management of chronic heart failure.

Posology
The treatment of stable chronic heart failure with PENTOCOR has to be initiated with a titration phase as given in the description below: The treatment with PENTOCOR 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
• 10 mg once daily for maintenance therapy.

After initiation of treatment with 1,25 mg, the patients should be observed over a period of approximately 4 hours (especially with regards to blood pressure, heart rate, conduction disturbances and signs of worsening of heart failure). The maximum recommended dose is 10 mg once daily. Occurrence of adverse events may prevent all patients being treated with the maximum recommended dose. If necessary, the dose reached can also be decreased step by step. The treatment may be interrupted if necessary and reintroduced as appropriate. During the titration phase, in case of worsening of the heart failure or intolerance, it is recommended to first reduce the dose of PENTOCOR, or to stop immediately if necessary (in cases of severe hypotension, worsening of heart failure with acute pulmonary oedema, cardiogenic shock, symptomatic bradycardia or AV block).

Treatment of stable chronic heart failure with PENTOCOR is generally a long-term treatment. The treatment with PENTOCOR is not recommended to be stopped abruptly since this might lead to transitory worsening of heart failure. If discontinuation is necessary, the dose should be gradually decreased by dividing into halves, weekly. There is wide interindividual variation in sensitivity to one single high dose of bisoprolol. Therefore, it is mandatory to initiate the treatment of these patients with a gradual up titration according to the scheme given.

Special populations
Elderly patients are more likely to have age-related peripheral vascular disease which may require caution.
Paediatric population
Safety and efficacy in children have not been established.

Method of administration
PENTOCOR should be taken in the morning and can be taken with food. They should be swallowed with liquid and should not be chewed.

PENTOCOR is contra-indicated in chronic heart failure patients with:

• hypersensitivity to bisoprolol or to any of the ingredients
• acute heart failure or during episodes of heart failure decompensation requiring IV inotropic therapy
• cardiogenic shock
• AV block of second or third degree (without a pacemaker)
• sick sinus syndrome
• sinoatrial block
• bradycardia with less than 50 beats/min before the start of therapy
• hypotension (systolic blood pressure less than 100 mmHg)
• bronchial asthma, bronchitis and severe chronic obstructive pulmonary disease
• peripheral arterial occlusive disease
• Raynaudu2019s syndrome
• phaeochromocytoma
• metabolic acidosis
• pregnancy and lactation (see section 4.6)
• hyperthyroidism, as clinical manifestations may be masked
• peripheral vascular disease
• sinus bradycardia

PENTOCOR must be used with caution in:

• Concomitant treatment with inhalation anaesthetics
• diabetes mellitus with large fluctuations in blood glucose values; symptoms of hypoglycaemia can be masked, and responses to hypoglycaemia are diminished
• strict fasting
• ongoing desensitisation therapy
• AV block of first degree
• Prinzmetalu2019s angina

Beta-blockers, including PENTOCOR, may increase the number of chest pain attacks in patients who have Prinzmetalu2019s angina.

PENTOCOR may aggravate the symptoms of peripheral arterial occlusive disease (PAOD) or Raynaud's syndrome (due to unopposed arteriolar alpha-sympathetic activation). Severe peripheral vascular disease and even peripheral gangrene may be precipitated.

There is no therapeutic experience of PENTOCOR 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 <80 ml/min)
• impaired liver function
• patients older than 80 years
• restrictive cardiomyopathy
• congenital heart disease
• haemodynamically significant organic valvular disease
• myocardial infarction within 3 months

u03b2-blockers, such as PENTOCOR, may cause bronchospasm in patients with asthma (see section 4.3). Bisoprolol may increase both the sensitivity towards allergens and the severity of anaphylactic reactions. Epinephrine (adrenaline) treatment does not always give the expected therapeutic effect. Psoriasis may be aggravated by PENTOCOR and therefore must only be given PENTOCOR after careful consideration of the risks and benefits.

The symptoms of thyrotoxicosis may be masked under treatment with PENTOCOR. Initiation of treatment with PENTOCOR necessitates regular monitoring. The cessation of therapy with PENTOCOR should not be done abruptly unless clearly indicated. Patients should be advised to limit the extent of their physical activity during the period in which PENTOCOR is being discontinued.

In patients undergoing general anaesthesia beta-blockade reduces the incidence of arrhythmias and myocardial ischaemia during induction and intubation, and the postoperative period. The anaesthetist must be aware of beta-blockade because of the potential for interactions with other medicines, resulting in bradydysrhythmias, attenuation of the reflex tachycardia and the decreased reflex ability to compensate for blood loss.

A patientu2019s normal tachycardiac response to hypovolaemia or blood loss may be obscured during or after surgery. Particular caution should be taken in this regard. In the event of surgery, the anaesthetist should be informed of therapy with PENTOCOR prior to any operation. If the decision is made to withdraw PENTOCOR before anaesthesia, at least 48 hours should be allowed to elapse between the last dose and surgery. If the medicine is to be continued, care should be taken when using halogenated anaesthetics.

Atropine (1 u2013 2 mg IV) may be used to correct vagal dominance. The patient must be maintained on their usual dosage peri-operatively. In the peri-operative period it is generally unwise to reduce the dosage to which the patient is accustomed, as there may be danger of aggravation of angina pectoris or hypertension. In patients suffering from ischaemic heart disease, treatment should not be discontinued abruptly.

The dosage of PENTOCOR should be adjusted in severe renal impairment. Care should be taken in prescribing PENTOCOR together with Class 1 antidysrhythmic medicines such as disopyramide, myocardial depressants and inhibitors of AV conduction such as calcium antagonists. Caution should be exercised when transferring a patient from clonidine, as the withdrawal of clonidine may result in the release of large amounts of catecholamines that may give rise to a hypertensive crisis. If PENTOCOR is administered in these circumstances, the unopposed alpha receptor stimulation may potentiate this effect. If PENTOCOR and clonidine are given concurrently the clonidine should not be discontinued until several days after the withdrawal of PENTOCOR, as severe rebound hypertension may occur.

PENTOCOR should be used with caution in combination with verapamil in patients with impaired ventricular function. This combination should not be given to patients with conduction abnormalities. Neither medicine should be administered intravenously within 48 hours of discontinuing the other. The intravenous administration of calcium antagonists and antidysrhythmic medicines is not recommended during therapy with PENTOCOR. The intravenous administration of verapamil in patients on treatment with PENTOCOR may lead to profound hypotension and atrioventricular block.

PENTOCOR modifies the tachycardia associated with hypoglycaemia. Patients with phaeochromocytoma usually require treatment with an alpha-adrenergic blocker. PENTOCOR may increase both the sensitivity towards allergens and the severity of anaphylactic reactions. Adrenaline treatment does not always give the expected therapeutic effect. PENTOCOR may mask the symptoms of hyperthyroidism. The normal dose should be reduced in elderly patients, or in patients suffering from renal dysfunction. A patient's normal tachycardiac response to hypovolaemia or blood loss may be obscured during or after surgery. Particular caution should be taken in this regard. Cases of coronary vasospasm have been observed. Despite its high beta 1-selectivity, angina attacks cannot be completely excluded when PENTOCOR is administered to patients with Prinzmetal's angina. Utmost caution must be exercised. Treatment with PENTOCOR must not be withdrawn abruptly unless clearly indicated (see section 4.2). Abrupt discontinuation of therapy with PENTOCOR may cause exacerbation of angina pectoris in patients suffering from ischaemic heart disease, myocardial infarction, ventricular dysrhythmias and in some cases could lead to sudden death. Discontinuation of PENTOCOR should be gradual over a period of 1 to 2 weeks, and patients should be advised to limit the extent of their physical activity during the period that PENTOCOR is being discontinued. Caution is warranted when treating patients with hypertension or angina pectoris and concomitant heart failure with PENTOCOR. Digitalisation of patients receiving long-term beta-blocker therapy including PENTOCOR may be necessary if congestive cardiac failure is likely to develop. This combination can be considered despite the potentiation of the negative chronotropic effect of the two medicines. Careful control of dosages, and of the individual patient's response (and notably pulse rate), is essential in this situation.

Beta-blockers, including PENTOCOR, may unmask myasthenia gravis. Although cardioselective (beta1) beta-blockers may have less effect on lung function than nonselective 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, PENTOCOR may be used with caution.

In bronchial asthma or other chronic obstructive pulmonary diseases, which may cause symptoms, concomitant bronchodilating therapy is recommended. Occasionally an increase of the airway resistance may occur in patients with asthma, therefore, the dose of beta 2-stimulants may have to be increased.

Paediatric population
Safety and efficacy in children have not been established.

It can be dangerous to administer PENTOCOR with the following medicines:

• Concomitant use of PENTOCOR with hypoglycaemic medicines, phenothiazines and various antidysrhythmic medicines can have life-threatening consequences, e.g. - profound hypoglycaemia with oral hypoglycaemic medicines and insulin; - myocardial depression with antidysrhythmic medicines.
• Beta-adrenoceptor stimulating medicines (e.g. isoprenaline, dobutamine) may antagonise the effects of PENTOCOR. Combination with PENTOCOR may reduce the effect of both medicines. Higher doses of epinephrine (adrenaline) may be necessary for treatment of allergic reactions.
• Sympathomimetics that activate both beta- and alpha-adrenoceptors (e.g. norepinephrine(noradrenaline), epinephrine (adrenaline)): Combination with PENTOCOR may unmask the alpha-adrenoceptor-mediated vasoconstrictor effect of these medicines leading to blood pressure increase and exacerbated intermittent claudication.
• Alpha-adrenoceptor stimulants can dangerously affect the vasoconstrictor effects and adrenergic neuron blocking medicines may lead to life-threatening vasoconstriction when used in combination with PENTOCOR.
• PENTOCOR and digoxin may be used concomitantly for patients with congestive heart failure provided that the pulse rate and patient response is monitored. It can be dangerous to administer PENTOCOR with digoxin which can lead to a reduction of heart rate and an increase of atrio-ventricular conduction time.
• Dihydropyridine-type calcium antagonists such as nifedipine and amlodipine, should not be used in combination with PENTOCOR since this may increase the risk of hypotension. In patients with heart failure, an increase in the risk of further deterioration of the ventricular pump function cannot be excluded.
• Atrio-ventricular conduction time, as well as negative inotropic effect, may be increased when PENTOCOR is used concurrently with Class-I antidysrhythmic medicines (e.g. disopyramide and quinidine, lidocaine, phenytoin, flecainide, propafenone). Atrioventricular conduction time may also be increased when PENTOCOR is taken concomitantly with Class-III antidysrhythmic medicines (e.g. amiodarone). The half-life of PENTOCOR can be slightly shortened by the simultaneous administration of rifampicin. An increase in the dose is generally unnecessary.
• Calcium antagonists, such as verapamil, and to a lesser degree diltiazem, have a negative influence on contractility, atrio-ventricular conduction and blood pressure (see section 4.4). In patients on PENTOCOR, the I.V. administration of verapamil may cause profound atrioventricular block and hypotension. The use of PENTOCOR in combination with calcium antagonists is therefore not recommended.
• Clonidine and other centrally acting antihypertensives medicines such as methyldopa, moxonodine and rilmenidine may further decrease heart rate, cardiac output and vasodilation if taken together with PENTOCOR. Beta-blockers, such as PENTOCOR may exacerbate the u201crebound hypertensionu201d which can occur in case of abrupt withdrawal of centrally acting antihypertensive medicines (e.g. Clonidine). If the two medicines are co-administered, the u03b2-blocker should be withdrawn several days before discontinuing clonidine. If replacing clonidine by u03b2-blocker therapy, the introduction of u03b2-blockers should be delayed for several days after clonidine administration has stopped.
• Mono amine oxidase inhibitors (except MAO-B inhibitors) enhance the hypotensive effect of u03b2-blockers as well as the risk of hypertensive crisis.
• The pharmacokinetics of bisoprolol is not significantly influenced by cimetidine.
• The following combinations should be used with caution together with bisoprolol:
• Class-I antidysrhythmic medicines (e.g. disopyramide, quinidine), due to a potentiated effect on the atrial conduction time and an increased negative inotropic effect.
• Class-III antidysrhythmic medicines (e.g. amiodarone), where the effect an atrial conduction time may be potentiated.
• Parasympathomimetic medicines (including tacrine), where atrio-ventricular conduction time and risk of bradycardia may be increased.
• Other u03b2-blockers, including eye drops, have additive effects.
• Insulin and oral antidiabetic medicines, where it can lead to an intensification of the blood sugar lowering effect. Blockade of u03b2-adrenoceptors may mask symptoms of hypoglycaemia.
• Anaesthetic medicines which can lead to attenuation of reflex tachycardia and increase the risk of hypotension. Continuation of u03b2-blockade reduces the risk of dysrhythmia during induction and intubation. The anaesthetist should be informed when the patient is receiving PENTOCOR.
• Prostaglandin synthetase inhibiting medicines, where the hypotensive effect is decreased.
• Ergotamine derivatives which can lead to an exacerbation of peripheral circulatory disturbances.
• Combinations of sympathomimetic medicines with PENTOCOR may reduce the effect of both medicines. Higher doses of epinephrine (adrenaline) may be necessary for treatment of allergic reactions.
• PENTOCOR in combination with tricyclic antidepressants, barbiturates, phenothiazines, as well as other antihypertensive medicines, can lead to an increased blood pressure lowering effect.
• The combination of PENTOCOR with mefloquine should be considered, as there is an increased risk of bradycardia.

Pregnancy
The use of PENTOCOR during pregnancy is not recommended (see section 4.3). PENTOCOR has pharmacological effects that may cause harmful effects on pregnancy and/or the foetus/newborn. PENTOCOR reduce placental perfusion, which has been associated with growth retardation, intrauterine death, abortion or early labour. Administration of PENTOCOR to pregnant mothers shortly before birth or during labour may result in hypotonia, collapse or hypoglycaemia in the newborn. (See section 4.3).

Breastfeeding
It is not known whether PENTOCOR passes into breast milk. Therefore, breastfeeding is not recommended during treatment with PENTOCOR.

Fertility
No effect on fertility was observed in male or female rats treated with bisoprolol at oral doses up to 150 mg/kg/day.

PENTOCOR may cause drowsiness and dizziness. Do not drive or use any tools or machines until you know how the tablets affect you.

a) Summary of the safety profile
Adverse reactions are more common in patients with renal decompensation.

b) Tabulated list of adverse reactions

• Frequency unknown- cannot be estimated from the available data.

System Organ Class Adverse effect Frequency
Blood and the lymphatic system disorders Leukopenia, thrombocytopenia, agranulocytosis, non-thrombocytopenia purpura, transient eosinophilia Less frequent: Immune system disorders Hypersensitivity reactions (itching, flush, rash), systemic lupus erythematosus (SLE) Less frequent Metabolism and nutrition disorders Metabolic disturbances Less frequent Hypoglycaemia, hyperglycaemia, increase in uric acid levels, hypercholesterolaemia Increased triglycerides, increased liver enzymes (ALAT, ASAT). Frequency unknown Psychiatric disorders Sleep disturbances, depression, nightmares, hallucinations, overt psychosis, amnesia, anxiety, nervousness, sleep disorders or trouble sleeping, nightmares and vivid dreams, hallucinations, confusion. Less frequent Restlessness Frequency unknown Nervous system disorders Lassitude, fatigue, dizziness, mild headache, unusual tiredness/weakness, exhaustion, headache (these symptoms generally occur at the beginning of treatment), Frequent Sleep disorders, coma, convulsions Less frequent Eye disorders Conjunctivitis, decreased tear production, blurred vision, soreness, disturbances of vision Less frequent Disturbances of vision Frequency unknown Ear and labyrinth disorders Transient hearing loss, hearing impairment Less frequent Cardiac disorders Bradycardia, heart block, fluid retention, syncope, congestive cardiac failure, AV-stimulus disturbances, worsening of heart failure. Less frequent Vascular disorders Cold extremities, hypotension, paraesthesia, feeling of coldness and numbness in the extremities Frequent Paradoxical hypertension, exacerbation of peripheral vascular disease or the development of Raynaudu2019s phenomenon, restlessness, severe peripheral vascular disease and peripheral gangrene, orthostatic hypertension. Less frequent Respiratory, thoracic and mediastinal disorders Bronchospasm in patients with bronchial asthma or history of obstructive airways disease, shortness of breath, dyspnea, pneumonia, pulmonary fibrosis, pleurisy Less frequent Gastrointestinal disorders Nausea, vomiting, diarrhoea, constipation, abdominal cramping and other gastro-intestinal disturbances Frequent Stomatitis Frequency unknown Hepatobiliary disorders Hepatotoxicity, hepatitis Less frequent Skin and subcutaneous tissue disorders Perspiration Frequent Skin rash, allergic reactions Less frequent Alopecia, rash, pruritus, exacerbation of psoriasis Frequency unknown Musculoskeletal, connective tissue and bone disorders Muscle weakness, cramps, myopathies, back and joint pain Less frequent Reproductive system and breast disorders Decreased sexual ability Frequent Potency disorders, impotence Less frequent General disorders and administrative conditions Fatigue*, lassitude Frequent Mass gain, asthenia Less frequent Sclerosing peritonitis, retroperitoneal fibrosis. Frequency unknown *This symptom especially occurs at the beginning of therapy. It is generally mild and often disappears within 1 u2013 2 weeks.

Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicine is important. It allows continued monitoring of the benefit/risk balance of the medicine. Health care providers are requested to report any suspected adverse drug reactions to SAHPRA via the Med Safety APP (Medsafety X SAHPRA) and eReporting platform (who-umc.org) found on SAHPRA website.

Overdosage may produce bradycardia and severe hypotension. Bronchospasm and heart failure may be produced in certain individuals as well as acute cardiac insufficiency, cardiac conduction block, heart failure, cardiogenic shock and hypoglycaemia. Coma and convulsions have also been reported, and some patients may develop severe and occasionally fatal cardiovascular depression. Cases of overdose should be observed for at least 4 hours, as apnoea and cardiovascular collapse may appear suddenly.

Treatment
Generally, in cases of overdose, the patient should stop taking PENTOCOR and supportive and symptomatic treatment should be provided. Repeated activated charcoal is necessary in severe overdose The data available suggest that bisoprolol is not dialysable to any extent.

Atropine may be administered intravenously to treat severe bradycardia. If the response is inadequate, isoprenaline or another medicine with positive chronotropic properties may be given cautiously. Under some circumstances, transvenous pacemaker insertion may be necessary Alternatively, dobutamine may be required to reverse beta-blockade. Cardiac pacing may be required for severe bradycardia. Hypotension: Vasopressors and I.V. fluids should be administered. Glucagon may be given intravenously, with sympathomimetics used as an alternative or given with glucagon. AV block (second or third degree): Monitor patients closely and treat with isoprenaline infusion or insert a cardiac pacemaker. Acute worsening of heart failure: Recommended treatment includes I.V. diuretics, inotropic medicines and vasodilating medicines. Bronchospasm should be treated with bronchodilator therapy such as isoprenaline, u03b22-sympathomimetic medicines and/or aminophylline. Beta-agonist (e.g. salbutamol) or xanthines may also be given. Hypoglycaemia: I.V. glucose or glucagon can be administered.