Core Safety Profile. Date of FAR:

Transcription

1 Core Safety Profile Active substance: Bisoprolol + Hydrochlorothiazide Pharmaceutical form(s)/strength: Film-coated tablet: 2.5 mg / 6.25 mg, 5 mg / 6.25 mg, 10 mg / 6.25 mg, 5 mg / 12.5 mg, 10 mg / 25 mg; Strengths 5 mg / 12.5 mg and 10 mg / 25 mg are not registered in the P-RMS P - RMS: FR/H/PSUR/0031/001 Date of FAR:

2 * This document aims to support the complex actual CSI situation of the bisoprolol and hydrochlorothiazide combiation products. It contains the Core Safety Information as the MAH anticipates to be reflected in the future agreed Core Safety Profile. It is based on Annex 1, includes the content of Annex 2 and reflects the wording of the intended variation to remove the statement on mild to moderate impairment of liver function in the dosage and administration section. This potential EU Core Safety Profile (CSP) is presented in QRD format containing the complete Core Safety Information of CSDS 3.0 provided with the PSUR. Editorial remarks Please note that the text in italics identifies only notes for correct implementation of the respective information; it is not intended to appear in any derived national product information. All core safety statements mentioned in the CSP do not refer to a specific tradename. In place of the tradename, the following code is used throughout the document: {Tradename} represents the local product name of any formulation. {Tradename 5/12.5} represents the local tradename and strength of the combination containing 5 mg bisoprolol and 12.5 mg hydrochlorothiazide. {Tradename 10/25} represents the local tradename and strength of the combination containing 10 mg bisoprolol and 25 mg hydrochlorothiazide. {Tradename 2.5/6.25} represents the local tradename and strength of the combination containing 2.5 mg bisoprolol and 6.25 mg hydrochlorothiazide. {Tradename 5/6.25} represents the local tradename and strength of the combination containing 5 mg bisoprolol and 6.25 mg hydrochlorothiazide. {Tradename 10/6.25} represents the local tradename and strength of the combination containing 10 mg bisoprolol and 6.25 mg hydrochlorothiazide. 2/11

3 4.2 Posology and method of administration The safety information presented in this document refers to the instructions for use according national Marketing Authorisation. Administration Special Populations Renal or hepatic impairment applies only to {Tradename 5/12.5, 10/25} In mild-to-moderate impairment of kidney or liver function the elimination of the HCTZ component of {Tradename} 5 mg/12.5 mg and 10 mg/25 mg is reduced, so that preference may have to be given to the lower dose form ({Tradename} 5 mg/12.5 mg). Paediatric patients There is no paediatric experience with {Tradename}, therefore its use cannot be recommended for children. 4.3 Contraindications {Tradename} is contra-indicated in patients with hypersensitivity to bisoprolol, hydrochlorothiazide, other thiazides, sulphonamides, or any of the excipients acute heart failure or during episodes of heart failure decompensation requiring intravenous inotropic therapy cardiogenic shock second or third degree AV block sick sinus syndrome sinoatrial block symptomatic bradycardia severe bronchial asthma or severe chronic obstructive pulmonary disease severe forms of peripheral arterial occlusive disease or severe forms of Raynaud's syndrome untreated phaeochromocytoma severe renal impairment (creatinine clearance 30 ml/min) 3/11

4 severe hepatic impairment metabolic acidosis refractory hypokalaemia applies only to {Tradename 5/12.5, 10/25} lactation severe hyponatraemia hypercalcaemia gout 4.4 Special warnings and precautions for use Treatment with bisoprolol must not be withdrawn abruptly unless clearly indicated, since abrupt withdrawal of bisoprolol may lead to an acute deterioration of the patient's condition in particular in patients with ischaemic heart disease. {Tradename} must be used with caution in patients with accompanying heart failure diabetes mellitus showing large fluctuations in blood glucose values; symptoms of hypoglycaemia can be masked strict fasting first degree AV block Prinzmetal's angina peripheral arterial occlusive disease. Aggravation of symptoms may occur especially when starting therapy hypovolaemia impaired liver function As with other beta-blockers, bisoprolol may increase both the sensitivity towards allergens and the severity of anaphylactic reactions. This also applies to desensitisation therapy. Epinephrine treatment may not always yield 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 of benefits against risks. The symptoms of thyrotoxicosis may be masked under treatment with bisoprolol. 4/11

5 In patients with phaeochromocytoma bisoprolol must not be administered until after alphareceptor blockade. In patients undergoing general anaesthesia. The anaesthetist must be aware of betablockade. If it is thought necessary to withdraw beta-blocker therapy before surgery, this should be done gradually and completed about 48 hours before anaesthesia. 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 beta2-stimulants may have to be increased. If photosensitivity reactions occur, it is recommended to protect exposed areas to the sun or to artificial UVA light. In severe cases it may be necessary to stop the treatment. Long-term, continuous administration of hydrochlorothiazide may lead to fluid and electrolyte disturbances, in particular to hypokalaemia and hyponatraemia, also to hypomagnesaemia and hypochloraemia, and hypercalcaemia. Hypokalaemia facilitates the development of severe arrhythmias, particularly torsade de pointes, which may be fatal. During long term-therapy with {Tradename}, monitoring of serum electrolytes (especially potassium, sodium, calcium), creatinine and urea, the serum lipids (cholesterol and triglycerides), uric acid as well as blood glucose is recommended. In patients with hyperuricaemia the risk for attacks of gout may be increased. 4.5 Interaction with other medicinal products and other forms of interaction Combinations not recommended Lithium: {Tradename} may intensify the cardiotoxic and neurotoxic effect of lithium through a reduction of lithium excretion. Calcium antagonists of the verapamil type and the diltiazem type: Negative effect on contractility and atrio-ventricular conduction. Intravenous administration of verapamil in patients on ß-blocker treatment may lead to profound hypotension and atrioventricular block. Centrally-acting antihypertensive agents: Concomitant use of centrally-acting antihypertensive agents may lead to a further reduction in heart rate and cardiac output 5/11

6 and to vasodilatation. Abrupt withdrawal, may increase the risk of 'rebound hypertension'. Combinations to be used with caution Calcium antagonists of the dihydropyridine type: 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. Concomitant use with other antihypertensive agents or with other medicinal products with blood pressure lowering potential may increase the risk of hypotension. ACE inhibitors, Angiotensin II antagonists: Risk of significant fall in blood pressure and/or acute renal failure during initiation of ACE inhibitor therapy in patients with preexisting sodium depletion (particularly in patients with renal artery stenosis). If prior diuretic therapy has produced sodium depletion, either stop the diuretic 3 days before starting ACE inhibitor therapy, or initiate ACE inhibitor therapy at a low dose. Class-I antiarrhythmic agents: Effect on atrio-ventricular conduction time may be potentiated and negative inotropic effect increased. Class-III antiarrhythmic agents: Effect on atrio-ventricular conduction time may be potentiated. Antiarrhythmic agents that may induce torsade de pointes: Hypokalaemia may facilitate the occurrence of torsades de pointes. Nonantiarrhythmic agents that may induce torsade de pointes: Hypokalaemia may facilitate the occurrence of torsades de pointes. Parasympathomimetic agents: Concomitant use may increase atrio-ventricular conduction time and the risk of bradycardia. Topical beta-blockers (e.g. eye drops for glaucoma treatment) may add to the systemic effects of bisoprolol. Insulin and oral antidiabetic agents: Increase of blood sugar lowering effect. Blockade of beta-adrenoceptors may mask symptoms of hypoglycaemia. Anaesthetic agents: Attenuation of the reflex tachycardia and increase of the risk of hypotension. Digitalis glycosides: Increase of atrio-ventricular conduction time, reduction in heart rate. If hypokalaemia and/or hypomagnesaemia develop during treatment with {Tradename} the myocardium may show increased sensitivity to cardiac glycosides, leading to an enhanced effect and adverse effects of the glycosides. 6/11

7 Non-steroidal anti-inflammatory drugs (NSAIDs): NSAIDs may reduce the hypotensive effect. In patients developing hypovolaemia the concomitant administration of NSAIDs can trigger acute renal failure. Beta-sympathomimetics: Combination with bisoprolol may reduce the effect of both agents. Sympathomimetics that activate both beta- and alpha-adrenoceptors: Combination with bisoprolol may lead to blood pressure increase. Such interactions are considered to be more likely with nonselective beta-blockers. Potassium-wasting medicinal products may result in increased potassium losses. Methyldopa: haemolysis due to the formation of antibodies to hydrochlorothiazide has been described in isolated cases. The effect of uric-acid-lowering agents may be attenuated in concomitant administration of {Tradename}. Cholestyramine, colestipol: reduces the absorption of the hydrochlorothiazide component of {Tradename}. Combinations to be considered Mefloquine: increased risk of bradycardia. Corticosteroids: Reduced antihypertensive effect. 4.6 Pregnancy and lactation Pregnancy For all strengths (2.5/6.25, 5/6.25, 10/6.25, 5/12.5 and 10/25): Bisoprolol Bisoprolol has pharmacological effects that may cause harmful effects on pregnancy and/or the foetus/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. Hydrochlorothiazide 7/11

8 There is limited experience with hydrochlorothiazide during pregnancy, especially during the first trimester. Animal studies are insufficient. Hydrochlorothiazide crosses the placenta. Based on the pharmacological mechanism of action of hydrochlorothiazide its use during the second and third trimester may compromise foeto-placental perfusion and may cause foetal and neonatal effects like icterus, disturbance of electrolyte balance and thrombocytopenia. Hydrochlorothiazide should not be used for gestational oedema, gestational hypertension or preeclampsia due to the risk of decreased plasma volume and placental hypoperfusion, without a beneficial effect on the course of the disease. Hydrochlorothiazide should not be used for essential hypertension in pregnant women except in rare situations where no other treatment could be used. Lactation applies only to {Tradename 5/12.5, 10/25}: {Tradename}must not be used in breastfeeding women. Hydrochlorothiazide can inhibit the milk production. applies only to {Tradename 2.5/6.25, 5/6.25, 10/6.25} {Tradename} is not recommended in breastfeeding women. Hydrochlorothiazide can inhibit the milk production. 4.7 Effects on ability to drive and use machines In general {Tradename} has no or neglible influence on the ability to drive and use machines. However, depending on the individual patients response to treatment the ability to drive a vehicle or to use machines may be impaired. This needs to be considered particularly at start of treatment, upon change of medication, or in conjunction with alcohol. 4.8 Undesirable effects Common ( 1% and < 10%), uncommon ( 0.1% and < 1%), rare ( 0.01% and < 0.1%), very rare (< 0.01%) including isolated cases. Blood and lymphatic system disorders 8/11

9 Rare: leucopenia, thrombocytopenia Very rare: agranulocytosis Metabolism and nutrition disorders Uncommon: loss of appetite Very rare: metabolic alkalosis applies only to {Tradename 5/12.5, 10/25} Common: hyperglycaemia, hyperuricaemia, disturbances of fluid and electrolyte balance (in particular hypokalaemia and hyponatraemia, also hypomagnesaemia and hypochloraemia as well as hypercalcaemia) applies only to {Tradename 2.5/6.25, 5/6.25, 10/6.25} Uncommon: hyperglycaemia, hyperuricaemia, disturbances of fluid and electrolyte balance (in particular hypokalaemia and hyponatraemia, also hypomagnesaemia and hypochloraemia as well as hypercalcaemia) Psychiatric disorders Uncommon: depression, sleep disorders Rare: nightmares, hallucinations Nervous system disorders Common: dizziness*, headache* Eye disorders Rare: reduced tear flow (to be taken into consideration in patients wearing contact lenses), visual disturbances Very rare: conjunctivitis Ear and labyrinth disorders Rare: hearing disorders Cardiac disorders Uncommon: bradycardia, AV-conduction disturbances, worsening of pre-existing heart failure Vascular disorders Common: feeling of coldness or numbness in extremities Uncommon: orthostatic hypotension Respiratory, thoracic and mediastinal disorders Uncommon: bronchospasm in patients with bronchial asthma or history of obstructive airways disease Rare: allergic rhinitis 9/11

10 Gastrointestinal disorders Common: gastrointestinal complaints such as nausea, vomiting, diarrhoea, constipation Uncommon: abdominal complaints applies only to {Tradename 5/12.5, 10/25} Uncommon: pancreatitis applies only to {Tradename 2.5/6.25, 5/6.25, 10/6.25} Very rare: pancreatitis Hepatobilary disorders Rare: hepatitis, jaundice Skin and subcutaneous tissue disorders Rare: hypersensitivity reactions such as itching, flush, rash, photodermatitis, purpura, urticaria Very rare: alopecia, cutaneous lupus erythematosus. Beta-blockers may provoke or worsen psoriasis or induce psoriasis-like rash. Musculoskeletal and connective tissue disorders Uncommon: muscle weakness, muscle cramps Reproductive system and breast disorders Rare: potency disorders General disorders Common: fatigue* Uncommon: asthenia Very rare: chest pain Investigations: Uncommon: increase in amylase, reversible increase of serum creatinine and urea Rare: increase in liver enzymes (ASAT, ALAT) applies only to {Tradename 2.5/6.25, 5/6.25, 10/6.25} Uncommon: increased triglyceride and cholesterol levels, glucosuria applies only to {Tradename 5/12.5, 10/25} Common: increased triglyceride and cholesterol levels, glucosuria *These symptoms occur in particular at the start of treatment. They are generally mild and mostly disappear within 1-2 weeks. 10/11

11 4.9 Overdose Symptoms The most common signs expected with overdose of a beta-blocker are bradycardia, hypotension, bronchospasm, acute cardiac insufficiency and hypoglycaemia. 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. The clinical picture in acute or chronic overdose of hydrochlorothiazide is characterised by the extent of fluid and electrolyte loss. Most common signs are dizziness, nausea, somnolence, hypovolaemia, hypotension, hypokalaemia. Management In general, if overdose occurs, discontinuation of {Tradename} and supportive and symptomatic treatment is recommended. Limited data suggest that bisoprolol is hardly dialysable. The degree to which hydrochlorothiazide is removed by haemodialysis has not been established. 11/11