Each film-coated tablet contains 20 mg betaxolol hydrochloride (equivalent to mg betaxolol).

Transcription

1 1. NAME OF THE MEDICINAL PRODUCT Betaxolol HCl Mylan 20 mg, filmomhulde tabletten 2. QUALITATIVE AND QUANTITATIVE COMPOSITION Each film-coated tablet contains 20 mg betaxolol hydrochloride (equivalent to mg betaxolol). Excipient with known effect Each film-coated tablet contains mg lactose monohydrate. For the full list of excipients, see section PHARMACEUTICAL FORM Film-coated tablet White, round, biconvex film-coated tablets with a break-line on one face. The tablet can be divided into equal doses. 4. CLINICAL PARTICULARS 4.1 Therapeutic indications Betaxolol Hydrochloride is indicated in adults for: Treatment of essential hypertension. Chronic, stable angina pectoris. 4.2 Posology and method of administration Posology Adults Essential hypertension The initial dose is 10 mg once daily. In case of insufficient effect this dosage can be increased to 20 mg per day. In moderate hypertension the standard dose is 20 mg once daily. In certain cases it could be necessary to increase the daily dose to 40 mg. Stable angina pectoris The dosage should be adjusted individually. The starting dose is 10 mg a day, which can be increased to the usual dose of 20 mg once daily. In certain cases it could be necessary to increase the daily dose to 40 mg. Patients with impaired renal or liver function

2 In patients with renal impairment (creatinine clearance up to 20 ml/minute) there is no need to adjust the daily dose, however, clinical monitoring at the beginning of the treatment until steady plasma levels of the medicinal product are attained (over 4 days on average) is recommended. In patients with severe renal impairment (creatinine clearance below 20 ml/minute) and in patients with haemo- or peritoneal dialysis the dose of 10 mg/day should not be exceeded. In patients on dialysis the daily dose can be given independent of the time of dialysis. In patients with liver failure there is no need to adjust the dose. Careful clinical monitoring is recommended at the beginning of the treatment. Elderly patients The treatment of elderly patients should be started cautiously with low doses and under close monitoring (see section 4.4). Paediatric population The safety and efficacy of betaxolol in children has not yet been established. Betaxolol hydrochloride should not be used in children (see section 4.4). Method of administration Oral use. Betaxolol Hydrochloride should always be taken at the same time of the day, preferably in the early morning. The tablets may be taken with or without food. 4.3 Contraindications Hypersensitivity to the active substance or to any of the excipients listed in section 6.1 Severe forms of bronchial asthma and chronic obstructive pulmonary disease Decompensated heart failure Cardiogenic shock Second and third degree atrioventricular block, unless a pacemaker is inserted Prinzmetal's variant angina pectoris (pure form and with monotherapy) Sick-sinus syndrome, including sinoatrial block Bradycardia (less than beats/min) Severe forms of Raynaud's phenomenon and peripheral arterial disorders Untreated pheochromocytoma Hypotension History of anaphylactic reaction Metabolic acidosis Concurrent administration with floctafenine or sultopride (see section 4.5) 4.4 Special warnings and precautions for use The treatment must not be discontinued suddenly in patients with stable angina pectoris: this could result in serious heart rhythm disorders, myocardial infarction or sudden death. Discontinuation of treatment

3 The treatment should not be discontinued suddenly, especially in patients with ischaemic heart disease. The doses should be reduced gradually, within a one to two-week period. If necessary, with simultaneous introduction of replacement therapy to prevent any aggravation of angina pectoris. Asthma and chronic obstructive lung disease Beta-blockers may be administered only in mild forms of the disease, cardio selective beta-blockers at the lowest possible doses should be preferably used and it is recommended to carry out pulmonary function tests before and after the start of beta-blocker treatment. During an asthma attack beta 2 -agonist bronchodilators may be used. Heart failure In patients with compensated heart failure, betaxolol can be administered in gradually increasing doses, if necessary. At the start of treatment very low doses should be administered. Close monitoring of the patient's condition is required. Bradycardia Beta-blockers may induce bradycardia. The dosage of betaxolol hydrochloride must be decreased, if the resting heart rate of the patient drops below beats per minute and symptoms of bradycardia appear. First degree atrioventricular block With respect to the negative dromotropic effect of beta-blockers, betaxolol should be administered with caution to patients with first-degree atrioventricular block. Prinzmetal variant of angina Beta-blockers may increase the number and duration of angina attacks in patients suffering from the Prinzmetal s variant angina pectoris (see section 4.3). Cardioselective beta-blockers may be used in minor and mixed forms, provided that a vasodilator is co-administered. Peripheral arterial disorders In patients with peripheral arterial disorders (Raynaud's syndrome or disease, arteritis, or chronic occlusive arterial disease of the lower limbs), beta-blockers should be used with great caution as they may result in an aggravation of the condition. In severe forms of Raynaud s phenomenon and peripheral arterial circulatory disorders, beta-blockers are contraindicated (see section 4.3). Pheochromocytoma The use of beta-blockers in the treatment of hypertension caused by treated pheochromocytoma requires close monitoring of the patient's blood pressure (see section 4.3).Beta blockers should only be used after prior administration if alpha inhibitors Paediatric population The safety and efficacy of betaxolol has not yet been established, therefore betaxolol is not recommended in children and adolescents. Elderly patients In elderly patients, the treatment should be initiated at low doses and the patient s clinical condition must be closely monitored (see section 4.2). Patients with renal impairment In patients with renal impairment, the dosage should be adjusted according to the serum creatinine levels or creatinine clearance (see section 4.2).

4 Diabetic patients Beta-blockers may mask some signs of hypoglycaemia, particularly tachycardia, palpitations and sweats (see section 4.5 and 4.8). The patient must be informed about the necessity of blood glucose monitoring at shorter intervals, in particular at the start of treatment. Psoriasis The benefit of beta-blockers in patients with a personal or family history of psoriasis should be carefully weighed, as it has been reported that psoriasis has been aggravated in patients treated with beta-blockers (see section 4.8). Allergic reactions In patients liable to have a severe anaphylactic reaction, irrespective of its cause, especially after the administration of iodine-containing contrast media or floctafenine (see sections 4.3 and 4.5) or during desensitising therapy, beta-blocker treatment may result in an aggravated allergic reaction and resistance to treatment by the usual doses of adrenaline. General anaesthesia Beta-blockers attenuate reflex tachycardia and increase the risk of hypotension. Continuation of betablocker therapy reduces the risk of arrhythmias, myocardial ischemia and hypertensive crisis. Anaesthetists should be informed that the patient is being treated with a beta-blocker. Anaesthetics with the least possible myocardial depressant effects should be used. It is necessary to take into account the probability of anaphylaxis. If discontinuation of the treatment is necessary, a 48-hour period is considered sufficient to restore the normal sensitivity to the catecholamines. In some cases, beta-blocker therapy should not be interrupted: in patients with coronary insufficiency, due to a risk associated with an abrupt beta-blocker withdrawal, it is advisable to continue the treatment until the surgery in emergency or in cases when discontinuation is impossible, the patient must be protected from parasympathetic predominance by a sufficient premedication with atropine, repeated as needed Ophthalmology Beta-adrenergic blockade reduces intraocular pressure and may hamper the glaucoma screening. The ophthalmologist should be informed that the patient is being treated with betaxolol. Patients with general and ocular beta-blocker therapy should be monitored due to a potential additive effect. Thyrotoxicosis Beta-blockers can mask the cardiovascular signs of thyrotoxicosis. Hypoglycaemia There is an increased susceptibility to hypoglycaemia, for example during prolonged fasting or heavy physical exertion. Excipients

5 Betaxolol hydrochloride contains lactose monohydrate. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine. 4.5 Interaction with other medicinal products and other forms of interaction Contraindicated combinations Floctafenine In the event of shock or hypotension caused by floctafenine, beta-blockers reduce the compensation reaction. Sultopride Disorders of cardiac automatism (excessive bradycardia) due to their common bradycardic effect. Not recommended combinations Amiodarone Concomitant use of beta-blockers with amiodarone can cause disturbances of contractility, cardiac automatism and conduction (suppression of sympathetic compensatory mechanisms). Verapamil Betaxolol should not be used during treatment with verapamil or within a few days after treatment with verapamil (and vice versa). Digitalis glycosides Concomitant use of betaxolol with these medicinal products can prolong atrioventricular conduction time and cause severe bradycardia. Fingolimod Treatment with fingolimod should not be initiated in patients taking beta blockers because of the increased bradycardiac effect. If treatment with fingolimod is necessary, appropriate monitoring is recommended at the start of treatment, lasting at least overnight. Monoamine oxidase inhibitors (except MAO-B inhibitors) Combinations requiring precautions Antiarrhythmics (propafenone and group Ia drugs: quinidine, hydroquinidine and disopyramide) Disturbances of contractility, cardiac automatism and conduction (suppression of sympathetic compensatory mechanisms). Electrocardiographic monitoring is recommended. Baclofen Increased risk of hypotension. Blood pressure should be monitored and if necessary, the antihypertensive agent dose should be adjusted. Insulin and hypoglycaemic sulfonamides (see section 4.4) All beta-blockers mask certain symptoms of hypoglycaemia, such as palpitations and tachycardia. The patient must be informed thereof as well as of the necessity of blood glucose monitoring at shorter intervals, in particular at the start of treatment.

6 Anaesthetics Concomitant administration of betaxolol and anaesthetics can result in an increased lowering of the blood pressure. The negative inotropic effects (i.e. reduction in cardiovascular compensatory reactions) of anaesthetics and betaxolol can be additive (the beta-blockade during the intervention may be compensated by a beta-mimetic). In general, betaxolol should not be discontinued under general anaesthesia or before application of peripheral muscle relaxants. Sudden discontinuation should be avoided in all cases (see section 4.4).The anaesthetist should be informed of the treatment with beta-blocker. A discontinuation of betaxolol, if deemed necessary, should occur 48 hours before anaesthesia to restore the normal sensitivity to the action of catecholamines (see section 4.4). Calcium channel blockers (bepridil, diltiazem and mibefradil) Disturbances of cardiac automatism (excessive bradycardia, sinus arrest), disturbances of sinoatrial and atrioventricular conduction and heart failure (synergistic effects). These combinations should only be used under strict electrocardiographic monitoring, in particular in the elderly or at the start of treatment. Lidocaine Interactions with propranolol, metoprolol and nadolol have been described. Increased lidocaine plasma concentrations with a possible augmentation of undesirable neurological and cardiac effects (decreased lidocaine metabolism in the liver). Dosage of lidocaine should be adjusted. Clinical and ECG monitoring and monitoring of lidocaine plasma concentrations during the beta-blocker therapy and after its discontinuation is recommended. Iodine-containing contrast media In the event of shock or hypotension caused by iodine-containing contrast media, beta-blockers decrease the cardiovascular compensation reactions. Whenever possible, beta-blocker therapy should be discontinued prior to radiological examination using contrast media. If it is necessary to continue beta-blocker therapy, the examination should be performed only if admission to intensive care unit is possible. Cimetidine, hydralazine and alcohol These drugs induce increased plasma concentrations of beta-blockers with hepatic metabolism. Combinations to be taken into consideration Calcium channel blockers: dihydropyridines such as nifedipine Hypotension and heart failure in patients with latent or uncontrolled heart failure (negative inotropic effect of dihydropyridines in vitro, varying according to the product concerned and probably additive to the negative inotropic effect of beta-blockers). Beta-blocker therapy may minimize the reflex sympathetic reaction after an excessive haemodynamic stress. Non-steroidal anti-inflammatory drugs (NSAIDs) Decreased anti -hypertensive effect (inhibition of vasodilative prostaglandins by NSAIDs and water and sodium retention with NSAID-pyrazolone derivatives). Sympathomimetic agents Risk of decreased effect of beta-blockers.

7 Tricyclic antidepressants related to imipramine and neuroleptics Increased antihypertensive effect and risk of orthostatic hypotension (additive effect). Corticosteroids and tetracosactides Decreased antihypertensive effect (water and sodium retention). Mefloquine Risk of bradycardia (additive bradycardic effect). Clonidine After abrupt discontinuation of clonidine while taking betaxolol the blood pressure could increase excessively (rebound hypertension). Therefore clonidine should only be discontinued when a few days earlier betaxolol has been discontinued first. Clonidine can then be gradually discontinued. 4.6 Fertility, pregnancy and lactation Pregnancy There are insufficient data on the use of betaxolol in pregnant women to assess its potential harmfulness. Animal studies have not shown evidence of teratogenicity or other direct or indirect harmful effects at therapeutic doses (see section 5.3). On the basis of its pharmacodynamic properties, adverse effects may occur in the foetus and newborn infanrt (especially hypoglycaemia, hypotension, bradycardia and resporatory distress). Due to lack of experience, the use of betaxolol during pregnancy is not recommended unless the potential benefits of the treatment outweigh the risks. Breast-feeding Betaxolol is excreted in breast milk. The quantities in milk may be high enough to cause pharmacological effects, such as bradycardia and hypoglycaemia, in the child. Therefore lactation is not recommended during adminstration of Betaxolol Hydrochloride. Fertility No adverse effects on fertility known. 4.7 Effects on ability to drive and use machines There are no studies evaluating the effect of betaxolol on the ability to drive. When driving vehicles or operating machines, an occasional occurrence of dizziness and fatigue should be taken into account. 4.8 Undesirable effects In order to characterise the frequency of undesirable effects, the following terminology will be used: Frequency estimate: Very common ( 1/10); ( 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). System Organ Class Metabolism and nutrition disorders Very rare Adverse drug reaction Hypoglycaemia, hyperglycaemia.

8 System Organ Class Psychiatric disorders Rare Very rare Nervous system disorders Very rare Not known Eye disorders Very rare Cardiac disorders Rare Vascular disorders Rare Respiratory, thoracic and mediastinal disorders Rare Gastrointestinal disorders Skin and subcutaneous tissue disorders Rare Not known Reproductive system and breast disorders Adverse drug reaction Asthenia, insomnia Depression Hallucinations, confusion, nightmares Especially in early treatment phase fatigue, dizziness, headache and sweating Distal paraesthesia lethargy Impaired vision Bradycardia, possibly severe bradycardia Heart failure, drop in blood pressure, atrioventricular conduction time shortened, or aggravation of existing atrioventricular block Cold extremities Raynaud's syndrome, aggravation of existing intermittent claudication Bronchospasm Gastralgia, diarrhoea, nausea and vomiting Allergic skin reactions (redness, itching, rash), alopecia Psoriasis aggravation Urticaria Impotence Investigations:

9 Rarely an occurrence of antinuclear antibodies has been observed: these have been associated only with clinical signs such as systemic lupus erythematosus in exceptional cases and they have resolved after the treatment discontinuation. During betaxolol treatment lipid metabolism disorders may occur (decrease in HDL-cholesterol, increased triglycerides). 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 het Nederlands Bijwerkingen Centrum Lareb, website: Overdose Symptoms Symptoms of overdose: severe hypotension, bradycardia up to cardiac arrest, acute cardiac failure, cardiogenic shock, bronchospasm and occasionally generalised seizures. Management In the event of life threatening bradycardia or an excessive drop in blood pressure, the following medicines could be administered: atropine glucagon sympatheticomimetics depending on weight and effect: dopamine, dobutamine, orciprenaline and adrenaline In case of bronchospasm, beta 2 -agonists as an aerosol (in case of insufficient effect also intravenously) or aminophylline i.v. could be administered. In case of generalised seizures slow intravenous administration of diazepam i.v. is recommended. In haemodialysis or peritoneal dialysis betaxolol and its metabolites could be eliminated only to a little extent. In the event of cardiac decompensation in the newborn of a mother treated with beta-blockers: glucagon hospitalisation in a neonatal intensive care unit isoprenaline and dobutamine: prolonged treatment usually with high doses requiring specialised monitoring 5. PHARMACOLOGICAL PROPERTIES 5.1 Pharmacodynamic properties Pharmacotherapeutic group: Beta blocking agents, selective, ATC code: C07AB05. Betaxolol is a cardioselective beta 1 -adrenoceptor blocking agent with a long duration of action. The blocking activity is measurable for 24 hours after oral administration of 20 mg betaxolol. Following administration of therapeutic doses of betaxolol, a significant decrease in arterial blood pressure, heart rate and stroke volume are observed.

10 Betaxolol is characterised by a low membrane stabilising effect and no intrinsic sympathomimetic activity (ISA). Betaxolol does not reduce the renal excretion of sodium. Betaxolol reduces the plasma renin activity. The known effects of beta blockers on blood lipids are less pronounced for betaxolol. 5.2 Pharmacokinetic properties Absorption After oral administration, the active ingredient is completely and rapidly absorbed with minimal first-pass hepatic metabolism in the liver and a high bioavailability of approximately 85%, leading to a small inter and intra-individual variability in blood levels during chronic treatment. Distribution About 50% betaxolol is bound to plasma proteins. The volume of distribution is about 6 L/kg. Biotransformation Betaxolol is metabolised primarily to inactive metabolites, of which 10-15% is excreted unchanged in the urine Elimination Betaxolol has a half-life of hours. 5.3 Preclinical safety data Non-clinical data revealed no special hazards for humans based on conventional studies on safety, pharmacology, repeated dose toxicity, genotoxicity and carcinogenicity. In reproductive toxicity studies in rats and rabbits orally administered betaxolol hydrochloride was associated with adverse effects only at dosages well above the therapeutic dosage (presumably because of the pharmacodynamic effects of high systemic exposure). Teratogenic effects were not observed. 6. PHARMACEUTICAL PARTICULARS 6.1 List of excipients Core Cellulose, microcrystalline (E460) Lactose monohydrate Sodium starch glycolate Silica, colloidal anhydrous (E551) Magnesium stearate (E470b) Film-coating Hypromellose (E464) Titanium dioxide (E171) Macrogol 400 (E1521)

11 6.2 Incompatibilities Not applicable. 6.3 Shelf life 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/Aluminium blisters in cartons. 28, 30 90, 98 and 100 tablets. Not all pack sizes may be marketed. 6.6 Special precautions for disposal No special requirements for disposal. 7. MARKETING AUTHORISATION HOLDER Mylan B.V. Dieselweg LB Bunschoten 8. MARKETING AUTHORISATION NUMBER(S) RVG DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION Datum van eerste verlening van de vergunning: 19 oktober DATE OF REVISION OF THE TEXT De laatste gedeeltelijke wijziging betreft rubrieken 4.5 en 4.8: 18 januari 2018