SUMMARY OF PRODUCT CHARACTERISTICS NAME OF THE MEDICINAL PRODUCT BETAC® 20 mg film-coated tablets
2. QUALITATIVE AND QUANTITATIVE COMPOSITION
Each film-coated tablet contains 20 mg betaxolol hydrochloride. Excipients: One tablet contains 100 mg lactose monohydrate. For a full list of excipients, see section 6.1. 3. PHARMACEUTICAL
Film-coated tablet White, round, convex, scored film-coated tablet. The tablet can be divided into equal halves. 4. CLINICAL PARTICULARS 4.1 Therapeutic indications
Betaxolol is indicated for the treatment of hypertension. Betaxolol is indicated as prophylactic treatment of stable effort angina pectoris. 4.2 Posology and method of administration Betaxolol is administered once a day. Food does not affect the behaviour of the drug. Hypertension Usual dose is 20 mg once a day. In some patients the efficacy was proven with 10 mg daily. Prophylactic treatment of stable effort angina pectoris The usual dose is 20 mg once daily. In some cases the daily dose can be increased to 40 mg depending on the clinical response. Renal failure Renal dysfunction results in a decrease in betaxolol clearance. The dose must be adjusted according to the renal impairment. In patients with creatinine clearance more than 20 ml/min the dose does not need to be adjusted, but clinical supervision is recommended in the first week after initiation of therapy. In patients with sever renal impairment (creatinine clearance less 20 ml/min) and in patient on dialysis (haemodialysis or peritoneal dialysis) initial dose 5 mg/day is recommended irrespective of frequency and time of dialysis. Increases by 5 milligrams every 2 weeks to a maximum of 20 milligrams daily are recommended (see section 4.4). Hepatic failure No dose adjustment is necessary, but clinical supervision is recommended at therapy initiation. Elderly
Geriatric patients are more susceptible to bradycardia, one of the adverse reactions of betaxolol, which appears to be dose related. Reduction of initial dose to 5 milligrams once daily should be considered (see section 4.4). Children and adolescents (<18 years) Betaxolol is not recommended for use in children and adolescents below 18 years due to a lack of data on safety and efficacy (see section 4.4). 4.3 Contraindications Betac is also contraindicated in the following cases:
Hypersensitivity to betaxolol or to any other excipients of the tablet. Untreated heart failure Cardiogenic shock Second and third degree AV block (without pacemaker) Severe sinus bradycardia (< 45 – 50 beats/min) Prinzmetal’s (variant) angina pectoris (it’s pure form in monotherapy (see section 4.4.) Sino-atrial dysfunction (including sino-atrial block) Severe forms of Raynaud syndrome and peripheral arterial disease Untreated pheochromocytoma Hypotension Metabolic acidosis Co-administration of floctafenine or sultopride History of anaphylactic shock severe form of bronchial asthma and chronic obstructive pulmonary disease
4.4 Special warnings and precautions for use Warning Abrupt discontinuation of treatment should be avoided in patients with angina pectoris. Abrupt discontinuation can severely affect the of heart rhythm, or can cause myocardial infarction or sudden cardiac death. Cautions Discontinuation of therapy Abrupt discontinuation of treatment should be avoided especially in patients with ischemic heart disease. Dose must be gradually decreased within one to two weeks. Substitution therapy should be started at the same time, if needed, to avoid the aggravation of angina pectoris. Asthma and chronic obstructive pulmonary disease Beta blockers may be administered only in the patients with moderate forms of the disease; beta- 1 selective beta blockers in as low as possible initial doses must be chosen. Functional pulmonary tests before initiation of treatment are recommended. If asthma attack occurs during treatment, beta-2 selective bronchodilatators may be used. Heart failure
In patients with heart failure controlled by treatment, if needed, betaxolol may be administered in gradually increasing doses and under close medicinal observation. Very low doses should be used on initiation of treatment. Bradycardia Dose must be decreased if the patient’s resting heart rate is less than 50-55 beats per minute and bradycardia-related symptoms are observed. First degree atrio-ventricular (AV) block Due to negative dromotropic effect of beta blockers, betaxolol should be administered with caution in patients with first degree AV block. Prinzmetal´s (variant) angina pectoris Number and duration of angina attacks may be increased during administration of beta blockers in patients with Prinzmetal´s type of angina. Cardioselective beta-blockers may be used in mild and mixed forms provided that a vasodilatation agent is administered simultaneously. Peripheral arterial disease Beta blockers can cause aggravation of the condition in patients suffering from peripheral arterial diseases (Raynaud syndrome or disease, arteritis or chronic occlusive arterial disease of lower limbs). Pheochromocytoma Use of beta-blockers in treatment of hypertension caused by treated pheochromocytoma requires close control of patient’s blood pressure Children and adolescents (<18 years) Safety and efficiency in paediatric patients have not been established. Therefore betaxolol is not recommended in children (see section 4.2). Elderly In elderly, the therapy should be started with low doses under close monitoring of the patient (see section 4.2). Patients with renal impairment In patients with renal failure the dose should be adjusted according to the serum creatinine level and creatinine clearance (see section 4.2). Diabetic patients Patients should be warned that at the beginning of the therapy monitoring of glucose level is necessary. Initial symptoms of hypoglycaemia may be masked especially tachycardia, palpitation and sweating (see section 4.5 and 4.8). Psoriasis The effect of administration of betablockers in patients with psoriasis must be carefully considered, as they can cause aggravation of the condition (see section 4.8).
Hypersensitivity reactions In patients predisposed to severe anaphylactic reaction of any origin, especially to iodine-containing contrast substances or floctafenine (see section 4.5) or during desensibilisation therapy, treatment with betablockers can lead to exacerbation of allergic reaction and resistance to adrenaline therapy in usual doses. General anaesthesia Betablockers decrease reflex tachycardia and increase risk of hypotension. Continuous treatment with beta-blockers reduces the risk of arrhythmia, myocardial ischemia and hypertensive crisis. If the patient is taking a beta-blocker, the anaesthesiologist should be informed on it.
If the discontinuation of treatment with betablockers is needed, 48-hour interval is
sufficient for the achievement of sensitivity to catecholamines.
In some patients therapy cannot be discontinued:
- In patients with coronary insufficiency and possible risk associated with abrupt
discontinuation of betablocker therapy it is recommended to continue in treatment until the surgery.
- In emergencies or if discontinuation of therapy is not possible, patient must be
protected from parasympathic reaction by adequate atropine premedication, repeated as necessary. Anaesthetic agents with the lowest possible cardiodepressive effect should be used.
Risk of anaphylaxis must be taken into consideration
Ophthalmology β-adrenergic block reduces intraocular pressure and may interfere in screening test for glaucoma. Ophthalmologist should be informed that patient is taking betaxolol. Patients receiving intraocular and also general treatment with beta-blocker should be more strictly monitored due to potential additive effect. Thyrotoxicosis Betablockers may mask cardiovascular signs of thyrotoxicosis. Sportsmen Sportsmen should be advised that this medicine contains active substance that can cause positive reaction in anti-doping testing. Excipients This medicine 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 Floctaphenine: In case of floctaphenine-induced shock or hypotension, beta-blockers decrease the cardio-vascular compensatory reactions.
Sultopride: The administration of betaxolol and sultopride can cause automatism impairment (severe bradycardia) due to cumulative bradycardic effects. Not recommended combinations Amiodarone: Co-administration of betaxolol and amiodarone may lead to impairment of cardiac contractility, automatism and conduction (suppression of sympatical compensatory mechanism). Digitalis glycosides: This interaction may prolong the atrio-ventricular conduction time and lead to bradycardia.
Combinations which require caution
Volatile halogenated anaesthetics: Betablockers decrease cardiovascular compensatory reactions. (Beta-adrenergic inhibition can be removed during intervention by using beta-mimetics.) The abrupt discontinuation of the administration of beta-blockers should generally be avoided. The anaesthesiologist must be informed on the treatment with betablockers. Calcium channel blockers (bepridil, diltiazem, verapamil, mibefradil): The co-administration of betaxolol and calcium channel blockers may affect the cardiac automatism (leading to excessive bradycardia, sinus arrest), the AV conductivity and may cause to heart failure (synergic effect). Antiarrhytmics (propaphenon and class Ia: chinidine, hydroxychinidine and disopyramide): Cardiac contractility, automatism and conductivity (suppression of compensatory reactions) may be affected by the simultaneous administration. Baclofen: increased antihypertensive effect. Blood pressure should be monitored and the dose of antihypertensive agent adjusted, if necessary. Insulin and hypoglycaemic sulphonamides: All betablockers can mask some symptoms of hypoglycaemia (e.g. palpitations and tachycardia). The patient should be warned on the necessity of glucose level monitoring especially at the beginning of the treatment. Lidocaine: Interactions with propranolol, metoprolol and nadolol have been described. Increased lidocaine plasma concentrations with possible increase of neurological and cardiological undesirable effects (due decreased lidocaine metabolism of in the liver) were reported. Lidocaine dose should be adjusted. If it is possible, plasma concentration of lidocaine should be monitored during treatment with betablockers and following their discontinuation and clinical and electrocardiograph monitoring should be performed. Iodine containing contrast substances: In case of shock or hypotension caused by iodine containing contrast substances, betablockers cause a reduction of cardiovascular compensatory reactions. Whenever possible, treatment with betablockers should be discontinued before radiodiagnostic contrast examination. If continuation of the treatment is needed, examination should be performed only if intensive care unit is readily available.
Combination which should be considered
Non steroidal anti-inflammatory drugs: Decrease of antihypertensive effect (inhibition of vasodilatating prostaglandins by non steroidal anti-inflammatory drugs) and water and sodium retention with pyrazolone derivatives. Blockers of calcium canal (dihydropyridines as nifedipine): hypotension, heart failure in patients with latent or untreated heart failure (negative inotropic effect of dihydropyridines in vitro, that depends on corresponding product and probably increases negative inotropic effect of betablockers). Imipramine-type antidepressants (tricyclic), neuroleptics: Increased antihypertensive effect and risk of postural hypotension (additive effect). Corticosteroids and tetracosactides: decreased antihypertensive effect (water and sodium retention by corticosteroids). Mefloquine: Risk of bradycardia (additive effect inducing bradycardia). Sympathomimetics: Risk of decreasing betablocker´s effect. 4.6 Pregnancy and lactation Pregnancy Teratogenicity: No teratogenic effects were observed in animal studies. No teratogenic effects were reported in humans. Beta-blockers decrease placental perfusion, which may cause intra-uterine death, still birth, abortion or premature labour. Moreover the foetus may have adverse effects (particularly hypoglycaemia and bradycardia). Newborns: Beta-blockers effects are seen in newborns for several days after birth if the mothers are treated with beta blockers. There is a risk of cardiac and pulmonary complications in postnatal period. If heart failure occurs in newborn, hospitalization in intensive care unit is necessary (see section 4.9.) and plasma expanders must be avoided (due to the risk of acute pulmonary oedema). Bradycardia, respiratory distress syndrome and hypoglycaemia were also reported. Careful monitoring of newborns is recommended (heart rate, glycaemia) in neonatal intensive care unit during first three to five days after delivery. Administration of betaxolol is not recommended during pregnancy unless therapeutic effect exceeds the possible risks. Breast feeding Betaxolol is excreted in breast milk (see section 5.2.). Risk of bradycardia and hypoglycaemia in nurse-child was not evaluated, breast feeding is therefore not recommended. 4.7 Effects on ability to drive and use machines Studies evaluating influence of betaxolol on ability to drive are not available. Occasional dizziness or fatigue must be considered when driving a car or operating machinery. 4.8 Undesirable effects Betaxolol is generally well tolerated. Side effects are mild and they rarely demand discontinuation of the drug. The undesirable effects below are defined as follows: 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), including isolated reports Metabolism and nutrition disorders: Very rare: hypoglycaemia, hyperglycaemia. Psychiatric disorders: Common: asthenia, insomnia. Rare: depression. Very rare: hallucination, confusion, nightmares. Nervous system disorders: Common: dizziness, headache. Very rare: distal paraestesia. Eye disorders: Very rare: blurred vision. Cardiac disorders: Common: bradycardia including severe bradycardia. Rare: cardiac failure, decrease of blood pressure, or retardation of AV conduction or aggravation of existing AV block. Vascular disorders: Common: cold extremities. Rare: Raynaud´s syndrome, aggravation of existing intermittent claudication Respiratory, thoracic and mediastinal disorders: Rare: bronchospasm. Gastrointestinal disorders: Common: gastralgia, diarrhoea, nausea and vomiting. Skin and subcutaneous tissuedisorders: Rare: various types skin reactions including psoriasis eruption or aggravation of psoriasis (see section 4.4). Reproductive system and breast disorders: Common: impotence.
Investigations: In rare cases occurrence of antinuclear antibodies has been reported; these are in rare cases accompanied with clinical symptoms as systemic lupus erythematosus and disappear after discontinuation of therapy. 4.9 Overdose Signs of overdose are bradycardia, hypotension, bronchospasm, acute heart failure In case of bradycardia or excessive decrease of blood pressure the following medicines should be administered:
Atropine 1 – 2 mg i.v. glucagone 1mg, repeatedly, if necessary furthermore, if needed isoprenaline 25 µg by slow injection or dobutamine with the dose
In case of heart failure of neonate born to beta-blocker taking mother the following treatment should be administered
glucagone 0,3 mg/kg hospitalization in intensive care unit for newborns isoprenaline and dobutamine: prolonged therapy usually with high doses requiring
5. PHARMACOLOGICAL PROPERTIES 5.1 Pharmacodynamic properties Pharmacotherapeutic group: Beta blocking agents, selective ATC code: C07AB05
Betaxolol is a cardioselective beta-adrenoceptor blocking agent. The drug is characterized by a long duration of action, no intrinsic sympathomimetic activity, weak membrane stabilizing activity, and low lipid solubility. Betaxolol induces reduction of parietal pressure, increase coronary filling time (diastolic prolongation) and reduction of myocardial oxygen consumption. These effects are connected with mild negative inotropic and dromotropic effect. Betaxolol decreases also renin and aldosterone level, thereby it manages peripheral arterial resistance. 5.2 Pharmacokinetic properties Absorption Betaxolol is absorbed completely and quickly after oral administration. First-pass metabolism is very small. Bioavailability is high, approximately 85%; that leads to small intra- and inter- individually variability during long-term treatment. The time to reach peak plasma concentration (Tmax) for betaxolol is about 3 hours. Protein binding is about 50%; therefore the risk of drug interactions is limited. Metabolism The volume of distribution is about 6 l/kg. The most of betaxolol is metabolised to inactive metabolites. Active metabolites are cardioselective as well. Elimination Just 10 – 15% of given drug is excreted unchanged by urine. The elimination half-life is between 15 and 20 hours, which allows betaxolol to be administered once a day.
5.3 Preclinical safety data Its long term administration in several animal species has shown that betaxolol is well tolerated and that it has a wide therapeutic safety margin. Mutagenicity and carcinogenicity were not proved in pre-clinical studies. Studies in animals did not show teratogenic effect of betaxolol. In human there is not enough data available. No proofs of teratogenic potential of betaxolol in human were identified. 6. PHARMACEUTICAL PARTICULARS excipients
Core: Lactose monohydrate, Cellulose microcrystalline, Sodium starch glycolate (type A), Colloidal anhydrous silica, Magnesium stearate, Tablet coating: Titanium oxide (E171), Polyvinyl alcohol, Talc, Lecithin, Xanthan gum. 6.2 Incompatibilities Not applicable. 6.3 Shelf
3 years 6.4 Special precautions for storage Do not store above 25ºC. Store in the original package to protect tablets from light and moisture. 6.5 Nature and contents of container 10 tablets are folded into PVC-Aluminium blister. Boxes of 30, 50 and 100 tablets. Not all pack sizes may be marketed. 6.6 Special precautions for use and disposal No special requirements. 7. MARKETING AUTHORISATION HOLDER
Medochemie Ltd, 1-10 Constantinoupoleos street, 3011 Limassol, Cyprus 8. MARKETING AUTHORISATION NUMBER DATE OF FIRST AUTHORISATION/RENEWAL OF AUTHORISATION
April 20, 2004 / May 31, 2008 10. DATE OF REVISION OF THE TEXT September 2008
Kansanterveystieteen laitos Department of Public Health PL 41 (Mannerheimintie 172) 00014 Helsingin Yliopisto Kansanterveystieteen laitos Department of Public Health Julkaisut 2009 Publications 2009 Sirkka Koskinen Kansanterveystieteen laitos Department of Public Health P.O. Box 41 (Mannerheimintie 172) FIN-00014 University of Helsinki 9.10.2009 Kansanterveystieteen laitos Departm
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