PRODUCT INFORMATION NAME OF THE MEDICINE: TENSIG 50 mg Tablets. Non-proprietary name: atenolol. Chemical name:

Transcription

1 PRODUCT INFORMATION NAME OF THE MEDICINE: TENSIG 50 mg Tablets Non-proprietary name: atenolol Chemical name: (RS)-4-(2-hydroxy-3-isopropylaminopropoxy)phenylacetamide. CAS: Chemical structure: NH 2 CH 3 H 3 C N H O O OH Molecular Weight = C 14 H 22 N 2 O 3 DESCRIPTION Physical and Chemical characteristics: A white or almost white powder, sparingly soluble in water, soluble in ethanol; slightly soluble in dichloromethane; practically insoluble in ether. M.p. 152 C to 155 C. Excipients: Microcrystalline cellulose, carbomer 974P, calcium hydrogen phosphate, croscarmellose sodium, anhydrous colloidal silica, purified talc, hydrogenated vegetable oil, magnesium stearate. PHARMACOLOGY Atenolol is a beta-1 (cardioselective) beta-blocker, lacking intrinsic sympathomimetic and membrane stabilising activity. Selectivity decreases with increasing dose. Atenolol is a racemic mixture and its activity resides in the S(-) enantiomer. It has an anti-hypertensive effect whose mechanism of action is unknown. It inhibits release of renin by the kidneys and exercise-induced tachycardia. While predominantly blocking beta-1 receptors in cardiac tissue, blockade of beta-2 receptors in the bronchi and bronchioles does occur and may lead TENSIG- Product Information Page 1 of 10

2 to airways obstruction but less than that caused by non-selective beta-blockers. The anti-anginal effect is probably due to reduced myocardial oxygen requirements. The anti-arrhythmic action is attributed to blockade of adrenergic stimulation of cardiac pacemaker potentials. Although atenolol is effective and well tolerated in most ethnic populations, it has been reported that the response may be less in Afro-Caribbean black patients. A dose of 50 mg atenolol orally controls hypertension for 24 hours in patients with normal renal function. Because of their negative inotropic effects, beta-adrenoreceptor blocking agents should be avoided in uncontrolled heart failure. Pharmacokinetics: Analysis of the data of a bioequivalence study of two formulations of atenolol tablets 50 mg, showed there was no statistical differences between the test formulation (Tensig ) and the reference formulation (Tenormin ) in terms of C max, T max, AUC 0-t and AUC 0-. Tensig 50 mg tablets and Tenormin 50 mg tablets are therefore bioequivalent. Absorption: Absorption of atenolol following oral dosing is variable and incomplete (about 50%). Nevertheless, in comparison with most other beta-blockers, its systematic bioavailability is relatively consistent, due to minimal hepatic metabolism. Blood levels are in the range of g/ml following a single oral dose of 100 mg and peak at 2-4 hours. Blood levels are consistent, and the levels after chronic oral administration are in good agreement with those predicted from single dose studies. Distribution: Atenolol is distributed throughout body tissues and approximately 5-15% is bound to plasma. Metabolism: Less than 10% of the dose is eliminated as metabolites, and one urinary metabolite has been identified as a hydroxy derivative. Excretion: Atenolol is predominantly excreted in the urine and the remainder (unabsorbed) is excreted unchanged in the faeces. The plasma half-life is about 6 to 7 hours which is increased in patients with impaired renal function. INDICATIONS All grades of hypertension, including hypertension of renal origin. TENSIG- Product Information Page 2 of 10

3 Frequent disabling angina without evidence of cardiac failure. Cardiac arrhythmias: Oral maintenance treatment following control with intravenous atenolol. Myocardial infarction: Oral treatment following initial intravenous treatment in early intervention (within 12 hours); oral treatment in those patients who present more than 12 hours after suffering an acute myocardial infarction. CONTRAINDICATIONS Allergic disorders, including allergic rhinitis, suggestive of a predisposition to bronchospasm. Anaesthesia with agents that produce myocardial depression (e.g. ether, chloroform, cyclopropane). Bronchospasm.Beta-blockers, including cardioselective beta-blockers such as atenolol, are contra-indicated in patients with a history of airways obstruction or tendency to bronchospasm, as they may cause severe bronchospasm. Congestive heart failure. Hypersensitivity to atenolol or any of the excipients in Tensig tablets. Hypotension. Lactation (see Precautions). Metabolic acidosis. Pregnancy (see Precautions). Right ventricular failure secondary to pulmonary hypertension. Severe peripheral arterial circulatory disturbances. Sick sinus syndrome Significant right ventricular hypertrophy. Sinus bradycardia (less than 45 to 50 beats/minute) or sick sinus syndrome. Second and third degree atrioventricular block. Shock, including cardiogenic and hypovolaemic shock. Untreated phaeochromocytoma. TENSIG- Product Information Page 3 of 10

4 PRECAUTIONS Abrupt withdrawal. Atenolol should not be discontinued abruptly in patients with coronary artery disease. Severe exacerbation of angina and precipitation of myocardial infarction and ventricular arrhmythmias have occurred following abrupt discontinuation of -blockade in patients with ischaemic heart disease. The dosage should therefore be gradually reduced over a period of about 8 to 14 days during which time the patient' s progress should be reassessed. The drug may be temporarily re-instituted if the angina worsens. If the drug must be withdrawn abruptly, close observation is required. In the perioperative period, -blockers should not be withdrawn, unless indicated. Allergic conditions may be exaggerated by -blockade (e.g. allergic rhinitis during the pollen season and allergic reactions to bee and wasp stings). -blockers should not be administered if there is a risk of bronchospasm. Anaesthesia and the perioperative period. -blockade may be beneficial in decreasing the incidence of arrhythmias and myocardial ischaemia during anaesthesia and the postoperative period. It is currently recommended that maintenance -blockade be continued perioperatively. The anaesthetist must be made aware of -blockade because of the potential for interactions with other drugs, resulting in severe bradyarrhythmias and hypotension, the decreased reflex ability to compensate for blood loss, hypovolaemia and regional sympathetic blockade, and the increased propensity for vagal induced bradycardia. lncidents of protracted severe hypotension or difficulty restoring normal cardiac rhythm during anaesthesia have been reported. Modern inhalational anaesthetic agents are generally well tolerated, although older agents (ether, cyclopropane, methoxyflurane, trichlorethylene) were sometimes associated with severe circulatory depression in the presence of - blockade. Antiarrhythmic drugs. Interactions between -blockers and the following antiarrhythmic agents have been reported: class IA agents: disopyramide, and less frequently quinidine; class IB agents: tocainide, mexiletine and lignocaine; class IC agents: flecainide and propaferone (not available in Australia); class III agent: amiodarone; class IV agents. Care should therefore be taken in prescribing Tensig with antiarrhythmic drugs. Bradycardia. If a treated patient develops symptoms which may be attributable to a slow heart rate, the dose may be reduced. Cardiac failure. In some patients with a history of cardiac failure, -blockade depresses myocardial contractility and may precipitate cardiac failure, chronic myocardial insufficiency or unsuspected cardiomyopathy, as may occur in chronic alcoholism. Continuing depression of the myocardium may lead to cardiac failure in patients without a history of cardiac failure. If signs of cardiac failure appear, the patient should be fully digitalised and/or given an ACE inhibitor or vasodilators with or without a diuretic and carefully monitored. If cardiac failure persists, the -blocker should be withdrawn (see Abrupt withdrawal of therapy). TENSIG- Product Information Page 4 of 10

5 Please note that while congestive heart failure has been regarded as a contraindication to the use of -blockers, literature on the experimental use of -adrenergic blocking drugs in this indication is growing. However, additional clinical trials would be required to establish which patients would respond to which drugs; -blockers should therefore not normally be prescribed for heart failure outside of specialist centres. Clonidine. Concurrent use of -blockers and clonidine should be avoided because of the risk of adverse interaction and severe withdrawal symptoms. If administered concomitantly with Tensig, clonidine should not be discontinued until several days after withdrawal of Tensig. Concomitant therapy with calcium antagonists. Hypotension, bradycardia and asystole, particularly in patients with impaired ventricular function and/or SA or AV conduction abnormalities, may occur following concomitant administration of -blockers and calcium antagonists with myocardial depressant and sinus node activity, e.g. verapamil and to a lesser extent diltiazem. Extreme caution should therefore be exercised if such a calcium antagonist and Tensig are administrated together. The dihydropyridine calcium antagonists, e.g. nifedipine, however, have a weaker myocardial depressant effect and can be administered cautiously with -blockers. If excessive hypotension develops, the calcium antagonist should be stopped or the dosage reduced. Diabetes. Glucose metabolism is affected by -blockers which may mask some important premonitory signs of acute hypoglycaemia, such as tachycardia. -blockade may result in the loss of diabetic control and delayed recovery from hypoglycaemia in patients with insulin and non-insulin dependent diabetes, especially labile diabetes, or with a history of spontaneous hypoglycaemia. The dose of insulin or oral hypoglycaemic agent may need to be adjusted. Digitalis/digitalis glycosides. While digitalis/digitalis glycosides and -blockers are commonly used together, there have been reports of excessive bradycardia when digitalis intoxication has been treated with -blockers. Eye and skin reactions. Various skin rashes and conjunctival xerosis have been reported with -blocking agents (see Adverse Effects). Cross-reactions may occur between - blockers; therefore substitutions within the group may not necessarily predude occurrence of symptoms. During the long-term treatment with the -blocking drug, practolol, a specific rash bearing a superficial resemblance to psoriasis was occasionally described. In a number of patients affected, this rash was accompanied by adverse effects on the eye (xerophthalmia and/or keratoconjunctivitis) of varying severity. This condition is called the oculomucocutaneous or practolol syndrome. In a few patients, these eye changes occurred independently of a skin rash. On rare occasions, serous otitis media, sclerosing peritonitis, pericarditis and pleurisy have been reported. Although the practolol syndrome has not been observed in patients taking atenolol, the possibility of such side effects occurring should be borne in mind. More recently an association between Peyronie' s disease (a fibrosing induration of the penis) and various -blockers has been suggested but is not proven. Effect on ability to drive or operate machinery. Use of atenolol is unlikely to result in any TENSIG- Product Information Page 5 of 10

6 impairment of the ability of patients to drive or operate machinery. However, occasional dizziness or fatigue may occur. Euthyroid hyperthyroxinaemia. Elevations of serum free thyroxine (T 4 ) levels may occur as a result of the effects of -blockers on thyroid hormone metabolism. Hence, in the absence of any signs or symptoms of hyperthyroidism, additional investigations should be carried out before establishing a diagnosis of thyrotoxicosis. First degree heart block. Due to negative effect of atenolol on conduction time, caution must be exercised if atenolol is given to patients with first degree heart block. History of anaphylactic reaction. Patients with a history of anaphylactic reaction to a variety of allergens may have a more severe reaction on repeated challenge while taking - blockers. Such patients may not respond to the usual doses of adrenaline used to treat the allergic reactions. Hyperthyroidism. -blockers may mask the clinical signs of developing or continuing hyperthyroidism, resulting in symptomatic improvement without producing any change in thyroid hormone status. Hence, special care should be exercised in hyperthyroid patients who are also receiving Tensig. Other metabolic effects. -adrenergic receptors are involved in the regulation of lipid as well as carbohydrate metabolism. While some -blockers affect the lipid profile adversely, the long-term clinical significance of this change is unknown. Drugs with intrinsic sympathomimetic activity appear to have a lesser effect. Peripheral circulation. Impairment of the peripheral circulation and exacerbation of the symptoms of peripheral vascular disease may result from -blockade. Phaeochromocytoma. An alpha-blocking drug (e.g. phentolamine, phenoxybenzamine) should be administered before administering Tensig to patients with phaeochromocytoma, to avoid exacerbation of hypertension. Prinzmetal angina. Patients with Prinzmetal or variant angina are at risk of exacerbation of coronary artery spasm if treated with -blockers. If treatment with atenolol is essential in such patients, it should only be carried out in a coronary or intensive care unit. Significant cardiomegaly. lmpaired renal function. Haemodynamic changes following -blockade may impair renal function further in patients with severe renal disease. In patients with renal failure, the dose of -blockers, which are excreted mainly by the kidney, may require dose adjustment. Use of catecholamine depleting agents. Concomitant use of drugs such as reserpine and guanethidine requires careful monitoring since the added effect of a -blocker may produce an excessive reduction of the resting sympathetic nervous tone. Use in Pregnancy: Category C Beta-adrenergic blocking agents may cause pharmacological effects such as bradycardia in the fetus and newborn infant. During the later stages of pregnancy and birth, these drugs should be given only after weighing the needs of the mother against the risk to the fetus. TENSIG- Product Information Page 6 of 10

7 In pregnant women, atenolol crosses the placental barrier. Maternal and fetal blood levels of atenolol are approximately equal under steady state conditions. Studies on the use of atenolol in the first trimester have not been carried out and the possibility of fetal injury cannot be ruled out. Atenolol has been administered under close supervision in the third trimester for the treatment of hypertension. Administering atenolol to pregnant women for longer periods, for the management of mild to moderate hypertension, has been associated with intrauterine growth retardation. The anticipated benefits of using of atenolol in women who are, or who may become pregnant, should therefore be weighed against the possible risks, particularly in the first and second trimesters. A dose related increase in embryo/fetal resorptions in rats at doses equal to or greater than 50 mg/kg has been observed with atenolol. While similar effects were not seen in rabbits, the compound was not evaluated in rabbits at doses above 25 mg/kg. Use in Lactation: Atenolol passes into breast milk and is found in significant concentrations. Breast-fed infants, whose mothers are taking atenolol, should therefore be carefully observed and breast-feeding immediately discontinued if signs of beta-blockade, e.g. bradycardia, occur. INTERACTIONS WITH OTHER MEDICINES Anaesthetics: The anaesthetics e.g. ether, chloroform, cyclopropane, methoxyflurane and trichlorethylene are contraindicated with atenolol (see Precautions - Anaesthesia and the perioperative period). Antiarrhythmic drugs: Disopyramide, quinidine, tocainide, mexiletine, lignocaine, flecainide, propaferone (not available in Australia), amiodarone and class IV antiarrhythmic agents (see Precautions - Antiarrhythmic drugs). Calcium Antagonists with myocardial depressant effects: Verapamil, diltiazem and nifedipine (see Precautions - Concomitant therapy with calcium antagonists). Catecholamine Depleting Agents: Resperine and guanethidine (see Precautions - Use of catecholamine depleting agents). Clonidine (see Precautions - Clonidine). Digitalis/digitalis glycosides (see Precautions - Digitalis/digitalis glycosides). Insulin and oral hypoglycaemics (see Precautions - Diabetes). Sympathomimetic Agents Concomitant use of sympathomimetic agents, e.g. adrenaline may counteract the effects of beta-blockers. TENSIG- Product Information Page 7 of 10

8 Prostaglandin Synthetase Inhibiting Drugs Concomitant use of prostaglandin synthetase inhibiting drugs, e.g. ibuprofen and indomethacin, may decrease the hypotensive effects of beta-blockers. ADVERSE EFFECTS Adverse effects, including mild and transient reactions, may occur in up to 10% of patients. More common reactions Gastrointestinal: dry mouth, gastrointestinal disturbances including indigestion and constipation. Nervous system: fatigue, dizziness. Respiratory system: wheezing, bronchospasm (see Contraindications). Less common reactions Biochemical abnormalities: increases in AST, blood urea and serum creatinine. Cardiovascular system: bradycardia, left ventricular insufficiency, intermittent claudication may occur if already present, postural hypotension (which may be associated with syncope), intermittent claudication may occur if already present, Raynaud' s phenomonen, cold extremities, deterioration in heart failure, heart block. Skin: rash, alopecia, psoriasform skin reactions, exacerbation of psoriasis. Gastrointestinal: diarrhoea. Elevations of transaminase levels have been seen infrequently, rare cases of hepatic toxicity including intrahepatic cholestasis have been reported. Genitourinary: impotence. Musculoskeletal: ataxia. Nervous system: vivid dreams, nightmares, confusion, paraesthesia, tinnitus, vertigo, malaise, headache, insomnia, mood changes. Ocular: dry eyes, visual disturbances. Psychiatric: hallucinations, depression, psychoses. Respiratory: asthma, bronchospasm (See CONTRAINDICATIONS), dyspnoea, nasal congestion. Haematology: thrombocytopenia, purpura. An increase in Anti-Nuclear Antibodies (ANA) has been observed, however the clinical relevance of this observation is not clear. Severe or life-threatening reactions Myocardial insufficiency may require treatment with digitalis and diuretics. Bradycardia may respond to atropine. Bronchospasm may be reversed with a beta-2 stimulant. Hypotension, if severe, may require treatment with a vasopressor. DOSAGE AND ADMINISTRATION Hypertension, Adults: Commence treatment with Tensig 50 mg once daily, increasing, if necessary, in daily dose increments of 50 mg, at weekly intervals, to a maximum of 200 mg daily. Doses of 50 mg to 100 mg may be taken once daily, doses above 100 mg are taken in divided doses. If further reduction in blood pressure is required, Tensig may be combined with other antihypertensive agents, taking care that no interaction is involved (see Interactions with other medicines and Precautions). Patients can be changed over to Tensig from other antihypertensive agents, except clonidine (see Interactions with other medicines and TENSIG- Product Information Page 8 of 10

9 Precautions). Angina pectoris. Commence treatment with Tensig 50 mg daily, increasing, if necessary, to 100 mg daily as a single or divided dose. Increasing the dose further is unlikely to lead to additional benefit. Cardiac arrhythmias. Following control with intravenous atenolol, a suitable oral maintenance dosage is 50 mg to 100 mg daily. Acute myocardial infarction. For early intervention (within 12 hours), initial treatment with intravenous atenolol is followed by Tensig 50 mg orally 15 minutes and 12 hours later and thence 100 mg orally once daily for two days. Maintenance oral therapy of Tensig 50 mg daily is recommended for 1 to 3 years following myocardial infarction, beginning after early intervention, or immediately in those patients who present more than 12 hours after suffering an acute myocardial infarction. If bradycardia and/or hypotension requiring treatment or any other untoward effects occur, Tensig should be discontinued. Atenolol reduces infarct size, the incidence of ventricular dysrhythmias; the need for opiate analgesics and mortality in the first 7 days post infarction with most of the benefit occurring in the first 48 hours. Other -blocker trials suggest there is a significant reduction in mortality and a reduced incidence of non-fatal re-infarction if administration of the -blocker is continued for 1 to 3 years. lmpaired renal function. Dosage adjustment is necessary in severe renal impairment, as atenolol is excreted via the kidneys. Significant accumulation of atenolol does not occur at a creatinine clearance greater than 35 ml/minute/1.73 m 2 (normal range is 100 to 150 ml/minute/1.73 m 2 ). For patients with a creatinine clearance of 15 to 35 ml/minute/1.73 m 2 (equivalent to serum creatinine of 300 to 600 micromol/l), the oral dose is 50 mg daily or 100 mg on alternate days. For patients with a creatinine clearance less than 15 ml/minute/l.73 m 2 (equivalent to serum creatinine of greater than 600 micromol/l), the oral dose is 50 mg on alternate days or 100 mg every fourth day. Dialysis patients should be given 50 mg orally after each dialysis. As marked falls in blood pressure can occur, administration should be carried out under supervision in hospital. Use in Elderly Patients. The dosage levels and regimen for elderly patients is likely to be smaller and different, especially in the presence of impaired renal function. Use in Children. Tensig is not recommended for children, as there is no experience of its use in this age group. OVERDOSAGE Overdosage with atenolol has not been reported. Symptoms: Severe bradycardia and hypotension commonly occur following overdosage with other -blockers, as may acute heart failure and bronchospasm. TENSIG- Product Information Page 9 of 10

10 Treatment: Severe bradycardia: 1 to 2 mg of atropine may be administered intravenously to induce vagal blockade. Should bradycardia persist, intravenous isoprenaline (25 microgram initially) or orciprenaline (0.5 mg given by slow intravenous injection) may be given. The use of a cardiac pacemaker may be considered in refractory cases. Hypotension: A sympathomimetic amine, e.g. noradrenaline should counter severe hypotension. The use of glucagon hydrochloride should be considered in refractocy cases. Bronchospasm: A -stimulant, e.g. salbutamol or terbutaline, or aminophylline may be considered for treatment of bronchospasm. Acute cardiac failure: Immediately institute conventional therapy with digitalis, diuretics and oxygen. The use of intravenous isoprenaline, followed if necessary by glucagon hydrochloride or intravenous aminophylline, should be considered in refractory cases. PRESENTATION AND STORAGE CONDITIONS A white to off-white, round, uncoated tablet, one side embossed with T 50, the other side with a break bar, each containing 50mg atenolol, in calendar packs of 30 tablets. Storage: Store below 25 C. Protect from heat, light and moisture. POISON SCHEDULE OF THE MEDICINE S4 NAME AND ADDRESS OF THE SPONSOR Aspen Pharma Pty Ltd Chandos Street, St. Leonards NSW 2065 Australia DATE OF FIRST INCLUSION ON THE AUSTRALIAN REGISTER OF THERAPEUTIC GOODS (ARTG) May DATE OF MOST RECENT AMENDMENT 1 May 2014 TENSIG- Product Information Page 10 of 10