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AUSTRALIAN PRODUCT INFORMATION – LOPRESOR (METOPROLOL
TARTRATE) TABLET
1 NAME OF THE MEDICINE
Metoprolol tartrate.
2 QUALITATIVE AND QUANTITATIVE COMPOSITION
Lopresor tablets contain either 50 mg or 100 mg of metoprolol tartrate. Excipients with known effect: 50 mg tablets contain lactose. They also contain silica-colloidal anhydrous, cellulose - microcrystalline, povidone, sodium starch glycollate, magnesium stearate, hypromellose, and titanium dioxide. The 100 mg strength tablets also contain shellac and indigo carmine CI73015. The 50 mg strength tablets also contain lactose, polysorbate 80, talc - purified, and iron oxide red CI77491.
3 PHARMACEUTICAL FORM
Tablets 50mg: rose pink, heart-shaped, film-coated, marked HM, CIBA on reverse. Tablets 100mg: light blue, heart-shaped, film-coated, scored, marked IP, CIBA on reverse.
4 CLINICAL PARTICULARS
4.1 THERAPEUTIC INDICATIONS
− Hypertension: as monotherapy or for use in combination with other antihypertensives. − Angina pectoris: for long-term prophylaxis. Glyceryl trinitrate should be employed if necessary for alleviating acute attacks. − Confirmed or suspected myocardial infarction. − Prevention of migraine.
4.2 DOSE AND METHOD OF ADMINISTRATION
Dosage The maximum daily dose should not exceed 400 mg. Although twice daily dosage is optimal, in those patients whose maintenance dosage is 150 mg daily or less, it may be administered as a single dose. The dosage should be adapted to the requirements of the individual patient. The following dosage recommendations may be taken as a guide:
Hypertension: Mild: 50 or 100 mg, given once daily for one week Moderate to severe: 50 or 100 mg, given twice daily for one week Maintenance: 50 or 100 mg, given once or twice daily. Some patients may respond to 50 mg. A larger number will respond to 100 mg, given once daily as initial and maintenance therapy. Response is rarely improved by increasing the dose beyond 200 mg daily Angina pectoris: 50 mg to 100 mg, given two or three times daily Myocardial infarction: The recommended dosage can be reduced depending on the haemodynamic status of the patient. Initially, therapy should commence with 50 mg twice daily and be continued for 48 hours Maintenance: generally 100 mg, given twice daily Prevention of migraine: 100 to 150 mg, given in two divided doses (morning and evening) Method of Administration The film coated tablets should be swallowed whole with a glass of water. Lopresor should always be taken in standard relation to meals. For example, if it is decided that the patient should take Lopresor with breakfast, the patient should continue to take it with breakfast throughout the course of therapy.
4.3 CONTRAINDICATIONS
− known hypersensitivity to metoprolol and related derivatives − hypersensitivity to any of the excipients in Lopresor − sensitivity to other beta-blockers (cross-sensitivity between beta-blockers can occur) − atrioventricular block of second or third degree − congestive heart failure − sinus bradycardia (less than 45 to 50 beats/minute) − sick-sinus syndrome − severe peripheral arterial circulatory disorders
Beta-blockers, including Lopresor, should not be used in patients with untreated congestive heart failure. This condition should first be stabilised. Myocardial infarction: In patients with myocardial infarction, if significant hypotension occurs, Lopresor should be discontinued, and the hemodynamic status of the patient and the extent of myocardial ischemia carefully assessed. Intensive hemodynamic monitoring may be required and appropriate treatment modalities should be instituted. If hypotension is associated with significant bradycardia or atrioventricular block, treatment should be directed at reversing these. Prinzmetal angina: There is a risk of exacerbating the number and duration of coronary artery spasms if patients with Prinzmetal angina or variant angina pectoris are treated with a beta-blocker, including Lopresor. If this treatment is essential, it should only be undertaken in a Coronary or Intensive Care Unit. Conduction disorders: Very rarely a pre-existing A-V conduction disorder of moderate degree may become aggravated (possibly leading to A-V block). Lopresor should be administered with caution to patients with first degree A-V block (see Section 4.3 - CONTRAINDICATIONS). Phaeochromocytoma: In patients known to be, or suspected to be, suffering from a phaeochromocytoma, Lopresor should always be given in combination with an alpha-blocker (e.g. phentolamine or phenoxybenzamine) and only after the alpha blocker has been initiated to avoid exacerbation of hypertension. Diabetes: Lopresor should be used with caution in patients with diabetes mellitus, especially those who are receiving insulin or oral hypoglycaemic agents. Diabetic patients should be warned that beta- blockers, including Lopresor, affect glucose metabolism and may mask some important premonitory signs of acute hypoglycaemia, such as tachycardia. In patients with insulin or non-insulin dependent diabetes, especially labile diabetes, or with a history of spontaneous hypoglycaemia, beta-blockade may result in the loss of diabetic control and delayed recovery from hypoglycaemia. The dose of insulin or oral hypoglycaemic agent may need adjustment. Diabetic patients receiving Lopresor should be monitored to ensure that diabetes control is maintained. Allergic conditions: Allergic conditions may be exaggerated by beta-blockade (e.g. allergic rhinitis during the pollen season and allergic reactions to bee and wasp stings). Beta-blockers, including Lopresor, should be avoided if there is a risk of bronchospasm.
In patients taking beta-blockers, including Lopresor, anaphylactic shock assumes a more severe form and may be resistant to normal doses of adrenaline. Whenever possible, beta-blockers, including Lopresor, should be avoided in patients who are at increased risk of anaphylaxis. Hyperthyroidism: Because beta-blockers may mask the clinical signs of developing or continuing hyperthyroidism, resulting in symptomatic improvement without any change in thyroid status, special care should be exercised in those patients who are hyperthyroid and are also receiving beta-blockers. Where Lopresor is administered to patients having, or suspected of developing thyrotoxicosis, both thyroid and cardiac function should be monitored closely. Interactions Calcium channel blocker of the verapamil (phenylalkylamine) type should not be given intravenously to patients receiving Lopresor because there is a risk of cardiac arrest in this situation (see Section 4.5- INTERACTIONS WITH OTHER MEDICINES AND OTHER FORMS OF INTERACTIONS) Peripheral circulatory disorders: Beta-blockade may impair the peripheral circulation and exacerbate the symptoms of peripheral arterial circulatory disorders (for example, Raynaud’s disease or phenomenon, intermittent claudication) (see Section 4.3 – CONTRAINDICATIONS). Use in renal impairment Patients with renal impairment may usually be treated with normal doses. In patients with severe renal disease, haemodynamic changes following beta-blockade may impair renal function further. Caution in Lopresor dosing is recommended in patients with severe renal impairment. There is a possibility of accumulation of one of Lopresor’s less active metabolites in patients with a creatinine clearance below 5 mL/min but this accumulation would not influence the beta-blocking properties of metoprolol. Use in hepatic impairment Metoprolol is mainly eliminated by hepatic metabolism (see Section 5.2 – PHARMACOKINETIC PROPERTIES). Therefore, hepatic impairment may increase the systemic bioavailability of metoprolol and reduce its total clearance, leading to increased plasma concentrations. Lopresor blood levels are likely to increase substantially in patients with hepatic impairment. The elimination half-life of metoprolol is considerably prolonged, depending on severity (up to 7.2 h), in patients with liver impairment. Therefore, Lopresor should be initiated at low doses with cautious gradual dose titration according to clinical response. Possible Effects of Treatment: Effects on the heart rate: If the patient develops increasing bradycardia (heart rate less than 50 to 55 beats/min), the dosage of Lopresor should be gradually reduced or treatment gradually withdrawn (see Section 4.3 - CONTRAINDICATIONS).
Use in the elderly Caution in dosing is recommended due to increased likelihood of adverse events (see Section 5.2 – PHARMACOKINETIC PROPERTIES - pharmacokinetics in the elderly). Paediatric use No studies have been performed in paediatric patients. The safety and efficacy of Lopresor in paediatric patients have not been established. Effects on laboratory tests No data available.
4.5 INTERACTIONS WITH OTHER MEDICINES AND OTHER FORMS OF INTERACTIONS
Effect of other medicinal products on metoprolol The effects of Lopresor and other antihypertensive drugs on blood pressure are usually additive. Patients receiving concurrent treatment with catecholamine depleting drugs, other beta-blockers (including those in form of eye drops, such as timolol), or monoamine oxidase (MAO) inhibitors, should be carefully monitored. In addition, possibly significant hypertension may theoretically occur up to 14 days following discontinuation of the concomitant administration with an irreversible MAO inhibitor. The following medicinal products may increase the effect or plasma concentrations of metoprolol Antiarrhythmic drugs Beta-blockers may enhance the negative inotropic and negative chronotropic effect of anti- arrhythmic agents of the quinidine type. Care should be taken when prescribing beta-blockers with antiarrhythmic drugs. Interactions have been reported during concomitant beta-blocker therapy with the Class IA agents, disopyramide, procainamide, ajmaline and less frequently quinidine; Class IB agents, tocainide, mexiletine and lignocaine; Class IC agents, flecainide and propafenone (not available in Australia); the Class III agent, amiodarone; and the Class IV agents (e.g. verapamil). Particularly, in patients with pre-existing sinus node dysfunction, concomitant administration of amiodarone may result in additive electro-physiologic effects including bradycardia, sinus arrest, and atrioventricular block. Antihypertensive Drugs Lopresor enhances the effect of other antihypertensive drugs. The combined effects of Lopresor and other antihypertensive drugs on blood pressure are usually additive. Calcium antagonists The concomitant use of beta-blockers and calcium antagonists with myocardial depressant and sinus node activity, e.g. verapamil and to a lesser extent diltiazem, may cause hypotension, bradycardia and asystole. Extreme caution is required if these drugs have to be used together. A calcium channel blocker of the phenylalkylamine type (e.g. verapamil) should not be administered intravenously to patients receiving Lopresor because there is a risk of cardiac arrest in this situation. Concomitant
administration of a beta-adrenergic antagonist with a calcium channel blocker may produce an additive reduction in myocardial contractility due to negative chronotropic and inotropic effects. Patients taking an oral calcium channel blocker of this type in combination with Lopresor should be closely monitored. The dihydropyridine calcium antagonists (e.g. nifedipine) have a weaker myocardial depressant effect and can be administered cautiously with beta-blockers. If excessive hypotension develops, the calcium antagonist should be stopped or the dosage reduced. CYP2D6 Inhibitors Potent inhibitors of this enzyme may increase the plasma concentration of metoprolol. Strong inhibition of CYP2D6 would result in the change of phenotype into poor metaboliser. Caution should therefore be exercised when co-administering potent CYP2D6 inhibitors with metoprolol. Known clinically significant potent inhibitors of CYP2D6 are antidepressants such as fluvoxamine, fluoxetine, paroxetine, sertraline, bupropion, clomipramine, desipramine antipsychotics such as chlorpromazine, fluphenazine, haloperidol, thioridazine, antiarrhythmics such as quinidine or propafenone, antiretrovirals such as ritonavir, antihistamines such as diphenhydramine, antimalarials such as hydroxychloroquine or quinidine, antifungals such as terbinafine and medications for stomach ulcers such as cimetidine. Hydralazine Concomitant administration of hydralazine may inhibit presystemic metabolism of metoprolol leading to increased concentrations of metoprolol. General anaesthetics The necessity or desirability of withdrawing beta-blocking agents prior to major surgery is controversial. The impaired ability of the heart to respond to reflex adrenergic stimuli may augment the risks of general anaesthesia and surgical procedures. The benefits of continuing a treatment with a beta-blocker should be balanced against the risk of withdrawing it in each patient. In patients receiving beta-blocker therapy, inhalation anaesthetics may enhance the cardiodepressant effect. Beta-blockade may have beneficial effects in decreasing the incidence of arrhythmias and myocardial ischaemia during anaesthesia and the post-operative period. It is currently recommended that maintenance beta-blockade be continued peri-operatively. The anaesthetist must be made aware of beta-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. Incidents 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 beta-blockade. If it is thought necessary to withdraw beta-blocker therapy before surgery, this should be done gradually and completed about 48 hours before anaesthesia.
blockers; however, this is less likely with therapeutic doses of beta1-selective drugs than with non- selective beta-blockers. A watch should be kept for possible negative inotropic and chronotropic effects when metoprolol is given together with calcium antagonists and/or anti-arrhythmic agents. Patients receiving concurrent treatment with sympathetic nervous system inhibitors, other beta- blockers (also in the form of eye drops), or MAO inhibitors should be kept under surveillance. Interactions resulting in effects on other medicines Alcohol Metoprolol may modify the pharmacokinetic behaviour of alcohol when taken concomitantly. Catecholamine-depleting agents Concomitant use of drugs such as reserpine and guanethidine requires careful monitoring since the added effect of a beta-blocker may produce an excessive reduction of the resting sympathetic nervous tone. Anti-adrenergic agents Antihypertensive effect of alpha-adrenergic blockers such as guanethidine, betanidine, reserpine, alpha-methyldopa or clonidine may be potentiated by beta-blockers. Beta- adrenergic blockers may also potentiate the postural hypotensive effect of the first dose of prazosin, probably by preventing reflex tachycardia. Concurrent use of beta-blockers and clonidine should be avoided because of the risk of adverse interaction and severe withdrawal symptoms. If administered concomitantly, the clonidine should not be discontinued until several days after the withdrawal of the beta-blocker (the rebound hypertension associated with clonidine withdrawal can be exacerbated by the presence of a beta-blocker). Furthermore, if both drugs are withdrawn simultaneously, marked rise in blood pressure, and/or arrhythmias may result. Antidiabetic drugs and insulin Beta-blockers may interfere with the usual hemodynamic response to hypoglycemia and produce a rise in blood pressure associated with severe bradycardia. When treating diabetics with beta- blockers, caution is indicated and the dosage of antidiabetic medication may need to be adjusted. Lignocaine Metoprolol may reduce the clearance of other drugs (e.g. lignocaine, leading to increased lignocaine effects). Warfarin A limited number of reports have demonstrated a rise in AUC and concentration of warfarin when taken with another beta-blocker. This could potentially increase the anti-coagulant effect of warfarin.
Ergot alkaloid Concomitant administration with beta-blockers may enhance the vasoconstrictive action of ergot alkaloids. Dipyridamole In general, administration of a beta- blocker should be withheld before dipyridamole testing, with careful monitoring of heart rate following the dipyridamole injection.
4.6 FERTILITY, PREGNANCY AND LACTATION
Effects on fertility The effects of Lopresor on the fertility of humans have not been studied. While metoprolol tartrate showed reversible adverse effects on spermatogenesis (altered morphology and motility) in male rats at less than therapeutic doses, it had no effect on rates of conception in animal fertility studies at up to 11 times the maximum recommended daily dose on a body surface area adjusted basis. Use in pregnancy – Pregnancy Category C There are no adequate and well controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly indicated. Reproduction toxicity studies in mice, rats and rabbits did not indicate teratogenic potential for metoprolol tartarate. Embryotoxicity and/or fetotoxicity in rats and rabbits were noted as increases in preimplantation loss, decreses in the number of viable foetuses per doe, and/or decreses in neonatal survival starting at does of about 300mg/m2 (on a body surface area adjusted basis), similar to the maximum recommended therapeutic dose. High doses were associated with some maternal toxicity, and growth delay of the offspring in utero, which was reflected in minimally lower weights at birth. There is a limited amount of data on the use of metoprolol in pregnant women. Experience with metoprolol in the first trimester of pregnancy is limited, but no foetal malformations attributable to metoprolol have been reported. Beta-blockers may reduce placental perfusion and cause bradycardia in the foetus. During the later stages of pregnancy, these drugs should only be given after weighing the needs of the mother against the risk to the foetus. The lowest possible dose should be used and treatment should be discontinued at least 2 to 3 days before delivery to avoid increased uterine contractility and effects of beta-blockade in the newborn (e.g. bradycardia, hypoglycaemia). Use in lactation The concentration of Metoprolol in breast milk is approximately three times higher than in the mother’s plasma. However, in the normal dose range, the amount of metoprolol ingested via human milk seems to be negligible with regard to its beta-blocking effect on the infant. Nevertheless, breast-fed infants should be closely observed for signs or symptoms of beta-blockade.
Eye disorders
Very rare visual impairment (e.g. blurred vision), dry eyes, eye irritation
Ear and labyrinth disorders
Very rare tinnitus, hearing disorders^1 (e.g. hypoacusis or deafness)
Cardiac disorders
Common bradycardia
Rare cardiac failure, arrhythmias, palpitation
Very rare conduction disorders, precordial pain
Vascular disorders
Common orthostatic hypotension (occasionally with syncope), peripheral oedema,
hypertension (mild and transient), cold extremities, arterial insufficiency
Rare oedema, Raynaud's phenomenon
Very rare Gangrene^2
angina (mild and transient), intermittent claudication
Respiratory, thoracic and mediastinal disorders
Common dyspnea, exertional dyspnoea
Rare Bronchospasm^3
Very rare rhinitis
Gastrointestinal disorders
Common nausea and vomiting, abdominal pain, heartburn, flatulence, gastric pain
Rare diarrhoea or constipation
Very rare dry mouth, retroperitoneal fibrosis (relationship to Lopresor has not been
definitely established)
unstable diabetes
Hepatobiliary disorders
Very rare Hepatitis
Skin and subcutaneous tissue disorders
Common pruritis, rash
Rare rash (in the form of urticaria, psoriasiform and dystrophic skin lesions)
Very rare Photosensitivity reaction, hyperhydrosis, reversible alopecia, worsening of
psoriasis
sweating increased
Musculoskeletal, connective tissue disorders
Rare muscle spasms
Very rare arthritis
muscoskeletal pain
Reproductive system and breast disorders
Very rare erectile dysfunction ,libido disorder and potency, Peyronie's disease^4
Immune system disorders
hypersensitivity
General disorders and administration site conditions
Common fatigue
tiredness
Investigations
Very rare weight gain, liver function test abnormal
(^1) in doses exceeding those recommended (^2) in patients with pre-existing severe peripheral circulatory disorders (^3) which may occur in patients without a history of obstructive lung disease (^4) relationship to Lopresor has not been definitely established Discontinuation of the drug should be considered if any such reaction is not otherwise explicable. The oculomucocutaneous syndrome associated with the beta-blocker, practolol, has not been reported with Lopresor (see Section 4.4 SPECIAL WARNINGS AND PRECAUTIONS FOR USE). Post-marketing Data - Adverse drug reactions from spontaneous reports and literature cases (frequency not known) The following adverse reactions have been derived from post-marketing experience with Lopresor via spontaneous case reports and literature cases. Because these reactions are reported voluntarily from a population of uncertain size and are subject to confounding factors, it is not possible to reliably estimate their frequency which is therefore categorized as not known. Adverse drug
impairment of consciousness (or even coma), convulsions, nausea, vomiting and cyanosis and death. Concomitant ingestion of alcohol, antihypertensives, quinidine or barbiturates aggravate the signs and symptoms. The first manifestations of overdosage can appear in 20 minutes but are more commonly seen within 1 to 2 hours after the drug's ingestion. The effects of massive overdosage may persist for several days despite declining plasma concentrations. Treatment: Contact the Poisons Information Centre on 131 126 for advice on management. Patients suffering from overdosage of a beta-blocker should always be hospitalised so that vital functions can be monitored. In general, patients with acute or recent myocardial infarction may be more haemodynamically unstable than other patients and should be treated accordingly. Induction of vomiting or gastric lavage should be undertaken. Other clinical manifestations of overdose should be managed symptomatically based on modern methods of intensive care. In the presence of severe hypotension, bradycardia, and impending heart failure, administer a beta1-stimulant (e.g. isoprenaline) intravenously at 2 to 5 minute intervals until the desired effect is achieved. Where a beta 1 - stimulant is not available, administer 0.5 to 2.0 mg atropine sulphate i.v. in order to block the vagus nerve. If a satisfactory effect is not achieved, agents such as dopamine, dobutamine, or noradrenaline may be administered. Further measures: 1 to 5 (max 10) mg glucagon (glucagon activates the adenylcyclase system independently of the beta-receptor, augmenting contractility in the presence of beta-blockade); transvenous intracardiac pacemaker. To combat bronchospasm, a beta2-stimulant (e.g. salbutamol) or aminophylline can be given. i.v.
5 PHARMACOLOGICAL PROPERTIES
5.1 PHARMACODYNAMIC PROPERTIES
Pharmacotherapeutic group: cardio-selective beta-blocker; ATC Code: C07A B The stimulant effect of catecholamines on the heart is reduced or inhibited by metoprolol. This leads to a decrease in heart rate, cardiac contractility, and cardiac output. Metoprolol lowers elevated blood pressure in both the standing and lying position. It also reduces the extent of rises in blood pressure occurring in response to physical and mental stress. In angina pectoris, metoprolol reduces the frequency and severity of the attacks and the need for glyceryl trinitrate relief, and increases exercise tolerance. In cases of supraventricular tachycardia or atrial fibrillation, and in the presence of ventricular extrasystoles, metoprolol has a regulating effect on the heart rate. In patients with a suspected or confirmed myocardial infarction, metoprolol lowers mortality. This effect may possibly be attributable to a decrease in the incidence of severe ventricular arrhythmias, as well as to limitation of infarct size. Metoprolol has also been shown to reduce the incidence of recurrent myocardial infarction.
Due to its beta-blocking effect, metoprolol is suitable for the prevention of migraine. Metoprolol has been shown to reduce diuretic-induced increase in plasma renin activity. It inhibits catecholamine-induced insulin secretion to a far lesser degree than non-selective beta-blockers. Orthostatic reactions or disturbances of electrolyte balance have not been observed. Lopresor has less effect than non-selective beta-blockers on peripheral circulation and the bronchial muscles in therapeutic doses. However, it should be used with caution in patients with asthma, and concomitant use of an adrenergic bronchodilator, e.g. terbutaline or salbutamol, is recommended. Patients already on beta 2 - stimulants for reversible airways obstruction may require adjustment of dosage if metoprolol therapy is subsequently introduced. Lopresor inhibits catecholamine-induced lipolysis. The active metabolite of metoprolol (2-hydroxymetoprolol) does not contribute significantly to the therapeutic effect. Lopresor is a relatively lipid soluble compound i.e. less soluble than propranolol and more lipid soluble than atenolol. Based on four studies of metoprolol in healthy males (n=69), the mean maximal β1 blockade (Emax) measured by reduction in exercise heart rate was 28%, 95% CI [25%, 31%]. The mean metoprolol plasma concentration at 50% of Emax (C50) was 105 nmol/L, 95% CI [74, 135]. β1 blockade of 30% of maximum was arbitrarily considered the lower limit to obtain a significant effect and was achieved with a mean plasma concentration (C30) of 45 nmol/L, 95% CI [32, 58]. Mechanism of action Metoprolol, the active substance of Lopresor, is a relatively cardioselective beta-blocker, i.e. it acts on beta 1 - receptors mainly located in the heart at lower doses than those needed to influence the beta 2 - receptors mainly located in the bronchi and peripheral vessels. Metoprolol has little membrane-stabilising effect nor does it display partial agonist activity (i.e. intrinsic sympathomimetic activity = ISA) at doses required to produce beta-blockade. Clinical trials No data available.
5.2 PHARMACOKINETIC PROPERTIES
Absorption Metoprolol is rapidly and almost completely (more than 95%) absorbed from the gastro-intestinal tract. Metoprolol exhibits stereo-specific pharmacokinetics. Distribution Metoprolol is rapidly and extensively distributed to the extra-vascular tissue. The volume of distribution is 5.6 L/kg. The apparent volume of distribution at steady-state (Vss) in extensive metabolizers (4.84 L/kg) is relatively higher than poor metabolizers (2.83 L/kg). At therapeutic
Dose-response The duration of the beta-blocking effect is dose dependent (as measured by reduction of exercise heart rate). For instance, in healthy subjects the effect of 20 mg metoprolol given intravenously is halved after about 6 hours. Pharmacokinetics in the elderly The geriatric population may show slightly higher plasma concentrations of metoprolol and the active metabolite alphahydroxymetoprolol than the young as a combined result of a decreased elimination of metoprolol and the metabolite in elderly population and a decreased hepatic blood flow. However, this increase is not clinically significant or therapeutically relevant. Whilst the pharmacokinetics of metoprolol are similar in the young and elderly, there may be pharmacodynamic changes in the elderly such as changes in the number of receptors or decreased receptor sensitivity; therefore, caution in dosing is recommended.
5.3 PRECLINICAL SAFETY DATA
Genotoxicity Metoprolol tartarate was devoid of mutagenic/genotoxic potential in the bacterial cell system (Ames) test and in vivo assays involving mammalian somatic cells or germinal cells of male mice. Carcinogenicity Metoprolol tartarate was not carcinogenic in mice and rats after oral administration of doses up to 800 mg/kg for 21 to 24 months.
6 PHARMACEUTICAL PARTICULARS
Metoprolol tartrate is an aryloxypropanolamine derivative. It is a white, odourless or almost odourless, crystalline powder with a melting point of 120oC. It is very soluble in water, soluble in chloroform, methylene chloride and alcohol, and almost insoluble in benzene, diethyl ether and acetone.
6.1 LIST OF EXCIPIENTS
Refer to Section 2 - Qualitative and quantitative composition.
6.2 INCOMPATIBILITIES
Incompatibilities were either not assessed or not identified as part of the registration of this medicine.
6.3 SHELF LIFE
In Australia, information on the shelf life can be found on the public summary of the Australian Register of Therapeutic Goods (ARTG). The expiry date can be found on the packaging.
6.4 SPECIAL PRECAUTIONS FOR STORAGE
Store below 30°C. Protect from moisture. Keep out of reach of children.
6.5 NATURE AND CONTENTS OF CONTAINER
Tablets 50mg: bottle pack of 100's. Tablets 100mg: bottle pack of 60's.
6.6 SPECIAL PRECAUTIONS FOR DISPOSAL
In Australia, any unused medicine or waste material should be disposed of by taking to your local pharmacy.
6.7 PHYSICOCHEMICAL PROPERTIES
Chemical name: di-[(±)- 1 - (isopropylamino)- 3 - [p-(2-methoxyethyl) phenoxy]- 2 - propanol] L(+)-tartrate Molecular weight: 684. Molecular formula: (C 15 H 25 NO 3 ) 2 .(C 4 H 6 O 6 ) Chemical structure CAS number 56392 - 17 - 7
7 MEDICINE SCHEDULE (POISONS STANDARD)
Prescription Only Medicine (S4).
8 SPONSOR
NOVARTIS Pharmaceuticals Australia Pty Limited ABN 18 004 244 160 54 Waterloo Road MACQUARIE PARK NSW 2113 Telephone: (02) 9805 3555
