Medsafe Logo


INFORMATION FOR HEALTH PROFESSIONALS

Home  |  Consumers  |  Health Professionals  |  Regulatory  |  Other  |  Hot Topics  |  Search

Data Sheet

Betaloc CR

Metoprolol succinate 23.75 mg, 47.5 mg, 95 mg and 190 mg controlled-release tablets

PRESENTATION

CR tablets 23.75 mg - A controlled-release preparation in which the active substance metoprolol succinate, is embedded as coated beads in a disintegrating table. A white to off-white, oval, biconvex, film-coated tablet scored on both sides and engraved A/β on one side. Size: 5.5 x 10.5 mm. Average mass 0.17g. Each tablet contains 23.75 mg metoprolol succinate, bioequivalent to 25 mg metoprolol tartrate.

CR tablets 47.5 mg - A controlled-release preparation in which the active substance metoprolol succinate is embedded as coated beads in a disintegrating tablet. A white to off-white, circular, biconvex, film-coated tablet with a score on one side and engraving A/mO on the other side. Diameter 9 mm. Average mass 0.22 g. Each tablet contains 47.5 mg metoprolol succinate, bioequivalent to 50 mg metoprolol tartrate.

CR tablets 95 mg - A controlled-release preparation in which the active substance metoprolol succinate is embedded as coated beads in a disintegrating tablet. A white to off-white, circular, biconvex, film-coated tablet with a score on one side and engraving A/mS on the other side. Diameter 10 mm. Average mass 0.37 g. Each tablet contains 95 mg metoprolol succinate, bioequivalent to 100 mg metoprolol tartrate.

CR tablets 190 mg - A controlled-release preparation in which the active substance metoprolol succinate is embedded as coated beads in a disintegrating tablet. A white to off-white, oval, biconvex, film-coated tablet with a score on one side and engraving A/mY on the same side. Size 8.5 mm x 17 mm. Average mass 0.71 g. Each tablet contains 190 mg metoprolol succinate, bioequivalent to 200 mg metoprolol tartrate.

USES

ACTIONS

Metoprolol is a beta1-selective beta-blocker, i.e. it blocks beta1 -receptors at doses much lower than those needed to block beta2-receptors.

Metoprolol has an insignificant membrane-stabilising effect and does not display partial agonist activity.

Metoprolol reduces or inhibits the agonistic effect on the heart of catecholamines (which are released during physical and mental stress). This means that the usual increase in heart rate, cardiac output, cardiac contractility and blood pressure, produced by the acute increase in catecholamines, is reduced by metoprolol. During high endogenous adrenaline levels metoprolol interferes much less with blood pressure control than non-selective beta-blockers.

BETALOC CR gives an even plasma concentration time and effect profile (beta1-blockade) over 24 hours in contrast to conventional tablet formulations of beta1-selective blockers.

Due to the lack of pronounced peaks in plasma concentration, the clinical beta1-selectivity is improved with the BETALOC CR formulation when compared to the conventional tablet formulations of beta1-selective blockers. Furthermore the potential risk for peak plasma concentration related side-effects, such as bradycardia and leg fatigue is reduced.

When mandatory, BETALOC CR, in combination with a beta2-agonist, may be given to patients with symptoms of obstructive pulmonary disease. When given together with a beta2-agonist, BETALOC CR in therapeutic doses interferes less than non-selective beta-blockers with the beta2-mediated broncho-dilation caused by the beta2-agonist.

BETALOC CR interferes less with insulin release and carbohydrate metabolism than do non-selective beta-blockers.

BETALOC CR interferes much less with the cardiovascular response to hypoglycaemia than do non-selective beta-blockers.

Short term studies have shown that BETALOC CR may cause a slight increase in triglycerides and a decrease in free fatty acids in the blood. In some cases, a small decrease in the high density lipoproteins (HDL) fraction has been observed, although to a lesser extent than that following non-selective beta-blockers. However, a significant reduction in total serum cholesterol levels has been demonstrated after metoprolol treatment in one study conducted over several years.

Quality of life is maintained, uncompromised or improved during treatment with BETALOC CR. An improvement in quality of life has been observed after metoprolol treatment in patients after myocardial infarction. Furthermore, BETALOC CR has been shown to improve Quality of Life in patients with chronic heart failure.

Effect in hypertension

BETALOC CR lowers elevated blood pressure both in the standing and supine position. A short duration (a few hours) and clinically insignificant increase in peripheral resistance may be observed after the institution of metoprolol treatment. During long-term treatment total peripheral resistance may be reduced, due to reversal of hypertrophy in arterial resistance vessels. Long-term antihypertensive therapy with metoprolol has also been shown to reduce left ventricular hypertrophy and to improve left ventricular diastolic function and left ventricular filling.

In 144 paediatric patients (6 to 16 years of age) with essential hypotension, BETALOC CR has been shown in a 4-week study to reduced placebo-corrected systolic blood pressure for the 0.95 and 1.90 mg/kg doses (4 to 6 mmHg). For diastolic blood pressure, there was a placebo-corrected reduction for the 1.90 mg/kg dose (5 mmHg) and a dose-dependent reduction for the dose range 0.19, 0.95 and 1.90 mg/kg. No apparent differences in blood pressure reduction were observed based on age, Tanner stage, or race.

In men with mild to moderate hypertension metoprolol has been shown to reduce the risk of death from cardiovascular disease, mainly due to a reduced risk for sudden cardiovascular death, to reduce the risk for fatal and non-fatal infarction and for stroke.

Effect on angina pectoris

In patients with angina pectoris metoprolol has been shown to reduce the frequency, duration and severity of both angina attacks and silent ischemic episodes and to increase the physical working capacity.

Effect in chronic heart failure

In patients with symptoms of heart failure (New York Heart Association (NYHA) II-IV) and decreased ejection fraction (≤0.40) BETALOC CR when added to standard therapy has been shown to improve survival and to reduce the number of hospitalisations due to worsening heart failure. In addition, BETALOC CR therapy has increased ejection fraction, reduced left ventricular end systolic and end diastolic volumes, improved NYHA functional class and improved Quality of Life.

In the MERIT-HF (Metoprolol CR/XL Randomised Intervention Trial in Congestion Heart Failure) study treatment with metoprolol CR added to standard treatment with ACE inhibitors and diuretics in patients with decreased LVEF and symptoms of mild to severe chronic heart failure reduced:

Effect on cardiac rhythm

BETALOC CR is suitable for regulating the heart rate as it inhibits the cardiac effects of increased sympathetic activity leading to decreased automaticity in the pacemaker cells and reduction of supraventricular conduction velocity. Thus metoprolol controls heart rate in supraventricular tachycardia or atrial fibrillation, and in the presence of ventricular extrasystoles.

Effect on myocardial infarction

Metoprolol reduces mortality in patients with suspected or confirmed myocardial infarction mainly due to a reduction in the risk of sudden death. This effect is presumed to partly be due to the prevention of ventricular fibrillation. The anti-fibrillatory effect is believed to be due to a dual mechanism: a vagal effect within the blood-brain barrier beneficially influencing electrical stability of the heart, and a sympathetic direct cardiac anti-ischemic effect beneficially influencing contractility, heart rate and blood pressure. For both early and late intervention, the reduction in mortality is also present in high risk patients with previous cardiovascular disease; and in patients with diabetes mellitus.

Metoprolol has also been shown to reduce the risk for non-fatal myocardial infarction.

These anti-ischaemic effects of metoprolol are also reflected in a reduction in chest pain during the acute infarction phase. Metoprolol has also been shown to reduce the incidence of recurrent myocardial infarction.

Effect on hyperthyroidism

Metoprolol reduces the clinical manifestations in hyperthyroidism and can therefore be given as a supplementary medication.

Effect on heart disorders with palpitations

In patients with functional heart disorder with palpitations as a major symptom (which may be due to increased sympathetic activity) BETALOC CR is effective in reducing palpitations and improving the patient's general condition.

Effect on migraine

BETALOC CR is suitable for prophylactic treatment of migraine.

PHARMACOKINETICS

Absorption and distribution

BETALOC CR is completely absorbed after oral administration. The systemic bioavailability of metoprolol from a single oral dose is approximately 50%, owing to an extensive first-pass effect. The bioavailability is reduced by about 20-30% for the controlled release preparation compared to the conventional tablets, but this has been demonstrated to be of no significance for clinical efficacy, since the area under the effect curve (AUEC) for heart rate is the same as with conventional tablets. The plasma protein binding of metoprolol is low, approximately 5-10% and has a volume of distribution of 5.6 L/kg.

The controlled release tablet consists of several hundred beads of metoprolol succinate. Each bead is coated with a polymeric membrane which controls the rate of metoprolol release.

The tablet disintegrates rapidly after intake whereby the beads are dispersed in the gastrointestinal tract and release metoprolol continuously for about 20 hours. The elimination half-life of metoprolol averages 3.5 hours. Thus an even metoprolol plasma concentration is achieved over a dosage interval of 24 hours. The release rate is independent of physiological factors such as pH, food and peristalsis.

The rate of elimination is not affected by the formulation but, because of the prolonged absorption phase, administration of the CR tablet results in much less variation in plasma levels and pharmacological effects during a dosing interval compared with the plain tablet.

Metabolism and elimination

Metoprolol undergoes oxidative metabolism in the liver primarily by the CYP2D6 isoenzyme. The three main metabolites have been identified, though none of them have a clinically significant β-blocking effect.

As a rule over 95% of an oral dose can be recovered in the urine. About 5% of the given dose is excreted in the urine in unchanged form, this figure rising up to 30% in isolated cases. The elimination half-life of metoprolol in plasma averages 3.5 hours (extremes: 1 and 9 hours). The total clearance rate is approximately 1 litre/minute.

The elderly show no significant changes in the pharmacokinetics of metoprolol as compared to young persons. The systemic bioavailability and elimination of metoprolol is unchanged in patients with reduced renal function, however the excretion of metabolites is reduced. Significant accumulation of metabolites was observed in patients with a glomerular filtration rate (GFR) of less than 5 mL/minute. This accumulation of metabolites does not increase the beta-blockade.

The pharmacokinetics of metoprolol is little affected by decreased liver function due to its low protein binding. However, in patients with severe liver cirrhosis and a portacaval shunt, the bioavailability may increase and the total clearance may be reduced. Patients with a portacaval anastomosis had a total clearance of approximately 0.3 litres/minute and area under the plasma concentration-time curve (AUC) values of up to 6 times higher than in healthy subjects.

The pharmacokinetic profile of metoprolol in paediatric hypertensive patients aged 6-17 years is similar to the pharmacokinetics described previously in adults. Metoprolol apparent oral clearance (CL/F) increased linearly with body weight.

INDICATIONS

DOSAGE AND ADMINISTRATION

Dosage should always be adjusted to the patient's individual requirements.

BETALOC CR is intended for once-daily treatment and can be taken with or without food. The BETALOC CR tablets should be swallowed with liquid. The tablets and the divided halves should not be chewed or crushed.

The following dosage recommendations may be taken as a guide:

Hypertension

The recommended dose in patients with mild to moderate hypertension is 47.5 mg BETALOC CR given once daily. In patients not responding to 47.5 mg the dose can be increased to 95-190 mg once daily or combined with other antihypertensive agents.

Long-term antihypertensive treatment with metoprolol in daily doses of 95-190 mg has been shown to reduce total mortality, including sudden cardiovascular death, stroke and coronary events in hypertensive patients.

Angina Pectoris

95-190 mg daily given as a single dose in the morning. BETALOC CR can be combined with other antianginal agents if needed.

Chronic heart failure

The dose of BETALOC CR should be individually adjusted in patients with chronic heart failure stabilised on other heart failure treatment. A recommended initial dose during the first two weeks is a 23.75 mg tablet once daily. It is recommended that patients with NYHA functional classes III-IV begin with half a 23.75 mg tablet once daily for the first week. It is recommended that the dose then be doubled every second week up to a maximum target dose of 190 mg BETALOC CR once daily (or to the highest tolerated dose). During long-term treatment the aim should be to reach 190 mg BETALOC CR once daily (or the highest tolerated dose).

At each dose level the patient should be carefully evaluated with regard to tolerability. In the case of hypotension, a decrease in concomitant medication may be necessary. Initial hypotension does not necessarily mean that the dose cannot be tolerated in chronic treatment but the patient should be kept at the lower dose until stabilised.

Cardiac Arrhythmias

95-190 mg daily, given as a single dose once daily.

Myocardial Infarction

Treatment in the acute stage

BETALOC IV should be administered intravenously as soon as possible after symptoms indicating acute myocardial infarction. Such treatment should be initiated in a coronary care or similar unit immediately after the patient's haemodynamic condition has stabilised. Three 5 mg bolus injections should be given, at 2 minute intervals, depending on the haemodynamic status of the patient (ECG, blood pressure, heart rate). See BETALOC IV Datasheet CONTRAINDICATIONS and WARNINGS AND PRECAUTIONS.

In patients who tolerate the full intravenous dose (15 mg), BETALOC CR tablets 47.5 mg four times daily should be started 15 minutes after the last intravenous injection and be continued for 24 hours. Followed by BETALOC CR 95 mg twice daily for a further 24 hours. (See BETALOC IV Data Sheet).

Patients who do not tolerate the full intravenous (15 mg) dose of BETALOC IV should have their oral treatment initiated with caution starting with a lower dose.

Maintenance treatment after myocardial infarction

Long-term oral treatment with metoprolol in doses of 190 mg given once daily has been shown to reduce the risk of death (including sudden death) and to reduce the risk of reinfarction (also in patients with diabetes mellitus).

Functional Heart Disorder With Palpitations

The recommended dosage is 95 mg once daily. If necessary, the dose may be increased to 190 mg.

Migraine Prophylaxis

The recommended dosage is 95-190 mg once daily.

Hyperthyroidism

95-190 mg daily, given as a single dose in the morning. If necessary, the dose may be increased.

Impaired Renal Function

Dose adjustment is not needed in patients with impaired renal function

Impaired Hepatic Function

Dose adjustment is not normally needed in patients suffering from liver cirrhosis because metoprolol has low protein binding (5-10%). When there are signs of serious impairment of liver function (e.g. shunt-operated patients) a reduction in dose should be considered.

Elderly

Dose adjustment is not needed.

Hypertension in Children

The recommended initial dosage in hypertensive patients ≥ 6 years is 0.95 mg/kg Betaloc CR, not exceeding 47.5 mg once daily given approximated by dose strength. In patients not responding to 0.95 mg/kg, the dose can be increased to a maximum daily dose of 1.90 mg/kg. Doses above 190 mg once daily have not been studied in children and adolescents.

Efficacy and safety of use in children < 6 years have not been studied.

CONTRAINDICATIONS

Metoprolol should not be given to patients with suspected acute myocardial infarction as long as the heart rate is <45 beats/minute, the P-Q interval is > 0.24 seconds or the systolic blood pressure is <100 mmHg.

BETALOC CR is contraindicated in patients who have shown hypersensitivity to any component of the product or to other beta -blockers.

WARNINGS AND PRECAUTIONS

Intravenous administration of calcium antagonists of the verapamil-type should not be given to patients treated with beta-blockers.

The risk of BETALOC CR interfering with beta2-receptors is less than with conventional tablet formulations of beta1-selective blockers.

The risk of interfering with carbohydrate metabolism or masking hypoglycaemia is likely to be less with BETALOC CR than with conventional tablet formulations of beta1-selective blockers and much less than with non-selective beta-blockers.

Very rarely a pre-existing A-V conduction disorder of moderate degree may become aggravated (possibly leading to A-V block). If the patient develops increasing bradycardia, BETALOC CR should be given in lower doses or gradually withdrawn.

BETALOC CR may aggravate the symptoms of peripheral arterial circulatory disorders, mainly due to its blood pressure lowering effect.

Where BETALOC CR is prescribed for a patient known to be suffering from phaeochromocytoma, an alpha-blocker should be given concomitantly.

Abrupt withdrawal of beta-blockade is hazardous especially in high risk patients, and therefore should not be done. If there is a need to discontinue treatment with BETALOC CR, this should preferably be done gradually over at least two weeks when the dose is reduced by half in each step down to the final step when a whole 23.75 mg tablet is reduced to half a tablet. If symptoms occur, a slower withdrawal rate is recommended. Sudden withdrawal of beta-blockade may aggravate chronic heart failure and also increases the risk for myocardial infarction and sudden death

The anaesthetist should be informed that the patient is receiving BETALOC CR prior to surgery. It is not recommended to stop beta-blocker treatment in patients undergoing surgery. Acute initiation of high-dose metoprolol to patients undergoing non-cardiac surgery should be avoided, since it has been associated with bradycardia, hypotension and stroke including fatal outcome in patients with cardiovascular risk factors.

In patients taking beta-blockers anaphylactic shock assumes a more severe form.

USE IN PREGNANCY

As with most medicines, BETALOC CR should not be given during pregnancy and lactation unless its use is considered essential. As with all antihypertensive agents, beta-blockers may cause side effects (e.g. bradycardia) in the foetus and in the newborn and breast-fed infant.

USE IN LACTATION

The amount of metoprolol ingested via beast-milk seems to be negligible as regards beta-blocking effect in the infant if the mother is treated with metoprolol doses within the normal therapeutic range.

EFFECTS ON ABILITY TO DRIVE AND USE MACHINES

Patients should know how they react to BETALOC CR before they drive or use machines because occasionally dizziness or fatigue may occur.

ADVERSE EFFECTS

BETALOC CR is well tolerated and adverse reactions have generally been mild and reversible. The following events have been reported as adverse events in clinical trials or reported from routine use, mostly with conventional metoprolol (metoprolol tartrate). In many cases a relationship to treatment with metoprolol has not been established. The following definitions of frequencies are used: Very common (≥10%), common (1 - 9.9%), uncommon (0.1 - 0.9%), rare (0.01 - 0.09%) and very rare (<0.01%)

Cardiovascular system

Common: Bradycardia, postural disorders (very rarely with syncope), cold hands and feet, palpitations.

Uncommon: Deterioration of heart failure symptoms, cardiogenic shock in patients with acute myocardial infarction*, first degree heart block, oedema, precordial pain.

Rare: Disturbances of cardiac conduction, cardiac arrythmias.

Very rare: Gangrene in patients with pre-existing severe peripheral circulatory disorders.

* Excess frequency of 0.4% compared with placebo in a study of 46,000 patients with acute myocardial infarction where the frequency of cardiogenic shock was 2.3% in the metoprolol group and 1.9% in the placebo group in the subset of patients with low shock risk index. The stock risk index was based on the absolute risk of shock in each individual patient derived from age, sex, time delay, Killip class, blood pressure, heart rate, ECG abnormality, and prior history of hypertension. The patient group with low shock risk index corresponds to the patient in which metoprolol is recommended for use in acute myocardial infarction.

Central Nervous System

Very common: Fatigue

Common: Dizziness, headache.

Uncommon: Paraesthesiae, muscle cramps.

Gastrointestinal

Common: Nausea, abdominal pain, diarrhoea, constipation.

Uncommon: Vomiting

Rare: Dry mouth

Haematologic

Very rare: Thrombocytopenia

Hepatic

Rare: Liver function test abnormalities

Very rare: Hepatitis

Metabolism

Uncommon: Weight gain

Musculoskeletal

Very rare: Arthralgia

Psychiatric

Uncommon: Depression, concentration impaired, somnolence or insomnia, nightmares

Rare: Nervousness, anxiety, impotence / sexual dysfunction.

Very rare: Amnesia / memory impairment, confusion, hallucinations.

Respiratory

Common: Dyspnoea on exertion.

Uncommon: Bronchospasm

Rare: Rhinitis

Sense organs

Rare: Disturbances of vision, dry and/or irritated eyes, conjunctivitis

Very rare: Tinnitus, taste disturbances

Skin

Uncommon: Rash (in the form of urticaria psoriasiform and dystrophic skin lesions), increased sweating.

Rare: Loss of hair

Very rare: Photosensitivity reactions, aggravated psoriasis.

INTERACTIONS

Metoprolol is a metabolic substrate for the cytochrome P450 isoenzyme CYP2D6. Drugs that act as enzyme-inducing and enzyme-inhibiting substances may exert an influence on the plasma level of metoprolol. Plasma levels of metoprolol may be raised by co-administration of compounds metabolised by CYP2D6 eg. antiarrhythmics, antihistamines, histamine-2-receptor antagonists, antidepressants, antipsychotics and COX-2 inhibitors. The plasma concentration of metoprolol is lowered by rifampicin and may be raised by alcohol and hydralazine.

Patients receiving concomitant treatment with sympathetic ganglion blocking agents, other beta-blockers (i.e. eye drops) or monoamine oxidase inhibitors should be kept under close surveillance.

If concomitant treatment with clonidine is to be discontinued, the beta-blocker medication should be withdrawn several days before clonidine.

Increased negative inotropic and chronotropic effects may occur when metoprolol is given together with calcium antagonists of the verapamil and diltiazem type. In patients treated with beta-blockers, intravenous administration of calcium antagonists of the verapamil type should not be given.

Beta-blockers may enhance the negative inotropic and negative dromotropic effect of antiarrythmic agents (of the quinidine type and amiodarone).

Digitalis glycosides, in association with beta-blockers, may increase atrioventricular conduction time and may induce bradycardia.

In patients receiving beta-blocker therapy, inhalation anaesthetics enhance the cardiodepressant effect.

Concomitant treatment with indomethacin or other prostaglandin synthetase inhibiting agents may decrease the antihypertensive effect of beta-blockers.

Under certain conditions, when adrenaline is administered to patients treated with beta-blockers, cardioselective beta-blockers interfere much less with blood pressure control than non-selective beta-blockers.

The dosages of oral antidiabetics may have to be readjusted in patients receiving beta-blockers.

OVERDOSAGE

The symptoms of overdosage may include bradycardia, hypotension, acute cardiac insufficiency and bronchospasm.

General treatment should include:

Close supervision, treatment in an intensive care ward, the use of gastric lavage, activated charcoal and a laxative to prevent absorption of any drug still present in the gastrointestinal tract, the use of plasma or plasma substitutes to treat hypotension and shock.

Excessive bradycardia can be countered with atropine 1-2 mg intravenously and/or a cardiac pacemaker. If necessary, this may be followed by a bolus dose of glucagon 10 mg intravenously. If required, this may be repeated or followed by an intravenous infusion of glucagon 1-10 mg/hour depending on response. If no response to glucagon occurs or if glucagon is unavailable, a beta adrenoceptor stimulant such as dobutamine 2.5 to 10 micrograms/kg/minute by intravenous infusion may be given.

Dobutamine, because of its positive inotropic effect could also be used to treat hypotension and acute cardiac insufficiency. It is likely that these doses would be inadequate to reverse the cardiac effects of beta blockade if a large overdose has been taken. The dose of dobutamine should therefore be increased if necessary to achieve the required response according to the clinical condition of the patient.

Administration of calcium ions may also be considered. Bronchospasm can usually be reversed by bronchodilators.

Management

Induction of vomiting or gastric lavage. In the presence of severe hypotension, bradycardia and impending heart failure, administer a beta1-agonist until the desired effect is achieved. Where a selective beta1-agonist is not available, dopamine may be used; or atropine sulphate IV may be used in order to block the vagus nerve.

If a satisfactory effect is not achieved other sympathomimetic agents such as dobutamine or noradrenaline may be given.

Glucagon in a dose of 1-10 mg can also be administered. A pacemaker may be necessary. A beta2-agonist can be given IV to combat bronchospasm.

The dosages of agents (antidotes) needed to treat overdose of beta-blockade are much higher than normally recommended therapeutic dosages. This is because beta-receptors are occupied by the beta-blocker.

PHARMACEUTICAL PRECAUTIONS

Shelf-life

36 months.

Storage conditions

BETALOC CR 23.75 mg tablets should be stored at or below 30°C.

BETALOC CR 47.5, 90 and 190 mg tablets should be stored at or below 25°C.

MEDICINE CLASSIFICATION

Prescription Medicine.

PACKAGE QUANTITIES

BETALOC CR 23.75 mg tablets - 30's Memory pack.
BETALOC CR 47.5 mg tablets - 30's Memory pack.
BETALOC CR 95 mg tablets - 30's Memory pack.
BETALOC CR 190 mg tablets - 30's Memory pack

FURTHER INFORMATION

List of Excipients

Ethylcellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, microcrystalline cellulose, paraffin, polyethylene glycol, silicon dioxide, sodium stearyl fumarate and titanium dioxide (E 171).

NAME AND ADDRESS

AstraZeneca Limited
303 Manukau Rd, Epsom
PO Box 1301
Auckland
Telephone (09) 623 6300

DATE OF PREPARATION

11 May 2009

(CDS 0309)

Copyright - No part may be reproduced by any process without the prior written permission of AstraZeneca Limited