Betaloc SA

Metoprolol tartrate Ph. Eur. 200mg

Extended release formulation (Durules®)

In the management of angina pectoris and hypertension. Prophylaxis of migraine.

Betaloc SA should be swallowed with liquid. Betaloc SA should not be chewed or crushed.

The dose of metoprolol must always be titrated and adjusted to the individual requirements of the patient using other suitable formulations and doses. The following are guidelines:

Hypertension

Angina Pectoris

Migraine Prophylaxis

Impaired Renal Function

Impaired Hepatic Function

Elderly

Children

Betaloc SA, as with other beta–blockers, should not be used in patients with any of the following:

- Hypotension,

- AV block of second- or third-degree,

- Decompensated cardiac failure (pulmonary oedema, hypoperfusion or hypotension),

- Continuous or intermittent inotropic therapy acting through beta–receptor agonism,

- Bradycardia (<45bpm),

- Sick-sinus syndrome,

- Cardiogenic shock,

- Severe peripheral arterial circulatory disorder,

- Untreated phaeochromocytoma,

- Metabolic acidosis.

Known hypersensitivity to any component of Betaloc SA or other beta–blockers.

Betaloc SA is also contra-indicated when suspected acute myocardial infarction is complicated by bradycardia (<45bpm), first-degree heart block or systolic blood pressure <100mmHg and/or severe heart failure.

Betaloc SA as with other beta–blockers:

• should not be withdrawn abruptly. When possible, Betaloc should be withdrawn gradually over a period of 10-14 days, in diminishing doses to 25 mg daily for the last 6 days. During its withdrawal patients should be kept under close surveillance, especially those with known ischaemic heart disease. The risk for coronary events, including sudden death, may increase during the withdrawal of beta–blockade.

• must be reported to the anaesthetist prior to general anaesthesia. It is not generally recommended to stop Betaloc treatment in patients undergoing surgery. If withdrawal of metoprolol is considered desirable, this should, if possible, be completed at least 48 hours before general anaesthesia. However, in some patients it may be desirable to employ a beta-blocker as premedication. By shielding the heart against the effects of stress, the beta-blocker may prevent excessive sympathetic stimulation provoking cardiac arrhythmias or acute coronary insufficiency. If a beta-blocker is given for this purpose, an anaesthetic with little negative inotropic activity should be selected to minimise the risk of myocardial depression.

• although contra–indicated in severe peripheral arterial circulatory disturbances (see Section 4.3), may also aggravate less severe peripheral arterial circulatory disorders.

• may be administered when heart failure has been controlled. Digitalisation and/or diuretic therapy should also be considered for patients with a history of heart failure, or patients known to have a poor cardiac reserve. Betaloc should be used with caution in patients where cardiac reserve is poor.

• may cause patients to develop increasing bradycardia, in such cases the Betaloc SA dosage should be reduced or gradually withdrawn.

• due to the negative effect on conduction time, should only be given with caution to patients with first-degree heart block.

• may increase the number and duration of angina attacks in patients with Prinzmetal's angina, due to unopposed alpha–receptor mediated coronary artery vasoconstriction. Betaloc SA is a beta₁–selective beta–blocker; consequently, its use may be considered although utmost caution must be exercised.

• may mask the early signs of acute hypoglycaemia, in particular tachycardia. During treatment with Betaloc SA, the risk of interfering with carbohydrate metabolism or masking hypoglycaemia is less than with non–selective beta–blockers.

• may mask the symptoms of thyrotoxicosis.

• may increase both the sensitivity towards allergens and the seriousness of anaphylactic reactions.

Although cardioselective beta-blockers may have less effect on lung function than non-selective beta-blockers, as with all beta-blockers these should be avoided in patients with reversible obstructive airways disease unless there are compelling clinical reasons for their use. When administration is necessary, these patients should be kept under close surveillance. The use of a beta₂-bronchodilator (e.g. terbutaline) may be advisable in some patients. The dosage of the beta₂ agonist may require an increase when treatment with Betaloc SA is commenced.

The label shall state - “If you have a history of wheezing, asthma or any other breathing difficulties, you must tell your doctor before you take this medicine.”

Like all beta-blockers, careful consideration should be given to patients with psoriasis before Betaloc SA is administered.

In the presence of liver cirrhosis the bioavailability of Betaloc SA may be increased

In patients with a phaeochromocytoma, an alpha-blocker should be given concomitantly.

In labile and insulin-dependent diabetes it may be necessary to adjust the hypoglycaemic therapy.

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

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. Enzyme–inducing agents (e.g. rifampicin) may reduce plasma concentrations of Betaloc, whereas enzyme inhibitors (e.g. cimetidine, alcohol and hydralazine) may increase plasma concentrations.

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

If concomitant treatment with clonidine is to be discontinued, Betaloc SA 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 antiarrhythmic 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 indometacin and other prostaglandin synthetase inhibiting drugs may reduce the antihypertensive effect of beta-blockers.

The administration of adrenaline (epinephrine) to patients undergoing beta-blockade can result in an increase in blood pressure and bradycardia although this is less likely to occur with beta₁-selective drugs.

Betaloc SA will antagonise the beta₁-effects of sympathomimetic agents but should have little influence on the bronchodilator effects of beta₂-agonists at normal therapeutic doses.

Metoprolol may impair the elimination of lidocaine.

As with other beta-blockers, concomitant therapy with dihydropyridines e.g. nifedipine, may increase the risk of hypotension, and cardiac failure may occur in patients with latent cardiac insufficiency.

The dosages of oral antidiabetic agents and also of insulin may have to be readjusted in patients receiving beta-blockers.

As beta-blockers may affect the peripheral circulation, care should be exercised when drugs with similar activity e.g. ergotamine are given concurrently.

The effects of Betaloc SA and other drugs with an antihypertensive effect on blood pressure are usually additive. Care should be taken when combining with other antihypertensive drugs or drugs that might reduce blood pressure such as tricyclic antidepressants, barbiturates and phenothiazines. However, combinations of antihypertensive drugs may often be used with benefit to improve control of hypertension.

Pregnancy

Lactation

When driving vehicles or operating machines, it should be taken into account that occasionally dizziness or fatigue may occur.

The following events have been reported as adverse events in clinical trials or reported from routine use.

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%).

Infections and infestations

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

Blood and lymphatic system disorders

Very rare: Thrombocytopenia.

Psychiatric disorders

Uncommon: Depression, insomnia, nightmares.

Rare: Nervousness, anxiety.

Very rare: Confusion, hallucinations.

Nervous system disorders

Common: Dizziness, headache.

Uncommon: Concentration impairment, somnolence, paraesthesiae.

Very rare: Amnesia/memory impairment, taste disturbances.

Eye disorders

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

Ear and labyrinth disorders

Very rare: Tinnitus.

Cardiac disorders

Common: Bradycardia, palpitations.

Uncommon: Deterioration of heart failure symptoms, first degree heart block.

Rare: Disturbances of cardiac conduction, cardiac arrhythmias, increased existing AV block.

Vascular disorders

Common: Postural disorders (very rarely with syncope).

Rare: Raynauds phenomenon.

Very rare: Increase of pre-existing intermittent claudication.

Respiratory, thoracic and mediastinal disorders

Common: Dyspnoea on exertion.

Uncommon: Bronchospasm.

Rare: Rhinitis.

Gastrointestinal disorders

Common: Nausea, abdominal pain, diarrhoea, constipation.

Uncommon: Vomiting.

Rare: Dry mouth.

Hepato-biliary disorders

Very rare: Hepatitis.

Skin and subcutaneous tissue disorders

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

Rare: Loss of hair.

Very rare: Photosensitivity reactions, aggravated psoriasis.

Musculoskeletal and connective tissue disorders

Very rare: Arthralgia.

Uncommon: Muscle cramps.

Reproductive system and breast disorders

Rare: Impotence/sexual dysfunction.

General disorders and administration site disorders

Very common: Fatigue.

Common: Cold hands and feet.

Uncommon: Precordial pain, oedema.

Investigations

Uncommon: Weight gain.

Rare: Liver function test abnormalities, positive anti-nuclear antibodies (not associated with SLE).

The symptoms of overdose 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.

Metoprolol is a competitive beta-adrenoceptor antagonist. It acts preferentially to inhibit beta₁-adrenoceptors (conferring some cardioselectivity), is devoid of intrinsic sympathomimetic activity (partial agonist activity) and possesses beta-adrenoceptor blocking activity comparable in potency with propranolol.

A negative chronotropic effect on the heart is a consistent feature of metoprolol administration. Thus cardiac output and systolic blood pressure rapidly decrease following acute administration.

Metoprolol is almost completely absorbed over a large part of the gastrointestinal tract, but bioavailability after oral administration is 40-50% of that after i.v. injection, because of hepatic first pass metabolism. The bioavailability of metoprolol after CR tablet administration is about 70% of that after plain tablets.

The steady state V_D of metoprolol is 3.2 L/kg and protein binding is about 12%.

Metoprolol undergoes oxidative metabolism in the liver primarily by the CYP2D6 isoenzyme.

Elimination half life of metoprolol is usually between about 3 and 5 hours. Elimination is by liver metabolism and metabolites are largely inactive. With metoprolol CR T_max is prolonged to about 8 hours. Mean C_max after Betaloc SA was 519 nmol/L, achieved after 4 hours. Plasma levels at 24 hours were about 85 nmol/L after Betaloc SA.

Initial absorption of metoprolol CR was more rapid and AUC increased when given together with food.

Urine recovery of unchanged drug was about 4% after metoprolol CR and metoprolol plain tablets. The pharmacokinetics and beta-blocking effect of metoprolol are not significantly altered in patients with renal failure.

In healthy elderly volunteers there was no significant difference in the volume of distribution, elimination half life, total body clearance or bioavailability of metoprolol compared with young volunteers.

In patients with cirrhosis of the liver the bioavailability of metoprolol was increased and total body clearance reduced.

There is no toxicity data that would indicate that metoprolol tartrate is unsafe for use in the indications given. Signs in rats and dogs indicate that metoprolol can exert a cardiopressive action at high plasma levels.

Sodium aluminium silicate, paraffin, magnesium stearate, ethylcellulose, ethanol (used during manufacture), hydroxypropyl methylcellulose, polyethylene glycol, titanium dioxide (E171), hydrogen peroxide (30%) and water purified.

None known

5 years.

Store below 25ºC.

Blister strips (press through packs of thermoformed PVC) 7 tablets per strip - pack size 28.

Securitainers of 300 tablets.

Not applicable

AstraZeneca UK Ltd.,

600 Capability Green,

Luton, LU1 3LU, UK.

PL 17901/0107

28th May 2002 / 16th July 2005

12^th August 2008