AstraZeneca Pharmaceuticals (Ireland) Ltd

Betaloc 1 mg/ml Solution for Injection

Each ml of solution contains metoprolol tartrate 1 mg. Each ampoule contains 5 mg/5 ml metoprolol tartrate.

Each ml of solution contains 3.6 mg sodium, as sodium chloride. Each 5 ml ampoule contains 17.8 mg sodium, as sodium chloride.

For a full list of excipients, see section 6.1.

Solution for injection. (Injection)

A clear, colourless, sterile liquid contained in type I 5 ml ampoules.

Control of tachyarrhythmias, especially supraventricular tachyarrhythmias. The electrocardiogram should be monitored while undergoing treatment.

Betaloc has been shown to reduce mortality when administered to patients with acute myocardial infarction.

The dose must always be adjusted to the individual requirements of the patient. The following are guidelines:

Cardiac arrhythmias: Initially up to 5 mg injected intravenously at a rate of 1–2 mg per minute. The injection can be repeated at 5 minute intervals until a satisfactory response has been obtained. A total dose of 10–15 mg generally proves sufficient.

Because of the risk of a pronounced drop of blood pressure, the i.v. administration of Betaloc to patients with a systolic blood pressure below 100 mmHg should only be given with special care.

Myocardial infarction: Early intervention. To achieve optimal benefits from intravenous Betaloc, suitable patients should present within 12 hours of the onset of chest pain.

Such treatment should be initiated in a coronary care or similar unit immediately after the patient's haemodynamic condition has stabilised.

Therapy should commence with 5 mg i.v. every 2 minutes to a maximum of 15 mg total as determined by blood pressure and heart rate. The second or third dose should not be given if the systolic blood pressure is <90 mmHg, the heart rate is <40 beats/min and the P-Q time is >0.26 seconds, or if there is any aggravation of dyspnoea or cold sweating.

Oral therapy should commence 15 minutes after the last injection with 50 mg every 6 hours for 48 hours. Patients who fail to tolerate the full intravenous dose should be given half the suggested oral dose.

During anaesthesia: 2–4 mg injected slowly i.v. at induction is usually sufficient to prevent the development of arrhythmias during anaesthesia. The same dosage can also be used to control arrhythmias developing during anaesthesia. Further injections of 2 mg may be given as required to a maximum overall dose of 10 mg.

Impaired renal function: Dose adjustment is generally not needed in patients with impaired renal function.

Impaired hepatic function: Dose adjustment is normally not needed in patients suffering from liver cirrhosis because metoprolol has a low protein binding (5–10%). However, a reduction in dosage may be necessary, according to the severity of hepatic impairment.

Elderly: Several studies indicate that age-related physiological changes have negligible effects on the pharmacokinetics of metoprolol.

Children: There is limited experience with metoprolol treatment in children.

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

– AV block of second- or third-degree

– Unstable decompensated cardiac failure (pulmonary oedema, hypoperfusion or hypotension)

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

– Bradycardia (<45 bpm)

– Sick sinus syndrome

– Cardiogenic shock

– Severe peripheral arterial circulatory disorders

– Untreated phaeochromocytoma

– Metabolic acidosis

Known hypersensitivity to any component of Betaloc Injection or other beta-blockers.

Betaloc Injection is also contraindicated when suspected acute myocardial infarction is complicated by bradycardia (<45 bpm), first-degree heart block (the P-Q interval is>0.24 sec) or systolic blood pressure <100 mmHg.

Intravenous injections of Betaloc are suitable only for acute administration in hospitalised patients and should be given only if facilities are available for monitoring the electrocardiogram and blood pressure.

In cases where the systolic blood pressure is below 100 mmHg, Betaloc should only be given intravenously if special precautions are observed, because there is a risk that administration of the drug by this route may cause a further fall in blood pressure (i.e. in patients with cardiac arrhythmias).

When treating patients with suspected or definite myocardial infarction the haemodymanic status of the patient should be carefully monitored after each of the three 5 mg intravenous doses. The second or third dose should not be given if the heart rate is <40 beats/min, the systolic blood pressure is <90 mmHg and the P-Q time is>0.26 sec, or if there is any aggravation of dyspnoea or cold sweating.

Betaloc, as with other beta-blockers:

• During oral treatment should not be withdrawn abruptly. When possible, Betaloc Injection should be withdrawn gradually. 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 Injection 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.

• Although contraindicated 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.

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

• Due to the negative effect on conduction time, may aggravate pre-existing conduction time disorders of moderate degree, which may lead to AV block, and 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 Injection 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 Injection, 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 Injection is commenced.

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

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.

The initial treatment of severe malignant hypertension should be so designed as to avoid sudden reduction in diastolic blood pressure with impairment of autoregulatory mechanisms.

Betaloc Injection can reduce myocardial contractility and impair intracardiac conduction. Care should be exercised when drugs with similar activity, e.g. antiarrhythmic agents (of the quinidine type and amiodarone), or general anaesthetics, are given concurrently.

Increased negative inotropic and chronotropic effects may occur when Betaloc Injection is given together with calcium antagonists of the verapamil and diltiazem type, causing bradycardia, hypotension and asystole. In patients treated with beta-blockers intravenous administration of calcium antagonists of the verapamil type should not be given in combination.

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

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 Injection should be withdrawn several days before clonidine.

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

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 Injection may impair the elimination of lidocaine.

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, e.g. 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.

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.

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

The beta-blocker may mask some of the symptoms of thyrotoxicosis and of hypoglycaemia by inhibition of sympathetic nerve functions. The effects of hypoglycaemic agents may be increased, particularly by the non-cardioselective beta-blockers. The dosages of oral antidiabetics and also of insulin may have to be readjusted in patients receiving beta-blockers. The tachycardia of hypoglycaemia may be modified.

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 Injection and other antihypertensive drugs 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

Betaloc should not be used in pregnancy or nursing mothers unless the physician considers that the benefit outweighs the possible hazard to the foetus/infant. Beta-blockers reduce placental perfusion, which may result in intrauterine foetal death, immature and premature deliveries.

As with all beta-blockers, Betaloc Injection may cause side effects especially bradycardia and hypoglycaemia in the foetus, and in the newborn and breast-fed infant.

Betaloc Injection has, however, been used in pregnancy-associated hypertension under close supervision, after 20 weeks gestation. Although Betaloc Injection crosses the placental barrier and is present in the cord blood, as yet no evidence of foetal abnormalities has been reported.

Lactation

The amount of metoprolol ingested via breast milk should not produce significant beta-blocking effects in the neonate if the mother is treated with the normal therapeutic doses.

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

Betaloc Injection 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. A relationship to treatment with metoprolol has not always 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

*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 shock 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 patients in which metoprolol is recommended for use in acute myocardial infarction.

Central nervous system

Gastrointestinal

Haematologic

Hepatic

Metabolism

Musculoskeletal

Psychiatric

Respiratory

Sense organs

Skin

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 and 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 tartrate is a cardioselective beta-adrenoceptor blocking agent. The stimulant effects of catecholamines on the heart is reduced or inhibited by metoprolol. This leads to a decrease in heart rate, cardiac output, cardiac contractility and blood pressure

Metoprolol tartrate is almost completely absorbed from the gastrointestinal tract.

Plasma levels rise linearly in relation to dose. Peak plasma concentrations are attained after 1.5–2 hours.

Plasma half-life is approximately 3–5 hours. Protein binding is 12% at therapeutic concentrations.

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

See Sections 4.3 to 4.9

Sodium chloride

Water for injections.

In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products.

Unopened pack: 4 years.

The product should be used immediately after opening.

Do not store above 25°C. Keep the ampoules in the outer carton.

Type I, 5 ml glass ampoule. Carton of five ampoules.

For single use only. Discard any unused contents.

AstraZeneca UK Ltd.,

600 Capability Green,

Luton, LU1 3LU,UK.

PA 970/32/1

2^nd May 1983 / 2^nd May 2008

19^th May 2010