BETALOC Solution for injection Ref.[7777] Active ingredients: Metoprolol

When treating patients with suspected or definite myocardial infarction the haemodynamic 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 I.V. Injection, as with other beta blockers:

• should not be withdrawn abruptly during oral treatment. When possible, Betaloc I.V. Injection should be withdrawn gradually over a period of 10 – 14 days, in diminishing doses to 25 mg daily for the last 6 days.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 I.V. Injection 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. Routine initiation of high-dose metoprolol to patients undergoing non-cardiac surgery should be avoided, since it has been associated with bradycardia, hypotension, stroke and increased mortality in patients with cardiovascular risk factors. However in some patients it may be desirable to employ a beta-blocker as premedication. In such cases 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 I.V. Injection should be used with caution in patients where cardiac reserve is poor.
• may cause patients to develop increasing bradycardia, in such cases the Betaloc I.V. Injection dosage should be reduced or gradually withdrawn.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 I.V. 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 I.V. 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 I.V. Injection is commenced.

The label shall state - "Use with caution in patients who have a history of wheezing, asthma or any other breathing difficulties, see enclosed user leaflet."

Like all beta-blockers, careful consideration should be given to patients with psoriasis before Betaloc I.V. Injection 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.

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 I.V. Injection 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 I.V. Injection 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 I.V. 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.

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 I.V. Injection 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

Betaloc I.V. Injection should not be used in pregnancy or nursing mothers unless the physician considers that the benefit outweighs the possible hazard to the foetus/infant. In general, beta-blockers reduce placental perfusion, which has been associated with intrauterine death, abortion and early labour. It is therefore suggested that appropriate maternofoetal monitoring be performed in pregnant women treated with Betaloc I.V. Injection. As with all beta-blockers, Betaloc I.V. Injection may cause side-effects especially bradycardia and hypoglycaemia in the foetus, and in the newborn and breast-fed infant. There is an increased risk of cardiac and pulmonary complications in the neonate. Betaloc I.V. Injection has, however, been used in pregnancy-associated hypertension under close supervision, after 20 weeks gestation. Although Betaloc I.V. Injection crosses the placental barrier and is present in cord blood, no evidence of foetal abnormalities has been reported.

Breast-feeding

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

Betaloc I.V. Injection has minor influence on the ability to drive and use 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 (≥1/10), common (≥1/100 to <1/10), uncommon ((≥1/1,000 to <1/100), rare ((≥1/10,000 to <1/1,000) and very rare (<1/10,000).

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, cardiogenic shock in patients with acute myocardial infarction*, 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

Hepatobiliary 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).

* 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 corresponding excess frequency for patients in Killip class I was 0.7% (metoprolol 3.5% and placebo 2.8%). 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 indicated for use in acute myocardial infarction.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme. Website: www.mhra.gov.uk/yellowcard.

Not applicable.