4.1. Therapeutic indications

• Hypertension.

• Angina pectoris.

• Cardiac arrhythmias, especially supraventricular tachyarrhythmias.

• Adjunct to treatment of thyrotoxicosis.

• Early intervention with metoprolol in myocardial infarction reduces infarct size and the incidence of ventricular fibrillation. Pain relief may also decrease the need for opiate analgesics. Metoprolol has been shown to reduce mortality when administered to patients with acute myocardial infarction.

• Prophylaxis of migraine.

4.2. Posology and method of administration

Posology

The dose must always be adjusted to the individual requirements of the patient but should not exceed 400 mg/day. The following are guidelines:

Adults

Hypertension: initially a dose of 100 mg per day should be prescribed either as single or divided doses. Depending upon the response the dosage may be increased by 100 mg per day at weekly intervals to 200 mg daily given in single or divided doses. Over the dosage range most patients may be expected to respond rapidly and satisfactorily. A further reduction in blood pressure may be achieved if Metoprolol is used in conjunction with an antihypertensive diuretic or other hypotensive agent.

Metoprolol may be administered with benefit both to previously untreated patients with hypertension and to those in whom the response to previous therapy is inadequate. In the latter type of patient the previous therapy may be continued and Metoprolol added into the regime with adjustment of the previous therapy if necessary.

Angina pectoris: 50-100 mg twice or three times daily

In general a significant improvement in exercise tolerance and reduction of anginal attacks may be expected with a dose of 50-100 mg twice daily.

Cardiac arrhythmias: A dosage of 50 mg two or three times daily is usually sufficient. If necessary the dose can be increased up to 300 mg per day administered in divided doses.

Hyperthyroidism: 50 mg four times daily. The dosage should be progressively reduced as euthyroid state is slowly achieved.

Myocardial infarction:

Early intervention: 50 mg every 6 hours for 48 hours, preferably within 12 hours of the onset of chest pain.

Maintenance: the usual maintenance dose is 200 mg daily given in divided doses. The treatment should be continued for at least 3 months.

Prophylaxis of migraine: 100-200 mg daily, given in divided doses (morning and evening).

Termination of treatment: The dose should be withdrawn gradually over a period of 10 days, the doses diminishing to 25 mg for the last 6 days (see section 4.4).

Special populations

Elderly

There is no evidence to suggest that dosage requirements are different in otherwise healthy elderly patients. However, caution is indicated in elderly patients as an excessively pronounced decrease in blood pressure or pulse rate may cause the blood supply to vital organs to fall to inadequate levels. In patients with significant hepatic dysfunction the lower dosage recommendations will be more appropriate.

Hepatic impairment

In patients with significant hepatic dysfunction the lower dosage should be considered (see section 5.2).

Renal impairment

No dosage adjustment is usually needed in patients with renal insufficiency (see section 5.2).

Poor metabolisers

Poor metabolisers may require lower than normal doses (see section 5.2).

Children

Not recommended.

Method of administration

Metoprolol tablets should be administered with a drink of water.

4.3. Contraindications

• Hypersensitivity to the active substances, to related derivatives or to any of the excipients listed in section 6.1.

• Severe asthma or history of severe bronchospasm.

• Atrioventricular block of second or third degree.

• Uncontrolled heart failure.

• Clinically relevant sinus bradycardia.

• Sick-sinus syndrome.

• Severe peripheral arterial disease.

• Cardiogenic shock.

• Hypotension.

• Untreated phaeochromocytoma.

• Metabolic acidosis.

• Metoprolol is also contraindicated when myocardial infarction is complicated by significant bradycardia, first degree heart block, systolic hypotension (less than 100 mmHg) and/or severe heart failure.

4.4. Special warnings and precautions for use

A warning stating “Do not take this medicine if you have a history of wheezing or asthma” will appear on the label.

Although cardioselective beta-blockers, including metoprolol, 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 airway disease unless there are compelling clinical reasons for their use. Therapy with a beta2- stimulant may become necessary or current therapy require adjustment.

Metoprolol may aggravate bradycardia and symptoms of peripheral arterial circulatory disorders. If the patient develops increasing bradycardia, (heart rate less than 50 to 55 beats/min) metoprolol should be given in lower doses or gradually withdrawn.

In addition, anaphylactic reactions precipitated by other agents may be particularly severe in patients taking beta-blockers, and may be resistant to normal doses of adrenaline. Whenever possible, beta-blockers, including metoprolol, should be avoided for patients who are at increased risk of anaphylaxis.

Abrupt cessation of therapy with a beta-blocker should be avoided, especially in patients with ischaemic heart disease. When possible, metoprolol should be withdrawn gradually over a period of 10 days, the doses diminishing to 25 mg for the last 6 days. During its withdrawal, the patient should be kept under close surveillance and replacement therapy should be initiated where required.

Beta-blockers, including metoprolol, should not be used in patients with untreated congestive heart failure (see section 4.3).This condition should first be stabilised. Additional therapy should also be considered for patients with a history of heart failure or patients who are known to have a poor cardiac reserve, e.g. diuretics and/or digitalisation.

Because of their negative effect on atrioventricular conduction, beta-blockers, including metoprolol, should be given only with caution to patients with first degree atrioventricular block (see section 4.3).

Beta-blockers mask some of the clinical signs of thyrotoxicosis. Therefore, metoprolol should be administered with caution to patients having, or suspected of developing, thyrotoxicosis, and both thyroid and cardiac function should be monitored closely.

Metoprolol should be used with caution in patients with diabetes mellitus, especially those who are receiving insulin or oral hypoglycaemic agents (see section 4.5). In labile and insulin-dependent diabetes it may be necessary to adjust the hypoglycaemic therapy. Metoprolol may mask some of the symptoms of hypoglycaemia by inhibition of sympathetic nerve functions and patients should be warned accordingly.

Beta-blockers could further increase the risk of severe hypoglycaemia when used concurrently with sulfonylureas. Diabetic patients should be advised to carefully monitor blood glucose levels (see Section 4.5).

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

In patients with significant hepatic dysfunction it may be necessary to adjust the dosage because metoprolol undergoes biotransformation in the liver.

The administration of adrenaline 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.

Metoprolol therapy should be brought to the attention of the anaesthetist prior to general anaesthesia. The benefits of continuing a treatment with a beta-blocker, including metoprolol, should be balanced against the risk of withdrawing it in each patient. When it has been decided to interrupt a beta-blockade in preparation for surgery, therapy should be discontinued for at least 24 hours. Continuation of beta-blockade reduces the risk of arrhythmias during induction and intubation. However, the risk of hypertension may be increased. If treatment is continued, caution should be observed with the use of certain anaesthetic drugs. In a patient under beta-blockade, the anaesthetic selected should be one exhibiting as little negative inotropic activity as possible (halothane/nitrous oxide). The patient may be protected against vagal reactions by intravenous administration of atropine.

Beta-blockers may increase the number and duration of angina attacks in patients with Prinzmetal's angina (variant angina pectoris). However, relatively selective β1-receptor blockers, such as metoprolol, can be used in such patients, but only with the utmost care.

Patients with anamnestically known psoriasis should take beta-blockers only after careful consideration.

The full oculomucocutaneous syndrome, as described elsewhere with practolol, has not been reported with metoprolol. However, part of this syndrome (dry eyes either alone or, occasionally, with skin rashes) has occurred. In most cases the symptoms cleared when metoprolol treatment was withdrawn. Patients should be observed carefully for potential ocular effects. If such effects occur, discontinuation of metoprolol should be considered (see advice about discontinuation above).

Excipients

This medicinal product contains lactose monohydrate. Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medicine.

This medicine contains less than 1 mmol sodium (23 mg) per tablet; that is to say essentially “sodium-free”.

4.5. Interaction with other medicinal products and other forms of interaction

The effects of metoprolol and other antihypertensive drugs on blood pressure are usually additive, and care should be taken to avoid hypotension. However, combinations of antihypertensive drugs may often be used with benefit to improve control of hypertension.

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

Care should also be exercised when beta-blockers are given in combination with sympathetic ganglion blocking agents, other beta blockers (also in the form of eye drops) or MAO inhibitors.

Prazosin

The acute postural hypotension that can follow the first dose of prazosin may be increased in patients already taking a beta-blocker.

Clonidine

If combination treatment with clonidine is to be discontinued metoprolol should be withdrawn several days before clonidine. This is because the hypertension that can follow withdrawal of clonidine may be increased in patients receiving concurrent beta-blocker treatment.

Calcium channel blockers

Calcium channel blockers such as verapamil and diltiazem may potentiate the depressant effects of beta-blockers on blood pressure, heart rate, cardiac contractility and atrioventricular conduction. A calcium channel blocker of the verapamil (phenylalkylamine) type should not be given intravenously to patients receiving metoprolol because there is a risk of cardiac arrest in this situation. Patients taking an oral calcium channel blocker of the verapamil type in combination with metoprolol should be closely monitored.

CYP2D6 inhibitors

Potent inhibitors of this enzyme may increase the plasma concentration of metoprolol (see section 5.2). Caution should therefore be exercised when co-administering potent CYP2D6 inhibitors with metoprolol. Known clinically significant potent inhibitors of CYP2D6 are antidepressants such as fluoxetine, paroxetine or bupropion, antipsychotics such as thioridazine, antiarrhythmics such as 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.

Class I anti-arrhythmic drugs and amiodarone

Amiodarone, propafenone, and other class I anti-arrhythmic agents such as quinidine and disopyramide may potentiate the effects of beta-blockers on heart rate and atrioventricular conduction.

Nitroglycerin

Nitroglycerin may enhance the hypotensive effect of metoprolol.

Digitalis glycosides

Concurrent use of digitalis glycosides may result in excessive bradycardia and/or increase in atrioventricular conduction time.

Sympathomimetics

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

Insulin and oral hypoglycaemic drugs

In diabetic patients who use insulin, beta-blocker treatment may be associated with increased or prolonged hypoglycaemia. Beta-blockers may also antagonise the hypoglycaemic effects of sulfonylureas. The risk of either effect is less with a beta1-selective drug such as metoprolol than with a non- selective beta-blocker. However, diabetic patients receiving metoprolol should be monitored to ensure that diabetes control is maintained (see also section 4.4).

The concomitant use of beta-blockers with sulfonylureas could increase the risk of severe hypoglycaemia (see Section 4.4).

Non-steroidal anti-inflammatory drugs

Concurrent treatment with non-steroidal anti-inflammatory drugs such as indomethacin may decrease the antihypertensive effect of metoprolol.

Lignocaine

Metoprolol may impair the elimination of lignocaine.

General anaesthetics

Some inhalation anaesthetics may enhance the cardiodepressant effect of beta- blockers (see section 4.4).

Hepatic enzyme inducers/inhibitors

Enzyme inducing agents (e.g. rifampicin) may reduce plasma concentrations of metoprolol, whereas enzyme inhibitors (e.g. cimetidine) may increase plasma concentrations.

Alcohol

During concomitant ingestion of alcohol and metoprolol the concentration of blood alcohol may reach higher levels and may decrease more slowly.

4.6. Fertility, pregnancy and lactation

Metoprolol should not be used in pregnancy or lactation unless it is considered that the benefit outweighs the possible risk to the foetus/infant.

If metoprolol is used during pregnancy and lactation special attention should be paid to the foetus, neonate and breast-fed infant for undesirable effects of the drug's beta-blocking action (e.g. bradycardia, hypoglycaemia). 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 baby.

Pregnancy

Beta-blockers reduce placental perfusion which may result in intrauterine foetal death, immature and premature deliveries.

Metoprolol has, however, been used in pregnancy associated hypertension under close supervision after 20 weeks gestation. Although the drug crosses the placental barrier and is present in cord blood no evidence of foetal abnormalities have been reported. Animal experiments have shown neither teratogenic potential nor other adverse events on the embryo and/or foetus relevant to the safety assessment of the product.

Breast-feeding

The amount of metoprolol ingested via breast milk seems to be negligible with regard to its beta-blocking effects if the mother is treated in doses within the therapeutic range.

4.7. Effects on ability to drive and use machines

As with all beta-blockers, metoprolol may affect patients' ability to drive and operate machinery. Patients should be warned accordingly.

4.8. Undesirable effects

Tabulated list of adverse reactions

Adverse reactions have been ranked under headings of frequency using the following convention: 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); very rare (< 1/10,000); not known (cannot be estimated from the available data).

Blood and the lymphatic system disorders

Very rare

Thrombocytopenia

Psychiatric disorders

Rare

depression, nightmares

Very rare

personality disorder, hallucinations

Nervous system disorders

Common

dizziness, headache

Rare

alertness decreased, somnolence or insomnia, paraesthesia

Eye disorders

Very rare

visual disturbance (eg. blurred vision), dry eyes and/or eye irritation

Ear and labyrinth disorders

Very rare

tinnitus, and, in doses exceeding those recommended, hearing disorders (eg. hypoacusis or deafness)

Cardiac disorders

Common

Bradycardia

Rare

heart failure, cardiac arrhythmias, palpitation

Very rare

cardiac conduction disorders, precordial pain,

Vascular disorders

Common

orthostatic hypotension (occasionally with syncope)

Rare

oedema, Raynaud's phenomenon

Very rare

gangrene in patients with pre-existing severe peripheral circulatory disorders

Respiratory, thoracic and mediastinal disorders

Common

exertional dyspnoea

Rare

bronchospasm (which may occur in patients without a history of obstructive lung disease)

Very rare

Rhinitis

Gastrointestinal disorders

Common

nausea and vomiting, abdominal pain

Rare

diarrhoea or constipation

Very rare

dry mouth

Not known

retroperitoneal fibrosis (relationship to metoprolol has not been definitely established)

Hepatobiliary disorders

Not known

Hepatitis

Skin and subcutaneous tissue disorders

Rare

skin rash (in the form of urticaria, psoriasiform and dystrophic skin lesions)

Very rare

photosensitivity, hyperhydrosis, alopecia, worsening of psoriasis

Musculoskeletal and connective tissue disorders

Rare

muscle cramps

Very rare

Arthritis

Reproductive system and breast disorders

Very rare

disturbances of libido and potency

Not known

Peyronie's disease (relationship to metoprolol has not been definitely established)

General disorders and administration site conditions

Common

Fatigue

Investigations

Very rare

weight increase, liver function test abnormal

Post marketing experience

The following adverse reactions have been reported during post-approval use of metoprolol: confusional state, an increase in blood triglycerides and a decrease in high density lipoprotein (HDL). Because these reports are from a population of uncertain size and are subject to confounding factors, it is not possible to reliably estimate their frequency.

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: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9. Overdose

Symptoms

In more severe cases an overdosage of metoprolol may lead to severe hypotension, sinus bradycardia, atrioventricular block, heart failure, cardiogenic shock, cardiac arrest, bronchospasm, impairment of consciousness, coma, convulsions, nausea, vomiting, cyanosis, hypoglycaemia and occasionally hyperkalaemia.

The first manifestations of overdosage appear 20 minutes to 2 hours after ingestion of metoprolol. The effects of massive overdose may persist for several days, despite declining plasma concentrations.

Management

Patients should be admitted to hospital and, generally, should be managed in an intensive care setting, with continuous monitoring of cardiac function, blood gases, and blood biochemistry. Emergency supportive measures such as artificial ventilation or cardiac pacing should be instituted if appropriate. Even apparently well patients who have taken a small overdose should be closely observed for signs of poisoning for at least 4 hours.

In the event of a potentially life-threatening oral overdose, use induction of vomiting or gastric lavage (if within 4 hours after ingestion of metoprolol) and/or activated charcoal to remove the drug from the gastrointestinal tract. Metoprolol can not be effectively removed by haemodialysis.

Atropine may be given intravenously to control significant bradycardia. Intravenous beta-agonists such as prenalterol or isoprenaline should be used to treat bradycardia and hypotension; very high doses may be needed to overcome the beta-blockade. Dopamine, dobutamine or noradrenaline may be given to maintain blood pressure. Glucagon has positive inotropic and chronotropic effects on the heart that are independent of beta-adrenergic receptors, and has proved effective in the treatment of resistant hypotension and heart failure associated with beta-blocker overdose.

Diazepam is the drug of choice for controlling seizures. A β2-agonist or aminophylline can be used to reverse bronchospasm; patients should be monitored for evidence of cardiac arrhythmias during and after administration of the bronchodilator.