4.1. Therapeutic indications

In the management of:

• Hypertension

• Angina pectoris

• Cardiac arrhythmias (in particular supraventricular tachycardias)

• As an adjunctive treatment of thyrotoxicosis.

• Early intervention of metoprolol in acute myocardial infarction reduces infarct size and the incidence of ventricular fibrillation. Pain relief may also decrease the need for opiate analgesics.

• long-term prophylaxis after recovery from acute myocardial infarction.

• Prophylaxis of migraine.

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

Metoprolol is indicated in adults.

4.2. Posology and method of administration

Posology

The following dosage regimes are intended only as a guideline and should always be adjusted to the individual requirements of the patient but should not exceed 400 mg/day.

Adults:

Hypertension:

Initially 100 mg daily. This may be increased, if necessary to 200 mg daily in single or divided doses. Combination therapy with a diuretic or vasodilator may also be considered to further reduce blood pressure.

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: Usually 50-100 mg two or three times daily. In general a significant improvement in exercise tolerance and reduction of angina attacks may be expected with a dose of 50-100 mg twice daily.

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

Following the treatment of an acute arrhythmia with metoprolol tartrate injection, continuation therapy with metoprolol tablets should be initiated 4-6 hours later. The initial oral dose should not exceed 50mg twice daily.

Myocardial Infarction:

Early intervention: Orally, therapy should commence 15 minutes after the last intravenous injection with 50 mg every 6 hours for 48 hours and preferably within 12 hours of the onset of chest pain. Patients who fail to tolerate the full intravenous dose should be given half the suggested oral dose.

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

Thyrotoxicosis

50mg four times daily. Dose should be reduced progressively as euthyroid state is achieved.

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

Elderly

The optimum dose should be individually determined according to clinical response.

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 excessive decrease in blood pressure or pulse rate may cause the blood supply to vital organs to fall to inadequate levels.

Dosage should be reduced in the elderly where there is impairment of hepatic function.

Paediatric population

The safety and efficacy of Metoprolol in children has not been established. Metoprolol tartrate is not recommended in children

Hepatic impairment

In patients with significant hepatic dysfunction dosage reduction may be advised.

Renal impairment

Dose adjustment is not warranted in renal impairment.

Method of Administration

For oral administration.

4.3. Contraindications

• Known hypersensitivity to metoprolol, related derivatives, any other β-blockers or to any of the excipients listed in section 6.1.

• Second-or-third degree atrioventricular block

• Uncontrolled heart failure

• Clinically relevant sinus bradycardia (< 45-50 bpm)

• Sick sinus syndrome. (unless a pacemaker is in situ).

• Prinzmetal's angina

• Myocardial infarction complicated by significant bradycardia, first degree heart block, systolic hypotension (less than 100mmHg) and/or severe heart failure and cardiogenic shock.

• Severe peripheral arterial disease.

• Asthma and history of bronchospasm

• Untreated phaeochromocytoma

• Metabolic acidosis.

• Concomitant intravenous administration of calcium blockers of the type verapamil or diltiazem or other antiarrhythmics (such as disopyramide) is contraindicated (exception: intensive care unit).

• Hypotension

• Diabetes if associated with frequent episodes of hypoglycaemia

• Chronic obstructive pulmonary disease

4.4. Special warnings and precautions for use

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 25mg for the last 6 days. If necessary, at the same time, initiating replacement therapy, to prevent exacerbation of angina pectoris. In addition, hypertension and arrhythmias may develop. 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 betablockade reduces the risk of arrhythmias during induction and intubation, however the risk of hypertension may be increased as well. If treatment is continued, caution should be observed with the use of certain anaesthetic drugs. The patient may be protected against vagal reactions by intravenous administration of atropine. During its withdrawal the patient should be kept under close surveillance.

Although cardioselective beta-blockers may have less effect on lung function than non-selective beta-blockers these should be avoided in patients with reversible obstructive airway disease unless there are compelling clinical reasons for their use.

Although metoprolol has proved safe in a large number of asthmatic patients, it is advisable to exercise care in the treatment of patients with chronic obstructive pulmonary disease. Therapy with a beta2-stimulant may become necessary or current therapy require adjustment. Therefore, non selective beta blockers should not be used for these patients, and beta1-selective blockers only with the utmost care.

Discontinuation of the drug should be considered if any such reaction is not otherwise explicable. Cessation of therapy with a beta blocker should be gradual.

Metoprolol Tartrate tablets may not be administered to patients with untreated congestive heart failure. The congestive heart failure needs to be brought under control first of all. If concomitant digoxin treatment is taking place, it must be borne in mind that both medicinal products slow AV conduction and that there is therefore a risk of AV dissociation. In addition, mild cardiovascular complications may occur, manifesting as dizziness, bradycardia, and a tendency to collapse.

When a beta blocker is being taken, a serious, sometimes even life-threatening deterioration in cardiac function can occur, in particular in patients in whom the action of the heart is dependent on the presence of sympathetic system support. This is due less to an excessive beta-blocking effect and more to the fact that patients with marginal heart function tolerate poorly a reduction in sympathetic nervous system activity, even where this reduction is slight. This causes contractility to become weaker and the heart rate to reduce and slows down AV conduction. The consequence of this can be pulmonary oedema, AV block, and shock. Occasionally, an existing AV conduction disturbance can deteriorate, which can lead to AV block.

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

Before a patient undergoes an operation, the anaesthetist must be informed that metoprolol is being taken. 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.

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

Simultaneous administration of adrenaline (epinephrine), noradrenaline (norepinephrine) and β blockers may lead to increase in blood pressure and bradycardia.

Metoprolol may induce or aggravate bradycardia, symptoms of peripheral arterial circulatory disorders and anaphylactic shock. If the pulse rate decreases to less than 50-55 beats per minute at rest and the patient experiences symptoms related to the bradycardia, the dosage should be reduced.

Metoprolol 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.

Metoprolol may reduce the effect of diabetes treatment and mask the symptoms of hypoglycaemia. The risk of a carbohydrate metabolism disorder or masking of the symptoms of hypoglycaemia is lower when using metoprolol prolonged release tablets than when using regular tablet forms for beta1 selective beta blockers and significantly lower than when using nonselective beta blockers. In labile and insulin dependent diabetes, it may be necessary to adjust the hypoglycaemic therapy.

In case of unstable or insulin-dependent diabetes mellitus, it may be necessary to adjust the hypoglycaemic treatment (because of the likelihood of severe hypoglycaemic conditions).

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 significant hepatic dysfunction it may be necessary to adjust the dosage because metoprolol undergoes biotransformation in the liver. Patients with hepatic or renal insufficiency may need a lower dosage, and metoprolol is contraindicated in patients with hepatic or renal disease/failure (see section 4.3). The elderly should be treated with caution, starting with a lower dosage but tolerance is usually good in the elderly. It may be necessary to use a lower strength formulation in elderly patients and patients with hepatic or renal impairment and an alternative product should be prescribed.

Patients with anamnestically known psoriasis should take beta-blockers only after careful consideration as the medicine may cause aggravation of psoriasis.

Beta blockers may increase both the sensitivity towards allergens and the seriousness of anaphylactic reactions. Adrenaline (epinephrine) treatment does not always give the desired therapeutic effect in individuals receiving beta blockers (see also section 4.5).

Beta blockers may unmask myasthenia gravis.

In the presence of liver cirrhosis, the bioavailability of metoprolol may be increased, and dosage should be adjusted accordingly.

Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose galactose mal-absorption should not take this medicine.

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.

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

• Anaesthetic drugs may attenuate reflex tachycardia and increase the risk of hypotension. Metoprolol therapy should be reported to the anaesthetist before the administration of a general anaesthetic. If possible, withdrawal of metoprolol should be completed at least 48 hours before anaesthesia. However, for some patients undergoing elective surgery, it may be desirable to employ a betablocker as premedication. By shielding the heart against the effect of stress, metoprolol may prevent excessive sympathetic stimulation which is liable to provoke such cardiac disturbance as arrhythmias or acute coronary insufficiency during induction and intubation. Anaesthetic agents causing myocardial depression, such as cyclopropane and trichlorethylene, are best avoided. In a patient under beta-blockade an anaesthetic with as little negative inotropic activity as possible (halothane/nitrous oxide) should be selected.

• It may be necessary to adjust the dose of the hypoglycaemic agent in labile or insulin-dependent diabetes. Beta-adrenergic blockade may prevent the appearance of signs of hypo-glycaemia (tachycardia). The concomitant use of beta-blockers with sulfonylureas could increase the risk of severe hypoglycaemia (see Section 4.4).

• Like all beta-blockers, metoprolol should not be given in combination with calcium channel blockers i.e. verapamil and to a lesser extent diltiazem since this may cause bradycardia, hypotension, heart failure and asystole and may increase auriculoventricular conduction time. However, combinations of antihypertensive drugs may often be used with benefit to improve control of hypertension. Calcium blockers of the verapamil type should not be administered intravenously to patients receiving beta blockers (see section 4.3).

• Care should also be taken when beta-blockers are given in combination with sympathetic ganglion blocking agents, other beta blockers or MAO inhibitors. Concomitant administration of tricyclic antidepressants, barbiturates and phenothiazines as well as other antihypertensive agents may increase the blood pressure lowering effect.

• Calcium channel blockers (such as dihydropyridine derivatives e.g. nifedipine) should not be given in combination with metoprolol because of the increased risk of hypotension and heart failure. In patients with latent cardiac insufficiency, treatment with beta-blocking agents may lead to cardiac failure. Beta-blockers used in conjunction with clonidine increase the risk of “rebound hypertension”. If combination treatment with clonidine is to be discontinued, metoprolol should be withdrawn several days before clonidine.

• The effects of metoprolol and other antihypertensive drugs on blood pressure are usually additive, and care should be taken to avoid hypotension.

• NSAIDs (especially indometacin) may reduce the antihypertensive effects of beta-blockers possibly by inhibiting renal prostaglandin synthesis and/or causing sodium and fluid retention.

• Digitalis Glycosides and/or diuretics should be considered for patients with a previous history of heart failure or in patients known to have a poor cardiac reserve. Digitalis glycosides in association with beta-blockers may increase in auriculo-ventricular conduction time.

• The administration of adrenaline (epinephrine) or noradrenaline (norepinephrine) 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. As beta-blockers may affect the peripheral circulation, care should be exercised when drugs with similar activity e.g. ergotamine are given concurrently. Concurrent use of moxisylyte may result in possible severe postural hypotension.

• The effect of adrenaline (epinephrine) in the treatment of anaphylactic reactions may be weakened in patients receiving beta blockers (see also section 4.4).

• 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.

• Enzyme inducing agents (e.g. rifampicin) may reduce plasma concentrations of metoprolol, whereas enzyme inhibitors (e.g. cimetidine, hydralazine and alcohol), selective serotonin reuptake inhibitors (SSRIs) as paroxetine, fluoxetine and sertraline, diphenhydramine, hydroxychloroquine, celecoxib, terbinafine may increase plasma concentrations of hepatically metabolised beta blockers.

• As with all beta-blockers particular caution is called for when metoprolol is administered together with prazosin for the first time as the co-administration of metoprolol and prazosin may produce a first dose hypotensive effect.

• Class 1 antiarrhythmic drugs, e.g. disopyramide, quinidine and amiodarone may have potentiating effects on atrialconduction time and induce negative inotropic effect. Concurrent use of propafenone may result in significant increases in plasma concentrations and half-life of metoprolol. Plasma propafenone concentrations are unaffected. Dosage reduction of metoprolol may be necessary.

• During concomitant ingestion of alcohol and metoprolol the concentration of blood alcohol may reach higher levels and may decrease more slowly. The concomitant ingestion of alcohol may enhance hypotensive effects.

• Metoprolol may impair the elimination of lidocaine.

• Prostaglandin synthetase inhibiting drugs may decrease the hypotensive effects of beta-blockers.

• Concurrent use of oestrogens may decrease the antihypertensive effect of betablockers because oestrogeninduced fluid retention may lead to increased blood pressure.

• Concurrent use of xanthines, especially aminophylline or theophylline, may result in mutual inhibition of therapeutic effects.

• Xanthine clearance may also be decreased especially in patients with increased theophylline clearance induced by smoking.

• Concurrent use requires careful monitoring.

• Concurrent use of aldesleukin may result in an enhanced hypotensive effect.

• Concurrent use of alprostadil may result in an enhanced hypotensive effect.

• There is an increased risk of bradycardia following concomitant use of mefloquine with metoprolol.

• Concomitant use with anxiolytics and hypnotics may result in an enhanced hypotensive effect.

• Concomitant use with corticosteroids may result in antagonism of the hypotensive effect.

• The manufacturer of tropisetron advises caution in concomitant administration due to the risk of ventricular arrhythmias.

4.6. Fertility, pregnancy and lactation

Pregnancy:

It is recommended that metoprolol should not be administered during pregnancy or lactation unless it is considered that the benefit outweighs the possible risk to the foetus/infant. Should therapy with metoprolol be employed, special attention should be paid to the foetus, neonate and breast fed infant for any undesirable effects such as slowing of the heart rate.

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 has been reported. However, there is an increased risk of cardiac and pulmonary complications in the neonate in the postnatal period.

Beta blockers reduce placental perfusion and may cause foetal death and premature birth. Intrauterine growth retardation has been observed after long time treatment of pregnant women with mild to moderate hypertension. Beta blockers have been reported to cause bradycardia in the foetus and the newborn child, there are also reports of hypoglycaemia and hypotension in newborn children.

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. Treatment with metoprolol should be discontinued 48-72 hours before the calculated birth date. If this is not possible, the newborn child should be monitored for 24-48 hours post partum for signs and symptoms of beta blockade (e.g. cardiac and pulmonary complications).

Lactation:

The concentration of metoprolol in breast milk is approximately three times higher than the one in the mother's plasma. The risk of adverse effects in the breastfeeding baby would appear to be low after administration of therapeutic doses of the medicinal product (except in individuals with poor metabolic capacity). Cases of neonatal hypoglycaemia and bradycardia have been described with beta-blockers with low plasma protein binding. Metoprolol is excreted in human milk. Even though the metoprolol concentration in milk is very low, breast-feeding should be discontinued during treatment with metoprolol. In case of treatment during breast feeding, infants should be monitored carefully for symptoms of beta blockade.

4.7. Effects on ability to drive and use machines

As with all beta-blockers, metoprolol can affect patients' ability to drive and operate machinery. It should be taken into account that occasionally dizziness and fatigue may occur. Patients should be warned accordingly. If affected, patients should not drive or operate machinery.

4.8. Undesirable effects

Frequency estimates:

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 available data)

System Organ Class

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 lymphatic system disorders

Thrombocytopenia, agranulocytosis

Psychiatric disorders

.

Depression, nightmares, Nervousness, anxiety, impotence

Hallucinations, personality disorder, Amnesia/ memory impairment

Nervous system disorders

Dizziness, headache.

Alertness decrease, somnolence or insomnia paraesthesia.

Eye disorders

Visual disturbances (e.g. blurred vision), dry eye and/ or eye irritation

Ear and labyrinth disorders

Tinnitus, and in doses exceeding those recommended “hearing disorders (e.g. hypoacusis or deafness)

Cardiac disorders

Bradycardia

Heart failure, cardiac arrhythmia, palpitations.

Cardiac conduction disorder, precordial pain.

Increase in existing intermittent claudication

Vascular disorders

Orthostatic hypotension, occasionally with syncope.

Oedema, Raynaud's syndrome.

Gangrene in patients with pre-existing severe peripheral circulatorydisorders

Respiratory, thoracic and mediastinal disorders

Exertional dyspnoea.

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

Rhinitis

Gastrointestinal disorders

Nausea and vomiting. abdominal pain

Diarrhoea or constipation

Dry mouth

Retroperitoneal fibrosis *

Hepatobiliary disorders

Hepatitis

Skin and subcutaneous tissue disorders

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

Photosensitivity, hyperhidrosis,alopecia, worsening of psoriasis

Occurrence of antinuclearantibodies (not associated with SLE)

Musculoskeletal and connective tissue disorders

Muscle cramps

Arthritis

Reproductive system and breast disorders

Disturbances of libido and potency

Peyronie's disease *

General disorders and administration site conditions

Fatigue

Dysgeusia (Taste disturbances)

Investigations

Weight increase, liver function test abnormal

* (relationship to Metoprolol has not been definitely established).

Beta-blockers may mask the symptoms of thyrotoxicosis or hypoglycaemia.

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

4.9. Overdose

Poisoning due to an overdose of metoprolol may lead to severe hypotension, sinus bradycardia, atrioventricular block, heart failure, cardiogenic shock, cardiac arrest, bronchospasm, impairment of consciousness, coma, nausea, vomiting, cyanosis, hypoglycaemia and, occasionally, hyperkalaemia. The first manifestations usually appear 20 minutes to two hours after drug ingestion.

After ingestion of an overdose or in case of hypersensitivity, the patient should be kept under close supervision and be treated in an intensive- care ward. Absorption of any drug material still present in the gastrointestinal tract can be prevented by induction of vomiting, gastric lavage, administration of activated charcoal and a laxative. Artificial respiration may be required.

Bradycardia or extensive vagal reactions should be treated by administering atropine or methylatropine. Hypotension and shock should be treated with plasma/plasma substitutes and, if necessary, catecholamines. The beta-blocking effect can be counteracted by slow intravenous administration of isoprenaline hydrochloride, starting with a dose of approximately 5 micrograms/minute, or dobutamine, starting with a dose of 2.5micrograms/minute, until required effect has been obtained. In refractory cases isoprenaline can be combined with dopamine. If this does not produce the desired effect either, intravenous administration of 8-10mg glucagon may be considered. If required the injection should be repeated within one hour, to be followed – if required – by an intravenous infusion of glucagon at an administration rate of 1- 3mg/hour.

Administration of calcium ions, or the use of a cardiac pacemaker may also be considered. In patients intoxicated with hydrophilic beta-blocking agents haemodialysis or haemoperfusion may be considered.