Document: spc-doc_PL 00289-0743 change

• spc-doc_PL 00289-0743
• spc-doc_PL 20075-0304

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SUMMARY OF PRODUCT CHARACTERISTICS

1    NAME OF THE MEDICINAL PRODUCT

Metoprolol Tartrate 50mg Tablets

2    QUALITATIVE AND QUANTITATIVE COMPOSITION

Each tablet contains 50 mg of metoprolol tartrate.

Excipient(s) with known effect:

Each tablet contains 83 mg of lactose.

For the full list of excipients, see 6.1.

3    PHARMACEUTICAL FORM

Round, biconvex white tablet, engraved 4A5 with a breakline on reverse.

4.    CLINICAL PARTICULARS

4.1.    Therapeutic Indications

Metoprolol tablets are indicated for the management of hypertension, angina pectoris and cardiac arrhythmias, especially supraventricular tachyarrhythmias.

They may also be used as an adjunct in the treatment of hyperthyroidism. In the early treatment of acute myocardial infarction, metoprolol may be used to reduce infarct size and the incidence of ventricular fibrillation. By providing pain relief, the need for opiate analgesics may be decreased. When administered to patients with acute myocardial infarction, metoprolol has been demonstrated to reduce mortality. Metoprolol is also indicated for the prevention 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 400mg/day. The following are guidelines:

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

Migraine prophylaxis: The usual dosage is 100 to 200 mg daily, administered

in divided doses (morning and evening).

Children    Metoprolol is not recommended for use in children.

Older people    There is no evidence to suggest that dosage

requirements are different in otherwise healthy older patients. However, caution is indicated in older 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.

Initially the lowest possible dose should be used.

Hepatic dysfunction In patients with significant hepatic dysfunction, a

reduction in dosage may be necessary.

Method of administration

Metoprolol tablets should be administered orally and swallowed unchewed.

4.3 Contraindications

Hypersensitivity to the active substance(s) or to any of the excipients listed in section 6.1

Metoprolol is contraindicated in severe asthma or history of severe bronchospasm, atrioventricular block of second or third degree, uncontrolled heart failure, severe bradycardia, cardiogenic shock, hypotension, severe peripheral arterial disease, sick-sinus syndrome, metabolic acidosis, untreated phaeochromocytoma and known hypersensitivity to Metoprolol and related derivatives or to any of the excipients.

Metoprolol is also contra-indicated when myocardial infarction is complicated by significant bradycardia, first degree heart block, systolic hypotension (<100 mmHg) and/or severe heart failure.

4.4 Special warnings and precautions for use

Beta blockers increase sensitivity to allergens and also the severity of anaphylactoid reactions; patients with a history of anaphylaxis to an antigen may be more reactive to repeated challenge with the antigen while taking beta blockers. Whenever possible, beta blockers, including Metoprolol, should be avoided for patients who are at increased risk of anaphylaxis.

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

The labelling for Metoprolol will state - Do not take this medicine if you have a history of wheezing or asthma.

Although cardioselective beta-blockers, including Metoprolol, may have less effect on lung function than non-selective beta blockers, as with all beta blockers, it is prudent to avoid Metoprolol in the treatment of patients with reversible obstructive pulmonary disease. If compelling clinical reasons necessitate Metoprolol therapy, concurrent use of a beta₂-bronchodilator, e.g. terbutaline, may be advisable in some patients or current therapy requires adjustment.

Metoprolol may exacerbate bradycardia, symptoms of peripheral arterial circulatory disorders and anaphylactic shock. If patients develop 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.

Abrupt withdrawal of beta blockers has sometimes resulted in angina, myocardial infarction, ventricular arrhythmias, and death.

Abrupt cessation of beta-blocking therapy should be avoided, in particular those with known ischaemic heart disease. When possible, withdrawal of Metoprolol should be gradual over 10 days in decreasing doses, to 25 mg daily for the final 6 days. During the period of withdrawal, patients should be closely monitored 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). Metoprolol may be administered when heart failure has been controlled. For patients with a history of heart failure or those known to have poor cardiac reserve, digitalisation and/or diuretic therapy should be considered. Metoprolol should be used with caution in patients where cardiac reserve is poor.

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). It may be necessary to adjust hypoglycaemic therapy in labile and insulin-dependent diabetes. Metoprolol may mask some of the symptoms of hypoglycaemia by inhibition of sympathetic nerve functions and patients should be warned accordingly.

Beta blockers reduce the responses to the beta-adrenoceptor stimulating effects of adrenaline. Treatment must be started with the alpha blocker and only when alpha blockade is successfully established can tachycardia be controlled by the cautious use of a beta blocker.

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

In the presence of cirrhosis of the liver, it may be necessary to adjust the dosage because Metoprolol undergoes biotransformation in the liver, the bioavailability of Metoprolol may be enhanced. The use of adrenaline in patients undergoing beta-blockade can result in a rise in blood pressure and bradycardia. The possibility of this occurrence is reduced by the use of beta₁-selective drugs.

Prior to general anaesthesia, Metoprolol therapy should be reported to the anaesthetist. The benefits of continuing a treatment with a beta-blocker, including Metoprolol, should be balanced against the risk of withdrawing it in each patient. Should Metoprolol withdrawal be considered desirable, if possible, this should be completed at least 24 hours before anaesthesia. Conversely, in some individuals it may be desirable to employ a beta-blocker as pre-medication. By shielding the heart against stress, this may prevent excessive sympathetic stimulation provoking cardiac arrhythmias or acute coronary insufficiency. If a beta-blocker is administered for this purpose, an anaesthetic with little negative inotropic activity should be selected to minimise the risk of myocardial depression. 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 pi-receptor blockers, such as Metoprolol, can be used in such patients, but only with the utmost care.

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

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).

4.5 Interaction with other medicinal products and other forms of interaction

Pharmacodynamic interactions may occur with drugs whose actions enhance or antagonise the various effects of beta blockers at betal and beta2 receptors, including their antihypertensive effect.

Metoprolol and other anti-hypertensive drugs have an additive effect on blood pressure and care should be taken to avoid hypotension. However, combinations of anti-hypertensive agents are often used with benefit to improve control of hypertension.

As beta-blockers may affect the peripheral circulation, care should be exercised with concurrent therapy of drugs with similar activity, e.g. ergotamine.

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 therapy with clonidine is to be terminated, Metoprolol should be withdrawn several days prior to 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

As with all beta-blockers, Metoprolol should not be administered in combination with verapamil or diltiazem as they may induce bradycardia, hypotension and asystole. 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.

Use of calcium-channel blockers with beta blockers has resulted in hypotension, bradycardia, conduction defects

Metoprolol can reduce myocardial contractility and impair intracardiac conduction and care should be exercised when drugs of similar activity are administered concomitantly e.g. antiarrhythmia agents, general anaesthetics.

CYP2D6 inhibitors

Potent inhibitors of this enzyme may increase the plasma concentration of Metoprolol (see section 5.2). Caution should therefore be exercised when coadministering 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

Metoprolol should also not be administered with cardiac glycosides as they may induce 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. Enzyme inducing agents, e.g. rifampicin, may decrease plasma Metoprolol levels, whereas enzyme inhibitors, e.g. cimetidine, alcohol or hydralazine may enhance plasma concentrations.

Care should also be taken when beta-blockers are given concurrently with sympathomimetic ganglion blocking agents, other beta-blockers (e.g. eye drops) or MAO inhibitors.

Patients taking beta blockers may have an exaggerated hypertensive response to adrenaline

Insulin and oral hypoglycaemic agents

The dosages of oral anti-diabetic agents and also of insulin may have to be readjusted in patients receiving beta-blockers. 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 section 4.4).

Non-steroidal anti-inflammatory drugs

Indometacin and other prostaglandin synthetase inhibiting drugs may reduce the antihypertensive effect of beta-blockers.

Adrenaline

Metoprolol therapy can reduce the response to adrenaline during the treatment of an allergic reaction.

Anaphylactic reactions to stings and other antigens may be potentiated by beta blockers and the risk of serious reactions may be increased. In addition, beta blockers may antagonise the effects of adrenaline in the management of anaphylaxis (see Interactions under Sympathomimetics)

Lignocaine

The elimination of lidocaine may also be impaired by Metoprolol.

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

Pregnancy

Metoprolol should not be used in pregnancy or nursing mothers unless the physician considers the benefits to outweigh the possible risks to the foetus or infant. Beta-blockers reduce placental perfusion, which may result in intrauterine foetal death, immature and premature deliveries.

However, Metoprolol has been used in pregnancy associated hypertension under close surveillance after 20 weeks gestation. Although Metoprolol crosses the placental barrier and is present in cord blood, there have been no reports of foetal abnormalities. 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.

As with all beta-blockers, side effects may develop, including bradycardia and hypoglycaemia in the foetus, new born or breastfed infant. 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.

Breast-feeding

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

Effects on ability to drive and use machines

When driving or operating machines it should be taken into account that dizziness or fatigue may occasionally occur. Patients should be warned accordingly.

4.8 Undesirable effects

List of adverse reactions

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 form the available data).

Blood and the lymphatic system disorders
Very rare	thrombocytopenia
Immune system disorders
Not known	positive anti-nuclear antibodies
Psychiatric disorders
Rare	depression, nightmares
Very rare	Personality disorder, hallucinations
Nervous system disorders
Common	dizziness, headache
Rare	alertness decreased, somnolence or insomnia, paraesthesia
Not Known	amnesia/memory impairment, nervousness, anxiety, taste disturbance
Eye disorders
Very rare	visual disturbance (e.g. blurred vision), dry eyes and/or eye irritation
Not known	conjunctivitis
Ear and labyrinth disorders
Very rare	tinnitus, and, in doses exceeding those recommended, hearing disorders (e.g. 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
Not known	Increase of pre-existing intermittent claudication
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
Not Known	arthralgia
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 at: www.mhra.gov.uk/yellowcard.

4.9 Overdose

Signs and symptoms

Poisoning due to an overdose of Metoprolol may result in 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.

Initial manifestations usually arise within 20 minutes to 2 hours of Metoprolol ingestion. The effects of massive overdose may persist for several days, despite declining plasma concentrations.

Treatment

Patients should be admitted to hospital and, generally, should be managed in an intensive care setting, with continuous monitoring of cardiovascular, respiratory and renal function, and blood glucose and electrolytes. 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. If ingestion is recent, the induction of vomiting, gastric lavage or administration of activated charcoal may prevent further absorption. Cardiovascular complications should be treated symptomatically, which may require the use of sympathomimetic agents, eg. noradrenaline, metaraminol, atropine or inotropic agents, eg. dopamine, dobutamine. Temporary pacing may be required for AV block. An intravenous dose of 1 - 10 mg of glucagon can reverse the effects of excessive beta-blockade. Intravenous beta₂-stimulants, e.g. terbutaline may be required to relieve bronchospasm.

Metoprolol cannot be effectively removed by haemodialysis.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: beta blocking agents, selective ATC code: C07A B02.

Metoprolol is a cardioselective beta-adrenoceptor blocking agent.

Mechanism of Action

It has a relatively greater blocking effect on beta ^receptors (i.e. those mediating adrenergic stimulation of heart rate and contractility and release of free fatty acids from fat stores) than on beta2-receptors which are chiefly involved in broncho and vasodilation. It has no membrane-stabilising effect nor partial agonist (intrinsic sympathomimetic) activity.

The stimulant effect of catecholamines on the heart is reduced or inhibited by Metoprolol. This leads to a decrease in heart rate, cardiac contractility and cardiac output.

5.2 Pharmacokinetic properties

Absorption

Metoprolol is well absorbed after oral administration, peak plasma concentrations occurring 1.5 - 2 hours after dosing. The bioavailability of a single dose is approximately 50%, increasing to approximately 70% during repeated administration. The bioavailability also increases if Metoprolol is given with food.

Distribution

Approximately 10% of Metoprolol in plasma is protein bound. Metoprolol crosses the placenta, and is found in breast milk (see section 4.6).

Biotransformation

Metoprolol is extensively metabolised by enzymes of the cytochrome P450 system in the liver. The oxidative metabolism of Metoprolol is under genetic control with a major contribution of the polymorphic cytochrome P450 isoform 2D6 (CYP2D6). There are marked ethnic differences in the prevalence of the poor metabolisers (PM) phenotype. Approximately 7% of Caucasians and less than 1% Orientals are PMs.

CYP2D6 poor metabolisers exhibit several-fold higher plasma concentrations of Metoprolol than extensive metabolisers with normal CYP2D6 activity. None of the metabolites of Metoprolol contribute significantly to its betablocking effect.

Elimination

Elimination is mainly by hepatic metabolism and the average elimination halflife is 3.5 hours (range 1 to 9 hours). Rates of metabolism vary between individuals, with poor metabolisers (approximately 10%) showing higher plasma concentrations and slower elimination than extensive metabolisers. Within individuals, however, plasma concentrations are stable and reproducible.

Characteristics in Patients

Because of variation in rates of metabolism, the dose of Metoprolol should always be adjusted to the individual requirements of the patient. As the therapeutic response, adverse effects and relative cardioselectivity are related to plasma concentration, poor metabolisers may require lower than normal doses. Dosage adjustment is not routinely required in older people or in patients with renal failure, but dosage may need to be reduced in patients with significant hepatic dysfunction when Metoprolol elimination may be impaired.

5.3 Preclinical safety data

Pre-clinical information has not been included because the safety profile of Metoprolol has been established after many years of clinical use. Please refer to section 4.

6    PHARMACEUTICAL PARTICULARS

6.1    List of excipients

The tablets contain:

Microcrystalline cellulose (E460)

Lactose monohydrate Sodium starch glycolate Colloidal anhydrous silica Magnesium stearate

6.2. Incompatibilities

Not applicable.

Shelf-Life

48 months.

6.4.    Special Precautions for Storage

Store at or below 25°C. Protect from light.

6.5.    Nature and Content of Container

HDPE or polypropylene containers with caps or child resistant closures in packs of 100 or 500 tablets.

Blister strips in packs of 28, 30, 56 or 60 tablets.

Not all pack sizes may be marketed.

6.6.    Special precautions for disposal and other handling

No special requirements for disposal.

Any unused medicinal product or waste material should be disposed of in accordance with local requirements.

7    MARKETING AUTHORISATION HOLDER

TEVA UK Limited,

Brampton Road, Hampden Park,

Eastbourne, BN22 9AG.

8    MARKETING AUTHORISATION NUMBER(S)

PL 00289/0743

9    DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

28/12/2005

10 DATE OF REVISION OF THE TEXT

31/03/2015