Emzok

Overdose

Symptoms

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, the use of gastric lavage, activated charcoal and a laxative to prevent absorption of any drug still present in the gastrointestinal tract, 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 (dobutamine, isoprenaline, noradrenaline) may be given. Dobutamine can be administered at 2.5 to 10 micrograms/kg/minute by intravenous infusion.

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.

Emzok price

Contraindications

Emzok I.V. Injection, as with other beta blockers, should not be used in patients with any of the following:

-

- Hypotension.

- AV block of second- or third-degree.

- Decompensated cardiac failure (pulmonary oedema, hypoperfusion or hypotension).

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

- Bradycardia (<45 bpm).

- Sick sinus syndrome (unless a permanent pacemaker is in place).

- Cardiogenic shock.

- Severe peripheral arterial circulatory disorder.

- Untreated phaeochromocytoma.

- Metabolic acidosis.

Known hypersensitivity to any component of Emzok I.V. Injection or other beta-blockers.

Emzok I.V. Injection is also contra-indicated when suspected acute myocardial infarction is complicated by bradycardia (<45 bpm), first-degree heart block or systolic blood pressure <100 mmHg and/or severe heart failure.

- Hypersensitivity to the active ingredient, other β-blockers or to any of the excipients.

- Second-or third-degree AV block

- Patients with unstable or acute decompensated heart failure (pulmonary oedema, hypoperfusion, or hypotension), in which case intravenous inotropic therapy is indicated

- Patients who are receiving, continuously or periodically, inotropic β receptor agonist therapy

- Severe bradycardia (<50 bpm)

- Sick sinus syndrome

- Cardiogenic shock

- Severe peripheral arterial disease

- Asthma or a history of bronchospasm

- Untreated phaeochromocytoma

- Metabolic acidosis

- The concomitant intravenous administration of calcium antagonists of verapamil and Diltiazem, due to the risk of hypotension, AV conduction disturbances, or left ventricular insufficiency occurring

- Hypotension

Emzok is not indicated for patients with myocardial infarction and a heart rate of <50 beats/minutes, a P-Q interval of >0.24 seconds, or systolic blood pressure of <100 mg Hg and/or severe congestive heart failure.

- Hypersensitivity to the active ingredient, other β-blockers or to any of the excipients.

- Second-or third-degree AV block

- Patients with unstable or acute decompensated heart failure (pulmonary oedema, hypoperfusion, or hypotension), in which case intravenous inotropic therapy is indicated

- Patients who are receiving, continuously or periodically, inotropic β receptor agonist therapy

- Severe bradycardia (<50 bpm)

- Sick sinus syndrome

- Cardiogenic shock

- Severe peripheral arterial disease

- Asthma or a history of bronchospasm

- Untreated phaeochromocytoma

- Metabolic acidosis

- The concomitant intravenous administration of calcium antagonists of verapamil and Diltiazem, due to the risk of hypotension, AV conduction disturbances, or left ventricular insufficiency occurring

- Hypotension

Metoprolol is not indicated for patients with myocardial infarction and a heart rate of <50 beats/minutes, a P-Q interval of >0.24 seconds, or systolic blood pressure of <100 mg Hg and/or severe congestive heart failure.

Undesirable effects

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).

* 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.

Emzok is well tolerated, and the undesirable effects are generally mild and reversible. The most commonly reported adverse reactions during treatment is fatigue. Gangrene (in patients with severe peripheral circulatory disorder), thrombocytopenia and agranulocytosis may occur very rarely (less than 1 case per 1,0000 patients).The following undesirable effects have been reported during the course of clinical studies or have been reported after routine use. In many cases, a link with the use of Emzok (tartrate) has not been firmly established.

The following definitions of incidence have been used:

Very common (> 1/10), common (> 1/100, < 1/10), uncommon (> 1/1,000, < 1/100), rare (> 1/10,000, <1/1,000), and very rare (< 1/10,000). The data include also reports of isolated cases.

*Excess frequency of 0.4% compared with placebo observed in the COMMIT trial in 46,000 patients with acute myocardial infarction where the frequency of cardiogenic shock was 2.3% in patients who received Emzok (up to 15 mg intravenous then 200 mg oral) 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 Emzok is recommended for use in acute myocardial infarction.

Post Marketing Experience

The following adverse reactions have been reported during post-approval use of Emzok: 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.

Metoprolol is well tolerated, and the undesirable effects are generally mild and reversible. The most commonly reported adverse reactions during treatment is fatigue. Gangrene (in patients with severe peripheral circulatory disorder), thrombocytopenia and agranulocytosis may occur very rarely (less than 1 case per 1,0000 patients).The following undesirable effects have been reported during the course of clinical studies or have been reported after routine use. In many cases, a link with the use of metoprolol (tartrate) has not been firmly established.

The following definitions of incidence have been used:

Very common (> 1/10), common (> 1/100, < 1/10), uncommon (> 1/1,000, < 1/100), rare (> 1/10,000, <1/1,000), and very rare (< 1/10,000). The data include also reports of isolated cases.

*Excess frequency of 0.4% compared with placebo observed in the COMMIT trial in 46,000 patients with acute myocardial infarction where the frequency of cardiogenic shock was 2.3% in patients who received metoprolol (up to 15 mg intravenous then 200 mg oral) 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.

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.

Preclinical safety data

Non-clinical data reveal no special hazard for humans based on studies of repeated dose toxicity, genotoxicity, carcinogenic potential and toxicity to reproduction.

Therapeutic indications

Control of tachyarrhythmias, especially supraventricular tachyarrhythmias.

Early intervention with Emzok I.V. Injection in acute myocardial infarction reduces infarct size and the incidence of ventricular fibrillation. Pain relief may also decrease the need for opiate analgesics.

Emzok I.V. Injection has been shown to reduce mortality when administered to patients with acute myocardial infarction.

- Hypertension

- Angina pectoris

- Tachyarrhythmias, in particular supraventricular tachycardia

- Maintenance treatment after a myocardial infarction

- Prophylaxis of migraine

Emzok is indicated in adults.

- Hypertension

- Angina pectoris

- Tachyarrhythmias, in particular supraventricular tachycardia

- Maintenance treatment after a myocardial infarction

- Prophylaxis of migraine

Metoprolol is indicated in adults.

Pharmacotherapeutic group

Pharmacodynamic properties

Pharmacotherapeutic group: Beta blocking agents, selective

ATC code: C07AB02

Mechanism of action

Metoprolol is a competitive beta-adrenoceptor antagonist. It acts preferentially to inhibit beta-adrenoceptors (conferring some cardioselectivity), is devoid of intrinsic sympathomimetic activity (partial agonist activity) and possesses beta-adrenoceptor blocking activity comparable in potency with propranolol.

Pharmacodynamic effects

A negative chronotrophic effect on the heart is a consistent feature of metoprolol administration. Thus, cardiac output and systolic blood pressure rapidly decrease following acute administration.

Clinical efficacy and safety

The intention to treat trial COMMIT included 45,852 patients admitted to hospital within 24 hours of the onset of symptoms of suspected acute myocardial infarction with supporting ECG abnormalities (i.e. ST elevation, ST depression or left bundle-branch block). Patients were randomly allocated to metoprolol (up to 15 mg intravenous then 200 mg oral) or placebo and treated until discharge or up to 4 weeks in hospital. The two co-primary outcomes were: (1) composite of death, reinfarction or cardiac arrest; and (2) death from any cause during the scheduled treatment period. Neither of the co-primary outcomes was significantly reduced by metoprolol. However, metoprolol treatment was associated with fewer people having reinfarction and ventricular fibrillation but an increased rate of cardiogenic shock during the first day after admission. There was substantial net hazard in haemodynamically unstable patients. There was moderate net benefit in those who were stable, particularly after days 0-1.

Pharmacotherapeutic category: Beta blocking agents, selective, ATC code: C07AB02

Emzok is a competitive β1-selective beta blocker: it blocks β1 receptors at dosages that are much lower than those necessary to block β2 receptors.

Due to these properties, Emzok is suitable for the treatment of hypertension, angina pectoris, various types of arrhythmia, hyperthyroidism, and moderate to serious congestive heart failure in patients with idiopathic dilated cardiomyopathy and for the prevention of the reoccurrence of infarction and mortality in patients who have had a myocardial infarction and in whom there is a considerable risk of a further infarction or sudden cardiac death.

Emzok has a non-significant membrane-stabilising effect and displays no partial agonist activity. Emzok reduces or inhibits the agonist effect of catecholamines on the heart. Catecholamines are released when a person is under physical or mental stress. This means that the usual increase in heart rate, cardiac minute volume, cardiac contractility, and blood pressure caused by an acute increase in levels of catecholamine is reduced by Emzok. In the presence of high levels of endogenous adrenaline, Emzok interferes far less with the control of blood pressure than non-selective beta blockers. Emzok has less of an effect on the release of insulin and the carbohydrate metabolism than nonselective beta blockers. Emzok has much less of an effect on the cardiovascular reaction to hypoglycaemia than non-selective beta blockers. Short-term studies have shown that Emzok can cause a slight increase in the levels of triglycerides and a reduction in the levels of free fatty acids in the blood. In a few cases, a slight reduction in the HDL (high density lipoprotein) fraction was observed, although this was less pronounced than in the case of nonselective beta blockers.

Pharmacotherapeutic category: Beta blocking agents, selective, ATC code: C07AB02

Metoprolol is a competitive β1-selective beta blocker: it blocks β1 receptors at dosages that are much lower than those necessary to block β2 receptors.

Due to these properties, metoprolol is suitable for the treatment of hypertension, angina pectoris, various types of arrhythmia, hyperthyroidism, and moderate to serious congestive heart failure in patients with idiopathic dilated cardiomyopathy and for the prevention of the reoccurrence of infarction and mortality in patients who have had a myocardial infarction and in whom there is a considerable risk of a further infarction or sudden cardiac death.

Metoprolol has a non-significant membrane-stabilising effect and displays no partial agonist activity. Metoprolol reduces or inhibits the agonist effect of catecholamines on the heart. Catecholamines are released when a person is under physical or mental stress. This means that the usual increase in heart rate, cardiac minute volume, cardiac contractility, and blood pressure caused by an acute increase in levels of catecholamine is reduced by metoprolol. In the presence of high levels of endogenous adrenaline, metoprolol interferes far less with the control of blood pressure than non-selective beta blockers. Metoprolol has less of an effect on the release of insulin and the carbohydrate metabolism than nonselective beta blockers. Metoprolol has much less of an effect on the cardiovascular reaction to hypoglycaemia than non-selective beta blockers. Short-term studies have shown that metoprolol can cause a slight increase in the levels of triglycerides and a reduction in the levels of free fatty acids in the blood. In a few cases, a slight reduction in the HDL (high density lipoprotein) fraction was observed, although this was less pronounced than in the case of nonselective beta blockers.

Pharmacokinetic properties

Biotransformation

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

Elimination

Metoprolol is eliminated mainly by hepatic metabolism, the average elimination half-life is 3.5 hours (range 1-9 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.

Absorption

Emzok is absorbed fully after oral administration. Within the therapeutic dosage range, the plasma concentrations increase in a linear manner in relation to dosage. Peak plasma levels are achieved after approx. 1.5-2 hours. Even though the plasma profile displays a broader interindividual variability, this appears to be easily reproducible on an individual basis. Due to the extensive first-pass effect, bioavailability after a single oral dose is approx. 50%. After repeated administration, the systemic availability of the dose increases to approx. 70%. After oral intake with food, the systemic availability of an oral dose increases by [SIC] approx. 30-40%.

Distribution

The medicinal product is approx. 5-10% bound to plasma proteins.

Metabolism and elimination

Emzok is metabolised through oxidation in the liver mainly by the CYP2D6 isoenzyme. Even though three main metabolites have been identified, none of them has a clinically significant beta-blocking effect. Generally, 95% of an oral dose is found in the urine. Only 5% of the dose is excreted unmodified via the kidneys; in isolated cases, this figure can reach as high as 30%. The elimination half-life of Emzok averages 3.5 hours (with extremes of 1 and 9 hours). Total clearance is approx. 1 litre/minute.

Special population

Elderly:

In comparison with administration to younger patients, the pharmacokinetics of Emzok when administered to older patients shows no significant differences.

Renal impairment:

Renal dysfunction has barely any effect on the bioavailability of Emzok. However, the excretion of metabolites is reduced. In patients with a glomerular filtration rate of less than 5 ml/minute, a significant accumulation of metabolites has been observed. This accumulation of metabolites, however, produces no increase in the beta blockade.

Hepatic impairment:

The pharmacokinetics of Emzok are influenced only minimally by reduced hepatic function. However, in patients with serious hepatic cirrhosis and a portacaval shunt, the bioavailability of Emzok can increase, and the total clearance can be reduced. Patients with portacaval anastomosis had a total clearance of approx. 0.3 litres/minute and AUC values that were 6 times higher than those found in healthy persons.

Absorption

Metoprolol is absorbed fully after oral administration. Within the therapeutic dosage range, the plasma concentrations increase in a linear manner in relation to dosage. Peak plasma levels are achieved after approx. 1.5-2 hours. Even though the plasma profile displays a broader interindividual variability, this appears to be easily reproducible on an individual basis. Due to the extensive first-pass effect, bioavailability after a single oral dose is approx. 50%. After repeated administration, the systemic availability of the dose increases to approx. 70%. After oral intake with food, the systemic availability of an oral dose increases by [SIC] approx. 30-40%.

Distribution

The medicinal product is approx. 5-10% bound to plasma proteins.

Metabolism and elimination

Metoprolol is metabolised through oxidation in the liver mainly by the CYP2D6 isoenzyme. Even though three main metabolites have been identified, none of them has a clinically significant beta-blocking effect. Generally, 95% of an oral dose is found in the urine. Only 5% of the dose is excreted unmodified via the kidneys; in isolated cases, this figure can reach as high as 30%. The elimination half-life of metoprolol averages 3.5 hours (with extremes of 1 and 9 hours). Total clearance is approx. 1 litre/minute.

Special population

Elderly:

In comparison with administration to younger patients, the pharmacokinetics of metoprolol when administered to older patients shows no significant differences.

Renal impairment:

Renal dysfunction has barely any effect on the bioavailability of metoprolol. However, the excretion of metabolites is reduced. In patients with a glomerular filtration rate of less than 5 ml/minute, a significant accumulation of metabolites has been observed. This accumulation of metabolites, however, produces no increase in the beta blockade.

Hepatic impairment:

The pharmacokinetics of metoprolol are influenced only minimally by reduced hepatic function. However, in patients with serious hepatic cirrhosis and a portacaval shunt, the bioavailability of metoprolol can increase, and the total clearance can be reduced. Patients with portacaval anastomosis had a total clearance of approx. 0.3 litres/minute and AUC values that were 6 times higher than those found in healthy persons.

Name of the medicinal product

Qualitative and quantitative composition

Special warnings and precautions for use

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.

Emzok I.V. Injection, as with other beta blockers:

- should not be withdrawn abruptly during oral treatment. When possible, Emzok 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 Emzok 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 , 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. Emzok 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 Emzok 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. Emzok 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 Emzok 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 Emzok 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 Emzok 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.

A sudden discontinuation of beta blockade can be hazardous and should therefore be avoided. If treatment with Emzok tartrate needs to be discontinued, then this should be effected, as a rule, over at least 2 weeks, by halving the dosage incrementally until the patient is taking 25 mg of Emzok per dose (half a 50 mg tablet). This lowest dosage should be taken for at least 4 days until treatment is discontinued completely. Throughout this period, above all patients with ischaemic heart disease should be carefully monitored, since the risk of coronary events, including sudden cardiac death, is elevated whilst beta blockade is being discontinued. Hypertension and arrhythmia can also occur.

Even though Emzok, at the usual dosages, has less of a negative impact on the bronchial musculature than non-selective beta blockers, care should still be taken. In patients with bronchial asthma who are being treated with Emzok, bronchodilators that selectively stimulate β2 receptors, e.g. terbutaline, may be prescribed concomitantly if necessary. If the patient is already taking a β2 receptor stimulator, it may sometimes be necessary to adjust the dosage thereof.

Since beta blockers can affect the glucose metabolism, vigilance is advisable in patients with diabetes mellitus. The impact on the glucose metabolism and the masking effect on the symptoms of hypoglycaemia are less pronounced in patients treated with Emzok than in those treated with non-selective beta blockers (in particular tachycardia).

Emzok 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 the case of increasing bradycardia, the dosage should be reduced, or treatment, gradually discontinued.

Although contra-indicated in severe peripheral arterial circulatory disturbances , in the case of peripheral circulatory disorders, such as Raynaud's disease or peripheral arterial disease, the clinical picture may deteriorate, principally due to the medicinal product's hypotensive effect. Beta blockers should be administered with great caution if a deterioration in the clinical picture occurs.

If Emzok tartrate is prescribed to a patient with a phaeochromocytoma, an alpha blocker also needs to be administered.

Before a patient undergoes an operation, the anaesthetist must be informed that Emzok is being taken. In patients who have to undergo an operation, it is not recommended that beta blocker treatment be discontinued. Acute initiation of high-dose Emzok 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.

In patients who are taking a beta blocker, the occurrence of an anaphylactic shock is more serious.

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

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 β 1-selective drugs

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 Emzok, 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.

In the presence of liver cirrhosis the bioavailability of Emzok may be increased.

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.

Dry eyes either alone or, occasionally, with skin rashes has occurred. In most cases the symptoms cleared when Emzok treatment was withdrawn. Patients should be observed carefully for potential ocular effects. If such effects occur, discontinuation of Emzok should be considered.

A sudden discontinuation of beta blockade can be hazardous and should therefore be avoided. If treatment with Emzok needs to be discontinued, then this should be effected, as a rule, over at least 2 weeks, by halving the dosage incrementally until the patient is taking 25 mg of metoprolol per dose (half a 50 mg tablet). This lowest dosage should be taken for at least 4 days until treatment is discontinued completely. Throughout this period, above all patients with ischaemic heart disease should be carefully monitored, since the risk of coronary events, including sudden cardiac death, is elevated whilst beta blockade is being discontinued. Hypertension and arrhythmia can also occur.

Even though metoprolol, at the usual dosages, has less of a negative impact on the bronchial musculature than non-selective beta blockers, care should still be taken. In patients with bronchial asthma who are being treated with Metoprolol, bronchodilators that selectively stimulate β2 receptors, e.g. terbutaline, may be prescribed concomitantly if necessary. If the patient is already taking a β2 receptor stimulator, it may sometimes be necessary to adjust the dosage thereof.

Since beta blockers can affect the glucose metabolism, vigilance is advisable in patients with diabetes mellitus. The impact on the glucose metabolism and the masking effect on the symptoms of hypoglycaemia are less pronounced in patients treated with metoprolol than in those treated with non-selective beta blockers (in particular tachycardia).

Emzok 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 the case of increasing bradycardia, the dosage should be reduced, or treatment, gradually discontinued.

Although contra-indicated in severe peripheral arterial circulatory disturbances , in the case of peripheral circulatory disorders, such as Raynaud's disease or peripheral arterial disease, the clinical picture may deteriorate, principally due to the medicinal product's hypotensive effect. Beta blockers should be administered with great caution if a deterioration in the clinical picture occurs.

If Emzok is prescribed to a patient with a phaeochromocytoma, an alpha blocker also needs to be administered.

Before a patient undergoes an operation, the anaesthetist must be informed that metoprolol is being taken. In patients who have to undergo an operation, it is not recommended that beta blocker treatment be discontinued. 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.

In patients who are taking a beta blocker, the occurrence of an anaphylactic shock is more serious.

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

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 β 1-selective drugs

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.

In the presence of liver cirrhosis the bioavailability of metoprolol may be increased.

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.

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.

Effects on ability to drive and use machines

Emzok 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.

As with all beta-blockers, Emzok has influence on the ability to drive and use machines because of dizziness and fatigue. This applies to a greater extent at the beginning of treatment. Patient should be warned accordingly.

As with all beta-blockers, metoprolol has influence on the ability to drive and use machines because of dizziness and fatigue. This applies to a greater extent at the beginning of treatment. Patient should be warned accordingly.

Dosage (Posology) and method of administration

Posology

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 Emzok I.V. Injection to patients with a systolic blood pressure below 100 mmHg should only be given with special care.

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.

Myocardial infarction:

Intravenous Emzok I.V. Injection should be initiated in a coronary care or similar unit when 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.

Renal impairment:

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

Hepatic Impairment:

Dose adjustment is normally not needed in patients suffering from liver cirrhosis because metoprolol has a low protein binding (5 - 10 %). However, in patients with severe hepatic dysfunction a reduction in dosage may be necessary.

Elderly:

Several studies indicate that age related physiological changes have negligible effects on the pharmacokinetics of metoprolol. Dose adjustment is not needed in the elderly, but careful dose titration is important in all patients.

Paediatric population:

The safety and efficacy of metoprolol in children has not been established.

Emzok tartrate tablets should be administered orally.

The tablets should be taken on an empty stomach.

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

Posology

Hypertension

The usual dose is 100mg to 200mg daily, given as a single dose in the morning, or in divided doses (morning and evening). Begin with 50mg twice daily or 100mg once daily. Dose increments should be at weekly intervals thereafter according to individual patient responses. Maximum dose, usually 200mg daily. If necessary, it may be taken in combination with other antihypertensive drugs.

Angina pectoris

The usual dose is 100 to 200 mg daily, given in divided doses (morning and evening). Begin with 50mg twice daily. Dose increments should be at weekly intervals thereafter according to individual patient responses. Maximum dose, usually 200mg daily (in divided doses). If necessary, it may be taken in combination with other antianginal drugs.

Cardiac arrhythmias

The usual dose is 100 to 150 mg per day, in divided doses (in the morning and in the evening). This dosage may be increased, where necessary.

Myocardial infarctions

Maintenance therapy

The oral treatment can be initiated once the patient is haemodynamically stable. The maintenance dose is 100 mg of Emzok tartrate twice a day (in the morning and in the evening).

Prophylaxis of migraine

The usual dose is 100 to 200 mg per day, in divided doses, in the morning and evening.

Impaired renal function

The dosage does not need to be adjusted in patients with reduced renal function.

Impaired hepatic function

Usually a dose adjustment in patients suffering from liver cirrhosis is not necessary because Emzok has a low protein binding (5-10%).However, in patients with severe hepatic dysfunction a reduction in dosage may be necessary.

Elderly patients

No dosage adjustment is required in otherwise healthy elderly patients. However, caution is advised in elderly patients as a fall in blood pressure or excessive bradycardia may have more pronounced effects.

Children

The experience in children is limited, therefore Emzok tartrate is not recommended in children.

Emzok tablets should be administered orally.

The tablets should be taken on an empty stomach.

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

Posology

Hypertension

The usual dose is 100mg to 200mg daily, given as a single dose in the morning, or in divided doses (morning and evening). Begin with 50mg twice daily or 100mg once daily. Dose increments should be at weekly intervals thereafter according to individual patient responses. Maximum dose, usually 200mg daily. If necessary, it may be taken in combination with other antihypertensive drugs.

Angina pectoris

The usual dose is 100 to 200 mg daily, given in divided doses (morning and evening). Begin with 50mg twice daily. Dose increments should be at weekly intervals thereafter according to individual patient responses. Maximum dose, usually 200mg daily (in divided doses). If necessary, it may be taken in combination with other antianginal drugs.

Cardiac arrhythmias

The usual dose is 100 to 150 mg per day, in divided doses (in the morning and in the evening). This dosage may be increased, where necessary.

Myocardial infarctions

Maintenance therapy

The oral treatment can be initiated once the patient is haemodynamically stable. The maintenance dose is 100 mg of Emzok twice a day (in the morning and in the evening).

Prophylaxis of migraine

The usual dose is 100 to 200 mg per day, in divided doses, in the morning and evening.

Impaired renal function

The dosage does not need to be adjusted in patients with reduced renal function.

Impaired hepatic function

Usually a dose adjustment in patients suffering from liver cirrhosis is not necessary because Metoprolol has a low protein binding (5-10%).However, in patients with severe hepatic dysfunction a reduction in dosage may be necessary.

Elderly patients

No dosage adjustment is required in otherwise healthy elderly patients. However, caution is advised in elderly patients as a fall in blood pressure or excessive bradycardia may have more pronounced effects.

Children

The experience in children is limited, therefore Emzok is not recommended in children.

Special precautions for disposal and other handling

No special requirements.

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