Metoprolol succinate

- Hypertension

- Angina pectoris

- Tachyarrhythmias, in particular supraventricular tachycardia

- Maintenance treatment after a myocardial infarction

- Prophylaxis of migraine

Metoprolol is indicated in adults.

Metoprolol succinate 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 Metoprolol succinate 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 Metoprolol succinate is not recommended in children.

- 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.

A sudden discontinuation of beta blockade can be hazardous and should therefore be avoided. If treatment with Metoprolol succinate 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).

Metoprolol succinate 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 Metoprolol succinate 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.

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.

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.

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.

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.

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.

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

No special requirements.

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