Betaloc

Metoprolol tartrate.

Each tablet contains metoprolol tartrate 50 or 100 mg.
50 mg: The score line is only to facilitate breaking for ease of swallowing and not to divide into equal doses.
100 mg: The tablet can be divided into equal halves by breaking along the score lines.
Excipients/ Inactive Ingredients: Metoprolol tartrate tablets 50 mg and 100 mg: lactose, magnesium stearate, microcrystalline cellulose, polyvinylpyrrolidone, silicon dioxide and sodium starch glycolate.

ATC-code: C07A B02.
Pharmacology: Pharmacodynamics: Metoprolol is a β₁-selective β-blocker, i.e. it blocks β₁-receptors at doses much lower than those needed to block β₂-receptors.
Metoprolol has an insignificant membrane-stabilising effect and does not display partial agonistic activity.
Metoprolol reduces or inhibits the agonistic effect on the heart of catecholamines (which are released during physical and mental stress). This means that the usual increase in heart rate, cardiac output, cardiac contractility and blood pressure, produced by the acute increase in catecholamines, is reduced by metoprolol. During high endogenous adrenaline levels metoprolol interferes much less with blood pressure control than non-selective β-blockers. When required, metoprolol, in combination with a β₂-agonist, may be given to patients with symptoms of obstructive pulmonary disease. When given together with a β₂-agonist, metoprolol in therapeutic doses interferes less than non-selective β-blockers with the β₂-mediated bronchodilation caused by the β₂-agonist.
Metoprolol interferes less with insulin release and carbohydrate metabolism than do non-selective β-blockers.
Metoprolol interferes much less with the cardiovascular response to hypoglycaemia than do non-selective β-blockers.
Short term studies have shown that metoprolol may cause a slight increase in triglycerides and a decrease in free fatty acids in the blood. In some cases, a small decrease in the high density lipoproteins (HDL) fraction has been observed, although to a lesser extent than that following non-selective β-blockers. However, a significant reduction in total serum cholesterol levels has been demonstrated after metoprolol treatment in one study conducted over several years.
Quality of Life is maintained uncompromised or improved during treatment with metoprolol.
An improvement in Quality of Life has been observed after metoprolol treatment in patients after myocardial infarction.
Effect in hypertension: Metoprolol lowers elevated blood pressure both in the standing and lying position. A short-lasting (a few hours) and clinically insignificant increase in peripheral resistance may be observed after the institution of metoprolol treatment. During long-term treatment total peripheral resistance may be reduced, due to reversal of hypertrophy in arterial resistance vessels. Long-term antihypertensive therapy with metoprolol has also been shown to reduce left ventricular hypertrophy and to improve left ventricular diastolic function and left ventricular filling.
In men with mild to moderate hypertension metoprolol has been shown to reduce the risk of death from cardiovascular disease mainly due to a reduced risk for sudden cardiovascular death, to reduce the risk of fatal and non-fatal myocardial infarction and for stroke.
Effect on angina pectoris: In patients with angina pectoris metoprolol has been shown to reduce the frequency, duration and severity of both angina attacks and silent ischemic episodes and to increase the physical working capacity.
Effect on cardiac rhythm: In cases of supraventricular tachycardia or atrial fibrillation, and in the presence of ventricular extrasystoles, metoprolol slows the ventricular rate and reduces ventricular extrasystoles.
Effect on myocardial infarction: In patients with suspected or confirmed myocardial infarction metoprolol lowers mortality mainly due to a reduction in the risk of sudden death. This effect is presumed to partly be due to the prevention of ventricular fibrillation.
The anti-fibrillatory effect is believed to be due to a dual mechanism: a vagal effect within the blood-brain barrier beneficially influencing electrical stability of the heart, and a sympathetic direct cardiac anti-ischemic effect beneficially influencing contractility, heart rate and blood pressure. For both early and late intervention the reduction in mortality is also present in high risk patients with previous cardiovascular disease; and in patients with diabetes mellitus.
Metoprolol has also been shown to reduce the risk of non-fatal myocardial re-infarction.
Effect on heart disorders with palpitations: Metoprolol is suitable for the treatment of functional heart disorders with palpitations.
Effect on migraine: Metoprolol is suitable for prophylactic treatment of migraine.
Effect on hyperthyroidism: Metoprolol reduces the clinical manifestations in hyperthyroidism and can therefore be given as supplementary medication.
Pharmacokinetics: Absorption and distribution: Metoprolol is completely absorbed after oral administration. Within the therapeutic dosage range the plasma concentrations rise linearly in relation to the size of the dose. Peak plasma concentrations are attained after approx 1.5 - 2 hours. Although the plasma profiles exhibit wide inter-subject variability, they show good reproducibility within each individual.
Owing to an extensive first-pass effect, the systemic bioavailability of metoprolol from a single oral dose is approximately 50%. Upon repeated administration, the systemically available portion of the dose increases to approx 70%. Ingestion together with food may raise the systemic availability of an oral dose by approx 30-40%. The plasma protein binding of metoprolol is low, approximately 5-10%.
Metabolism and elimination: Metoprolol undergoes oxidative metabolism in the liver primarily by the CYP2D6 isoenzyme. Three main metabolites have been identified, though none of them have a β-blocking effect of clinical importance.
As a rule, over 95% of an oral dose can be recovered in the urine. About 5% of the given dose is excreted in the urine in unchanged form, this figure rising up to 30% in isolated cases. The elimination half-life of metoprolol in plasma averages 3.5 hours (extremes: 1 and 9 hours). The total clearance rate is approximately 1 litre/minute.
Elderly show no significant changes in the pharmacokinetics of metoprolol as compared with young persons. The systemic bioavailability and elimination of metoprolol is unchanged in patients with reduced renal function. The excretion of metabolites, however, is reduced. Significant accumulation of metabolites was observed in patients with a glomerulus filtration rate (GFR) of less than 5 mL/min. This accumulation of metabolites, however, does not increase the β-blockade.
The pharmacokinetics of metoprolol is minimally affected by decreased liver function. However, in patients with severe liver cirrhosis and a portacaval shunt the bioavailability of metoprolol may increase and the total clearance may be reduced. Patients with a portacaval anastomosis had a total clearance of approximately 0.3 litres/min and area under the plasma concentration-time curve (AUC) values up to 6 times higher than in healthy subjects.
Toxicology: Preclinical safety data: No findings of any relevance.

Hypertension: to reduce blood pressure and to reduce the risk of cardiovascular and coronary mortality (including sudden death), and morbidity; Angina pectoris; Disturbances of cardiac rhythm including especially supraventricular tachycardia; Maintenance treatment after myocardial infarction; Functional heart disorders with palpitations; Migraine prophylaxis; Hyperthyroidism.

The tablets should be taken on an empty stomach.
Hypertension: The recommended dosage in patients with hypertension is 100-200 mg daily, given as a single dose in the morning or in divided doses (morning and evening). If needed, other antihypertensive agents may be added.
Long-term antihypertensive treatment with metoprolol in daily doses of 100-200 mg has been shown to reduce total mortality, including sudden cardiovascular death, stroke and coronary events in hypertensive patients.
Angina pectoris: The recommended dosage is 100-200 mg daily, given in divided doses (morning and evening). If needed, other antianginal agents may be added.
Cardiac arrhythmias: The recommended dosage is 100-200 mg daily given in divided doses (morning and evening). If needed, other antiarrhythmic agents may be added.
Maintenance treatment after myocardial infarction: Long-term oral treatment with metoprolol in doses of 200 mg daily, given in divided doses (morning and evening) has been shown to reduce the risk of death (including sudden death), and to reduce the risk of reinfarction (also in patients with diabetes mellitus).
Functional heart disorders with palpitations: The recommended dosage is 100 mg once daily, given as a single dose in the morning. If needed, the dose can be increased to 200 mg.
Migraine prophylaxis: The recommended dosage is 100-200 mg daily, given in divided doses morning and evening.
Hyperthyroidism: The recommended dosage is 150-200 mg daily, divided in 3-4 doses. If needed, the dose can be increased.
Impaired renal function: Dose adjustment is not needed in patients with impaired renal function.
Impaired hepatic function: Dose adjustment is normally not needed in patients suffering from liver cirrhosis because metoprolol has a low protein binding (5-10 %). When there are signs of serious impairment of liver function (e.g. shunt-operated patients) a dose reduction should be considered.
Elderly: Dose adjustment is not needed in the elderly.
Children: There is limited experience with metoprolol treatment in children.

Symptoms: The symptoms of overdosage may include bradycardia and bradyarrhythmia, hypotension, cardiac insufficiency, cardiac conduction disturbances and bronchospasm.
Management: Care should be provided at a facility that can provide appropriate supporting measures, monitoring, and supervision.
If justified, gastric lavage and/or activated charcoal can be administered.
Atropine, adreno stimulating drugs or pacemaker to treat bradycardia and conduction disorders.
Hypotension, acute cardiac failure, and shock to be treated with suitable volume expansion, injection of glucagon (if necessary, followed by an intravenous infusion of glucagon), intravenous administration of adrenostimulating drugs such as dobutamine, with α₁ receptor agonistic drugs added in presence of vasodilation. Intravenous use of Ca²⁺ can also be considered.
Bronchospasm can usually be reversed by bronchodilators.

Atrioventricular block of second or third degree; patients with unstable decompensated cardiac failure (pulmonary oedema, hypoperfusion or hypotension), and patients with continuous or intermittent inotropic therapy acting through β-receptor agonism; clinically relevant sinus bradycardia, sick-sinus syndrome (unless a permanent pacemaker is in place), cardiogenic shock; severe peripheral arterial circulatory disorder.
Metoprolol should not be given to patients with suspected acute myocardial infarction as long as the heart rate is <45 beats/min, the P-Q interval is > 0.24 sec or the systolic blood pressure is <100 mm Hg.
Metoprolol tartrate tablets are contraindicated in patients who have shown hypersensitivity to any component of the products or to other β-blockers

Intravenous administration of calcium antagonists of the verapamil-type should not be given to patients treated with β-blockers.
Generally when treating patients with asthma, concomitant therapy with a β₂-agonist (tablet and/or inhalation) should be administered. The dosage of β₂-agonists may require adjustment (increase) when treatment with metoprolol is started.
During treatment with metoprolol, the risk of interfering with carbohydrate metabolism or masking hypoglycaemia is less than with non-selective β-blockers. Patients suffering from heart failure should have their decompensation treated both before and during treatment with metoprolol.
Very rarely, a pre-existing A-V conduction disorder of moderate degree may become aggravated (possibly leading to A-V block).
If the patients develop increasing bradycardia, metoprolol should be given in lower doses or gradually withdrawn.
Metoprolol may aggravate the symptoms of peripheral arterial circulatory disorders.
Where metoprolol is prescribed for a patient known to be suffering from a pheochromocytoma, an alpha-blocker should be given concomitantly.
Abrupt interruption of the medication is to be avoided. If treatment has to be withdrawn it should, when possible, be done gradually. Many patients can be withdrawn over a 14 day period.
This can be done by cutting the daily dose in sequential steps reaching a final dose of 25 mg once a day (half a 50 mg tablet).
During this period especially patients with known ischemic heart disease should be kept under close surveillance. The risk for coronary events, including sudden death, may increase during the withdrawal of β-blockade.
Prior to surgery the anaesthetist should be informed that the patient is receiving metoprolol. It is not recommended to stop β-blocker treatment in patients undergoing surgery. 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 taking β-blockers anaphylactic shock assumes a more severe form.
Effects on ability to drive and use machines: Patients should know how they react to metoprolol before they drive or use machines because occasionally dizziness or fatigue may occur.

Metoprolol should not be given during pregnancy and lactation unless its use is considered essential. In general, β-blockers reduce placental perfusion, which has been associated with growth retardation, intrauterine death, abortion and early labour. It is therefore suggested that appropriate maternofetal monitoring be performed in pregnant women treated with metoprolol. β-blockers may cause side-effects, e.g. bradycardia, in the fetus and in the newborn and breast-fed infant.
The amount of metoprolol ingested via breast milk, however, seems to be negligible as regards β-blocking effect in the infant if the mother is treated with metoprolol in doses within the normal therapeutic range.

Metoprolol is well tolerated and adverse reactions have generally been mild and reversible. The following events have been reported as adverse events in clinical trials or reported from routine use. In many cases a relationship to treatment with metoprolol has not been established.
The following definitions of frequencies are used: Very common (≥10%), common (1-9.9%), uncommon (0.1-0.9%), rare (0.01-0.09%) and very rare (<0.01%).
Cardiovascular system: Common: Bradycardia, postural disorders (very rarely with syncope), cold hands and feet, palpitations. Uncommon: Deterioration of heart failure symptoms, cardiogenic shock in patients with acute myocardial infarction*, first degree heart block, oedema, precordial pain. Rare: Disturbances of cardiac conduction, cardiac arrhythmias. Very rare: Gangrene in patients with pre-existing severe peripheral circulatory disorders.
*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 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.
Central nervous system: Very common: Fatigue. Common: Dizziness, headache. Uncommon: Paraesthesiae, muscle cramps.
Gastrointestinal: Common: Nausea, abdominal pain, diarrhoea, constipation. Uncommon: Vomiting. Rare: Dry mouth.
Haematologic: Very rare: Thrombocytopenia.
Hepatic: Rare: Liver function test abnormalities. Very rare: Hepatitis.
Metabolism: Uncommon: Weight gain.
Musculoskeletal: Very rare: Arthralgia.
Psychiatric: Uncommon: Depression, concentration impaired, somnolence or insomnia, nightmares. Rare: Nervousness, anxiety, impotence/sexual dysfunction. Very rare: Amnesia/memory impairment, confusion, hallucinations.
Respiratory: Common: Dyspnoea on exertion. Uncommon: Bronchospasm. Rare: Rhinitis.
Sense organs: Rare: Disturbances of vision, dry and/or irritated eyes, conjunctivitis. Very rare: Tinnitus, taste disturbances.
Skin: Uncommon: Rash (in the form of urticaria psoriasiform and dystrophic skin lesions), increased sweating. Rare: Loss of hair. Very rare: Photosensitivity reactions, aggravated psoriasis.

Metoprolol is a metabolic substrate for the Cytochrome P450 isoenzyme CYP2D6. Drugs that act as enzyme-inducing and enzyme-inhibiting substances may exert an influence on the plasma level of metoprolol. Plasma levels of metoprolol may be raised by co-administration of compounds metabolised by CYP2D6, e.g. antiarrhythmics, antihistamines, histamine-2-receptor antagonists, antidepressants, antipsychotics, and COX-2-inhibitors. The plasma concentration of metoprolol is lowered by rifampicin and may be raised by alcohol and hydralazine.
Patients receiving concomitant treatment with sympathetic ganglion blocking agents, other β-blockers (i.e. eye drops), or Mono Amine Oxidase (MAO) inhibitors should be kept under close surveillance.
If concomitant treatment with clonidine is to be discontinued, the β-blocker medication should be withdrawn several days before clonidine.
Increased negative inotropic and chronotropic effects may occur when metoprolol is given together with calcium antagonists of the verapamil and diltiazem type. In patients treated with β-blockers intravenous administration of calcium antagonists of the verapamil-type should not be given.
β-blockers may enhance the negative inotropic and negative dromotropic effect of antiarrhythmic agents (of the quinidine type and amiodarone).
Digitalis glycosides, in association with β-blockers, may increase atrioventricular conduction time and may induce bradycardia.
In patients receiving β-blocker therapy, inhalation anaesthetics enhance the cardiodepressant effect.
Concomitant treatment with indomethacin or other prostaglandin synthetase inhibiting drugs may decrease the antihypertensive effect of β-blockers.
Under certain conditions, when adrenaline is administered to patients treated with β-blockers, cardioselective β-blockers interfere much less with blood pressure control than non-selective β-blockers.
The dosages of oral antidiabetics may have to be readjusted in patients receiving β-blockers.

Incompatibilities: Not applicable.
Instructions for use, handling and disposal: Not applicable.

Store at a temperature not exceeding 30°C.

Beta-Blockers

C07AB02 - metoprolol ; Belongs to the class of selective beta-blocking agents. Used in the treatment of cardiovascular diseases.

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