Betazok

Metoprolol succinate.

23.75 mg: Each tablet of metoprolol controlled-release (CR) contains 23.75 mg of metoprolol succinate corresponding to 25 mg of metoprolol tartrate.
95 mg: Each tablet of metoprolol controlled-release (CR) contains 95 mg of metoprolol succinate corresponding to 100 mg of metoprolol tartrate.
Excipients/Inactive Ingredients: Ethylcellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, microcrystalline cellulose, paraffin, polyethylene glycol, silicon dioxide, sodium stearyl fumarate and titanium dioxide (E 171).

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.
Metoprolol CR (BETAZOK) gives an even plasma concentration time profile and effect (β₁-blockade) over 24 hours in contrast to conventional tablet formulations of β₁-selective blockers including metoprolol tartrate formulations.
Due to the lack of pronounced peaks in plasma concentration, the clinical β₁-selectivity is improved with the Metoprolol CR (BETAZOK) formulation when compared to conventional tablet formulations of β₁-selective blockers. Furthermore, the potential risk for peak plasma concentration related side-effects, such as bradycardia and leg fatigue is reduced. When required, Metoprolol CR (BETAZOK), 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 CR (BETAZOK) in therapeutic doses interferes less than non-selective β-blockers with the β₂-mediated broncho-dilation caused by the β₂-agonist.
Metoprolol CR (BETAZOK) interferes less with insulin release and carbohydrate metabolism than do non-selective β-blockers.
Metoprolol CR (BETAZOK) interferes much less with the cardiovascular response to hypoglycaemia than do non-selective β-blockers.
Short term studies have shown that Metoprolol CR (BETAZOK) 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 CR (BETAZOK). An improvement in quality of life has been observed after metoprolol treatment in patients after myocardial infarction. Furthermore, Metoprolol CR (BETAZOK) has been shown to improve Quality of Life in patients with chronic heart failure.
Effect in hypertension: Metoprolol CR (BETAZOK) 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 144 paediatric patients (6 to 16 years of age) with essential hypertension, Metoprolol CR (BETAZOK) has been shown in a 4-week study to reduce placebo-corrected systolic blood pressure for the 1.0 and 2.0 mg/kg doses (4 to 6 mmHg). For diastolic blood pressure, there was a placebo-corrected reduction for the 2.0 mg/kg dose (5 mmHg) and a dose-dependent reduction for the dose range 0.2, 1.0 and 2.0 mg/kg. No apparent differences in blood pressure reduction were observed based on age, Tanner stage, or race.
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 CR (BETAZOK) 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 CR (BETAZOK) is suitable for the treatment of functional heart disorders with palpitations.
Effect on migraine: Metoprolol CR (BETAZOK) is suitable for prophylactic treatment of migraine.
23.75 mg: Effect in chronic heart failure: In patients with symptoms of heart failure (NYHA II-IV) and decreased ejection fraction (≤0.40) Metoprolol CR (BETAZOK) has been shown to increase survival and to reduce the number of hospitalisations due to worsening heart failure. In addition, Metoprolol CR (BETAZOK) therapy has increased ejection fraction, reduced left ventricular end systolic and end diastolic volumes, improved NYHA functional class and improved Quality of Life.
In the MERIT-HF (Metoprolol CR/XL Randomized Intervention Trial in Congestion Heart Failure) study treatment with metoprolol CR added to standard treatment with ACE inhibitors and diuretics in patients with decreased LVEF and symptoms of mild to severe chronic heart failure reduced: All cause mortality by 34% (p=0.0062 (adjusted); p=0.00009 (nominal)).
Combined endpoint of all cause mortality, and all cause hospitalisation (time to first event) by 19% (p=0.00012).
Combined endpoint of all cause mortality, and hospitalisation due to worsening heart failure (time to first event) by 31% (p=<0.00001).
Combined endpoint of death and heart transplantation (time to first event) by 32% (p=0.0002).
Cardiovascular death by 38% (p=0.00003).
Sudden death by 41% (p=0.0002).
Death from worsening heart failure by 49% (p=0.0023).
The pooled incidence of cardiac death and non-fatal acute MI by 39% (p=<0.00001).
Combined endpoint of all cause mortality, hospitalisation due to worsening heart failure, and emergency room (ER) visit due to worsening heart failure (time to first event) by 32% (p=<0.00001).
The number of hospitalisations due to worsening heart failure by 30% and the number of hospitalisations due to cardiovascular (CV) causes by 15% (p=0.0003).
Pharmacokinetics: Absorption and distribution: Metoprolol CR (BETAZOK) is completely absorbed after oral administration. Owing to an extensive first-pass effect, the systemic bioavailability of metoprolol from a single oral dose is approximately 50%. The bioavailability is reduced by about 20-30% for the controlled-release preparation compared with a conventional tablet. However, this has been demonstrated to be of no significance for clinical efficacy, since the area under the effect curve (AUEC) for heart rate is the same as with conventional tablets. The plasma protein binding of metoprolol is low, approximately 5-10%.
The controlled-release tablet consists of several hundred beads of metoprolol succinate. Each bead is coated with a polymeric membrane, which controls the rate of metoprolol release.
The tablet disintegrates rapidly after intake whereby the beads are dispersed in the gastrointestinal tract and release metoprolol continuously for about 20 hours. The elimination half-life of metoprolol averages 3.5 hours (see Metabolism and elimination). Thus, an even metoprolol plasma concentration is achieved over a dosage interval of 24 hours. The release rate is independent of physiological factors such as pH, food and peristalsis.
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 younger 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.
The pharmacokinetic profile of metoprolol in paediatric hypertensive patients aged 6-17 years is similar to the pharmacokinetics described previously in adults. Metoprolol apparent oral clearance (CL/F) increased linearly with body weight.
Toxicology: Preclinical safety data: No findings of 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.
23.75 mg: Symptomatic mild to severe chronic heart failure as an adjunct to other heart failure therapy: to increase survival, reduce hospitalisation, improve left ventricular function, improve New York Heart Association (NYHA) functional class and improve Quality of Life.

Metoprolol CR (BETAZOK) is intended for once daily treatment and can be taken with or without food. The Metoprolol CR (BETAZOK) tablet should be swallowed with liquid. The tablets and the divided halves should not be chewed or crushed.
Hypertension: The recommended dosage in patients with mild to moderate hypertension is 50 mg Metoprolol CR (BETAZOK) given once daily. In patients not responding to 50 mg the dose could be increased to 100-200 mg once daily and/or combined with other antihypertensive agents.
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 Metoprolol CR (BETAZOK) given once daily. If needed, Metoprolol CR (BETAZOK) can be combined with other anti-anginal agents.
Cardiac arrhythmias: The recommended dosage is 100-200 mg Metoprolol CR (BETAZOK) given once daily.
Maintenance treatment after myocardial infarction: Long-term treatment with metoprolol in doses of 200 mg given once daily 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. If needed, the dose can be increased to 200 mg.
Migraine prophylaxis: The recommended dosage is 100-200 mg once daily.
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 and adolescents: The recommended initial dosage in hypertensive patients ≥6 years is 1.0 mg/kg Metoprolol CR (BETAZOK), not exceeding 50 mg, once daily given approximated by dose strength. In patients not responding to 1.0 mg/kg, the dose can be increased to a maximum daily dose of 2.0 mg/kg. Doses above 200 mg once daily have not been studied in children and adolescents.
Efficacy and safety of use in children < 6 years have not been studied.
23.75 mg: Chronic heart failure: The dose of Metoprolol CR (BETAZOK) should be individually adjusted in patients with chronic heart failure stabilised on other heart failure treatment. A recommended initial dose during the first two weeks is a 25 mg tablet once daily. It is recommended that patients with NYHA functional classes III-IV begin with half a 25 mg tablet once daily the first week. It is recommended that the dose then be doubled every second week up to a maximum target dose of 200 mg Metoprolol CR (BETAZOK) once daily (or to the highest tolerated dose). During long-term treatment, the aim should be to reach 200 mg Metoprolol CR (BETAZOK) once daily (or the highest tolerated dose).
At each dose level the patient should be carefully evaluated with regard to tolerability. In case of hypotension, decrease in concomitant medication may be necessary. Initial hypotension does not necessarily mean that the dose cannot be tolerated in chronic treatment but the patient should be kept at the lower dose until stabilised.

The symptoms of overdosage 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 such as dobutamine 2.5 to 10 micrograms/kg/minute by intravenous infusion may be given.
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.

Atrioventricular block of second or third degree; patients with unstable decompensated cardiac heart 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, 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 CR (BETAZOK) is contra-indicated in patients who have shown hypersensitivity to any component of the product 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 CR (BETAZOK) is started. The risk of Metoprolol CR (BETAZOK) interfering with β₂-receptors is however less than with conventional tablet formulations of β₁-selective blockers.
During treatment with Metoprolol CR (BETAZOK), the risk of interfering with carbohydrate metabolism or masking hypoglycaemia is likely to be less than during treatment with conventional tablet formulations of β1-selective blockers and much less than with nonselective β-blockers.
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 CR (BETAZOK) should be given in lower doses or gradually withdrawn.
Metoprolol CR (BETAZOK) may aggravate the symptoms of peripheral arterial circulatory disorders.
Where Metoprolol CR (BETAZOK) is prescribed for a patient known to be suffering from a phaeochromocytoma, an alpha-blocker should be given concomitantly.
Abrupt withdrawal of β-blockade is hazardous especially in high risk patients, and should therefore not be done.
If there is a need to discontinue treatment with Metoprolol CR (BETAZOK), this should preferably be done gradually over at least two weeks when the dose is reduced by half in each step down to the final step when a whole 25 mg tablet is reduced to a half tablet.
The final dose should be taken for at least four days before discontinuation. If symptoms occur, a slower withdrawal rate is recommended. Sudden withdrawal of β-blockade may aggravate chronic heart failure and also increase the risk of myocardial infarction and sudden death.
Prior to surgery the anaesthetist should be informed that the patient is receiving Metoprolol CR (BETAZOK). 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 CR (BETAZOK) before they drive or use machines because occasionally dizziness or fatigue may occur.

Metoprolol CR (BETAZOK) should not be given during pregnancy and lactation unless its use is considered essential. 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 CR (BETAZOK) 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, mostly with conventional metoprolol (metoprolol tartrate). 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 46000 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.

Rx