Betaloc Zok

Betaloc Zok





Full Prescribing Info
Metoprolol succinate.
Each tablet contains metoprolol succinate 95 mg corresponding to 100 mg of metoprolol tartrate. The score mark is not intended to divide the tablet into two equal doses. It is only intended to facilitate swallowing.
Excipients/Inactive Ingredients: Ethylcellulose, hydroxypropyl cellulose, hypromellose, microcrystalline cellulose, paraffin, macrogol, silicon dioxide, sodium stearyl fumarate, titanium dioxide (E 171).
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 mandatory, Betaloc ZOK, in combination with a β2-agonist, may be given to patients with symptoms of obstructive pulmonary disease. When given together with a β2-agonist, Betaloc ZOK in therapeutic doses interferes less than non-selective β-blockers with the β2-mediated bronchodilation caused by the β2-agonist.
Betaloc ZOK gives an even plasma concentration time profile and effect (β1-blockade) over 24 hours in contrast to conventional tablet formulations of β1-selective blockers.
Due to the lack of pronounced peaks in plasma concentration, the clinical β1-selectivity is improved with the Betaloc ZOK 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.
Betaloc ZOK interferes less with insulin release and carbohydrate metabolism than do non-selective β-blockers.
Betaloc ZOK interferes much less with the cardiovascular response to hypoglycaemia than do non-selective β-blockers.
Short term studies have shown that Betaloc ZOK 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 Betaloc ZOK.
An improvement in quality of life has been observed after metoprolol treatment in patients after myocardial infarction.
Pharmacokinetics: Absorption and distribution: Betaloc ZOK 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, but 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 elimination half-life of metoprolol averages 3.5 hours. Thus, an even metoprolol plasma concentration is achieved over a dosage interval of 24 hours.
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.
Due to its low protein binding the pharmacokinetics of metoprolol is little affected by decreased liver function. However, in patients with severe liver cirrhosis and a portacava 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.
Hypertension: to reduce blood pressure and to reduce the risk of cardiovascular and coronary mortality (including sudden death), and morbidity.
Angina pectoris.
Prevention of cardiac death and reinfarction after the acute phase of myocardial infarction.
Cardiac arrhythmias especially including supraventricular tachycardia, reduction of ventricular rate in atrial fibrillation and in ventricular extrasystoles.
Migraine prophylaxis.
Dosage/Direction for Use
Betaloc ZOK is intended for once daily treatment and is preferably taken in the morning. The Betaloc ZOK tablet should be swallowed with liquid. The tablets and the divided halves should not be chewed or crushed. Concomitant intake of food does not influence the bioavailability.
Dosage should be adjusted to avoid bradycardia.
Hypertension: The recommended dosage in patients with mild to moderate hypertension is 50 mg Betaloc ZOK 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.
Angina pectoris: The recommended dosage is 100-200 mg Betaloc ZOK given once daily. If needed, Betaloc ZOK can be combined with other antianginal agents.
Cardiac arrhythmias: The recommended dosage is 100-200 mg Betaloc ZOK given once daily.
Prophylactic treatment after myocardial infarction: Long-term oral 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: There is limited experience with Betaloc ZOK treatment in children.
Symptoms: Symptoms of overdosage may include hypotension, cardiac insufficiency, bradycardia and bradyarrhythmia, 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 administrated. 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 adreno stimulating 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 heart failure (pulmonary oedema, hypoperfusion or hypotension), and patients with continuous or intermittent inotropic therapy acting through β-receptor agonism; marked 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.
Betaloc ZOK is contraindicated in patients who have shown hypersensitivity to any component of the product or to other β-blockers.
Special Precautions
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 Betaloc ZOK is started. The risk of Betaloc ZOK interfering with β2-receptors is however less than with conventional tablet formulations of β1-selective blockers.
During treatment with Betaloc ZOK, 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 non-selective β-blockers.
Patients suffering from heart failure should have their decompensation treated both before and during treatment with Betaloc ZOK.
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, Betaloc ZOK should be given in lower doses or gradually withdrawn.
Betaloc ZOK may aggravate the symptoms of peripheral arterial circulatory disorders, mainly due to its blood pressure lowering effect.
Where Betaloc ZOK is prescribed for a patient known to be suffering from a phaeochromocytoma, an alpha-blocker should be given concomitantly.
Prior to surgery the anaesthetist should be informed that the patient is receiving Betaloc ZOK. 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.
Abrupt interruption of the medication is to be avoided. Sudden withdrawal of β-blockade is hazardous, especially in high-risk patients and increase the risk of myocardial infarction and sudden death. Any withdrawal of Betaloc ZOK should therefore, if possible, be made gradually over at least two weeks when the dose is reduced by half in each step, down to the final dose when a 50-mg tablet is reduced to half a tablet. The final dose should be given for at least four days before discontinuation. If symptoms occur, a slower withdrawal rate is recommended.
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 Betaloc ZOK before they drive or use machines because occasionally dizziness or fatigue may occur.
Use In Pregnancy & Lactation
As with most drugs, Betaloc ZOK 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.
As with all antihypertensive agents, β-blockers may cause side-effects, e.g. bradycardia, in the foetus 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.
Adverse Reactions
Betaloc ZOK 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 Betaloc (metoprolol tartrate). In many cases a relationship to treatment with Betaloc has not been established.
The following definitions of frequencies are used: Very common (≥1:10), common (≥1:100 - <1:10), uncommon (≥1:1000 - <1:100), rare (≥1:10000 - <1:1000), and very rare (<1:10000).
Cardiovascular system: Common: Bradycardia, postural disorders (very rarely with syncope), cold hands and feet, palpitations.
Uncommon: Transient deterioration of heart failure symptoms, cardiogenic shock in patients with acute myocardial infarction*, AV-block I, 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.
Musculoskeletal: Very rare: Arthralgia.
Metabolism: Uncommon: Weight gain.
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
Drug Interactions
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.
A watch should be kept for possible negative inotropic and chronotropic effects when metoprolol is given together with calcium antagonists of the verapamil and diltiazem type and/or antiarrhythmic agents. 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.
Caution For Usage
Incompatibilities: Not applicable.
Do not store above 30°C.
MIMS Class
ATC Classification
C07AB02 - metoprolol ; Belongs to the class of selective beta-blocking agents. Used in the treatment of cardiovascular diseases.
CR tab 100 mg (white to off-white, circular, scored on the one side and marked mAs on the other side) x 2 x 15's.
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