Each prolonged-release tablet contains metoprolol succinate 23.75 and 47.5 mg corresponding to metoprolol tartrate 25 and 50 mg, respectively.
The tablet can be divided into equal doses. The score line is only to facilitate breaking for ease of swallowing and not to divide into equal doses.
Excipients/Inactive Ingredients: Ethylcellulose, hydroxypropyl cellulose, hypromellose, microcrystalline cellulose, paraffin, macrogol, silicon dioxide, sodium stearyl fumarate and titanium dioxide (E171).
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 nonselective 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 nonselective 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 hrs 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 adverse reactions, e.g. bradycardia and leg fatigue is reduced.
Betaloc ZOK interferes less with insulin release and carbohydrate metabolism than do nonselective β-blockers.
Betaloc ZOK interferes much less with the cardiovascular response to hypoglycaemia than do nonselective 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 nonselective β-blockers. However, a significant reduction in total serum cholesterol levels has been demonstrated after metoprolol treatment in a study conducted over several years.
Quality of life is maintained, uncompromised or improved during treatment with Betaloc ZOK.
An improvement in the quality of life has been observed after metoprolol treatment in patients after myocardial infarction (MI).
In MERIT-HF, a survival study comprising 3991 patients with chronic heart failure [new york heart association (NYHA) II-IV] and decreased ejection fraction (≤0.4), Betaloc ZOK has been shown to increase survival and to reduce the number of hospitalisations. In long-term treatment, the patients experience a general improvement of symptoms (NYHA class and Overall Treatment Evaluation score).
In addition, it has been shown that Betaloc ZOK therapy increases the ejection fraction, and reduces the left ventricular end systolic and end diastolic volumes.
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 prolonged-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 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 (3) 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 hrs (extremes: 1 hour and 9 hours). The total clearance rate is approximately 1 litre/min.
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 glomerular filtration rate (GFR) of <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 less likely affected by decreased liver function. However, in patients with severe liver cirrhosis and a portacaval shunt, the bioavailability of metoprolol may increase and total clearance may be reduced. Patients with a portacaval anastomosis had a total clearance of approximately 0.3 L/min and area under the plasma concentration-time curve (AUC) values up to 6 times higher than in healthy subjects.
Hypertension: Reduce blood pressure and reduce the risk of cardiovascular and coronary mortality (including sudden death) and morbidity.
Angina pectoris; stable symptomatic chronic heart failure with impaired systolic left ventricular function as an adjunct to existing heart failure therapy; 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.
Mild to Moderate Hypertension: Recommended Dose: 50 mg once daily. In patients not responding to 50 mg, the dose could be increased to 100-200 mg once daily and/or in combination with other antihypertensive agents.
Angina Pectoris: Recommended Dose: 100-200 mg once daily. If needed, Betaloc ZOK can be in combination with other antianginal agents.
Stable Symptomatic Chronic Heart Failure with Impaired Systolic Left Ventricular Function as an Adjunct to Existing Heart Failure Therapy: The patients should have a stable chronic heart failure, without acute failure for the last 6 weeks and an essentially unchanged basal therapy for the last 2 weeks.
Treatment of heart failure with β-blockers may sometimes cause a temporary exacerbation of the symptoms picture. In some cases, it is possible to continue the therapy or reduce the dose, and in other cases, it may be necessary to discontinue the treatment. Initiation of Betaloc ZOK therapy in patients with severe heart failure (NYHA IV) should only be made by physicians especially trained in treatment of heart failure (see Precautions).
Patients with Stable Heart Failure, Function Class II: Recommended Initial Dose: 25 mg once daily for the first 2 weeks.
After 2 weeks, the dose can be increased to 50 mg once daily and thereafter it can be doubled every 2nd week. The target dose for long-term treatment is 200 mg once daily.
Patients with Stable Heart Failure, Function Classes III-IV: Recommended Initial Dose: 12.5 mg (1/2 of a 25-mg tablet) given once daily. The dose should be individually adjusted and the patient should be closely monitored during the increase of the dosage as heart failure symptoms may be aggravated in some patients. After 1-2 weeks, the dose can be raised to 25 mg given once daily. Then, after further 2 weeks, the dosage can be increased to 50 mg given once daily. In those patients who tolerate a higher dose, the dosage can be doubled every 2nd week up to a maximal dose of 200 mg daily.
In case of hypotension and/or bradycardia, decrease in concomitant medication or lowering of the Betaloc ZOK dose may be necessary. Initial hypotension does not necessarily mean that the dose of Betaloc ZOK cannot be tolerated in chronic treatment, but the dose must not be raised until the condition has been stabilized and increased control of renal function, among other things, may be required.
Cardiac Arrhythmias: Recommended Dose: 100-200 mg 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).
Children: There is limited experience with Betaloc Zok treatment in children.
Elderly: Dose adjustment is not needed in the elderly.
Renal Impairment: Dose adjustment is 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%). When there are signs of serious impairment of liver function (e.g. shunt-operated patients), a dose reduction should be considered.
Administration: Betaloc ZOK is intended for once-daily treatment and is preferably taken in the morning. The Betaloc ZOK tab 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.
Toxicity: 7.5 g to an adult caused lethal intoxication. 100 mg to a 5-year old gave no symptoms after gastric lavage. 450 mg to a 12-year old and 1.4 g to an adult gave moderate intoxication, 2.5 g to an adult caused serious intoxication, and 7.5 g to an adult gave very serious intoxication.
Symptom: Cardiovascular symptoms are most important, but in some cases, especially in children and young individuals, CNS symptoms and respiratory depression may dominate. Bradycardia, AV-block I-III, QT-prolongation (exceptional cases), asystole, fall in blood pressure, poor peripheral perfusion, cardiac insufficiency, cardiogenic shock. Respiratory depression, apnoea. Others: Fatigue, confusion, unconsciousness, fine tremor, cramps, perspiration, paraesthesiae, bronchospasm, nausea, vomiting, possibly oesophageal spasm, hypoglycaemia (especially in children) or hyperglycaemia, hyperkalaemia. Effect on the kidneys. Transient myasthenic syndrome. Concomitant ingestion of alcohol antihypertensives, quinidine or barbiturates may aggravate the patient's condition. The first signs of overdosing may be seen 20 minutes to 2 hours after ingestion.
Management: Care should be provided at a unit that can offer suitable support measures, monitoring and supervision.
If justified, gastric lavage and/or activated charcoal can be used.
Atropine, adrenoceptor stimulant or pacemaker for treatment of bradycardia and conduction disorders.
Intubation and mechanical ventilation should be done with very broad indication. Pacemaker is option. With circulatory arrest in connection with overdose, resuscitation measures for several hours may be warranted.
Hypotension, acute myocardial infarction and shock should be treated with appropriate volume expansion, administration of glucagon (followed by intravenous infusion of glucagon if necessary), intravenous administration of an adrenoceptor stimulant, such as dobutamine, with the addition of α1 receptor agonists upon vasodilation. Intravenous use of Ca2+ may also be considered.
Bronchospasm can usually be reversed through bronchodilators.
Betaloc ZOK is contraindicated in patients who have shown hypersensitivity to any component of the product or to other ß-blockers.
Atrioventricular (AV) block of 2nd- or 3rd-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 (unless a permanent pacemaker is in place); cardiogenic shock and severe peripheral arterial circulatory disorder.
Metoprolol should not be given to patients with suspected acute MI 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.
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 hypoglycemia is likely to be less than during treatment with conventional tablet formulations of β1-selective blockers and much less than with nonselective β-blockers.
Patients suffering from heart failure should have their decompensation treated both before and during treatment with Betaloc ZOK.
Very rarely, a preexisting AV conduction disorder of moderate degree may become aggravated (possibly leading to AV 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 α-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 noncardiac surgery should be avoided, since it has been associated with bradycardia, hypotension and stroke including fatal outcome in patients with cardiovascular risk factors.
Efficacy/safety data from controlled clinical studies in severe stable symptomatic heart failure (NYHA class IV) are limited. Treatment of heart failure in these patients should therefore only be initiated by physicians with special experience and training in this area (see Dosage & Administration).
Patients with symptomatic heart failure in association with acute MI and unstable angina pectoris were excluded from the study on which the indication of heart failure is found. Efficacy/safety conditions have therefore not been documented. Use in unstable decompensated heart failure is contraindicated (see Contraindications).
Abrupt interruption of the medication is to be avoided. Sudden withdrawal of β-blockade is hazardous, especially in high-risk patients, and may aggravate chronic heart failure as well as increase the risk of MI and sudden death. Any withdrawal of Betaloc ZOK should therefore, if possible, be made gradually over at least 2 weeks when the dose is reduced by half in each step, down to the final dose when a 25-mg tablet is reduced to half tablet. The final dose should be given for at least 4 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.
As with most drugs, Betaloc ZOK should not be given during pregnancy and lactation unless its use is considered essential. As with all antihypertensive agents, β-blockers may cause side effects, e.g. bradycardia, in the foetus and in the newborn and breastfed infant.
The amount of metoprolol ingested via breast milk, however, seems to be negligible with regards to the β-blocking effect in the infant if the mother is treated with metoprolol in doses within the normal therapeutic range.
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 (≥10%), common (1-9.9%), uncommon (0.1-0.9%), rare (0.01-0.09%) and very rare (<0.01%).
Common: Bradycardia, postural disorders (very rare with syncope), cold hands and feet, palpitations. Uncommon: Transient deterioration of heart failure symptoms, cardiogenic shock in patients with acute MI, AV block I, oedema, precordial pain. Rare: Disturbances of cardiac conduction, cardiac arrhythmias. Very Rare: Gangrene in patients with preexisting severe peripheral circulatory disorders.
Central Nervous System:
Very Common: Fatigue. Common: Dizziness, headache. Uncommon: Paraesthesia, muscle cramps.
Common: Nausea, abdominal pain, diarrhoea, constipation. Uncommon: Vomiting. Rare: Dry mouth.
Very Rare: Thrombocytopenia.
Rare: Liver function test abnormalities. Very Rare: Hepatitis.
Very Rare: Arthralgia.
Uncommon: Weight gain.
Uncommon: Depression, impaired concentration, somnolence or insomnia, nightmares. Rare: Nervousness, anxiety, impotence/sexual dysfunction. Very Rare: Amnesia/memory impairment, confusion, hallucinations.
Common: Dyspnoea on exertion. Uncommon: Bronchospasm. Rare: Rhinitis.
Rare: Disturbances of vision, dry and/or irritated eyes, conjunctivitis. Very Rare: Tinnitus, taste disturbances.
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 acts 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 (H2) receptor antagonists, antidepressants, antipsychotics and cyclooxygenase (COX)-2-inhibitors. The plasma concentration of metoprolol is lowered by rifampicin and may be raised by alcohol intake and hydralazine.
Patients receiving concomitant treatment with sympathetic ganglion-blocking agents, other β-blockers (i.e. eye drops) or monoamine 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, IV 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 ß-blockers, may increase AV 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 nonselective β-blockers.
The dosages of oral antidiabetics may have to be readjusted in patients receiving β-blockers.
C07AB02 - metoprolol ; Belongs to the class of selective beta-blocking agents. Used in the treatment of cardiovascular diseases.
PR tab 25 mg (white to off-white, oval with a size of 5.5 mm x 10.5 mm, scored on both sides and marked A/β on one side) x 1 x 14's. 50 mg (white to off-white, circular with a diameter of 9 mm, scored on one side and marked A/mO on the other) x 2 x 14's.