Betaloc ZOK film-coated tablets with delayed release 50 mg bottle No. 30

Instructions for use Betaloc ZOK film-coated tablets with delayed release 50 mg bottle No. 30

Composition

active ingredient: metoprolol;

1 tablet contains 23.75 mg or 47.5 mg or 95 mg of metoprolol succinate, corresponding to 25 mg or 50 mg or 100 mg of metoprolol tartrate;

excipients: ethylcellulose, hydroxypropylcellulose, hypromellose, microcrystalline cellulose, paraffin, macrogol, colloidal anhydrous silicon dioxide, sodium stearyl fumarate, titanium dioxide (E 171).

Dosage form

Film-coated, sustained-release tablets.

Main physicochemical properties:

25 mg: white or almost white, oval, biconvex, film-coated tablet, scored on both sides and engraved on one side;

50 mg: white or almost white, round, biconvex, film-coated tablet, scored on one side and engraved on the other side;

100 mg: white or almost white, round, biconvex, film-coated tablet, scored on one side and engraved on the other side.

Pharmacotherapeutic group

Selective beta-adrenergic blockers. Metoprolol.

ATX code C07A B02.

Pharmacological properties

Pharmacodynamics.

Metoprolol is a selective beta1-adrenoceptor blocker. Metoprolol acts on beta1-receptors of the heart at lower doses than are required to act on beta2-receptors of peripheral vessels and bronchi. The selectivity of the drug Betalok Zok is dose-dependent, but the maximum plasma concentration when using the sustained-release dosage form is significantly lower than when taking the same dose in the form of a regular tablet. A higher degree of beta1-selectivity is achieved due to dosing in the sustained-release dosage form.

Metoprolol has no beta-stimulating effect and exhibits a slight membrane-stimulating effect. Beta-receptor blockers demonstrate a negative inotropic and chronotropic effect. Treatment with metoprolol reduces the effect of catecholamines on the heart during physical and psychoemotional stress and leads to a decrease in heart rate, cardiac output and blood pressure. In stressful situations accompanied by increased release of adrenaline from the adrenal glands, metoprolol does not interfere with normal physiological vasodilation. In therapeutic doses, metoprolol has a less spasmolytic effect on the bronchial muscles than non-selective beta-blockers. This property makes it possible to treat patients with bronchial asthma or other severe obstructive pulmonary diseases with metoprolol in combination with beta2-receptor stimulants. Metoprolol has less effect on insulin release and carbohydrate metabolism than non-selective beta-blockers, so it can also be prescribed to patients with diabetes. Metoprolol has less effect on the cardiovascular response to hypoglycemia, such as tachycardia, and the return of blood sugar levels to normal occurs more quickly than with non-selective beta-blockers.

In arterial hypertension, Betaloc Zok significantly reduces blood pressure for more than 24 hours both in the supine and standing positions, as well as during physical exertion. At the beginning of treatment with metoprolol, an increase in peripheral vascular resistance is observed. However, with prolonged treatment, a decrease in blood pressure may occur due to a decrease in total peripheral vascular resistance and unchanged cardiac output.

Children.

In a 4-week study in 144 patients aged 6 to 16 years with essential hypertension, Betaloc Zok at doses of 1 and 2 mg/kg reduced placebo-adjusted systolic blood pressure by 4–6 mm Hg. Diastolic blood pressure showed a placebo-adjusted reduction of 5 mm Hg. at higher doses, and a dose-dependent reduction in blood pressure at doses of 0.2, 1, and 2 mg/kg. No significant differences were found by age, Tanner Scale (Adolescent Physical Development Scale), or race.

Metoprolol reduces the risk of cardiovascular mortality in men with moderate/severe hypertension. No electrolyte disturbances were observed.

Effect in chronic heart failure: In the MERIT-HF study (a survival study involving 3991 patients with chronic heart failure (NYHA class II–IV) and reduced ejection fraction (≤ 0.40)), Betaloc Zok showed an increase in survival rates and a decrease in the number of hospitalizations. With long-term treatment, patients achieved an overall improvement in symptoms (according to New York Heart Association classes and the Global Assessment of Treatment Scale).

In tachyarrhythmias, the effect of increased sympatholytic activity is blocked, and this leads to a lower heart rate, primarily due to a decrease in automatic function in pacemaker cells, as well as due to a prolonged supraventricular conduction time. Metoprolol reduces the risk of recurrent infarction and cardiac death, especially sudden death after myocardial infarction.

Pharmacokinetics.

The Betaloc Zok sustained-release tablet consists of microcapsules containing granules of metoprolol succinate, and each capsule is a separate unit of content. Each capsule is coated with a polymer membrane that controls the rate of release of the drug. The tablet quickly disintegrates upon contact with liquid, after which the capsules are distributed over a significant surface of the gastrointestinal tract. The release does not depend on the pH of the surrounding fluid and continues at an almost constant rate for 20 hours. This dosage form of the drug provides a uniform concentration of metoprolol succinate in the blood plasma and a duration of action of 24 hours.

Betaloc Zok is completely absorbed after oral administration, and the substance is absorbed along the entire digestive tract, as well as in the colon. The bioavailability of the drug Betaloc Zok is 30-40%. Metoprolol is metabolized in the liver, mainly by CYP2D6. Three major metabolites have been identified, although none of them has a clinically significant beta-blocking effect. Approximately 5% of metoprolol is excreted unchanged by the kidneys, the rest of the dose is excreted as metabolites.

The pharmacokinetics of metoprolol in children and adolescents (6–17 years) resemble those in adults. Oral clearance of metoprolol (CL/F) increases linearly with body weight.

Indication

Arterial hypertension.

Angina pectoris.

Stable symptomatic chronic heart failure with impaired left ventricular systolic function.

Prevention of cardiac death and recurrent infarction after the acute phase of myocardial infarction.

Cardiac arrhythmias, including supraventricular tachycardia, decreased ventricular rate in atrial fibrillation, and ventricular extrasystoles.

Functional disorders of cardiac activity accompanied by palpitations.

Migraine prevention.

Contraindication

Cardiogenic shock. Sick sinus syndrome (in the absence of a permanent pacemaker). Atrioventricular block of the II and III degree. Heart failure in the stage of decompensation (pulmonary edema, hypoperfusion or arterial hypotension); prolonged or intermittent inotropic therapy aimed at stimulating beta receptors. Symptomatic bradycardia or arterial hypotension.

Metoprolol should not be prescribed to patients with suspected acute myocardial infarction with a heart rate < 45 beats/min, PQ interval > 0.24 s, systolic blood pressure < 100 mm Hg. In the presence of symptoms of heart failure, the condition of patients with repeated blood pressure readings below 100 mm Hg. in the supine position should be re-evaluated before starting treatment. Serious peripheral vascular disease with the threat of gangrene. Hypersensitivity to any of the components of the drug or to other beta-blockers.

Interaction with other medicinal products and other types of interactions

Metoprolol is a substrate of the CYP 2D6 enzyme. The plasma concentration of metoprolol may be affected by drugs that inhibit CYP 2D6, such as quinidine, terbinafine, paroxetine, fluoxetine, sertraline, celecoxib, propafenone and diphenhydramine. At the beginning of treatment with these drugs, it may be necessary to reduce the dose of Betaloc Zok.

The simultaneous use of Betalok Zok with the following medicines should be avoided:

Barbituric acid derivatives: barbiturates (studied for pentobarbital) stimulate the metabolism of metoprolol by enzyme induction.

Propafenone: In four patients treated with metoprolol, plasma concentrations of metoprolol increased 2-5-fold after administration of propafenone, and two patients experienced side effects typical of metoprolol. The interaction was confirmed in eight healthy volunteers. This interaction is probably due to the fact that propafenone, like quinidine, inhibits the metabolism of metoprolol via the cytochrome P450 2D6 system. The outcome of this combination is likely to be unpredictable, since propafenone also has beta-blocking properties.

Verapamil: In combination with beta-blockers (described for atenolol, propranolol and pindolol), verapamil may cause bradycardia and a decrease in blood pressure. Verapamil and beta-blockers have an additive inhibitory effect on atrioventricular conduction and sinus node function.

Concomitant use of Betalok Zok with the following medicines may require dose adjustment:

Class I antiarrhythmics: Class I antiarrhythmics and beta-blockers have an additive negative inotropic effect that may lead to serious hemodynamic side effects in patients with impaired left ventricular function. This combination should also be avoided in patients with sick sinus syndrome and atrioventricular conduction disorders. This interaction is best described for disopyramide.

Nonsteroidal anti-inflammatory/antirheumatic drugs (NSAIDs): NSAIDs have been shown to antagonize the antihypertensive effects of beta-blockers. Indomethacin has been studied primarily. This interaction is unlikely to occur with sulindac. A negative interaction study has been conducted with diclofenac.

Digitalis glycosides: Concomitant administration of digitalis glycosides and beta-blockers may increase atrioventricular conduction time and cause bradycardia.

Diphenhydramine: Diphenhydramine reduces (by 2.5-fold) the clearance of metoprolol to alpha-hydroxymetoprolol via the CYP 2D6 system in individuals who are rapid hydroxylators. The effects of metoprolol are enhanced.

Diltiazem: Diltiazem and β-blockers have additive inhibitory effects on atrioventricular conduction and sinus node function. Severe bradycardia has been observed (case reports) when used in combination with diltiazem.

Epinephrine: Severe hypertension and bradycardia have been reported (approximately 10 reports) following administration of epinephrine (adrenaline) to patients receiving non-selective beta-blockers (including pindolol and propranolol). These clinical observations have been confirmed in a study in healthy volunteers. It has also been suggested that epinephrine, which is found in local anesthetics, may precipitate these reactions when administered intravascularly. The risk is likely to be lower with cardioselective beta-blockers.

Phenylpropanolamine: Phenylpropanolamine (norephedrine) in a single dose of 50 mg may cause a pathological increase in diastolic blood pressure in healthy volunteers. Propranolol generally counteracts the increase in blood pressure caused by phenylpropanolamine. However, beta-blockers may provoke paradoxical hypertensive reactions in patients receiving high doses of phenylpropanolamine. Two cases of hypertensive crisis have been described during treatment with phenylpropanolamine alone.

Quinidine: Quinidine inhibits the metabolism of metoprolol in so-called extensive metabolisers (more than 90% in Sweden) with a significant increase in plasma levels and, consequently, increased beta-receptor blockade. A similar interaction may occur with other beta-blockers metabolised by the same enzyme (cytochrome P450 2D6).

Clonidine: Beta-blockers may potentiate the hypertensive reaction upon abrupt withdrawal of clonidine. If concomitant clonidine therapy must be discontinued, the beta-blocker should be discontinued several days before clonidine is discontinued.

Rifampicin: Rifampicin may stimulate the metabolism of metoprolol, leading to a decrease in its plasma levels.

Patients receiving other beta-blockers (e.g. eye drops) or monoamine oxidase inhibitors (MAOIs) concomitantly with metoprolol should be closely monitored. Administration of inhalation anesthetics to patients receiving beta-blocker therapy increases the cardiodepressive effect. Patients receiving beta-blockers may require re-adjustment of the dose of oral antidiabetic agents. Plasma concentrations of metoprolol may increase if cimetidine or hydralazine are administered concomitantly.

Application features

Patients receiving beta-blocker therapy should not receive intravenous verapamil.

Metoprolol may worsen symptoms of peripheral arterial circulatory disorders, such as intermittent claudication. In case of severe renal impairment, serious acute conditions with metabolic acidosis and concomitant treatment with digitalis drugs, patients should be given special attention.

In patients with Prinzmetal's angina, the frequency and severity of angina attacks may increase due to alpha-receptor-mediated coronary vasoconstriction. Therefore, non-selective beta-blockers should not be prescribed to such patients. Selective beta1-blockers should be used with caution.

In the treatment of patients with bronchial asthma or other obstructive pulmonary diseases, adequate bronchodilator therapy should be administered concurrently. It may be necessary to increase the dose of beta2-receptor stimulants.

During treatment with metoprolol, the risk of affecting carbohydrate metabolism or the risk of developing latent hypoglycemia is lower than with non-selective beta-blockers.

Very rarely, the condition of patients with moderate atrioventricular conduction disturbances may worsen (possibly to complete atrioventricular block).

Beta-blocker therapy may complicate the treatment of anaphylactic reactions. Treatment with adrenaline at usual doses does not always lead to the expected therapeutic effect.

There are limited data from controlled clinical trials on the efficacy and safety of the medicinal product in patients with severe stable symptomatic heart failure (NYHA class IV). Treatment of such patients should only be carried out by physicians with special skills and experience (see section "Method of administration and dosage").

Patients with symptomatic heart failure accompanied by acute myocardial infarction and unstable angina were excluded from the study, which established the possibility of using the drug in heart failure. Therefore, the efficacy and safety of the treatment of acute myocardial infarction accompanied by heart failure has not been documented. Betaloc Zok is contraindicated in unstable, uncompensated heart failure (see section "Contraindications").

Abrupt withdrawal of beta-blockers is dangerous, especially for high-risk patients, and may worsen chronic heart failure, as well as increase the risk of myocardial infarction and sudden death. Therefore, discontinuation of treatment with Betaloc Zok for any reason should be done, if possible, gradually, over a period of at least 2 weeks, with the dose of the drug being halved at each stage to a final dose of 12.5 mg (half a 25 mg tablet). The last dose should be taken for at least 4 days before complete withdrawal of the drug. In case of recurrence of symptoms, it is recommended to slow down the dose reduction.

In case of surgical intervention, it is necessary to warn the anesthesiologist that the patient is taking Betaloc Zok. It is not recommended to stop treatment with beta-blockers in patients who are to undergo surgery. Urgent initiation of high doses of metoprolol in patients undergoing non-cardiac surgery should be avoided, as this is associated with the development of bradycardia, hypotension and stroke, including fatal outcome in patients with cardiovascular risk factors.

This medicinal product contains less than 1 mmol (23 mg) sodium/dose, i.e. essentially sodium-free.

Use during pregnancy or breastfeeding

Pregnancy

Betaloc Zok should not be used during pregnancy and breastfeeding unless the doctor considers that the benefit outweighs the potential harm to the fetus/child. In general, beta-blockers reduce placental blood flow, which can lead to fetal growth retardation, intrauterine fetal death, miscarriage and premature birth.

Therefore, it is recommended that appropriate monitoring of the pregnant woman and the fetus be carried out if the woman is treated with metoprolol. Beta-blockers may cause bradycardia in the fetus and newborn, which should be taken into account when these drugs are prescribed in the last trimester and in connection with childbirth. Betaloc Zok should be gradually discontinued 48-72 hours before the planned delivery. If this is not possible, the newborn should be monitored for 48-72 hours after delivery for symptoms of beta-blockade (such as cardiac and pulmonary complications).

Breast-feeding

Breastfeeding is not recommended. The amount of metoprolol excreted in breast milk is not expected to result in significant beta-blocking effects in the newborn if the mother uses usual therapeutic doses.

The ability to influence the reaction speed when driving or working with other mechanisms

Dizziness and fatigue may occur during treatment with Betalok Zok. Patients whose activities require mental alertness, such as driving and operating machinery, should be warned about the possibility of such effects.

Method of administration and doses

Betaloc Zok should be taken once a day, preferably in the morning. The prolonged-release tablets can be divided, but should not be chewed or crushed. The tablets should be swallowed with at least 0.5 cup of liquid. Simultaneous food intake does not affect the bioavailability of the drug.

The dose should be selected individually to avoid the development of bradycardia. The following dosage is recommended:

Arterial hypertension

50–100 mg once daily. If a dose of 100 mg is insufficient to achieve a therapeutic effect, the drug can be combined with other antihypertensive drugs, preferably diuretics and dihydropyridine-type calcium antagonists, or the dose of the drug can be increased.

Angina pectoris

100–200 mg once a day. If necessary, Betaloc Zok can be combined with nitrates or the dose can be increased.

Adjunctive therapy in the treatment of stable symptomatic heart failure with angiotensin-converting enzyme inhibitors, diuretics and possibly digitalis drugs.

Treatment of heart failure with beta-blockers may lead to temporary worsening of symptoms. In some cases, further continuation of therapy or reduction of the dose of the drug is possible, in some cases, discontinuation of the drug may be required. In patients with severe heart failure (IV functional class according to the NYHA classification), treatment with the drug Betaloc Zok should be initiated only by an experienced specialist (see section "Special instructions").

Stable heart failure, functional class II.

The recommended starting dose of Betaloc Zok in the first two weeks is 25 mg once a day. After 2 weeks, the dose can be increased to 50 mg once a day, and then the dose can be doubled every 2 weeks. The target dose of Betaloc Zok for long-term treatment is 200 mg once a day.

Stable heart failure, functional class III–IV.

The recommended initial dose is 12.5 mg (half a 25 mg tablet) once a day. The dose of the drug is adjusted individually. During the period of increasing the dose, the patient should be under close medical supervision, as in some patients the symptoms of heart failure may worsen. After 1-2 weeks of taking Betaloc Zok, the dose of the drug can be increased to 25 mg once a day. After 2 weeks, the dose of the drug can be increased to 50 mg once a day. Patients who tolerate higher doses well can double the dose every 2 weeks until the maximum dose of 200 mg per day is reached.

In case of development of arterial hypotension and/or bradycardia it may be necessary to reduce the dose of the concomitant medicinal product or to reduce the dose of the drug Betaloc Zok. Arterial hypotension at the beginning of therapy does not necessarily indicate that the dose of the drug Betaloc Zok needs to be reduced. However, the dose should not be increased until the patient's condition is stabilized. It may also be necessary to carefully monitor renal function.

Cardiac arrhythmia.

100–200 mg once daily. The dose can be increased if necessary.

Prophylactic treatment after myocardial infarction.

The recommended maintenance dose is 200 mg once daily.

Functional disorders of cardiac activity accompanied by palpitations.

100 mg once a day. The dose can be increased if necessary.

Migraine prevention.

100–200 mg once a day.

Patients with renal impairment.

It is not necessary to adjust the dose of the drug, since the rate of excretion depends only slightly on renal function.

Patients with liver dysfunction.

In general, patients with cirrhosis should be given Betaloc Zok at the same dose as patients with normal liver function. Only in cases of very severe liver dysfunction (e.g., in patients after bypass surgery) may a dose reduction be necessary.

Elderly patients.

No dose adjustment is necessary.

Children

The safety and efficacy of the drug Betalok Zok for the treatment of children for the indicated indications have not yet been established. Data are not available.

Overdose

Toxicity.

In an adult, a dose of 7.5 g caused fatal intoxication. Ingestion of 100 mg of the drug by a 5-year-old child was not accompanied by symptoms of intoxication after gastric lavage. Moderate intoxication was caused by a dose of 450 mg in a 12-year-old child and a dose of 1.4 g in an adult, serious intoxication in an adult was caused by a dose of 2.5 g, and very serious intoxication was caused by a dose of 7.5 g.

Symptoms.

The most important are the cardiovascular symptoms, but in some cases, especially in children and young people, symptoms from the central nervous system and respiratory depression may prevail. Bradycardia, atrioventricular block I-III degree, prolongation of the QT interval (exceptional cases), asystole, drop in blood pressure, insufficient peripheral perfusion, heart failure, cardiogenic shock. Respiratory depression, respiratory arrest. Others: fatigue, confusion, loss of consciousness, fine tremor, convulsions, sweating, paresthesias, bronchospasm, nausea, vomiting, possibly esophageal spasm, hypoglycemia (especially in children) or hyperglycemia, hyperkalemia. Effects on the kidneys. Transient myasthenic syndrome. Concomitant use of alcohol, antihypertensive drugs, quinidine or barbiturates may worsen the patient's condition. The first signs of overdose may occur 20 minutes to 2 hours after taking the medicine.

Treatment.

Treatment is provided in a unit that is capable of offering support measures, monitoring and supervision.

If warranted, gastric lavage, activated charcoal, atropine, adrenergic stimulator, or pacemaker may be used to treat bradycardia and conduction disturbances.

Hypotension, acute myocardial infarction, and shock should be treated with appropriate fluid resuscitation, glucagon (followed by an intravenous infusion of glucagon if necessary), intravenous adrenergic agonists such as dobutamine, with the addition of α1-receptor agonists after vasodilation. Intravenous Ca2+ may also be considered.

Bronchospasm is usually compensated by the use of bronchodilators.

Side effects

Adverse reactions occur in approximately 10% of patients and are usually dose-related. Adverse reactions associated with the use of metoprolol are listed below by system organ class and frequency. Frequencies are defined as follows: very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1,000 to < 1/100); rare (≥ 1/10,000 to < 1/1,000); very rare (< 1/10,000); frequency unknown (cannot be estimated from the available data).

Reporting of suspected adverse reactions

It is important to report adverse reactions after a medicine has been authorised. This allows the benefit-risk balance of the medicine to be monitored. Healthcare professionals are obliged to report any suspected adverse reaction.

Expiration date

3 years.

Storage conditions

Keep out of the reach of children. Store at a temperature not exceeding 30 °C.

Packaging

25 mg tablets: 14 tablets in a blister, 1 blister in a cardboard box.

50 mg tablets: 30 tablets in a bottle, 1 bottle in a cardboard box.

100 mg tablets: 30 tablets in a bottle, 1 bottle in a cardboard box.

Vacation category

According to the recipe.

Producer

AstraZeneca AB.

Location of the manufacturer and its business address

Hertúnevegen, Södertälje, 152 57, Sweden