Instructions for Corvitol 50 tablets 50 mg No. 50
Composition
active ingredient: metoprolol;
1 tablet contains metoprolol tartrate 50 mg or 100 mg;
excipients: lactose monohydrate, povidone (K-30), croscarmellose sodium, magnesium stearate, talc, colloidal anhydrous silicon dioxide.
Dosage form
Pills.
Main physicochemical properties: white, round, plano-parallel tablets with beveled edges and a score line on one side.
Pharmacotherapeutic group
Selective β-adrenergic receptor blockers. ATC code C07A B02.
Pharmacological properties
Pharmacodynamics.
Metoprolol is a b-adrenergic receptor blocker without intrinsic sympathomimetic activity. It specifically blocks the action of catecholamines at the level of b1-adrenergic receptors. It reduces myocardial oxygen demand during exercise, which has a positive effect on long-term treatment of angina (reducing the frequency of pain attacks). It reduces systolic blood pressure, especially after exertion, and prevents the development of reflex orthostatic hypotension. A decrease in diastolic blood pressure occurs after several weeks of regular use - metoprolol reduces plasma renin activity.
Pharmacokinetics.
Absorption and distribution. After oral administration, metoprolol is completely absorbed. The concentration of metoprolol in the blood plasma is linearly dependent on the dose taken within the therapeutic dose range. The maximum plasma concentration (Cmax) is reached approximately 1.5-2 hours after administration (Tmax). Although the plasma concentration varies between individuals, the individual reproducibility is good. As a result of the important first pass effect during the passage through the liver, the systemic bioavailability of metoprolol after a single oral dose reaches approximately 50%. After repeated administration, it increases to 70%. Administration with food can increase the bioavailability by 30-40%. The binding of metoprolol to plasma proteins is low (approximately 5-10%).
Biotransformation. Metoprolol undergoes almost complete oxidative metabolism in the liver by cytochrome P450 enzymes (mainly the CYP2D6 isoenzyme). There is a significant ethnic difference in the distribution of poor metabolizers. The number of poor metabolizers is 7% in Caucasians, but less than 1% in Mongoloids. In patients with poor metabolizers via the CYP2D6 system, plasma concentrations of metoprolol may be several times higher than in patients with normal metabolizers via the CYP2D6 system. However, the metabolism of metoprolol by CYP2D6-
dependent pathway may have no or only a minor effect on the safety and tolerability of metoprolol. In cirrhosis of the liver, an increase in plasma levels of unmetabolized metoprolol should be expected due to a decrease in the rate of metabolism.
Metabolism and elimination: Metoprolol is metabolized in the liver to form three metabolites that do not have clinically significant β-blocking effects.
Usually more than 95% of an oral dose of the drug is excreted in the urine. Approximately 5% of this dose is excreted in the urine unchanged; in some cases, the amount of the drug excreted in the urine unchanged may reach 30%. The half-life is 3.5 hours (1-9 hours). The total rate of elimination from the blood plasma (clearance) is approximately 1000 ml/min.
In elderly patients, no significant changes in the pharmacokinetics of metoprolol are observed compared to those in young patients.
The systemic bioavailability and elimination of metoprolol are not altered in patients with renal insufficiency. However, the elimination of metabolites is reduced in such patients. In patients with a glomerular filtration rate of less than 5 ml/min, there is a significant accumulation of metabolites. This accumulation of metabolites has no β-blocking effect.
In patients with reduced liver function, the pharmacokinetics of metoprolol (due to low protein binding) are slightly altered. However, in patients with cirrhosis of the liver, the bioavailability of metoprolol may increase and the total clearance may decrease.
Indication
- Arterial hypertension.
- Angina pectoris (including post-infarction).
- Arrhythmia (including supraventricular tachycardia).
- Prevention of cardiac death and recurrent infarction after the acute phase of myocardial infarction.
- As part of complex therapy for thyrotoxicosis.
- Prevention of migraine attacks.
Contraindication
- Hypersensitivity to any component of the drug or to other β-blockers;
- atrioventricular block (II and III degrees), sinoatrial block;
- sick sinus syndrome;
- decompensated heart failure (pulmonary edema, hypoperfusion syndrome or arterial hypotension);
- pronounced bradycardia (heart rate ≤ 50 per 1 min);
- shock;
- severe peripheral circulatory disorders with pain or trophic changes;
- arterial hypotension (systolic blood pressure < 100 mm Hg);
- bronchial asthma, a severe form of chronic obstructive bronchopulmonary diseases;
- acidosis;
- untreated pheochromocytoma;
- the use of metoprolol is contraindicated in patients receiving intravenous calcium antagonists such as verapamil and diltiazem or other antiarrhythmic drugs (such as disopyramide);
- concomitant therapy with monoamine oxidase inhibitors (MAOIs).
Metoprolol should not be prescribed to patients with suspected acute myocardial infarction with a heart rate less than 50 beats/min, a P–Q interval >0.24 s, or a systolic blood pressure <100 mm Hg.
Note: For patients with decompensated heart failure who are well tolerated by other
Similar drugs, the use of metoprolol is possible with individual dose titration.
Interaction with other medicinal products and other types of interactions
Patients should be closely monitored if they are taking ganglioblockers or other β-blockers (e.g. eye drops) simultaneously with Corvitol®.
Caution is advised in the case of concomitant use of certain antiarrhythmic drugs, such as quinidine or amiodarone, and propafenone, since beta-blockers may potentiate negative inotropic and negative dromotropic effects. Concomitant administration with propafenone should be avoided. Propafenone inhibits the metabolism of metoprolol via cytochrome P450 2D6. The outcome of such a combination is unpredictable, since propafenone also has β-blocking properties.
The cardiodepressive effect of Corvitol® and antiarrhythmic drugs (e.g. amiodarone, propafenone and other antiarrhythmic drugs) may be additive. The effect of amiodarone (significant sinus bradycardia) may persist for a long time after discontinuation of the drug.
With the concomitant use of Corvitol® and cardiac glycosides, reserpine, α-methyldopa, guanfacine or clonidine, a significant decrease in heart rate or slowing of conduction may occur.
Abrupt withdrawal of clonidine from β-blocker therapy may result in an increase in blood pressure. If concomitant clonidine therapy is to be discontinued, the β-blocker should be discontinued several days prior to clonidine discontinuation.
In patients who are taking calcium antagonists of the verapamil type or diltiazem and/or drugs for the treatment of arrhythmias simultaneously with Corvitol®, negative inotropic and chronotropic effects are possible. Patients taking β-blockers should not be prescribed intravenous verapamil (due to the risk of cardiac arrest).
In patients treated with β-blockers, inhalation anesthetics enhance the cardiodepressive effect. Inducers or inhibitors of metabolism may affect the plasma concentration of metoprolol. The plasma concentration of metoprolol is reduced by rifampicin or may be increased by cimetidine, phenytoin, alcohol, hydralazine and serotonin reuptake inhibitors (paroxetine, fluoxetine and sertraline).
Concomitant use of metoprolol with lidocaine may delay the elimination of lidocaine from the body.
Iodinated radiopaque agents for intravenous administration increase the risk of anaphylactic reactions.
Concomitant use of metoprolol and neuromuscular relaxants (e.g. suxamethonium, tubocurarine) may enhance neuromuscular blockade.
Concomitant use of Corvitol® with non-steroidal anti-inflammatory drugs, such as indomethacin, may reduce the antihypertensive effect of metoprolol.
Cardioselective β-blockers have a much smaller effect on blood pressure when patients are given adrenaline than nonselective β-blockers.
Since beta-blockers may affect peripheral circulation, caution should be exercised when using drugs with similar effects, such as ergotamine, at the same time.
Beta-blockers may provoke paradoxical hypertensive reactions in patients taking high doses of phenylpropanolamine.
When β-blockers are taken concomitantly with insulin or oral antidiabetic agents, their effect may be enhanced or prolonged. In this case, the symptoms of hypoglycemia (especially tachycardia and tremor) may be masked or disappear. In such cases, regular monitoring of blood glucose levels is necessary, with possible dose adjustment of antihyperglycemic agents if necessary.
Concomitant administration with barbiturates should be avoided, as barbiturates (studied with pentobarbital) stimulate the metabolism of metoprolol by enzyme induction. Plasma concentrations 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 metoprolol.
Concomitant use of digitalis glycosides and β-blockers may prolong atrioventricular conduction time and cause bradycardia. Diphenhydramine reduces (by 2.5-fold) the clearance of metoprolol to α-hydroxymetoprolol via the CYP 2D6 system in individuals with rapid hydroxylation. The effects of metoprolol are enhanced. Diphenhydramine may inhibit the metabolism of other CYP 2D6 substrates.
Rifampicin may stimulate the metabolism of metoprolol, leading to a decrease in its plasma levels.
Concomitant therapy with dihydropyridine calcium channel blockers (e.g. nifedipine) with metoprolol, as with other beta-blockers, increases the risk of hypotension and heart failure in patients with latent heart failure.
Metoprolol antagonizes the beta1-effects of sympathomimetic agents but has little effect on the bronchodilator effect of beta2-agonists at normal therapeutic doses.
Application features
When taking metoprolol tartrate, as with other
β-blockers, it is necessary to monitor heart rate (HR) and blood pressure (BP) (initially daily, then once a month).
Patients taking β-blockers should not be given intravenous verapamil-type calcium antagonists.
As a rule, in the treatment of asthma patients, β2-agonists (in tablets or aerosol) should be prescribed as concomitant therapy. In cases where these patients start taking the drug, an increase in the dose of β2-agonists may be necessary. The risk that the drug will affect β2-receptors is lower than in the case of the use of conventional non-selective β1-blockers in tablets.
Particularly careful medical supervision is necessary in the treatment of patients with diabetes mellitus (blood glucose control), patients with unstable blood sugar levels, when using a strict fasting diet. During treatment with metoprolol, there is a minimal risk of affecting sugar metabolism or masked hypoglycemia compared to treatment with non-selective b-blockers.
Metoprolol may mask some clinical manifestations of thyrotoxicosis (e.g. tachycardia). Abrupt withdrawal of the drug in patients with thyrotoxicosis is contraindicated due to possible exacerbation of symptoms.
Patients undergoing treatment for heart failure should be treated for this disease before starting metoprolol and during this treatment.
Very rarely, pre-existing mild forms of AV conduction disorders may worsen and lead to more severe AV block. Patients with first degree AV block should be treated with this drug with great caution.
Metoprolol should be used with caution in patients with myasthenia gravis.
In case of development of bradycardia (heart rate less than 50-55 beats/min) during treatment with metoprolol, the dose should be reduced and/or the drug should be gradually discontinued.
Due to its hypotensive effect, the drug may increase the symptoms of peripheral circulatory disorders, such as intermittent claudication.
If the drug is used in patients with pheochromocytoma, an α-sympatholytic drug should be used in parallel.
If it is not possible to stop taking Corvitol® before a procedure under general anesthesia or before using a peripheral muscle relaxant, the anesthesiologist should be informed about the patient's use of Corvitol®. It is not recommended to stop treatment during surgery. If the drug must be discontinued, it should be discontinued no later than 48 hours before surgery, except in special cases, such as thyrotoxicosis or pheochromocytoma.
If treatment must be discontinued and whenever possible, it should be discontinued over a period of 10-14 days with a daily dose reduction of 25 mg per day for the last 6 days. During this period, special attention should be paid to patients with ischemic heart disease. The risk of heart attacks, including sudden death, may increase when treatment with β-blockers is discontinued. Treatment should not be discontinued abruptly due to the possibility of withdrawal syndrome (increased angina attacks, increased blood pressure).
Metoprolol may cause a slight increase in triglyceride levels and a decrease in free fatty acids in the blood. In some cases, a slight decrease in high-density lipoprotein (HDL) levels was observed, and this was significantly less than with non-selective β2-blockers. However, one long-term study showed a significant decrease in total cholesterol after treatment with metoprolol for several years.
Data on the efficacy and safety of the drug in patients with severe stable heart failure (NYHAIV) are limited. Treatment of such patients should be carried out by physicians with special skills and experience.
In patients with Prinzmetal's angina, the frequency and severity of angina attacks may increase due to α-receptor-mediated coronary vasoconstriction. Therefore, nonselective β-blockers should not be prescribed to such patients, and selective β1-blockers should be used with caution.
Anaphylactic shock is severe in patients treated with b-blockers.
Patients with a history of severe allergic reactions should be treated with metoprolol with great caution. Particular attention should also be paid to patients with allergic reactions who are treated with vaccines (desensitization therapy). The effect of the administration of usual doses of adrenaline may be absent.
Patients who wear contact lenses should be aware that the drug may reduce tear secretion.
Special attention should be paid to patients with severe renal impairment, with serious acute conditions and patients receiving combination treatment with digitalis preparations.
The drug contains lactose, so it should not be prescribed to patients with hereditary lactase deficiency, galactose intolerance or glucose/galactose metabolism disorders.
Patients with acute myocardial infarction or unstable angina within the previous 28 days, as well as patients with impaired liver function, aged over 80 years or less than 40 years; patients with hemodynamically significant valvular disease, hypertrophic obstructive cardiomyopathy, during or within 4 months after cardiac surgery should be treated only under the supervision of a physician with specialized skills and experience.
Use during pregnancy or breastfeeding
Metoprolol, like other drugs, should not be used during pregnancy or breastfeeding unless clearly necessary. Like other β-blockers, metoprolol may cause side effects, such as bradycardia and hypoglycemia, in the fetus and newborn or in the breastfed infant.
Typically, β-blockers inhibit placental blood flow, which can cause delayed
fetal growth. Metoprolol may cause bradycardia, hypotension, hypoglycemia, and respiratory depression in newborns, so its use should be discontinued 48-72 hours before the expected onset of labor. If this is not possible, the infant should be closely monitored for 48-72 hours after birth.
On the other hand, the amount of metoprolol that the infant receives in breast milk to exert a potential β-blockade effect is insignificant if the mother's metoprolol dose is within the normal therapeutic range. Breastfed infants should be closely monitored for potential β-blockade effects.
In order to keep the concentration of the active ingredient in breast milk low, the child should not be fed for 3-4 hours after taking the drug.
Ability to influence reaction speed when driving vehicles or other mechanisms
The use of the drug may affect activities that require high speed of mental and physical reactions, quick decision-making (for example, driving vehicles, servicing machines and mechanisms, working at heights), therefore, during the treatment period, you should refrain from driving vehicles, servicing machines and mechanisms, and working at heights.
Method of administration and doses
Metoprolol is intended for daily use, preferably in the morning. The tablet should be taken without chewing, washed down with a sufficient amount of drinking water. During the period of dose selection, the heart rate should be monitored to prevent bradycardia. The maximum daily dose is 400 mg. If, after prolonged use of the drug, treatment must be discontinued, this should be done gradually and slowly, because sudden withdrawal of the drug can lead to a sharp increase in blood pressure, cardiac ischemia with exacerbation of angina pectoris or myocardial infarction.
Arterial hypertension
The recommended dose is 100 mg (once in the morning or divided into two doses - morning and evening). If the therapeutic effect is not achieved with this dosage, the daily dose can be increased to 200 mg (once in the morning or divided into two doses - morning and evening) or the drug should be combined with other antihypertensive drugs.
Angina pectoris
The recommended dose of the drug is 50-100 mg 2-3 times a day. If necessary, the drug can be combined with other drugs for the treatment of angina pectoris.
Arrhythmia
The recommended dose is 50 mg 2-3 times a day. If necessary, the daily dose can be increased to 300 mg, divided into 2-3 doses.
Myocardial infarction (it is recommended to start treatment within 12 hours after the onset of retrosternal pain.
The recommended dose is 50 mg every 6 hours for the first 48 hours. The recommended maintenance dose is 200 mg, taken in two divided doses. The treatment period should be at least 3 months.
Hyperthyroidism (thyrotoxicosis)
The recommended dose is 50 mg four times a day. The dose should be gradually reduced after achieving a therapeutic effect.
Prevention of migraine attacks
The recommended daily dose is 100-200 mg per day, divided into 2 doses.
Patients with renal impairment
There is no need to adjust the dose.
Patients with hepatic impairment
Dose adjustment (reduction of the metoprolol dose) is usually necessary for patients with limited liver function (e.g., patients with cirrhosis).
Elderly patients
There is no need to adjust the dose.
Children. The use of the drug is contraindicated in children.
Overdose
Symptoms: metoprolol overdose can lead to a severe decrease in blood pressure, sinus bradycardia, atrioventricular block I-III degree, prolongation of the QT interval, asystole, insufficient peripheral perfusion, heart failure, cardiogenic shock, cardiac arrest, bronchospasm, respiratory depression or arrest, increased fatigue, impaired or loss of consciousness, tremor, convulsions, increased sweating, paresthesia, coma, nausea, vomiting, esophageal spasms, hypoglycemia (especially in children), hyperglycemia, cyanosis, effects on the kidneys and 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 due to
20 minutes to 2 hours after overdose.
Treatment is carried out in the intensive care unit. Administration of activated charcoal, if necessary - gastric lavage. In case of severe hypotension, bradycardia or threat of heart failure, a β1-agonist should be administered intravenously (for example, prenalterol) with an interval of 2-5 minutes, or by infusion until a therapeutic effect is achieved. In the absence of a selective β1-agonist, dopamine or atropine sulfate can be administered intravenously for vagal blockade. Atropine (0.25-0.5 mg for adults, 10-20 μg/kg body weight for children) should be administered before gastric lavage due to the risk of vagal stimulation. Incubation and use of an artificial respiration apparatus may be required; adequate restoration of circulating blood volume; glucose infusion; ECG monitoring; repeated intravenous administration of atropine 1-2 mg (mainly for vagal symptoms). If a therapeutic effect is not achieved, other sympathomimetics such as dobutamine or noradrenaline can be used.
Glucagon should also be administered at a dose of 50-150 mcg/kg body weight intravenously, as well as amrinone. In case of significant bradycardia that is refractory to drug therapy, an artificial cardiac pacemaker should be used. For relief of bronchospasm, intravenous
β2-agonist. It should be noted that the doses of antidotes required to eliminate the symptoms of β-blocker overdose are much higher than therapeutic, since β-receptors are bound
β-blockers.
In the case of generalized seizures, slow administration of diazepam is recommended.
Adverse reactions
The frequencies of adverse reactions are defined as follows: very common: > 1/10; common: > 1/100 - < 1/10; uncommon: > 1/1000 - < 1/100; rare: > 1/10000 - < 1/1000; very rare: < 1/10000; unknown: cannot be estimated from the available data.
Blood and lymphatic system disorders: Very rare: thrombocytopenia, leukopenia. Not known: agranulocytosis.
Metabolic and nutritional disorders: Uncommon: diabetes mellitus, exacerbation of diabetes mellitus. Very rare: weight gain. Not known: hypoglycaemia.
Psychiatric disorders: Uncommon: sleep disturbances, drowsiness, insomnia, nightmares, depression, concentration disorder, confusion, hallucinations. Rare: anxiety. Very rare: memory problems, amnesia, nervousness, personality changes, mood swings.
Nervous system disorders: Uncommon: dizziness, headache, paresthesia. Very rare: taste disturbance.
On the part of the organs of vision: Rare: dry eyes or conjunctivitis. Very rare: visual impairment.
Hearing and balance disorders: Very rare: sensation of noise/ringing in the ears, hearing impairment.
Cardiac disorders: Common: postural disorders (very rarely with dizziness), bradycardia. Uncommon: cold extremities, pericardial pain, chest pain, first-degree atrioventricular block, cardiogenic shock in patients with acute myocardial infarction. Rare: second- or third-degree atrioventricular block, transient worsening of heart failure symptoms, arrhythmias. Very rare: worsening of angina pectoris, cardiac conduction disorders, hypotension, palpitations.
Vascular disorders: Rare: hypotension, syncope. Very rare: gangrene in patients with pre-existing severe peripheral circulatory disorders, worsening of intermittent claudication. Not known: Raynaud's syndrome.
Respiratory, thoracic and mediastinal disorders: Uncommon: bronchospasm. Rare: dyspnoea on exertion, rhinitis.
Gastrointestinal: Uncommon: nausea, vomiting, abdominal pain, diarrhoea, constipation. Rare: dry mouth. Not known: heartburn.
Hepatobiliary system: Very rare: hepatitis.
Skin and subcutaneous tissue disorders: Uncommon: hypersensitivity reactions, including rash (in the form of psoriatic and dystrophic skin lesions), urticaria, pruritus, erythema, photosensitivity, increased sweating. Very rare: psoriasis, worsening of psoriasis, hair loss, allergic rhinitis. Not known: lipid metabolism disorders.
Musculoskeletal and connective tissue disorders: Rare: muscle spasms, muscle weakness. Very rare: arthritis.
Reproductive system and breast disorders: Very rare: impotence/sexual dysfunction, Peyronie's disease.
Renal and urinary disorders: Very rare: renal failure.
Laboratory parameters: Very rare: abnormal liver function tests. Not known: decreased high-density lipoprotein (HDL) cholesterol and increased triglycerides with normal total cholesterol, appearance of antinuclear antibodies (not associated with systemic lupus erythematosus).
Metoprolol can mask the symptoms of thyrotoxicosis and manifestations of latent diabetes mellitus.
Expiration date
3 years.
Do not use the drug after the expiration date indicated on the package!
Storage conditions
Store at a temperature not exceeding 30 ° C. Keep the medicine out of the reach of children.
Packaging
10 tablets in a blister; 3 or 5 blisters in a cardboard box.
Vacation category
According to the recipe.
Producer
BERLIN-CHEMI AG.
Location of the manufacturer and its business address
Glienicker Weg 125, 12489 Berlin, Germany.
