Metoprolol - instructions for use, dose, side effects, contraindications

Excipients: lactose monohydrate (milk sugar) - 180,0 mg, cellulose microcrystalline - 62.0 mg, croscarmellose sodium - 16.0 mg, sodium carboxymethyl starch 12,0 mg, povidone (polyvinylpyrrolidone) - 16.0 mg, magnesium stearate - 8.0 mg, silicon dioxide colloid - 6.0 mg.

Description:

Tablets are white or white with a grayish shade of color, round, flat, with a risk on one side and a facet on both sides.

Pharmacotherapeutic group:beta1-blocker selective

ATX: & nbsp

C.07.A.B Selective beta-blockers

C.07.A.B.02 Metoprolol

Pharmacodynamics:

Cardioselective blocker of β-adrenergic receptors,has an insignificant membrane-stabilizing effect and does not possess internal sympathomimetic activity.

It has antihypertensive, antianginal and antiarrhythmic action. Blocking low-dose beta-adrenoreceptors of the heart, reduces catecholamine-stimulated formation of cyclic adenosine monophosphate (cAMP) from adenosine triphosphate (ATP), reduces the intracellular current of calcium ions (Ca²⁺), has a negative chrono-, dromo-, batmo- and inotropic effect (urezhaet heart rate (heart rate), inhibits conduction and excitability, reduces myocardial contractility).

The total peripheral vascular resistance at the beginning of beta-blockers (in the first 24 hours after oral administration) increases (as a result of a reciprocal increase in the activity of alpha-adrenergic receptors and elimination of stimulation beta₂-adrenoreceptors), which returns to the original one 1-3 days later, and decreases with a long value.

Antihypertensive action is due to a decrease in cardiac output and renin synthesis, inhibition of renin-angiotensin-aldosterone system (RAAS) activity (important in patients with initial renin hypersecretion) and central nervous system,restoration of the sensitivity of the aortic arch baroreceptors (there is no increase in their activity in response to a decrease in blood pressure) and, ultimately, a decrease in peripheral sympathetic influences. Reduces elevated blood pressure (BP) at rest, with physical stress and stress.

Antianginal effect is determined by a decrease in myocardial oxygen demand as a result of a decrease in the heart rate (diastole elongation and improvement of myocardial perfusion) and contractility, as well as a decrease in myocardial sensitivity to sympathetic innervation. Reduces the number and severity of angina attacks and increases the tolerance of exercise.

Arterial pressure decreases after 15 minutes, maximum - after 2 hours and lasts for 6 hours, diastolic blood pressure changes more slowly: a stable decrease is observed after several weeks of regular intake.

Antiarrhythmic effect is caused by elimination of arrhythmogenic factors (tachycardia, increased activity of the sympathetic nervous system, increased cAMP, arterial hypertension),a decrease in the rate of spontaneous excitation of sinus and ectopic pacemakers and slowing of atrioventricular conduction (predominantly in the antegrade and, to a lesser extent, retrograde directions through the AV node) and along additional pathways. With supraventricular tachycardia, atrial fibrillation, sinus tachycardia in functional heart diseases and hyperthyroidism, it decreases the heart rate, or even can lead to the restoration of sinus rhythm.

Prevents the development of migraine.

When used in average therapeutic doses, in contrast to non-selective beta-blockers, it exerts a less pronounced effect on organs containing beta₂- adrenergic receptors (pancreas, skeletal muscles, smooth muscles of peripheral arteries, bronchi and uterus) and carbohydrate metabolism.

With many years of intake reduces the concentration of cholesterol in the blood.

When used in large doses (more than 100 mg / day) has a blocking effect on both subtypes of beta adrenoreceptors.

Pharmacokinetics:

Suction

Ingestion metoprolol almost completely absorbed (about 95%) from the gastrointestinal tract.Food intake increases bioavailability by 20-40%. It is subjected to intensive presystemic metabolism, therefore the system bioavailability is about 35%. The maximum concentration in the blood plasma is achieved after 1.5-2 hours after ingestion.

Distribution

Relationship with plasma proteins 12%. The volume of distribution is 5.6 l / kg. Penetrates through the blood-brain and placental barrier. Excreted in breast milk in small amounts.

Metabolism

Metoprolol is almost completely metabolized in the liver, mainly with the participation of the CYP2D6 isoenzyme. The half-life is between 3 and 4 hours, but in patients with "slow" metabolism it can increase up to 7-8 hours. Metabolites of o-desmethylmethoprolol and a-hydroxymethoprolol have a weak beta-adrenergic blocking activity.

Excretion

It is excreted mainly by the kidneys (about 95%), about 10% is excreted unchanged. It is not excreted by hemodialysis.

In patients with cirrhosis of the liver and portocaval anastomosis bioavailability increases, and clearance decreases. In patients with portocaval anastomosis, the AUC (area under the concentration-time curve) can increase by a factor of 6, and the clearance can be reduced to 0.3 ml / min.

Indications:

- Arterial hypertension (in monotherapy or in combination with other antihypertensive drugs);

- functional disorders of cardiac activity, accompanied by tachycardia;

- Ischemic heart disease: myocardial infarction (secondary prevention - complex therapy), prevention of angina attacks;

- heart rhythm disturbances (supraventricular tachycardia, ventricular extrasystole);

- hyperthyroidism (complex therapy);

- prevention of migraine attacks.

Contraindications:

- Hypersensitivity to metoprolol or other ingredients of the drug;

- lactose intolerance, lactase deficiency and glucose-galactose malabsorption syndrome;

- cardiogenic shock;

- atrioventricular blockade (AV) of II and III degree (without artificial pacemaker);

- Sinoatrial blockade;

- syndrome of weakness of the sinus node;

- pronounced bradycardia (heart rate (heart rate) less than 50 bpm);

severe violations of peripheral circulation;

- heart failure in the stage of decompensation;

- bronchial hyperreactivity (for example, in severe bronchial asthma patients receiving permanent or intermittent therapy with inotropic drugs acting on beta-adrenergic receptors,chronic obstructive pulmonary disease (COPD) in the acute stage);

- Prinzmetal angina;

- arterial hypotension (in the case of secondary prevention of myocardial infarction - systolic blood pressure less than 100 mm Hg);

- with suspected acute myocardial infarction (heart rate is less than 45 beats per minute, PQ interval is more than 0.24 seconds or systolic blood pressure is less than 100 mmHg);

- pheochromocytoma (without simultaneous use of alpha-blockers);

- the period of breastfeeding;

- simultaneous intravenous administration of blockers of "slow" calcium channels like verapamil (see section "Interaction with other drugs");

- simultaneous administration of monoamine oxidase inhibitors (MAO) (see section "Interaction with other drugs");

- age under 18 years (efficiency and safety not established).

Carefully:

Diabetes mellitus, metabolic acidosis, impaired liver function and / or renal impairment (creatinine clearance (CC) of less than 40 ml / min), myasthenia gravis, AV block I degree, thyrotoxicosis, depression (including history), psoriasis, allergic reactions anamnesis (possibly increased sensitivity to allergens,weighting of arterial hypertension and decreased therapeutic response to adrenaline), bronchial asthma, chronic obstructive pulmonary disease, emphysema, chronic obstructive bronchitis, obliterating peripheral vascular disease ("intermittent" lameness, Raynaud's syndrome), elderly age.

See also "Special instructions".

Pregnancy and lactation:

In pregnancy Metoprolol appoint only according to strict indications if the intended benefit to the mother exceeds the potential risk to the fetus (due to the possible development of fetal bradycardia, arterial hypotension, hypoglycemia). Beta-adrenoblockers reduce the permeability of the placenta, which can lead to premature birth or fetal death.

The risk of complications from the heart and lungs increases in the postpartum period in those newborns whose mothers receive metoprolol. The drug should be discontinued 48-72 hours before delivery. In cases where this is not possible, it is necessary to ensure strict observation of newborns within 48-72 hours after birth.

Metoprolol is excreted in breast milk.Children who are breastfed should be under medical supervision in connection with the possible development of the blockade symptoms of beta-adrenergic receptors.

If it is necessary to use the drug Metoprolol breastfeeding is recommended to be canceled.

Dosing and Administration:

A drug Metoprolol should be taken orally, during or immediately after meals, the tablets can be divided in half (but not chewed) and washed down with liquid.

Arterial hypertension:

The initial daily dose is 50-100 mg in 1-2 doses (in the morning and in the evening) (1/2 tablets of 100 mg - 1 tablet). With insufficient therapeutic effect, the daily dose can be increased to 100-200 mg or additionally used other antihypertensive drugs. The maximum daily dose is 200 mg.

With arrhythmia, for the prevention of attacks of angina and migraine:

100-200 mg per day in two divided doses (morning and evening).

Secondary prevention of myocardial infarction:

200 mg per day in two divided doses (morning and evening).

Functional disorders of cardiac activity, accompanied by tachycardia:

100 mg per day in two divided doses (morning and evening).

With hyperthyroidism - 150-200 mg per day in 2 divided doses (morning and evening).

Elderly patients it is recommended to begin treatment with 50 mg (1/2 tablets of 100 mg) per day.

In case of violations of kidney function no dose adjustment is required.

With hepatic insufficiency a dose adjustment may be required depending on the clinical condition of the patient.

If there is a need to interrupt or stop treatment with the drug Metoprolol after prolonged therapy, the dosage of the drug should be gradually reduced by 2 times for a minimum of 2 weeks.

When there is a syndrome of "cancellation", the dose reduction should be slower. A sharp discontinuation of the drug may cause myocardial ischemia and may lead to an exacerbation of the course of angina pectoris or myocardial infarction, and also to increase arterial hypertension.

Side effects:

The incidence of side effects is classified according to the recommendations of the World Health Organization: very often - not less than 10%; often - not less than 1%, but less than 10%; infrequently - not less than 0,1%, but less than 1%; rarely - not less than 0.01%, but less than 0.1%; very rarely - less than 0.01%.

From the hematopoietic system: very rarely - thrombocytopenia, leukopenia.

From the side of the cardiovascular system: often - sinus bradycardia, postural disorders (very rarely accompanied by syncope), "cooling" of the limbs, a feeling of palpitations; infrequently - a temporary increase in symptoms of heart failure, atrioventricular blockade of the I degree; cardiogenic shock in patients with acute myocardial infarction, peripheral edema, pain in the heart; rarely - other violations of myocardial conductivity, arrhythmia; very rarely - gangrene in patients with previous severe impairment of peripheral circulation.

From the nervous system: very often - increased fatigue; often - headache, dizziness; infrequently - paresthesia, convulsions, depression, decreased concentration, drowsiness or insomnia, nightmares; rarely - increased nervous excitability, anxiety, impotence / sexual dysfunction, Peyronie's disease; very rarely - amnesia / memory impairment, depression, hallucinations.

From the sense organs: rarely - visual impairment, dryness and / or eye irritation, conjunctivitis, hearing impairment and tinnitus.

From the digestive system: often - nausea, abdominal pain, diarrhea, constipation; infrequently - vomiting; rarely dryness of the oral mucosa; very rarely - a violation of taste.

From the side of the liver: rarely - violations of the liver, increased activity of "liver" transaminases; very rarely - hepatitis.

From the skin: infrequently - hives, increased sweating; rarely - alopecia; very rarely - photosensitivity, exacerbation of psoriasis.

From the respiratory system: often shortness of breath with physical effort; infrequently bronchospasm; rarely rhinitis.

From the endocrine system: rarely hypo-, hyperglycemia in patients with type 1 diabetes mellitus, masking the symptoms of thyrotoxicosis.

From the side of the musculoskeletal system: very rarely - arthralgia.

From the side of metabolism: infrequently - weight gain; rarely - aggravation of the course of latent diabetes mellitus.

Laboratory indicators: very rarely - a decrease in the concentration of high-density cholesterol and an increase in triglycerides in blood plasma.

Overdose:

Symptoms: severe sinus bradycardia, dizziness, nausea, vomiting, cyanosis, marked decrease in arterial pressure, arrhythmia, ventricular extrasystole, bronchospasm, syncope, with acute overdose - cardiogenic shock, loss of consciousness, coma,atrioventricular block (up to the development of complete transverse blockade and cardiac arrest), cardialgia, hypoglycemia, hyperkalemia, convulsions, respiratory arrest.

The first signs of an overdose appear after 20 minutes-2 hours after taking the drug. In case of an overdose or a threatening decrease in heart rate and / or blood pressure, medication Metoprolol must be discontinued immediately.

Treatment: gastric lavage and the appointment of absorbents; symptomatic therapy: with a marked reduction in blood pressure - the patient should be in the Trendelenburg position; in the case of excessive reduction in blood pressure, bradycardia and heart failure - in / in, with an interval of 2-5 minutes; beta-adrenomimetics - to achieve the desired effect or iv in 0.5-2 mg of atropine. In the absence of a positive effect - dopamine, dobutamine or norepinephrine (norepinephrine).

As a follow-up, it is possible to stage an artificial pacemaker. When bronchospasm should be introduced in / in beta₂-adrenomimetics. Metoprolol poorly excreted by hemodialysis.

Interaction:

It is not recommended simultaneous use with monoamine oxidase (MAO) inhibitors due to a significant increase in antihypertensive action. A break in treatment between taking MAO inhibitors and metoprolol should be at least 14 days.

Beta-adrenostimulants, theophylline, cocaine, estrogens (sodium retention), indomethacin and other non-steroidal anti-inflammatory drugs (sodium retention and blockage of prostaglandin synthesis by the kidneys) weaken the antihypertensive effect of metoprolol.

With simultaneous application with hypoglycemic agents for oral administration, a decrease in their effect is possible; with insulin - increased risk of developing hypoglycemia, increasing its severity and duration; masking of some symptoms of hypoglycemia (tachycardia / increased sweating, increased blood pressure).

With simultaneous use with antihypertensive agents, diuretics, angiotensin converting enzyme inhibitors, nitroglycerin or blockers of "slow" calcium channels, a sharp drop in blood pressure may develop (special caution is necessary when combined with prazosin); the risk increasesBradycardia when combined with mefloquine; marked decrease in blood pressure and bradycardia when combined with epinephrine; expressed reduction in heart rate and inhibition of atrioventricular conduction up to complete blockade - with metoprolol with verapamil, diltiazem, reserpine, methyldopa, clonidine, guanfacin and cardiac glycosides, for general anesthesia (along with cardiodepressive and antihypertensive effects).

Simultaneous iv injection of verapamil may provoke cardiac arrest.

Drugs that induce or inhibit the isoenzyme CYP2D6 can affect the concentration of metoprolol in the blood plasma. The concentration of metoprolol in the blood plasma may increase with simultaneous administration with other drugs that are a substrate for the isoenzyme CYP2D6, for example, antiarrhythmic drugs, antihistamines, antagonists H₂-receptors, antidepressants (selective serotonin reuptake inhibitors, for example, paroxetine, fluoxetine, sertraline), neuroleptics and cyclooxygenase-2 inhibitors.

Class I antiarrhythmic drugs can lead to a negativeinotropic effect with the development of severe hemodynamic side effects in patients with left ventricular dysfunction (this combination should be avoided in patients with sinus node weakness syndrome and atrioventricular conduction disorder).

Quinidine inhibits metabolism of metoprolol in patients with "fast" metabolism, leading to a significant increase in the concentration of metoprolol in the blood plasma and enhancing its beta-adrenergic blocking effect.

The combination with amiodarone increases the risk of pronounced sinus bradycardia (including after a long time after the abolition of amiodarone, due to its long half-life).

If metoprolol and clonidine take simultaneously, then with the cancellation of metoprolol clonidine cancellation after a few days (due to the risk of the syndrome of "withdrawal").

Inductors of microsomal liver enzymes (rifampicin, barbiturates) lead to increased metabolism of metoprolol, a decrease in the concentration of metoprolol in the blood plasma and a decrease in the effect. Inhibitors (cimetidine, oral contraceptives, phenothiazines) - increase the concentration of metoprolol in the blood plasma.

Diphenhydramine reduces the clearance of metoprolol, enhancing its effect.

Simultaneous use with high doses of phenylpropanolamine can lead to a paradoxical increase in blood pressure (right up to the hypertensive crisis).

Allergens used for immunotherapy, or allergen extracts for skin tests when combined with metoprolol increase the risk of systemic allergic reactions or anaphylaxis; iodine-containing radiopaque substances for intravenous administration increase the risk of developing anaphylactic reactions.

Reduces the clearance of xanthines (except diphylline), especially in patients with initially elevated clearance of theophylline under the influence of smoking.

Reduces the clearance of lidocaine, increases the concentration of lidocaine in the blood plasma.

Strengthens and prolongs the effect of antidepolarizing, muscle relaxants; prolongs the anticoagulant effect of coumarins.

When combined with anxiolytics and drugs with hypnotics, the antihypertensive effect is enhanced, with the risk of a marked decrease in blood pressure increased with ethanol and the inhibitory effect on the central nervous system increases.

There is an increased risk of peripheral circulatory disorders - with ergot alkaloids.

Special instructions:

Patients taking beta-blockers should not be administered intravenously blockers of "slow" calcium channels such as verapamil.

Monitoring the condition of patients taking beta-blockers includes regular monitoring of heart rate (heart rate) and blood pressure, blood glucose concentration in patients with diabetes mellitus.

If necessary, for patients with diabetes, the dose of insulin or hypoglycemic drugs administered orally should be selected individually.

It is necessary to teach the patient how to calculate heart rate and instruct about the need for medical consultation at heart rate less than 50 beats per minute.

When taking a dose above 200 mg per day, cardioselectivity decreases.

With heart failure, metoprolol treatment is started only after reaching the compensation stage.

Patients with Prinzmetal angina are not recommended to prescribe non-selective beta-blockers.

It is possible to intensify the severity of hypersensitivity reactions (against the background of a weighed allergic anamnesis) and the absence of the effect of the administration of usual doses of epinephrine (adrenaline).

In patients taking beta-adrenoblockers, anaphylactic shock occurs in a more severe form.

It can intensify the symptoms of peripheral arterial circulation.

Cancellation of the drug is carried out gradually, reducing the dose for 14 days. With a sharp cessation of treatment, there may be a "cancellation" syndrome (an increase in angina attacks, an increase in blood pressure). Particular attention should be paid to patients with angina when the drug is withdrawn.

With angina pectoris, the selected dose of the drug should provide a heart rate at rest in the range of 55-60 beats / min, with a load - no more than 110 beats / min.

Patients who use contact lenses should take into account that against the background of treatment with beta-adrenoblockers, tear production can be reduced.

Metoprolol may mask certain clinical manifestations of hyperthyroidism (eg, tachycardia). Sharp abolition in patients with thyrotoxicosis is contraindicated, as it can strengthen symptoms.

In diabetes mellitus can mask tachycardia caused by hypoglycemia. In contrast to nonselective beta-blockers, it does not actually increase insulin-inducedhypoglycemia and does not delay the restoration of blood glucose to normal levels.

If it is necessary to appoint patients with bronchial asthma as a concomitant therapy, therapy should be prescribed beta_2-adrenomimetic. It is necessary to prescribe a minimally effective dose of metoprolol, and an increase in dose may be required beta₂-adrenomimetics.

Patients with pheochromocytoma, in parallel with the drug Metoprolol, it is necessary to appoint an alpha-blocker.

If it is necessary to perform a surgical procedure, it is necessary to warn the anesthesia doctor about the therapy (choice of a means for general anesthesia with minimal negative inotropic action), the drug cancellation is not recommended.

It should avoid the appointment of high doses of metoprolol immediately without prior titration to patients undergoing non-cardiac surgery, as in patients with cardiovascular risk factors it was associated with bradycardia, arterial hypotension and stroke, including fatalities.

Drugs that reduce catecholamine stocks (for example, reserpine), can enhance the action of beta-blockers, so patients taking such combinations of drugs should be under constant observation of the doctor for the detection of excessive reduction in blood pressure or bradycardia.

In elderly patients, it is recommended to regularly monitor liver function.

Correction of the dosing regimen is required only if older bradycardia develops in the elderly (less than 50 beats per minute), a marked decrease in blood pressure (systolic blood pressure below 100 mm Hg), atrioventricular blockade, bronchospasm, ventricular arrhythmias, severe liver function disorders . Sometimes it is necessary to stop treatment.

Patients with severe renal insufficiency are advised to exercise control.

Special monitoring of the condition of patients with depressive disorders taking Metoprolol; In the case of depression, caused by the use of beta-blockers, it is recommended to stop therapy.

Effect on the ability to drive transp. cf. and fur:During the period of therapy, care must be taken when driving vehicles and engaging in other potentially hazardous activities,requiring increased concentration of attention and speed of psychomotor reactions.

Form release / dosage:

Tablets, 100 mg.

Packaging:

For 10, 25, 30 tablets in a contour mesh box made of polyvinylchloride film and aluminum foil printed lacquered.

For 10, 20, 25, 30, 40, 50, 60, 70, 80, 90 or 100 tablets in cans of polyethylene terephthalate for medicinal products or polymeric cans for medicinal products.

One jar or 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 contour mesh packages together with the instruction for use are placed in a cardboard package.

Storage conditions:

In a dry, the dark place at a temperature of no higher than 25 ° C.

Keep out of the reach of children.

Shelf life:

3 years.

Do not use after the expiration date.

Terms of leave from pharmacies:On prescription

Registration number:LP-001760

Date of registration:02.07.2012 / 22.09.2015

Expiration Date:02.07.2017

The owner of the registration certificate:OZONE, LLC OZONE, LLC Russia

Manufacturer: & nbsp

OZONE, LLC Russia

Representation: & nbspOZONE LLC OZONE LLC Russia

Information update date: & nbsp24.07.2016

Illustrated instructions

Instructions

Metoprolol (Metoprolol )