Universal reference book for medicines
Name of the preparation: EHILOK ® S (EGILOK ® S)

Active substance: metoprolol succinate

Type: Beta 1- blocker

Manufacturer: EGIS Pharmaceuticals (Hungary) manufactured by INTAS PHARMACEUTICALS (India)
Composition, form of production and packaging
Tablets of prolonged action, covered with a film coating of
white color, oval, biconcave, with a risk on both sides.

1 tab.

metoprolol succinate 25 mg,

which corresponds to the content of metoprolol 23.75 mg

Excipients: microcrystalline cellulose - 73.9 mg, methylcellulose - 11.87 mg, glycerol - 0.24 mg, corn starch - 1.94 mg, ethylcellulose - 11.43 mg, magnesium stearate - 1.87 mg.

Composition of the film sheath: sepiphilm LP 770 white - 3.75 mg (microcrystalline cellulose 5-15%, hypromellose 60-70%, stearic acid 8-12%, titanium dioxide (E171) 10-20%).

10 pieces.
- blisters (3) - packs of cardboard.
10 pieces.
- blisters (10) - packs of cardboard.
Tablets of prolonged action, covered with a film coating of white color, oval, biconcave, with a risk on both sides.

1 tab.

metoprolol succinate 50 mg,

which corresponds to the content of metoprolol 47.5 mg

Excipients: microcrystalline cellulose - 147.8 mg, methyl cellulose - 23.75 mg, glycerol - 0.48 mg, corn starch - 3.87 mg, ethyl cellulose - 22.85 mg, magnesium stearate - 3.75 mg.

The composition of the film sheath: sepiliphil LP 770 white - 7.5 mg (microcrystalline cellulose 5-15%, hypromellose 60-70%, stearic acid 8-12%, titanium dioxide (E171) 10-20%).

10 pieces.
- blisters (3) - packs of cardboard.
10 pieces.
- blisters (10) - packs of cardboard.
Tablets of prolonged action, covered with a film coating of white color, oval, biconcave, with a risk on both sides.

1 tab.

metoprolol succinate 100 mg,

which corresponds to the content of metoprolol 95 mg

Excipients: microcrystalline cellulose - 295.6 mg, methylcellulose - 47.5 mg, glycerol - 0.95 mg, corn starch - 7.75 mg, ethyl cellulose - 45.7 mg, magnesium stearate - 7.5 mg.

Composition of the film sheath: LP 770 septiphilic white - 15 mg (microcrystalline cellulose 5-15%, hypromellose 60-70%, stearic acid 8-12%, titanium dioxide (E171) 10-20%).

10 pieces.
- blisters (3) - packs of cardboard.
10 pieces.
- blisters (10) - packs of cardboard.
Tablets of prolonged action, covered with a film coating of white color, oval, biconcave, with a risk on both sides.

1 tab.

metoprolol succinate 200 mg,

which corresponds to the content of metoprolol 190 mg

Excipients: microcrystalline cellulose - 591.2 mg, methylcellulose - 95 mg, glycerol - 1.9 mg, corn starch - 15.5 mg, ethyl cellulose - 91.4 mg, magnesium stearate - 15 mg.

Composition of the film sheath: septiphilm LP 770 white - 30 mg (microcrystalline cellulose 5-15%, hypromellose 60-70%, stearic acid 8-12%, titanium dioxide (E171) 10-20%).

10 pieces.
- blisters (3) - packs of cardboard.
10 pieces.
- blisters (10) - packs of cardboard.
INSTRUCTION FOR THE SPECIALIST.

Description of the drug approved by the manufacturer for the printed edition of 2016.

PHARMACHOLOGIC EFFECT

Beta 1- blocker blocking?
1- adrenoreceptors at doses significantly lower than the doses required for blocking? 2- adrenoreceptors.
Metoprolol has an insignificant membrane-stabilizing effect and does not exhibit the activity of a partial agonist.

Metoprolol reduces or inhibits the agonistic effect that catecholamines exerted on nervous activity by nervous and physical stresses on cardiac activity.
This means that metoprolol has the ability to interfere with the increase in heart rate, minute volume and increased cardiac contractility, as well as increased blood pressure caused by a sharp release of catecholamines.
Unlike conventional tableted medicinal forms of selective beta- 1- adrenoceptor blockers (including metoprolol tartrate), when metoprolol succinate is prolonged, a constant plasma concentration of the drug is observed and a stable clinical effect (beta 1- adrenoblockade) is maintained for more than 24 hours. Due to the lack of significant maximum concentrations in blood plasma, the drug is characterized by a higher?
1- selectivity in comparison with conventional tableted forms of metoprolol. In addition, the potential risk of side effects observed at maximum drug concentrations in the blood plasma, for example, bradycardia and weakness in the legs when walking, is significantly reduced. Patients with symptoms of obstructive pulmonary disease, if necessary, can be prescribed metoprolol succinate prolonged action in combination with beta 2 -adrenomimetics. When co-administered with beta 2 -adrenomimetics, metoprolol sustained-release succinate in therapeutic doses has less effect on the bronchodilation induced by beta 2 -adrenomimetics than non-selective beta-blockers.
Metoprolol, to a lesser extent than non-selective beta-blockers, affects insulin production and carbohydrate metabolism.
The effect of the drug on the cardiovascular system in conditions of hypoglycemia is much less pronounced in comparison with nonselective beta-blockers.
The use of the drug with arterial hypertension leads to a significant decrease in blood pressure for more than 24 hours, both in the supine and standing position, and under physical exertion.
At the beginning of metoprolol therapy, an increase in vascular resistance is noted. However, with prolonged admission, a decrease in blood pressure is possible due to a decrease in vascular resistance with a constant cardiac output.
PHARMACOKINETICS

Suction

In each tablet metoprolol succinate prolonged action contains a large number of micro pellets (pellets), allowing a controlled release of metoprolol succinate.
Outside, each micro pellet (pellet) is coated with a polymer coating, which allows for a controlled release of the drug substance.
The effect of prolonged tablets comes quickly.
In the GIT, the tablet disintegrates into separate micro pellets that act as independent units and provide a uniform controlled release of metoprolol (zero order kinetics) for more than 20 hours. The release rate of the active substance depends on the acidity of the medium. The duration of the therapeutic effect after taking the drug in the dosage form of the sustained-release tablet is more than 24 hours.
The drug is completely absorbed after ingestion.
Systemic bioavailability after oral administration of a single dose is approximately 30-40%.
Metabolism and distribution

Metoprolol is subjected to oxidative metabolism in the liver.
The three main metabolites of metoprolol showed no clinically significant beta-adrenergic blocking effect. About 5% of the dose for oral administration is excreted by the kidneys unchanged, the rest of the drug is excreted as metabolites. Binding to plasma proteins is low, about 5-10%.
Excretion

T 1/2 of free metoprolol averages 3.5-7 hours.

INDICATIONS

- arterial hypertension;

- angina pectoris;

- stable chronic heart failure with the presence of clinical manifestations (II-IV functional class according to the NYHA classification) and violation of systolic function of the left ventricle (as an auxiliary therapy to the main treatment of chronic heart failure);

- reduction in mortality and frequency of recurrent myocardial infarction after an acute phase of myocardial infarction;

- violations of the heart rhythm, including supraventricular tachycardia, a reduction in the frequency of ventricular contraction in atrial fibrillation and ventricular extrasystoles;

- functional disorders of cardiac activity, accompanied by tachycardia;

- prevention of migraine attacks.

DOSING MODE

The drug is intended for daily administration 1 time / day, it is recommended to take the drug in the morning.
The tablet should be swallowed with a liquid. Tablets (or tablets, divided in half) should not be chewed or crushed. Eating does not affect the bioavailability of the drug.
When choosing a dose, it is necessary to avoid the development of a bradycardia.

Arterial hypertension

Assign 50-100 mg 1 time / day.
If necessary, the dose can be increased to 200 mg / day or add another antihypertensive agent, preferably a diuretic and a blocker of slow calcium channels. The maximum daily dose is 200 mg.
Angina pectoris

Assign 100-200 mg 1 time / day.
If necessary, another antianginal drug may be added to the therapy.
Stable chronic heart failure with the presence of clinical manifestations and a violation of the systolic function of the left ventricle

Patients should be in the stage of stable chronic heart failure without episodes of exacerbation during the last 6 weeks and without changes in the main therapy within the last 2 weeks.

The therapy of chronic heart failure with beta-adrenoblockers can sometimes lead to a temporary worsening of the course of chronic heart failure.
In some cases, it is possible to continue therapy or reduce the dose, in some cases it may be necessary to cancel the drug.
Stable chronic heart failure, II functional class

The recommended initial dose of the drug in the first 2 weeks is 25 mg 1 time / day.
After 2 weeks of therapy, the dose can be increased to 50 mg once a day, and then can be doubled every 2 weeks.
The maintenance dose for long-term treatment is 200 mg 1 time / day.

Stable chronic heart failure, III-IV functional class

The recommended initial dose in the first 2 weeks is 12.5 mg 1 time / day.
The dose is selected individually. During the period of increasing the dose, the patient should be under observation, since In some patients, the symptoms of chronic heart failure may progress. After 1-2 weeks, the dose can be increased to 25 mg 1 time / day. Then, after 2 weeks, the dose can be increased to 50 mg 1 time / day. Patients who tolerate the drug well can double their dose every 2 weeks until the maximum dose of 200 mg is reached 1 time / day.
In the case of arterial hypotension and / or bradycardia, you may need to adjust the doses of the main therapy or reduce the dose of the drug.
Arterial hypotension at the beginning of therapy does not necessarily indicate that this dose will not be tolerated with further long-term treatment. However, an increase in the dose is only possible after stabilization of the patient's condition. You may need to monitor kidney function.
Heart rhythm disturbances

Assign 100-200 mg 1 time / day.

Supportive treatment after myocardial infarction

The target dose is 100-200 mg / day, in 1 or 2 divided doses.

Functional disorders of cardiac activity, accompanied by tachycardia

Assign 100 mg 1 time / day.
If necessary, the dose can be increased to 200 mg / day.
Preventing migraine attacks

Assign 100-200 mg 1 time / day.

Special patient groups

There is no need to adjust the dose in patients with impaired renal function.

If the liver function is impaired, usually because of the low degree of communication with plasma proteins, correction of the dose of the drug is not required.However, with a severe impairment of liver function (in patients with severe cirrhosis or portocaval anastomosis), a dose reduction may be required.

There is no need to adjust the dose in elderly patients .

SIDE EFFECT

The drug is well tolerated by patients, side effects are mostly light and reversible.

The following criteria were used to assess the incidence of cases: very often (> 10%), often (1-9.9%), infrequently (0.1-0.9%), rarely (0.01-0.09%) and very rarely (<0.01%).

From the cardiovascular system: often - bradycardia, orthostatic hypotension (very rarely accompanied by syncope), cold extremities, palpitations;
infrequent - peripheral edema, pain in the heart, temporary increase in symptoms of heart failure, AV-blockade I degree, cardiogenic shock in patients with acute myocardial infarction; rarely - other disorders of cardiac conduction, arrhythmia; very rarely - gangrene in patients with previous severe impairment of peripheral circulation.
From the side of the central nervous system: very often - increased fatigue;
often - dizziness, headache; infrequently - paresthesia, convulsions, depression, loss of attention, drowsiness or insomnia, nightmares; rarely - increased nervous excitability, anxiety, impotence / sexual dysfunction; very rarely - amnesia / memory disorders, depression, hallucinations.
From the digestive system: often - nausea, abdominal pain, diarrhea, constipation;
infrequently - vomiting; rarely - dryness of the oral mucosa, impaired liver function;very rarely - hepatitis.
From the skin: rarely - rash (in the form of urticaria), increased sweating;
rarely - hair loss; very rarely - photosensitivity, exacerbation of psoriasis.
From the respiratory system: often - shortness of breath with physical effort;
infrequently bronchospasm; rarely rhinitis.
From the senses: rarely - visual impairment, dryness and / or eye irritation, conjunctivitis;
very rarely - ringing in the ears, a violation of taste.
From the musculoskeletal system: very rarely - arthralgia.

Other: infrequently - weight gain;
very rarely - thrombocytopenia.
CONTRAINDICATIONS

- AV blockade II and III degree;

- heart failure in the stage of decompensation;

- patients receiving long-term or course therapy with inotropic agents and acting on β-adrenoceptors;

- clinically significant sinus bradycardia (heart rate <50 bpm);

- SSSU;

- cardiogenic shock;

- severe violations of peripheral circulation with the threat of gangrene;

- arterial hypotension (systolic blood pressure <90 mm Hg);

- pheochromocytoma without simultaneous administration of alpha-blockers;

- suspected acute myocardial infarction at a heart rate <45 bpm;

- the interval PQ> 0.24 s;

- systolic blood pressure <100 mm Hg;

- simultaneous use of MAO inhibitors (with the exception of MAO inhibitors type B);

- intravenous administration of blockers of slow calcium channels such as verapamil;

- age under 18 years (effectiveness and safety not established);

- Hypersensitivity to metoprolol, other components of the drug or to other beta-blockers.

With caution:
AV-blockade of the first degree, angina Prinzmetal, bronchial asthma, COPD, diabetes mellitus, severe renal failure, severe hepatic insufficiency, metabolic acidosis, simultaneous use with cardiac glycosides, myasthenia gravis, pheochromocytoma (with simultaneous administration of alpha-adrenoblockers), thyrotoxicosis, depression, psoriasis, obliterating diseases of peripheral vessels (intermittent claudication, Raynaud's syndrome), elderly age.
PREGNANCY AND LACTATION

Since no well-controlled studies on the use of metoprolol in pregnancy have been conducted, the use of Egilok® C in the treatment of pregnant women is possible only if the benefit to the mother exceeds the risks for the embryo / fetus.

Like other antihypertensives, beta-blockers can cause side effects, for example, bradycardia in the fetus, newborns or breastfed babies.
The amount of metoprolol released into breast milk and the beta-adrenergic blocking effect in a breastfed infant (when metoprolol is taken by the mother at therapeutic doses) are minor. Despite the fact that in children who are breast-feeding, with the appointment of therapeutic doses of the drug, the risk of side effects is low (except for children with metabolic disorders), it is necessary to carefully monitor the appearance of signs of blockade of? -adrenoceptors.
APPLICATION FOR FUNCTIONS OF THE LIVER

With caution should prescribe the drug for chronic kidney failure.

In elderly patients, patients with impaired renal function , and if hemodialysis is necessary, a change in the dosage regimen is not required.

APPLICATION FOR VIOLATIONS OF THE FUNCTION OF KIDNEYS

With caution should prescribe the drug for liver failure.

In patients with impaired liver function, the dose of the drug should be selected individually depending on the clinical condition.

APPLICATION FOR CHILDREN

Contraindicated: age under 18 years (efficacy and safety not established).

APPLICATION IN ELDERLY PATIENTS

Caution should be given to elderly patients.

SPECIAL INSTRUCTIONS

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

Patients with obstructive pulmonary disease should not be prescribed beta-blockers.
In case of poor tolerability of other antihypertensive drugs or their ineffectiveness, metoprolol can be prescribed, since it is a selective drug. It is necessary to prescribe a minimally effective dose, if necessary, the appointment of beta 2 -adrenomimetics.
It is not recommended to prescribe non-selective beta-blockers to patients with Prinzmetal angina.
To this group of patients selective beta-blockers should be administered with caution.
When using beta 1 -adrenoblokatorov the risk of their effect on carbohydrate metabolism or the ability to mask symptoms of hypoglycemia is significantly less than with the use of nonselective beta-blockers.

In patients with chronic heart failure in the stage of decompensation, it is necessary to achieve a compensation stage both before and during treatment with the Egilok® C preparation.

Very rarely, patients with AV-conduction disorder may experience deterioration (a possible outcome is AV blockade).
If bradycardia develops against the background of treatment, the dose of Egilok ® C should be reduced or the drug should be gradually withdrawn.
Metoprolol may worsen the symptoms of peripheral circulatory disorders mainly due to lowering blood pressure.

Care should be taken when prescribing the drug to patients with severe renal failure, metabolic acidosis, co-administration with cardiac glycosides.

In patients taking beta-adrenoblockers, anaphylactic shock occurs in a more severe form.
The use of epinephrine in therapeutic doses does not always lead to the desired clinical effect against metoprolol.
Patients with pheochromocytoma, simultaneously with the preparation Egilok ® C should be prescribed alpha-blocker.

In the case of surgery should inform the anesthetist that the patient is taking Egilok ® C patients undergoing surgery, discontinue treatment for beta-blockers is not recommended.
These clinical studies for efficacy and safety in patients with severe stable heart failure patients (IV class NYHA classification) are limited.
Patients with symptoms of heart failure in combination with acute myocardial infarction and unstable angina were excluded from the study, which were determined on the basis of the indications. Efficacy and safety has not been described for this group of patients. Application for heart failure decompensation contraindicated.
Abrupt withdrawal of beta-blockers may exacerbate the symptoms of congestive heart failure and increased risk of myocardial infarction and sudden death, especially in high-risk patients, and therefore, should be avoided. If necessary, drug withdrawal, should be carried out gradually, over a period of at least 2 weeks, with a twofold decrease in dose at each stage, to achieve a final dose of 12.5 mg, which should be at least 4 days prior to complete withdrawal of the drug. If you have symptoms it is recommended a slower withdrawal of the drug regime.
Impact on the ability to drive vehicles and manage mechanisms

Caution should be exercised when driving and classes of potentially hazardous activities that require high concentration, due to the risk of dizziness and fatigue when using the drug Egilok ® S.
OVERDOSE

symptoms:an overdose of metoprolol most serious are the symptoms of the cardiovascular system, but sometimes, especially in children and adolescents, may predominate symptoms of the central nervous system and the suppression of lung function, bradycardia, AV-blockade of I-III degree, asystole, marked reduction in blood pressure, poor peripheral perfusion, cardiac failure, cardiogenic shock; inhibition of lung function, sleep apnea, as well as fatigue, altered mental status, loss of consciousness, tremors, convulsions, sweating, paresthesia, bronchospasm, nausea, vomiting, possible esophageal spasm, hypoglycaemia (especially in children) or hyperglycaemia, hyperkalaemia, dysfunction kidney transient myasthenic syndrome; concomitant use of alcohol, antihypertensives, quinidine or barbiturates may aggravate the patient's condition.The first signs of overdose can be observed after 20 min-2 hr after dosing.
Treatment: The purpose of the activated charcoal, if necessary gastric lavage.
Atropine (0.25-0.5 mg / in adults, 10-20 mg / kg for children) should be assigned to gastric lavage (due to the risk of stimulation of the vagus nerve). If necessary to maintain airway patency (intubation) and adequate ventilation. Volume replacement and glucose infusion. ECG monitoring. Atropine 1.2 mg / in repeated administration (particularly in the case of vagal symptoms) as necessary. In the case of (suppression) myocardial depression shown dobutamine infusion or dopamine. It is also possible to apply the glucagon 50-150 .mu.g / kg / in intervals of 1 min. In some cases it may be effective to add therapy epinephrine (adrenaline). If ventricular fibrillation and expanded (QRS) complex is administered by infusion of 0.9% sodium chloride or sodium hydrogencarbonate. The possibility of setting an artificial pacemaker.In cardiac arrest due to an overdose may require resuscitation measures for several hours. Terbutaline can be used for relief of bronchospasm (injection or by inhalation). Symptomatic treatment.
DRUG INTERACTION

Metoprolol is a substrate for the isoenzyme CYP2D6, and therefore, drugs that inhibit isoenzyme CYP2D6 (quinidine, terbinafine, paroxetine, fluoxetine, sertraline, celecoxib, propafenone and diphenhydramine) may affect the plasma concentration of metoprolol.
Avoid joint use drug Egilok ® C with the following drugs
derivatives of barbituric acid: barbiturates (study was conducted with pentobarbital) increase metoprolol metabolism due to enzyme induction.
propafenone:propafenone when assigning the four patients treated with metoprolol, metoprolol showed an increase in the plasma concentration of 2-5, with two patients had side effects typical of metoprolol. Probably due to inhibition of the interaction of propafenone, like quinidine, metoprolol metabolism by cytochrome P450 isoenzyme CYP2D6. Taking into account the fact that propafenone has the properties of a beta blocker, metoprolol, and co-administration of propafenone is not recommended.
verapamil:a combination of beta-blockers (atenolol, propranolol and pindolol) and verapamil may cause bradycardia and lead to a reduction in blood pressure. Verapamil and beta-blockers have mutually inhibitory effect on the AV-conduction and sinus node function.
Combination preparation Egilok ® C with the following medications may require correction dose
Amiodarone: concomitant use of amiodarone and metoprolol may lead to severe sinus bradycardia. Taking into account the extremely long T 1/2 amiodarone (50 days), you should take into account possible interactions take place some time after discontinuation of amiodarone.
Class I antiarrhythmic agents:antiarrhythmics of class I and beta-blockers can lead to the summation of negative inotropic effect, which may lead to serious adverse hemodynamic effects in patients with impaired left ventricular function. You should also avoid such a combination in patients with sick sinus syndrome and AV-conduction disorder.
The reaction described in Example disopyramide.
Nonsteroidal anti-inflammatory drugs (NSAIDs): NSAIDs weaken the antihypertensive effect of beta-blockers. This reaction is documented for indomethacin. Probably described interaction will not be marked by reaction with sulindac. Negative interaction has been observed in studies with diclofenac.
diphenhydramine:Diphenhydramine reduces the metabolism of metoprolol before? -gidroksimetoprolola 2.5 times. At the same time strengthening the metoprolol action observed.
Diltiazem: Diltiazem and beta-blockers reinforce inhibitory effect on AV-conduction and sinus node function. With the combination of metoprolol with diltiazem there were cases of severe bradycardia.
epinephrine:It reported 10 cases of severe hypertension and bradycardia in patients treated with non-selective beta-adrenergic blockers (including pindolol and propranolol) and treated with epinephrine. The interaction observed in healthy volunteers group. It is assumed that similar reactions may occur and the application of epinephrine with local anesthetic together with a random contact with the bloodstream. It is expected that this risk is much lower with cardioselective beta-blockers.
phenylpropanolamine:phenylpropanolamine (norephedrine) a single dose of 50 mg may cause an increase in diastolic blood pressure to pathological values in healthy volunteers. Propranolol generally prevents the increase in blood pressure caused by phenylpropanolamine. However, beta-blockers can cause paradoxical reaction of hypertension in patients receiving high doses of phenylpropanolamine. It reported several cases of hypertensive crisis while taking phenylpropanolamine.
quinidine:quinidine inhibits the metabolism of metoprolol in a special group of patients with rapid hydroxylation (in Sweden about 90% of the population), causing mostly a significant increase in the plasma concentration of metoprolol and increased beta-adrenoblockade. It is believed that this interaction is typical for other beta-blockers, metabolism involving isozyme CYP2D6.
Clonidine: hypertensive reactions during abrupt cancellation of clonidine may be increased when co-administered beta-blockers. In a joint application, in the case of clonidine, discontinuation of beta-blockers should start several days before clonidine.
rifampicin:rifampicin may enhance metabolism of metoprolol, reducing the plasma concentration of metoprolol. Patients concurrently taking metoprolol and other beta blockers (in the dosage form of eye drops) or MAO inhibitors must be monitored closely. While taking beta-blockers, inhalation anesthetics enhance cardiodepressive action. While taking beta-blockers to patients receiving hypoglycemic agents for oral administration, may need a dose adjustment last.
The plasma concentrations of metoprolol may increase when receiving cimetidine or hydralazine .
Cardiac glycosides when used in conjunction with beta-blockers may increase the AV-conduction time and induce bradycardia.
TERMS OF RELEASE FROM PHARMACY

The drug is released by prescription.

TERMS AND CONDITIONS OF STORAGE

The drug should be stored out of reach of children at a temperature of no higher than 30 ° C.
Shelf life - 3 years. Do not use after the expiration date printed on the package.
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