Thyrez - instructions for use, doses, side effects, contraindications

Excipients: glyceryl dibehenate 1.20 mg, calcium hydrophosphate 47.50 mg, silicon dioxide colloid 1.80 mg, crospovidone 3.60 mg, sodium lauryl sulfate 0.60 mg, microcrystalline cellulose 62.80 mg (for tablets 2.5 mg), or 60.30 mg (for tablets 5 mg), or 55.30 mg (for tablets 10 mg).

Sheath:

Tablets 2.5 mg: opadray white Y-1-7000 5.00 mg [hypromellose (E464) 3,1250 mg, macrogol 400 0.3125 mg, titanium dioxide (E171) 1.5625 mg].

Tablets 5 mg: opadray yellow 02 V 32859 5,00 mg [hypromellose (E464) 3,1250 mg, iron dye oxide yellow (E172) 0.0310 mg, macrogol 400 0.3125 mg, titanium dioxide (E171) 1.5315 mg].

Tablets 10 mg: opadray yellow 02 F 32202 5,00 mg [hypromellose (E464) 3.7433 mg, iron dye oxide yellow (E172) 0.1377 mg, macrogol 400 0.0535 mg, titanium dioxide (E171) 1.0695 mg].

Description:

Tablets 2.5 mg: round, biconcave tablets, covered with a film shell of white color, with a risk on one side. Cross-sectional view: white or almost white.

Tablets 5 mg: round, biconvex tablets, covered with a film coating of light yellow color, with a risk on one side. Cross-sectional view: white or almost white.

Tablets 10 mg: round, biconvex tablets, covered with a film coat of yellow with a weak brownish hue, with a risk on one side. Cross-sectional view: white or almost white.

Pharmacotherapeutic group:beta1-blocker selective

ATX: & nbsp

C.07.A.B Selective beta-blockers

C.07.A.B.07 Bisoprolol

Pharmacodynamics:

Selective beta₁-radic blocker, without its own sympathomimetic activity, does not possess membrane-stabilizing action. Reduces the activity of renin plasma, reduces the need for myocardium in oxygen, reduces the heart rate (heart rate) (at rest and with exercise).

Has antihypertensive, antiarrhythmic and anti-anginal action. Blocking in low doses 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, has a negative -chronic, dromo-, batmo-, and inotropic effect, inhibits conduction and excitability of the myocardium, slows AV-conduction.

When the dose is increased above the therapeutic dose, beta₂-adrenoblocking action.

The total peripheral vascular resistance (OPSS) at the beginning of the drug application, in the first 24 hours, increases (as a result of reciprocal increase, alpha-adrenergic receptor activity and elimination of beta stimulation₂-adrenoreceptors), which returns to the initial one after 1-3 days, and decreases with prolonged use.

Antihypertensive action is associated with a decrease in the minute volume of blood, sympathetic stimulation of peripheral vessels, a decrease in the activity of the renin-angiotensin-aldosterone system (important for patients with initial hypersecretion of renin), restoration of sensitivity in response to lowering blood pressure (BP) and affecting the central nervous system CNS). With arterial hypertension, the effect occurs after 2-5 days, a stable effect - after 1-2 months.

Antianginal action is caused by a decrease in myocardial oxygen demand as a result of a decrease in heart rate and a decrease in contractility, diastole lengthening, and improvement in myocardial perfusion. By increasing the end diastolic pressure in the left ventricle and increasing the stretching of the muscle fibers, the ventricles can increase the demand for myocardium in oxygen, especially in patients with chronic heart failure.

Antiarrhythmic action is caused by the elimination of arrhythmogenic factors (tachycardia,increased sympathetic nervous system activity, increased cAMP levels, hypertension), decrease the rate of spontaneous excitation of the sinus and ectopic pacemaker and deceleration AV-conducting (preferably antegrade and to a lesser extent, in the retrograde direction through the AV-node) and additional routes .

When used in average therapeutic doses, in contrast to non-selective beta-blockers, it exerts a less pronounced effect on organs containing beta₂-adrenoceptors (pancreas, skeletal muscles, smooth muscles of peripheral arteries, bronchial and uterine) and carbohydrate metabolism, does not cause delays sodium ions (Na +) in the body.

Pharmacokinetics:

Suction

Bisoprolol almost completely (> 90%) absorbed from the gastrointestinal tract (GIT), food intake does not affect absorption. Bisoprolol demonstrates linear kinetics, and its concentrations in the blood plasma are proportional to the administered dose in the range of 5 to 20 mg. The maximum concentration of bisoprolol in the blood plasma is reached after - 2-3 hours.

Distribution

The volume of distribution is 3.5 l / kg.The connection with blood plasma proteins is about 30%.

Metabolism

Metabolized by the oxidative pathway without subsequent conjugation; is slightly metabolized by the "first pass" through the liver (about 10-15%). All metabolites are polar. The main metabolites found in blood plasma and urine, do not show pharmacological activity. Data obtained as a result of experiments with microsomes of human liver in vitro, show that bisoprolol is metabolized, first of all, with the participation of the CYP3A4 isoenzyme (about 95%), and the CYP2D6 isoenzyme plays only a small role.

Excretion

Bisoprolol is excreted in two ways: 50% of the dose is metabolized in the liver with the formation of inactive metabolites; about 98% is excreted by the kidneys, 50% of them are unchanged, less than 2% - through the intestines (with bile). The total clearance is 12-18 l / h, and the renal clearance is 8-11 l / h, the half-life (T_1/2) - 10-12 h. Permeability through the blood-brain and placental barrier is low. The pharmacokinetics of bisoprolol is linear and does not depend on age. In patients with chronic heart failure, the plasma concentration of bisoprolol is higher, and T_1/2longer than in healthy volunteers.

Indications:

- Arterial hypertension;

- ischemic heart disease (prevention of attacks of stable angina);

chronic heart failure.

Contraindications:

- Hypersensitivity to bisoprolol or to any of the components drug and other beta-blockers;

- acute heart failure;

- chronic heart failure in the stage of decompensation, requiring application of intravenous ionotropic therapy;

- cardiogenic shock;

- AV blockade II and III degree, without pacemaker;

- syndrome of weakness of the sinus node;

- Sinoatrial blockade;

- pronounced bradycardia (heart rate <60 beats / min before the start of therapy);

- severe arterial hypotension (systolic blood pressure <100 mmHg);

- collapse;

- cardiomegaly (no signs of heart failure);

- severe forms of bronchial asthma and COPD in history;

- severe violations of peripheral circulation, Raynaud's syndrome;

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

metabolic acidosis;

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

- simultaneous administration of floktaphenin, sultopride;

- simultaneous intravenous administration of verapamil, diltiazem;

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

Carefully:

Desensitizing therapy; weighed allergic anamnesis; bronchospasm, in anamnesis (bronchial asthma, chronic obstructive pulmonary disease); a dose of 10 mg per day; angina of Prinzmetal; hyperthyroidism; Type 1 diabetes mellitus and diabetes mellitus with significant fluctuations in blood glucose concentration; AV-blockade of the 1st degree; marked renal failure (creatinine clearance less than 20 ml / min); severe liver dysfunction; psoriasis; restrictive cardiomyopathy; Congenital heart disease or heart valve disease with severe hemodynamic disorders; chronic heart failure with myocardial infarction during the last 3 months; pheochromocytoma (with concomitant use of alpha-blockers); violations of peripheral circulation (especially at the beginning of therapy); depression (including in the anamnesis); strict diet.

Pregnancy and lactation:

In pregnancy, the Tirez® drug should be recommended for use only if the benefit of treatment for the mother exceeds the risk of side effects in the fetus and / or the child.As a rule, beta-adrenoblockers reduce blood flow in the placenta and can affect the development of the fetus. It should monitor the blood flow in the placenta and uterus, as well as monitor the growth and development of the unborn child. In case of occurrence of undesirable phenomena concerning pregnancy and / or a fetus, to pass to alternative methods of therapy. In the case of beta-blockers during pregnancy, the newborn should be carefully screened after childbirth. In the first three days of life, bradycardia and hypoglycemia may occur.

There is no data on the isolation of bisoprolol in breast milk. Therefore, taking Tires® is not recommended during breastfeeding. If taking the drug during lactation is necessary, breastfeeding should be discontinued.

Dosing and Administration:

Inside, tablets should be taken with a small amount of liquid in the morning before breakfast, during or after it, once a day: The tablets should not be chewed or ground into powder.

Treatment with Tirez® is usually long-term and for each patient should be individual. Usually start with a low dose, which is gradually increased.If discontinuation of treatment is necessary, then the dosage of the drug should be reduced gradually.

Treatment of arterial hypertension and stable angina

In all patients, the dose is selected individually. Usually the initial dose is 5 mg once a day. The maintenance dose is 10 mg 1 time / day, the maximum recommended dose is 20 mg 1 time / day.

Treatment of chronic heart failure

The beginning of treatment of chronic heart failure requires mandatory carrying out of a special phase of titration and regular medical supervision. A prerequisite for treatment with Tirez® is stable chronic heart failure without signs of exacerbation in the previous six weeks; practically unchanged basic therapy in the previous two weeks; treatment with optimal doses of ACE inhibitors (or other vasodilators in case of intolerance to ACE inhibitors), diuretics and cardiac glycosides.

Treatment of chronic heart failure begins according to the scheme below, with individual adaptation depending on how well the patient tolerates the prescribed dose, i.е.The dose can be increased only if the previous dose is well tolerated. The recommended initial dose of Tirez® is 1.25 mg (1/2 tablet 2.5 mg) 1 time / day (1 week), with good tolerability, the dose is increased by 2.5 mg 1 time / day (2 weeks), with good tolerability dose increased by 3.75 mg 1 time / day (1¹/₂ 2.5 mg) (3 weeks), with good tolerability, the dose is increased by 5 mg once a day (4-7 weeks), with good tolerability, the dose is increased by 7.5 mg 1 time / day (1 tablet of 5 mg 1 tablet of 2.5 mg) (8-11 weeks), with good tolerability dose increased by 10 mg 1 time / day as maintenance therapy (12 weeks and beyond).

The maximum recommended dose of Tirez® in the treatment of chronic heart failure is 10 mg 1 time / day. If the increase in the dose of the drug is poorly tolerated by the patient, a dose reduction is possible. During titration, regular monitoring of blood pressure, heart rate and symptoms of chronic heart failure is recommended. The worsening of symptoms of chronic heart failure is possible already from the first day of application of the drug at a dose of 1.25 mg, therefore strict monitoring of the patient for 4 hours is required (heart rate control, blood pressure, conduction disorders, signs of deterioration of heart failure).During or after the titration phase, temporary deterioration in the course of chronic heart failure, arterial hypotension, or bradycardia may occur. In this case, it is recommended, first of all, to pay attention to the choice of the dose of concomitant standard therapy. It may also be necessary to temporarily reduce the dose of Tirez® or to cancel treatment. After stabilization of the patient's condition, a repeated titration of the dose should be performed, or the treatment should be continued. To date, there is insufficient data on the use of Tirez® in patients with chronic heart failure associated with type 1 diabetes mellitus, severe kidney and / or liver dysfunction, restrictive cardiomyopathy, congenital heart disease, hemodynamically significant heart disease. Also, until now, there has been insufficient data on patients with chronic heart failure with myocardial infarction during the last 3 months.

Dosage regimen for specific patient groups

Patients with impaired hepatic or renal function usually do not need to adjust the dose.

For patients with severe renal dysfunction (CC <20 ml / min) and liver the maximum daily dose of -10 mg 1 time / day.

When using the drug in elderly patients correction of the dose is not required.

Side effects:

The incidence of adverse reactions described below was determined according to the following classification:

- very often ≥ 1/10;

- often ≥1 / 100, <1/10;

- infrequently ≥ 1/1000, <1/100;

- rarely ≥ 1/10 000, <1/1000;

- very rarely <1/10 000.

From the side of the cardiovascular system

Very often: bradycardia (in patients with chronic heart failure).

Often: aggravation of symptoms of chronic heart failure (in patients with chronic heart failure), a feeling of cold or numbness in the limbs, a marked decrease in blood pressure, especially in patients with chronic heart failure.

Infrequent AV conduction disorder; bradycardia (in patients with hypertension or angina pectoris); exacerbation of symptoms of chronic heart failure (in patients with arterial hypertension or angina pectoris), orthostatic hypotension.

From the central nervous system

Often: dizziness, headache.

Rarely: loss of consciousness.

Mental disorders

Infrequently: depression, insomnia.

Rarely: hallucinations, nightmares.

From the side of the organ of vision

Rarely: decreased lacrimation (should be considered when wearing contact lenses).

Very rarely: conjunctivitis.

From the side of the hearing organ

Rarely: hearing impairment.

From the respiratory system

Infrequent: bronchospasm in patients with bronchial asthma or airway obstruction in anamnesis.

Rarely: allergic rhinitis.

From the digestive system

Often: nausea, vomiting, diarrhea, constipation.

Rarely: hepatitis.

From the side of the musculoskeletal system

Infrequently: muscle weakness, muscle cramps.

From the skin

Rarely: hypersensitivity reactions, such as pruritus, rash, hyperemia of the skin.

Very rarely: alopecia; beta-blockers can exacerbate the symptoms of psoriasis or cause a psoriasis-like rash.

From the side of the reproductive system

Rarely: a violation of potency.

Common violations

Often: asthenia (in patients with chronic heart failure), increased fatigue.

Infrequently: asthenia (in patients with hypertension or angina pectoris).

Laboratory indicators

Rarely: an increase in the concentration of triglycerides and the activity of "hepatic" transaminases in the blood (aspartate aminotransferase and alanine aminotransferase).

In patients with hypertension or angina, these symptoms appear more often at the beginning of the course of treatment, usually of a mild nature and usually take place within 1-2 weeks after the start of treatment.

Overdose:

Symptoms: severe bradycardia, arrhythmia, AV blockade, ventricular extrasystole, marked decrease in arterial pressure, difficulty breathing, bronchospasm, acute heart failure, cyanosis of fingernails or palms, dizziness, fainting, seizures, hypoglycemia.

Treatment: supportive and symptomatic therapy.

- With bradycardia - iv administration of atropine; temporary setting of an artificial pacemaker;

- with arterial hypotension - intravenous infusion of plasma-substituting solutions, vasopressor preparations;

- with AV block II or III degree - patients should be under constant supervision and receive treatment βadrenomimetics, such as epinephrine. If necessary, an artificial pacemaker;

- In case of exacerbation of heart failure, intravenous diuretics, inotropic vasodilating drugs must be administered;

- with bronchospasm - bronchodilators (isoprenaline), β₂sympatomimetics and / or aminophylline;

- with hypoglycemia - intravenous dextrose (glucose).

Interaction:

Treatment of arterial hypertension and stable angina

Unrecommended combinations

The blockers of the "slow" calcium channels of the verapamil group and, to a lesser extent, the diltiazem: a negative effect on the contractility of the myocardium and AV-conduction. Intravenous administration of verapamil in patients on beta-blocker therapy; can lead to the development of severe arterial hypotension and AV-blockade.

Hypotensive agents of central action, such as clonidine and others (eg, methyldopa, moxonidine, reserpine): lead to progression of heart failure due to a decrease in the central sympathetic tone (decrease in heart rate, cardiac output, vasodilation).Abrupt withdrawal of the drug, especially with the previous discontinuation of beta-adrenoblockers may lead to "ricochet hypertension."

Contraindicated combinations (because of the possibility of a decrease in activity) with floktaphenin, sultopride.

Combinations that should be used with caution

The blockers of "slow" calcium channels dihydropyridine series (for example, nifedipine, felodipine and amlodipine): lead to an increased risk of developing hypotension. Also, the risk of progressive deterioration of the contractile function of the ventricle in patients with heart failure can not be ruled out.

Antiarrhythmic drugs I class (for example, quinidine, disopyramide): AV-conduction is inhibited and negative inotropic effect is enhanced.

Antiarrhythmic drugs III class (for example, amiodarone): increase AV-conduction.

Beta-blockers of topical application (eg, eye drops for the treatment of glaucoma): strengthen the systemic effects of bisoprolol.

Parasympathomimetic means: have a negative effect on AV-conduction and promote bradycardia.

Insulin or hypoglycemic agents for ingestion: reinforcement hypoglycemic effect. Blockade of beta-adrenoreceptors can mask the symptoms of developing hypoglycemia (tachycardia, increased blood pressure).

Means for anesthesia: weaken the reflex tachycardia and enhance antihypertensive effect.

Cardiac glycosides: reduce heart rate, slow down AV-conduction.

Nonsteroidal anti-inflammatory drugs: weaken the hypotensive effect of bisoprolol.

Beta-sympathomimetics (for example, isoprenaline, dobutamine): lead to a weakening of the effects of both drugs.

Sympathomimetic agents acting on beta and alpha receptors (eg, epinephrine, norepinephrine): they cry and strengthen the alpha-adrenomimetic vasoconstrictor effect of these drugs, which leads to an increase in blood pressure and exacerbation of intermittent claudication. These interactions are more common when combined with nonselective beta-blockers.

Hypotensive drugs and drugs with hypotensive potential (eg, tricyclic antidepressants, imipramine, MAO inhibitors such as phenelzine barbiturate, phenothiazines such as chlorpromazine): reinforce antihypertensive effect.

Combinations that need to be considered

Mefloquine: increases the risk of bradycardia.

Monoamine oxidase inhibitors (except MAO inhibitor type B): increase the antihypertensive effect of beta-blockers or the risk of hypertensive crisis.

Derivatives of ergotamine: strengthen the symptoms of peripheral circulatory disorders

Treatment of chronic heart failure

Unrecommended combinations

The blockers of the "slow" calcium channels of the verapamil group and, to a lesser extent, diltiazem: a negative effect on the contractility of the myocardium and AV-conduction. Intravenous administration of verapamil in patients on beta-blocker therapy can lead to severe arterial hypotension and AV blockade.

Antiarrhythmic drugs I class (for example, quinidine, disopyramide, lidocaine, phenytoin, flecainide, propafenone): AV-conduction is inhibited and negative inotropic effect is enhanced.

Hypotensive means of central action, such as clonidine and others (for example, methyldopa, moxonidine, reserpine): lead to progression of heart failure due to a decrease in the central sympathetic tone (decrease in heart rate, cardiac output, vasodilation). Abrupt withdrawal of the drug, especially with the previous discontinuation of beta-blockers, can lead to "ricochet hypertension."

Contraindicated combinations (because of the possibility of a decrease in activity) with floktaphenin, sultopride.

Combinations that should be used with caution

The blockers of "slow" calcium channels dihydropyridine series (for example, nifedipine, felodipine and amlodipine): lead to an increased risk of developing hypotension. Also, the risk of progressive deterioration of the contractile function of the ventricle in patients with heart failure can not be ruled out.

Antiarrhythmic drugs III class (for example, amiodarone): increase AV-conductivity.

Beta-blockers topical application (eg, eye drops for the treatment of glaucoma): strengthen the systemic effects of bisoprolol.

Parasympathomimetic means: have a negative effect on AV-conduction and promote bradycardia.

Insulin or hypoglycemic agents for oral administration: increased hypoglycemic effect. Blockade of beta-adrenoreceptors can mask the symptoms of developing hypoglycemia (tachycardia, increased blood pressure).

Means for anesthesia: weaken the reflex tachycardia and enhance antihypertensive effect.

Cardiac glycosides: reduce heart rate, slow down AV-conduction.

Non-steroidal anti-inflammatory drugs: weaken the hypotensive effect of bisoprolol.

Beta-sympathomimetics (for example, isoprenaline, dobutamine): lead to a weakening of the effects of both drugs.

Sympathomimetic drugs, acting on beta and alpha receptors (for example, adrenaline, noradrenaline): cause and intensify the alpha-adrenomimetic vasoconstrictor effect of these drugs, which leads to an increase in blood pressure and exacerbation of intermittent claudication. These interactions are more common when combined with nonselective beta-blockers.

Hypotensive drugs and drugs with hypotensive potential (eg, tricyclic antidepressants, imipramine, MAO inhibitors, such as phenelzine, barbiturates, phenothiazines, such as chlorpromazine): increase the antihypertensive effect.

Combinations that need to be considered

Mefloquine: increases the risk of bradycardia.

Monoamine oxidase inhibitors (except MAO type B inhibitor): increase the antihypertensive effect of beta-adrenoblockers or the risk of hypertensive crisis.

Derivatives of ergotamine: enhance the symptoms of peripheral circulatory disorders.

Special instructions:

Control of patients receiving bisoprolol, should include monitoring of heart rate and blood pressure (at the beginning of treatment - every day, then once every 3-4 months), ECG, blood glucose concentration in patients with diabetes mellitus (1 every 4-5 months). In elderly patients it is recommended to follow the function of the kidneys (once every 4-5 months). After the beginning of treatment of chronic heart failure in a dose of 1.25 mg the patient should be examined within 4 hours (heart rate, blood pressure, ECG).

It is necessary to teach the patient how to calculate heart rate and instruct about the need for medical consultation at a heart rate of less than 60 beats / min.

Before the start of treatment, it is recommended to perform an external respiration function in patients with a history of bronchopulmonary anamnesis.

Approximately in 20% of patients with angina pectoris beta-adrenoblockers are ineffective. The main causes are severe coronary atherosclerosis with a low threshold of ischemia (heart rate less than 100 beats / min) and an increased LV BW disturbing subendocardial blood flow.

In "smokers" the effectiveness of beta-blockers is lower.

Patients who use contact lenses should take into account that, on the background of treatment, tear fluid production can be reduced.

In patients undergoing general anesthesia, beta-adrenoblockers reduce the risk of arrhythmia and myocardial ischemia during induction and intubation, and the postoperative period. Patients are not recommended to stop taking a maintenance dose of beta-blockers in the perioperative period. Before surgery, the anesthesiologist should be informed of the treatment with beta-blockers due to possible interaction with other drugs that can lead to bradyarrhythmia, weakening of reflex tachycardia, and a decrease in the ability to compensate for blood loss. If it is necessary to abolish beta-blockers before surgery, the dose should be gradually reduced and finished at 48 hours before anesthesia.

There is no therapeutic experience with bisoprolol in patients in the treatment of heart failure with the following diseases and conditions:

- NYHA class II heart failure;

- Type 1 diabetes mellitus (insulin-dependent);

- renal dysfunction (serum creatinine> 300 μmol / l);

- violations of the liver function;

- Patients over the age of 80;

- restrictive cardiomyopathy;

- Congenital heart disease;

- heart valve diseases that disrupt hemodynamics;

- less than 3 months after the transferred myocardial infarction.

It is not recommended simultaneous use of bisoprolol with calcium channel blockers of verapamil and diltiazem group with class I antiarrhythmics and antihypertensive drugs of central action.

In bronchial asthma or other chronic obstructive pulmonary diseases that can cause symptoms, it is necessary to prescribe bronchodilators simultaneously with beta-adrenoblockers. In the event of an increase in airway resistance, which may occur in patients with asthma, it may be necessary to increase the dose of beta₂-stimulators.

Like other beta-blockers, bisoprolol can increase the patient's sensitivity to allergens and the severity of anaphylactic reactions. Treatment with adrenaline does not always lead to the expected therapeutic effect.

Patients with psoriasis can be assigned beta-blockers only after a careful balance between benefit and risk.

With thyrotoxicosis bisoprolol can mask certain clinical signs of thyrotoxicosis (eg, tachycardia). Abrupt withdrawal in patients with thyrotoxicosis is contraindicated, since it can strengthen symptoms.

When used in patients with pheochromocytoma, there is a risk of developing paradoxical arterial hypertension (unless an effective alpha-adrenoblockade has been previously achieved).

In diabetes mellitus can mask tachycardia caused by hypoglycemia. In contrast to non-selective beta-blockers, it does not substantially increase insulin-induced hypoglycemia and does not delay the restoration of glucose concentration in the blood to a normal value.

With the simultaneous administration of clonidine, its administration can be stopped only a few days after the withdrawal of bisoprolol.

Reciprocal activation of the vagus nerve can be eliminated by intravenous administration of atropine (1-2 mg).

Drugs that reduce catecholamine stores (for example, reserpine), can enhance the action of beta-blockers, so patients who take such combinations of drugs should be under constant observation of the doctor for the diagnosis of arterial hypotension or bradycardia.

If older bradycardia (less than 50 beats per minute), arterial hypotension (systolic BP below 100 mmHg), AV blockade, bronchospasm, ventricular arrhythmias, severe impairment of liver and kidney function occur in elderly patients, it is necessary to reduce the dose or stop treatment .

It is recommended to stop therapy with the development of depression caused by the use of beta-blockers.

Possible positive result of anti-doping control in treatment bisoprolol.

It should be abolished before the study of blood and urine levels of catecholamines, normetanephrine and vanillylmandelic acid; titers of antinuclear antibodies.

Bisoprolol treatment can not be abruptly discontinued because of the risk of developing severe arrhythmias and myocardial infarction.Abolition is carried out gradually, reducing the dose for 2 weeks or more (reduce the dose by 25% in 3-4 days).

Features of actions when missing one or more doses of the drug:

Take the missed dose as soon as you establish an omission. If there are less than 8 hours left until the next dose is received, the intake should be skipped and continue treatment as usual. Do not take a double dose to replace the missed drug intake.

Effect on the ability to drive transp. cf. and fur:

During the treatment with Tirez®, caution should be exercised when driving vehicles and engaging in other potentially hazardous activities requiring increased attention and speed of psychomotor reactions.

Form release / dosage:

Film coated tablets, 2.5 mg, 5 mg and 10 mg.

Packaging:

10 tablets per blister perforated from aluminum foil and transparent three-layer film (PVC / TE / PVDC).

3 blisters (30 tablets), along with instructions for use, are placed in a cardboard box.

Storage conditions:

Store in the original packaging at a temperature not exceeding 25 ° C.

Keep out of the reach of children.

Shelf life:

Tablets 2.5 mg: 2 years.

Tablets 5 mg and 10 mg: 3 years.

Do not use after expiry date.

Terms of leave from pharmacies:On prescription

Registration number:LP-000983

Date of registration:18.10.2011

Date of cancellation:2016-10-18

The owner of the registration certificate:Alkaloid, JSCAlkaloid, JSC Macedonia

Manufacturer: & nbsp

ALKALOID, AD Macedonia

Representation: & nbspALKALOID, AOALKALOID, AO

Information update date: & nbsp26.11.2015

Illustrated instructions

Instructions

Thyrez® (Tirez® )