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

Excipients: calcium dihydrogen phosphate 53.42 mg, microcrystalline cellulose 20.62 mg, corn pregelatinized corn starch 5.16 mg, croscarmellose sodium 1.76 mg, silicon dioxide colloid 0.77 mg, magnesium stearate 0.77 mg;

composition of the shell: Opadrai II white 3.50 mg: lactose monohydrate 1.26 mg, hypromellose 0.98 mg, titanium dioxide (E 171) 0.92 mg, macrogol - 4000 0.34 mg.

Description:Round, biconvex tablets, covered with a film shell of white color, with a risk on one side and engraving "BIS 2.5 "on the other side.

Pharmacotherapeutic group:beta1-blocker selective

ATX: & nbsp

C.07.A.B Selective beta-blockers

C.07.A.B.07 Bisoprolol

Pharmacodynamics:

Selective beta₁- adrenoblocker, without its own sympathomimetic activity, does not possess membrane-stabilizing action.

Reduces the activity of renin in the blood plasma, reduces the need myocardium in oxygen, reduces or reduces the heart rate (heart rate) (at rest and under load). Has antihypertensive and antianginal action. Blocking in low doses of beta₁-adrenoceptors 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 chrono-, dromo-, batmo- and inotropic action (inhibits conduction and excitability, slows the atrioventricular conductivity).

If the therapeutic dose is exceeded, beta₂-adrenoblocking action.

The total peripheral vascular resistance at the beginning of the drug application, in the first 24 hours, increases somewhat (as a result of the reciprocal increase in the activity of alpha-adrenergic receptors and the elimination of beta stimulation₂-adrenoreceptors), returns to the initial value in 1-3 days, and decreases with long-term administration.

Antihypertensive effect 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 develops in 2-5 days, stable effect - after 1-2 months.

Antianginal effect is caused by a decrease in myocardial oxygen demand as a result of a decrease in heart rate, a slight decrease in contractility, diastole lengthening, and improvement in myocardial perfusion.

By increasing the final diastolic pressure in the left ventricle and increasing the stretching of the ventricular muscle fibers, the need for oxygen may increase, especially in patients with chronic heart failure (CHF).

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

Pharmacokinetics:

Suction. Bisoprolol almost completely (more than 90%) is absorbed from the gastrointestinal tract (GIT). Its bioavailability due to a slight effect of "primary passage" through the liver (at about 10%) is about 90% after ingestion. Eating does not affect bioavailability. Bisoprolol demonstrates linear kinetics, and its concentrations in the blood plasma are proportional to the dose taken in the range of 5 to 20 mg. The maximum concentration in the blood plasma is achieved in 2-3 hours.

Distribution. Bisoprolol is characterized by a wide distribution. The volume of distribution is 3.5 l / kg. The connection with plasma proteins is approximately 30%.

Metabolism. Metabolized by the oxidative pathway without subsequent conjugation. All metabolites are polar (water-soluble) and excreted by the kidneys. The main metabolites found in blood plasma and urine, do not have pharmacological activity. Data obtained as a result of experiments with microsomes of human liver in vitro, show that bisoprolol is metabolized primarily by isoenzyme CYP3A4 (about 95%), and isoenzyme CYP2D6 plays only a small role.

Excretion. Bisoprolol is characterized by a balanced clearance: about 50% is excreted by the kidneys unchanged, about 50% is metabolized in the liver to inactive metabolites, which are then excreted by the kidneys. The total ground clearance is 15 liters per hour. The half-life is 10-12 hours.

In patients with chronic heart failure, plasma concentrations of bisoprolol are higher, and the half-life is longer than in healthy volunteers.

The pharmacokinetics of bisoprolol in patients with CHF and simultaneous impairment of liver or kidney function has not been studied.

Indications:Chronic heart failure.

Contraindications:

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

- acute heart failure and chronic heart failure in the stage of decompensation, requiring intravenous inotropic therapy;

- cardiogenic shock;

- collapse;

- atrioventricular (AV) blockade II and III degree, without a pacemaker;

- syndrome of weakness of the sinus node;

- sinoatrial blockade;

- severe bradycardia (heart rate less than 60 beats / min before treatment);

- severe arterial hypotension (systolic blood pressure less than 90 mm Hg);

- cardiomegaly (no signs of heart failure);

- severe forms of bronchial asthma and chronic obstructive pulmonary disease (COPD) in history;

- severe peripheral circulatory disturbances;

- Raynaud's syndrome;

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

- metabolic acidosis;

- concomitant use of floktaphenin and sultopride;

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

- age to 18 years (efficacy and safety not established).

Carefully:

Bronchospasm (bronchial asthma, obstructive airway disease) holding desensitizing therapy, Prinzmetal angina, disorders of the peripheral circulation (at the beginning of therapy may be increased symptoms), general anesthesia, hyperthyroidism, diabetes type 1 and diabetes with considerable fluctuations in blood glucose concentration , AV blockade I extent, myasthenia gravis, severe renal failure (creatinine clearance of creatinine clearance less than 20 mL / min), severe liver dysfunction, psoriasis, restrictive cardiomyopathy, congenital heart defects or hemodynamically significant valvular heart disease, chronic heart failure, myocardial infarction within the past 3 months, depression (including history), pheochromocytoma (with simultaneous use of alpha-blockers), a strict diet, allergic history.

Pregnancy and lactation:

Bisoprolol does not have direct cytotoxic, mutagenic and teratogenic effects, but it has pharmacological effects that can have harmful effects on the course of pregnancy and / or on the fetus or newborn. Usually beta-adrenoblockers reduce placental perfusion, which leads to a slowing of fetal growth, fetal death, miscarriage or premature birth. The fetus and the newborn child may experience pathological reactions, such as intrauterine growth retardation, hypoglycemia, bradycardia.

Biol® should not be used during pregnancy, it can only be used if the benefit to the mother exceeds the risk of side effects in the fetus and / or the baby. When treatment with Biol® is considered necessary, blood flow in the placenta and uterus should be monitored, as well as fetal growth and development, and, if pregnancy and / or fetal adverse events occur, take alternative therapies . You should carefully examine the newborn after delivery.Symptoms of hypoglycemia and bradycardia usually arise during the first 3 days of life.

Breastfeeding period

There is no data on the penetration of bisoprolol into breast milk. Therefore, the use of Biol® is not recommended for women during lactation.

If you need to use the drug during lactation, breastfeeding should be discontinued.

Dosing and Administration:

Biol® tablets should be taken orally once a day with a small amount of liquid in the morning before breakfast, during or after it, without chewing.

In all cases, the regimen and dosage are selected by the doctor for each patient individually, in particular, taking into account the heart rate and the patient's condition.

The initiation of treatment with CHF with Biol® requires a special phase of titration and regular medical supervision. A prerequisite for treatment with Biol® is stable chronic heart failure without signs of decompensation.

Treatment of CHF with Biol® begins with the following titration scheme. In this case, individual adaptation may be required,how well the patient tolerates the prescribed dose, i.e., the dose can be increased only if the previous dose is well tolerated.

To ensure the appropriate titration process at the initial stages of treatment, it is recommended to use the drug in smaller doses.

1st week:	1.25 mg of Biol (1/2 tablet) once a day
2nd week:	2.5 mg of Biol (1 tablet) once a day
3rd week:	3.75 mg of Biol (1 and 14 tablets) once a day
4-th - 7-th week:	5 mg of Biol (2 tablets) once a day
8th -11th week:	7.5 mg of Biol (3 tablets) once a day
12th week of therapy and further:	10 mg Biol® (4 tablets) once a day as a supportive

If the increase in the dose of the drug is poorly tolerated by the patient, a dose reduction is possible.

The maximum daily dose for CHF is 10 mg of Biol ® once a day.

At a daily dose of 10 mg, Biol® can be used with a dosage of 5.0 mg or 10.0 mg.

During titration, regular monitoring of blood pressure, heart rate and symptoms of increased severity of CHF is recommended. The aggravation of the symptoms of CHF is possible from the first day of the drug.

During the titration phase or after it, temporary deterioration of the course of CHF, arterial hypotension or bradycardia may occur. In this case, it is recommended, first of all, to correct the doses of concomitant therapy. It may also be necessary to temporarily reduce the dose of Biol® or to cancel it. Treatment with Biol® should be discontinued only if absolutely necessary. After stabilization of the patient's condition, a titration of the dose should be repeated or Biol® should be restored if the drug was withdrawn.

Duration of treatment

Treatment of CHF with Biol® is usually prolonged.

Treatment should not be interrupted suddenly, especially in patients with ischemic heart disease. If discontinuation of treatment is necessary, then the dosage of the drug should be reduced gradually.

Special patient groups

Impaired renal or hepatic function:

- if a mild or moderate degree of hepatic or renal dysfunction is not usually required, the dose of Biol® should not be adjusted.

- with severe renal dysfunction (CC less than 20 ml / min) and in patients with severe liver disease the maximum daily dose is 10 mg.Increasing the dose in such patients should be carried out with extreme caution.

Elderly patients: correction of the dose is not required.

To date, there is insufficient data on the use of Biol ® in patients with CHF in combination with type 1 diabetes mellitus, severe renal and / or liver dysfunction, restrictive cardiomyopathy, congenital heart disease or heart valve disease with severe hemodynamic impairment. Also, sufficient data have not yet been obtained regarding patients with CHF with myocardial infarction during the last 3 months.

Side effects:

The incidence of adverse reactions listed below was determined according to the following (World Health Organization classification); 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%, including individual reports.

From the side of the cardiovascular system

Often: loss of heart rate (bradycardia, especially in patients with CHF), palpitations.

Often: marked decrease in blood pressure (especially in patients with CHF),aggravation of symptoms of CHF flow, manifestation of angiospasm (increased peripheral circulatory disturbance, chill sensation in the extremities (paresthesia).

Infrequently: violation of AV conduction (up to the development of complete transverse blockade and cardiac arrest), arrhythmias, orthostatic hypotension, chest pain.

From the nervous system

Often: dizziness, headache, asthenia, fatigue, sleep disorders, depression, anxiety.

Rarely: confusion or short-term memory loss, "nightmarish" dreams, hallucinations, myasthenia gravis, tremor, muscle cramps.

Usually, these phenomena are of an easy nature and usually pass within 1-2 weeks after the start of treatment.

From the sense organs

Rarely: impaired vision, reduced tearing (should be taken into account when wearing contact lenses), tinnitus, hearing loss, ear pain.

Rarely: dryness and soreness of the eyes, conjunctivitis, taste disorders.

From the respiratory system

Infrequently: bronchospasm in patients with bronchial asthma or obstructive airways diseases.

Rarely: allergic rhinitis, nasal congestion.

From the digestive system

Often: nausea, vomiting, diarrhea, constipation, dryness of the oral mucosa, abdominal pain.

Rarely: hepatitis, increased activity of "hepatic" transaminases (alanine aminotransferase (ALT), aspartate aminotransferase (ACT)), increased bilirubin concentration.

From the side of the musculoskeletal system

Infrequently: arthralgia, back pain.

From the skin

Rarely: increased sweating, skin hyperemia, exanthema, psoriasis-like skin reactions.

Rarely: alopecia, beta-blockers can aggravate the course of psoriasis.

Allergic reactions

Rarely: itching, rash, hives.

From the genitourinary system

Rarely: a violation of potency, a weakening of the libido.

Laboratory indicators

Rarely: increase in the concentration of triglycerides in the blood.

In some cases: thrombocytopenia, agranulocytosis, and leukopenia.

Other

The syndrome of "withdrawal" (increased frequency of angina attacks, increased blood pressure).

Overdose:

Symptoms

Arrhythmia, ventricular extrasystole, pronounced bradycardia, atrioventricular block,marked decrease in blood pressure acute heart failure, hypoglycemia, acrocyanosis, difficulty breathing, bronchospasm, dizziness, fainting, convulsions. The sensitivity to a single intake of a high dose of bisoprolol is marked by significant interindividual variability, and patients with CHF may have high sensitivity.

Treatment

In case of an overdose, first of all, stop taking the drug, rinse the stomach, prescribe adsorptive drugs and start supporting symptomatic therapy: with the developed atrioventricular blockade, intravenous injection of 1-2 mg of atropine, epinephrine or the setting of a temporary pacemaker; with ventricular extrasystole - lidocaine (preparations IA class do not apply); with severe bradycardia - intravenous atropine, with insufficient effect with caution, you can enter a drug that has a positive chronotropic effect, it may also require a temporary setting of an artificial pacemaker; with a marked decrease in blood pressure - the patient should be in the Trendelenburg position; if notsigns of pulmonary edema - plasma-substituting solutions intravenously, with inefficiency - the introduction of epinephrine, dopamine, dobutamine (to maintain chronotropic and inotropic action and eliminate the pronounced decrease in blood pressure); with an exacerbation of the course of CHF - intravenous injection of diuretics, drugs with a positive inotropic effect, as well as vasodilators; with convulsions - intravenously diazepam; when bronhospazme - the appointment of bronchodilators, including beta₂adrenomimetics and / or aminophylline; when hypoglycemia - intravenous glucagon or dextrose (glucose).

Interaction:

The effectiveness and tolerability of bisoprolol may be influenced by simultaneous intake of other drugs. This interaction can also occur when two drugs are taken in a short time. The doctor should be informed about the acceptance of other drugs, even if they are received without a doctor's prescription (ie, non-prescription drugs).

Unrecommended combinations

Antiarrhythmic drugs of the first class (for example, quinidine, disopyramide, lidocaine, phenytoin, flecainide, propafenone) with simultaneous application with bisoprolol may reduce AV conduction and contractility of the heart.

The blockers of "slow" calcium channels (BCCC) such as verapamil and, to a lesser extent, diltiazem with simultaneous application from bisoprolol may lead to a decrease in the contractility of the myocardium and a violation of AV conduction. In particular, intravenous administration of verapamil to patients taking beta-blockers can lead to severe arterial hypotension and AV blockade. Hypotensive agents of central action (such as clonidine, methyldopa, moxonidine, rilmenidine) can lead to decompensation of CHF due to a decrease in heart rate and a decrease in cardiac output, as well as to vasodilation due to a decrease in the central sympathetic tone. Abrupt cancellation, especially before the abolition of beta-blockers, may increase the risk of developing "ricochet" arterial hypertension.

Diuretics, sympatholytics, hydralazine and other antihypertensives can lead to excessive blood pressure lowering.

Combinations, requiring special care

BCCC derivatives of dihydropyridine (for example, nifedipine, felodipine, amlodipine) with simultaneous application with bisoprolol may increase the risk of developing arterial hypotension. In patients with heart failure, the risk of subsequent deterioration of the contractile function of the heart can not be ruled out.

Antiarrhythmic drugs of the III class (for example, amiodarone), and reserpine and guanfacine can increase the time AV carrying out.

The action of beta-blockers for topical application (eg, eye drops for the treatment of glaucoma) can enhance the systemic effects of bisoprolol (lowering blood pressure, decreasing heart rate).

Parasympatomimetics with simultaneous application with bisoprolol may increase the time AV and increase the risk of developing a bradycardia.

The effectiveness of insulin and hypoglycemic agents for oral administration may change with treatment with bisoprolol (masks the symptoms of developing hypoglycemia: tachycardia, increased blood pressure). Such interactions are more likely when using nonselective beta-blockers.

Phenytoin with intravenous administration, means for inhalation anesthesia (derivatives of hydrocarbons) increase the severity of cardiodepressive action and the likelihood of lowering blood pressure.

Cardiac glycosides with simultaneous application with bisoprolol can lead to the development of bradycardia and increase the time AV carrying out.

Antihypertensive effect weaken non-steroidal anti-inflammatory drugs (NSAIDs) (sodium ion delay and blockade of prostaglandin synthesis by the kidneys), glucocorticosteroids and estrogens (sodium ion delay).

The simultaneous use of bisoprolol with beta-adrenomimetics (eg, isoprenaline, dobutamine) can lead to a decrease in the effect of both drugs.

The clearance of lidocaine and xanthines (except theophylline) may decrease due to a possible increase in their concentration in the blood plasma, especially in patients with initially elevated clearance of theophylline under the influence of smoking.

The combination of bisoprolol with adrenomimetics, affecting beta and alpha-adrenoreceptors (for example, norepinephrine, epinephrine) may enhance the vasoconstrictor effects of these agents that occur with alpha-adrenergic receptors, leading to an increase in blood pressure.

Such interactions are more likely when using nonselective beta-blockers.

Hypotensive drugs,as well as other agents with a possible antihypertensive effect (for example, tricyclic antidepressants, barbiturates, phenothiazines) can enhance the antihypertensive effect of bisoprolol.

Mefloquine with simultaneous application with bisoprolol may increase the risk of developing bradycardia.

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 bisoprolol should be at least 14 days. Unhydrated ergot alkaloids increase the risk of peripheral circulatory disorders.

Ergotamine increases the risk of peripheral circulatory disorders.

Allergens used for immunotherapy, or allergen extracts for skin tests increase the risk of severe systemic allergic reactions or anaphylaxis in patients receiving bisoprolol.

Iodine-containing radiopaque diagnostic tools for intravenous administration increase the risk of anaphylactic reactions.

The effect of nondepolarizing muscle relaxants and the anticoagulant effect of coumarins during the treatment periodbisoprolol may be lengthened.

Sulfasalazine increases the concentration of bisoprolol in the blood plasma.

Rifampicin shortens the half-life of bisoprolol.

Special instructions:

Do not abruptly discontinue treatment with Biol^®because of the risk of developing severe arrhythmias and myocardial infarction. Cancellation is carried out gradually, reducing the dose by 25% every 3-4 days.

Monitoring the state of patients taking the drug Biol® should include measurement of heart rate and blood pressure (at the beginning of treatment - daily, then 1 every 3-4 months) holding an electrocardiogram, determination of blood glucose concentrations in diabetic patients (1 in 4 times -5 months)

In elderly patients it is recommended to monitor the kidney function (1 time in 4-5 months).

It is necessary to teach the patient how to calculate heart rate and instruct about the need for medical consultation at heart rate less 60 beats per minute.

In case of elderly patients increasing bradycardia (heart rate less than 60 beats / min), pronounced decrease in blood pressure (systolic blood pressure less than 100 mm Hg), atrioventricular block, it is necessary to reduce the dosage or discontinue treatment.

Before the start of treatment, it is recommended to perform an external respiration function in patients with a history of bronchopulmonary anamnesis.Patients who use contact lenses should take into account that against the background of drug treatment, a decrease in the production of tear fluid is possible.

When using Biol ® in patients with pheochromocytoma, there is a risk of developing paradoxical arterial hypertension (unless an effective blockade of alpha-adrenergic receptors has been previously achieved).

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

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 use of clonidine, its administration may be discontinued only a few days after the withdrawal of Biol®. It is possible to increase the severity of the reaction of hypersensitivity and the lack of effect from the usual doses of epinephrine against the background of a burdened allergological anamnesis.

If it is necessary to conduct routine surgical treatment, the drug should be discontinued 48 hours before the general anesthesia. If the patient has taken the drug before surgery, him should choose the drug for general anesthesia with a minimum negative inotropic effect.

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

Medicines that deplete the catecholamine depot (incl. reserpine), can enhance the action of beta-blockers, so patients who take such combinations of drugs should be under constant medical supervision to detect a marked decrease in blood pressure or bradycardia.

Patients with bronchospastic diseases can be cautiously prescribed cardioselective beta-blockers in the case of intolerance and / or ineffectiveness of other antihypertensive agents. Against the background of taking beta-blockers in patients with concomitant bronchial asthma, airway resistance can increase. When the dose of Biol® is exceeded in such patients, there is a danger of developing bronchospasm.

It is recommended to stop therapy with Biol ® in the development of depression.

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

It is necessary to cancel the drug before examining the concentration in the blood and urine of catecholamines, normetanephrine, vanillin-mandelic acid, antinuclear antibody titers.

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

Special precautions for destruction unused medicinal product

There is no need for special precautions when destroying an unused Biol® preparation.

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

During the period of treatment with Biol®, care must be taken when driving vehicles and engaging in other potentially hazardous activities requiring increased attention and speed of psychomotor reactions.

Form release / dosage:

Tablets, film-coated, 2.5 mg.

Packaging:

10 tablets are placed in Al/Al blister.

By 3, 5, or 10 blisters together with instructions for medical use are placed in a cardboard box.

Storage conditions:

Store at a temperature not exceeding 30 ° C.

Keep out of the reach of children.

Shelf life:

3 years.

Do not use the product after the expiry date printed on the package.

Terms of leave from pharmacies:On prescription

Registration number:LP-001864

Date of registration:01.10.2012

Expiration Date:01.10.2017

The owner of the registration certificate:Sandoz d.Sandoz d. Slovenia

Manufacturer: & nbsp

SALUTAS PHARMA, GmbH Germany

Representation: & nbspSANDOZ SANDOZ Switzerland

Information update date: & nbsp12.02.2017

Illustrated instructions

Instructions

Biol® (Byol®)