Bisoprolol CRKA 10 mg tablets No. 90 *

Bisoprolol KRKA (BISOPROLOL KRKA) user manual

Composition

active substance:

1 tablet contains 2.5 mg, or 5 mg or 10 mg of bisoprolol fumarate;

Auxiliary substances: microcrystalline cellulose, sodium starch (type A), povidone, silicon dioxide colloid, magnesium stearate, hypromellose, macrogol, titanium dioxide (E 171), talc, iron oxide yellow * (E 172), iron oxide red * (E 172).

* Contained in tablets of 5 mg and 10 mg.

Dosage form. Film-coated tablets.

Basic physical and chemical properties:

• tablets of 2.5 mg from white to almost white, oval, slightly biconcave, film-coated tablets, with a notch on one side
• tablets of 5 mg light brownish-yellow, oval, slightly biconcave, film-coated tablets, with a notch on one side
• tablets of 10 mg light brownish-yellow, round, slightly biconcave, film-coated tablets, with a notch on one side, with bevelled edges.

Pharmacological group

Selective blockers of beta-adrenergic receptors.

ATX Code C07 AB07.

Pharmacological properties.

Pharmacodynamics.

Mechanism of action

Bisoprolol is a highly selective beta-adrenergic blocker, it does not show intrashno-sympathomimetic activity and relative membrane-stabilizing activity. It shows a low affinity only with beta-adrenoreceptors of smooth muscles of the bronchi and vessels, and also with beta-adrenoreceptors responsible for the regulation of metabolism. Therefore, as a rule, do not expect that bisoprolol to affect airway resistance and metabolic effects mediated by beta-adrenergic receptors. Its beta-selectivity extends beyond the range of therapeutic dosing.

Pharmacodynamic effects

As with other β-blockers, the mechanism of action for hypertension is unknown, but it is known that bisoprolol significantly suppresses renin level in plasma.

In patients with angina, blockade of β-receptors reduces cardiac activity and thus reduces the need for oxygen.Therefore, bisoprolol is effective in eliminating or reducing the symptoms of angina pectoris.

With a single administration to patients with coronary heart disease without chronic heart failure, bisoprolol reduces heart rate and stroke volume and thus reduces the volume flow rate of the heart's blood and oxygen consumption.Raised at the initial stage, peripheral resistance decreases with constant admission.

Clinical efficacy and safety

A total of 2,447 patients were included in the CIBIS II study. 83% (n = 2202) had class III according to the classification of the New York Heart Association, 17% (n = 445) - class IV according to the classification of the New York Heart Association. They had stable symptomatic systolic heart failure (ejection fraction of 35%, based on echocardiography). Overall mortality was reduced from 17.3% to 11.8% (relative decline of 34%). There was a decrease in sudden death (3.6% versus 6.3%, a relative decrease of 44%) and a reduction in the number of episodes of heart failure requiring hospitalization (12% versus 17.6%, a relative decrease of 36%). As a result, the functional status of the New York Heart Association was significantly improved. At the beginning of treatment and titration of the dose of bisoprolol, there was hospitalization through bradycardia (0.53%), hypotension (0.23%) and acute decompensation (4.97%), but this occurred no more often than in the placebo group (0 %, 0.3% and 6.74%). The number of fatal cases and disabilities through strokes during the entire study period was 20 in the bisoprolol group and 15 in the placebo group.

The CIBIS III study involved 1010 patients ≥65 years of age with a mild or moderate chronic heart failure (class II or III according to the classification of the New York Heart Association) and a left ventricular ejection fraction ≤ 35% that had not previously been treated with ACE inhibitors, beta blockers or blockers of angiotensin receptors. Patients were treated with a combination of bisoprolol and enalapril for 6-24 months after the initial 6-month treatment with bisoprolol or enalapril.

There was a tendency to frequent occurrence of worsening of chronic heart failure with bisoprolol as an initial 6-month treatment. No benefit of initial treatment with bisoprolol or initial treatment with enalapril has been demonstrated in the analysis of the population by protocol. Both strategies for initiating treatment for chronic heart failure demonstrated a similar percentage of the primary combined end point of death and hospitalization (32.4% in the primary treatment group with bisoprolol compared with 33.1% in the primary enalapril treatment group, the protocol population) at the end of the study. The study shows that bisoprolol can be used in elderly patients with chronic heart failure with mild to moderate disease.

Pharmacokinetics

Absorption

Bisoprolol is absorbed and has a bioavailability of about 90% after ingestion.

distribution

The volume of distribution is 3.5 l / kg. Bisoprolol binding to plasma proteins is about 30%.

Metabolism and excretion

Bisoprolol is excreted from the body in two ways. 50% is metabolized in the liver to inactive metabolites, which are then excreted by the kidneys. The remaining 50% are excreted by the kidneys unchanged. The total clearance is approximately 15 l / h. The half-life period is 10-12 hours, which produces a 24-hour effect after taking 1 time per day.

Linearity

The kinetics of bisoprolol is linear and does not depend on age.

Special Populations

Dose adjustment for patients with impaired liver or kidney function is not required. The pharmacokinetics in patients with stable chronic heart failure and with impaired liver or kidney function have not been studied. In patients with chronic heart failure (class III according to the classification of the New York Heart Association), the level of bisoprolol in plasma is higher, and the half-life is longer than in healthy volunteers. The maximum plasma concentration in the stable state is 64 ± 21 ng / ml with a daily dose of 10 mg, and the half-life is 17 ± 5:00.

Indications

• Arterial hypertension.
• Ischemic heart disease (angina pectoris).
• Chronic heart failure with reduced systolic function of the left ventricle (in addition to ACE inhibitors and diuretics and, if necessary, cardiac glycosides).

Contraindications.

Bisoprolol is contraindicated in patients with:

• hypersensitivity to bisoprolol or to the auxiliary substance of the drug
• acute heart failure or during episodes of heart failure decompensation, requiring intravenous inotropic therapy;
• cardiogenic shock;
• AV blockade of II-III degree (without a pacemaker);
• syndrome of weakness of the sinus node;
• vyavlenyusino-atrial blockade;
• symptomatic bradycardia (heart rate less than 60 beats / min before the start of therapy)
• symptomatic hypotension (systolic blood pressure <100 mm Hg)
• severe bronchial asthma or severe chronic obstructive pulmonary dysfunction;
• severe forms of occlusive disease of peripheral arteries or severe forms of Raynaud's syndrome
• pheochromocytoma, was not treated;
• metabolic acidosis.

Interaction with other drugs and other types of interactions.

Combinations that are not recommended

Calcium antagonists, like verapamil and, to a lesser extent, diltiazem: a negative effect on the contractile function and AV-conduction. The administration of verapamil to patients treated with β-blockers can lead to expressive hypotension and AV blockade.

Class I antiarrhythmics (eg, kynidine, disopyramide, lidocaine, phenytoin, flecainide, propafenone): there may be an increased effect on AV conduction time, as well as a negative inotropic effect.

Such centrally acting antihypertensive drugs as clonidine, methyldopa, moxonodine, rilmenidine: simultaneous use of centrally acting antihypertensive drugs can increase heart failure by lowering the central sympathetic tone (decrease in heart rate and volume flow rate of the blood of the heart, vasodilation). A sharp discontinuation of a beta-blocker may increase the risk of "ricochet" hypertension.

Combinations that should be used with caution

Calcium antagonists dihydropyridine type, such as nifedipine, felodipine and amlodipine: simultaneous use increases the risk of hypotension, the risk of further impairment of ventricular pumping function in patients with heart failure should not be ruled out.

Class III antiarrhythmic drugs (eg, amiodarone): the effect on AV-conduction time may be enhanced.

Beta-blockers of local action (eg eye drops for the treatment of glaucoma) can supplement the systemic effects of bisoprolol.

Parasympatomimetic preparations: simultaneous application can prolong the AV-ventricular conduction time and cause bradycardia.

Insulin and oral antidiabetics: increasing the effect of reducing blood sugar. Blockade of beta-adrenoceptors can mask symptoms of hypoglycemia.

Anesthetics: weaken reflex tachycardia and increase the risk of hypotension.

Digitalis glycosides: decreased heart rate, prolonged AV-ventricular conduction.

Non-steroidal anti-inflammatory drugs: non-steroidal anti-inflammatory drugs can reduce the hypotensive effect of bisoprolol.

β-sympathomimetic drugs (eg isoprenaline, dobutamine): a combination with bisoprolol may reduce the effect of both drugs.

Sympathomimetics, which activate both β- and α-adrenergic receptors (eg noradrenaline, adrenaline): increase blood pressure. The combination with bisoprolol can open mediated through the α-adrenoreceptors the vasoconstrictive effects of these drugs, leading to increased blood pressure and exacerbating the Charcot syndrome. Such interactions are more likely with non-selective β-blockers.

Simultaneous use with antihypertensive drugs, as well as with other drugs with a potential for lowering blood pressure (eg tricyclic antidepressants, barbiturates, phenothiazines) increases the risk of hypotension.

Combinations, the application of which should be weighed

Mefloquin: increases the risk of bradycardia.

MAO inhibitors (with the exception of MAO-B inhibitors): enhance the antihypertensive effect of beta-blockers, as well as the risk of hypertensive crisis.

With the simultaneous use of the drug Bisoprolol CRKA with derivatives of ergotamine, perfusion of damaged tissue is enhanced. With the simultaneous use of bisoprolol KRKA rifampicin, a decrease in the half-life of bisoprolol is possible.Usually no dose adjustment is required.

Application features

Bisoprolol should be taken with caution when:

• stable chronic heart failure. Treatment of stable chronic heart failure with bisoprolol should begin with a special phase of titration;
• bronchospasm (bronchial asthma, history of obstructive airway disease);
• diabetes mellitus with large fluctuations in blood glucose levels, hypoglycemia symptoms (eg, tachycardia, heart palpitations or increased sweating) can be masked;
• strict post;
• therapy of desensitization;
• AV blockade of the first degree;
• angina of Prinzmetal;
• with occlusive disease of peripheral arteries (complications may increase during the initiation of therapy)
• general anesthesia.

In patients who are under general anesthesia, beta blockade reduces the incidence of arrhythmia and myocardial ischemia during induction and intubation and during the postoperative period. It is recommended that support for the beta blockade continues during the PERIOPERATIVE period. An anesthesiologist should know about the beta blockade through possible interaction with other drugs, leads to bradyarrhythmias, a weakening of reflex tachycardia and a decrease in the reflex capacity to compensate for blood loss. If it is considered necessary to discontinue beta blocker therapy for surgery, it should be done gradually and completed approximately 48 hours before anesthesia.

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

• insulin-dependent diabetes mellitus (type I);
• severe renal dysfunction
• severe liver dysfunction
• restrictive cardiomyopathy;
• hereditary heart disease;
• hemodynamically significant organic valve defect;
• myocardial infarction in the last 3 months.

The combination of bisoprolol with calcium antagonists such as verapamil or diltiazem, with anti-arrhythmic drugs of Class I and with centrally fertile antihypertensive drugs is usually not recommended.

With bronchial asthma or other chronic obstructive pulmonary diseases, bronchodilators should be treated concomitantly. Sometimes there may be an increase in airway resistance in patients with asthma, so it may be necessary to increase the dose of beta-stimulants.

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

Patients with psoriasis or with an anamnesis should take beta-blockers (eg bisoprolol) only after a thorough evaluation of the benefits and risks.

Patients with pheochromocytoma bisoprolol can not be prescribed until the moment of blocking the alpha receptors.

During treatment with bisoprolol, the symptoms of thyrotoxicosis can be masked.

The initiation of bisoprolol treatment requires monitoring of the patient's condition.

Treatment with bisoprolol should not be discontinued abruptly, except in extreme cases, especially in patients with coronary heart disease, as this can lead to a temporary deterioration of the heart.

Use during pregnancy or lactation.

Pregnancy

Bisoprolol can cause harmful effects on pregnancy and / or fetus / newborn. Usually, beta-adrenergic blockers reduce perfusion of the placenta, is associated with growth retardation, intrauterine death, abortion, or premature birth. Side effects (eg hypoglycemia and bradycardia) can occur in the fetus and the newborn. If treatment with beta-adrenoreceptor blockers is necessary, then it is desirable to use selective beta-adrenoreceptor blockers.

Bisoprolol should not be used during pregnancy unless absolutely necessary. If bisoprolol treatment is considered necessary, uterine placental blood flow and fetal growth should be checked. In case of harmful effects on pregnancy or fetus, alternative treatment should be considered. Carefully monitor the condition of the newborn. Symptoms of hypoglycemia and bradycardia are usually expected within the first 3 days.

Lactation

It is not known whether this drug is excreted in breast milk. Therefore, breast-feeding during treatment with bisoprolol.

The ability to influence the reaction rate when driving or working with other machinery.

In a study involving patients with coronary artery disease, bisoprolol does not affect the ability to drive. However, in some patients the ability to drive or work with machinery may be impaired. This is possible, in particular, at the beginning of treatment and after changing the dose of the drug, as well as in combination with alcohol.

Method of administration and dose.

For oral administration.

Tablets of the drug Bisoprolol CRKA should be taken in the morning, you can during meals. They should be swallowed with a liquid without chewing. If necessary, the tablet can be divided into equal parts.

Dosage

Arterial hypertension and ischemic heart disease (angina pectoris)

The recommended dose is 5 mg (1 tablet Bisoprolol CRKA, 5 mg) 1 time per day.

If necessary, the daily dose can be increased to 10 mg (1 tablet Bisoprolol CRKA, 10 mg) 1 time per day.

The maximum recommended dose is 20 mg once a day.

The dosage regimen changes and is adjusted individually by the doctor, depending on the patient's condition.

Bisoprolol CRKA should be used with caution in patients with hypertension or ischemic heart disease and with diseases that occur with heart failure.

Patients with impaired renal or hepatic function

For patients with the last stage of renal impairment (creatinine clearance <20 mL / min) or liver function, the dose should not exceed 10 mg of bisoprolol once a day.

Elderly patients

Normally no dose adjustment is required, but the dose is 5 mg per day may be sufficient for some patients; other adult dose can be reduced in cases of severely impaired renal or hepatic function.

Chronic heart failure

Standard treatment for heart failure includes chronic ACE inhibitor (or angiotensin receptor blocker in case of intolerance to ACE inhibitors), beta-blockers, diuretics and (where appropriate) cardiac glycosides. Patients should have stable state (without congestive heart failure) at the beginning of treatment with bisoprolol.

It is recommended that the doctor had some experience in the control of chronic heart failure.

During and after selection may occur timchasoveposilennya heart failure, hypotension and bradycardia.

titration period

Treatment of stable chronic heart failure with bisoprolol requires titration phase.

bisoprolol treatment should be started gradually increasing the dose, depending on the individual response:

• 1.25 mg 1 time per day for 1 week; if well tolerated increase to
• 2.5 mg 1 time per day for the next week; if well tolerated increase to
• 3.75 mg 1 time per day for the next week; if well tolerated increase to
• 5 1 mg once a day for 4 consecutive weeks is well tolerated if, to increase the
• 7.5 1 mg once a day for 4 consecutive weeks is well tolerated if, to increase the
• 10 mg 1 time per day during maintenance therapy.

Bisoprolol Krka is not suitable for initial treatment of chronic heart failure, as in the beginning of treatment to the lowest dose of bisoprolol.

The maximum recommended dose is 10 mg 1 time per day.

During the titration period recommended careful monitoring important vital signs (heart rate, blood pressure) and symptoms of heart failure. Symptoms may appear as early as the first day of therapy.

Changing regimens

If the maximum recommended dose is well tolerated, it is possible to apply a gradual reduction in dose.

In the temporary gain heart failure, hypotension, bradycardia or rescan recommended dosages of concomitant medication. It may also be necessary to temporarily lower the dose of bisoprolol, or to stop receiving. Re-start and / or increasing the dose of bisoprolol possible when the patient again to reach a stable state.

Treatment of stable chronic heart failure bisoprolol is usually long-term.

You should not stop treatment abruptly or change the recommended dose without first consulting the doctor who prescribed the drug, as it may lead to a deterioration in the patient's condition. If you want to stop the treatment, a gradual reduction in dose is recommended, since abrupt discontinuation can lead to acute deterioration of the patient's condition.

Patients with impaired renal or hepatic function

There is no information on the pharmacokinetics of bisoprolol in patients with chronic heart failure and with impaired liver or kidney function. Therefore, improving the dose in these populations should be carried out with extreme caution.

Elderly patients

Do not need any dose adjustments.

Children

Use of the drug is contraindicated for children due to lack of safety and efficacy data.

Overdose

Symptoms

In overdose (e.g., daily dose of 15 mg instead of 7.5 mg) reported AV-blockade of the third degree, bradycardia and vertigo. Typically, the most common manifestations that are expected with an overdose of beta-blockers, has bradycardia, hypotension, bronchospasm, acute cardiac insufficiency and hypoglycaemia. A few cases of overdose with bisoprolol (maximum 2000 mg) was observed in patients suffering from hypertension and / or coronary heart disease. They occurred bradycardia and / or hypotension all patients vyzdoroveli.Suschestvuet great individual variability sensitivity to a single high-dose bisoprolol; Patients with heart failure are probably very chuvstvitelnymi.Poetomu for these patients required a gradual increase in the dose in accordance with the scheme 4.2.

Control

In case of overdose with bisoprolol treatment should be stopped immediately and inform vracha.V depending on the extent of overdose, it should apply supportive and symptomatic treatment. Limited data suggests that bisoprolol almost does not rely on dialysis.

Bradycardia. Introduction of intravenous atropine. If no adequate reaction in response, can be carefully introduce isoprenaline or other preparation with positive chronotropic properties. Under some circumstances, it may need a transvenous pacemaker installation.

Hypotension. And the liquid to be administered vasoconstrictor drugs. It may be useful intravenous glucagon.

AV blockade (II-III degree). Patients should be monitored and apply isoprenaline infusion or transvenous pacemaker installation.

Acute exacerbation of heart failure. Introduction diuretics, inotropes, vasodilators.

Bronchospasm. Carrying bronchodilatory therapy, such as administration of isoprenaline, beta-sympathomimetics and / or aminophylline.

Hypoglycemia. Administration of glucose.

Adverse reactions

In most cases, when using the drug occur side reactions such as headache (2.9%), dizziness (1.9%), fatigue (1.0%).

Hydrochlorothiazide may cause or exacerbate hypovolaemia, which can lead to electrolyte imbalance.

this terminology has been used for the classification of frequency of adverse reactions: very common (1/10), common (1/100, <1/10), uncommon (1/1000, <1/100), rarely (≥ 1/10000, <1 / 1000), very rarely (≤ 1/10000).

violation of	Often	often	infrequently	rarely	Rarely
mental health			sleep disorders, depression	nightmares, hallucinations
From the nervous system		dizziness * headache *		syncope
The eye				slozotoku reduction (should be considered when the patient wears the lenses)	conjunctivitis
On the part of hearing and balance				hearing disorder
Cardiovascular disorders	bradycardia	strengthening of heart failure, the feeling of cold or numbness in the extremities, orthostatic hypotension	AV-conduction disturbances, orthostatic hypotension
Respiratory, thoracic and mediastinal			bronchospasm in patients with bronchial asthma or obstructive airway disease in history	nasal allergy
On the part of the gastrointestinal tract		nausea, vomiting, diarrhea, constipation
Liver and Biliary				hepatitis
Skin and subcutaneous tissue disorders				hypersensitivity reactions (itching, rash, flushing, rash)	beta-blockers can provoke or exacerbate psoriasis or psoriasis cause a similar rash, alopecia
On the part of the musculoskeletal system and connective tissue			weakness and muscle spasms
On the part of the reproductive system and breast				by potency disorders
General disorders and administration conditions		asthenia, fatigue *
Laboratory findings				elevated triglycerides, increased liver enzymes (alaninamino transferase, aspartate amino otransferazy)

* Applies only to patients with hypertension or ischemic heart disease. These symptoms occur mainly at the beginning of therapy. They are usually mild and usually disappear within the first 1-2 weeks.

At occurrence of any side effect or adverse reaction should inform the physician.

Shelf life

2 years.

Storage conditions

Store at a temperature not higher than 25 ° C in original package to protect against moisture and light. Keep out of the reach of children.

Packaging

• 10 tablets in a blister, 1, 2, 3, 5, 6, 9 or 10 blisters per box.
• 14 tablets in a blister, 2, 4 or 6 blisters per box.
• 15 tablets in a blister, 2, 4 or 6 blisters per box.

Category of leave

On prescription.