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

Excipients: calcium hydrophosphate anhydrous 93.75 mg, microcrystalline cellulose 37.00 mg, corn starch 11.25 mg, magnesium stearate 1.5 mg, silicon dioxide colloid 1.50 mg.

Composition of the tablet shell: Opapray II white (85F48105) 4.5 mg (polyvinyl alcohol 46.9%, macrogol-3350 23.60%, talcum powder 17.4%, titanium dioxide 12.1%).

1 tablet, film-coated 10 mg, contains:

Tablet core composition:

Active substance: bisoprolol fumarate 10 mg;

Excipients: calcium hydrophosphate anhydrous 88.75 mg, microcrystalline cellulose 37.00 mg, corn starch 11.25 mg, magnesium stearate 1.50 mg, silicon dioxide colloid 1.50 mg.

Composition of the tablet shell: Opapray II yellow (85F38201) 4.5 mg (polyvinyl alcohol 40%, titanium dioxide 24.48%, macrogol-3350 20.20%, talc 14.8%, iron oxide yellow 0.50%, iron oxide red 0.02%).

Description:

Tablets 5 mg

Tablets of round, biconcave form, covered film shell of white or almost white with a risk on one side. On the cross section, the core is white or almost white.

Tablets 10 mg

The tablets are round, biconvex, covered with a film coat from light yellow with a pinkish hue to yellow with a pinkish tinge.On the cross section, the core is 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- adrenoblocker, 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 of beta₁(adenosine triphosphate (ATP)), reduces the intracellular current of calcium ions, has a negative chrono-, dromo-, batmo-, and inotropic effect (AV) conductivity).

If the therapeutic dose is exceeded, beta₂-adrenoblocking action. The total peripheral vascular resistance at the beginning of the drug, in the first 24 hours,slightly increases (as a result of a reciprocal increase in the activity of alpha-adrenoreceptors), which returns to the initial one after 1-3 days, and decreases with long-term administration.

The 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 a decrease in blood pressure (BP) and influence on the central nervous system (CNS). With arterial hypertension, the effect occurs after 2-5 days, a stable effect - after 1-2 months.

The antianginal effect is due to 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.

Antiarrhythmic effect is due to the elimination of arrhythmogenic factors (tachycardia, increased activity of the sympathetic nervous system, increased cAMP, arterial hypertension), a decrease in the rate of spontaneous excitation of sinus and ectopic rhythm drivers anddeceleration AV conduct (mainly in antegrade and, to a lesser extent, in the retrograde direction through AV node) and on additional paths.

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 organism.

Pharmacokinetics:

Suction. Bisoprolol almost completely (> 90%) is absorbed from the gastrointestinal tract. Its bioavailability due to an insignificant metabolism "during 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 administered dose in the dose range of 5 to 20 mg. The maximum concentration in the blood plasma is achieved in 2-3 hours.

Distribution. Bisoprolol distributed fairly widely. 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 show 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 minor role.

Excretion. Bisoprolol clearance is determined by the balance between excretion by the kidneys in unchanged form (about 50%) and metabolism in the liver (about 50%) to metabolites, which are also excreted by the kidneys. The total ground clearance is 15 liters per hour. The half-life (T_1/2) is 10-12 hours.

Indications:

- Arterial hypertension;

- ischemic heart disease: prevention of attacks of stable angina pectoris;

- chronic heart failure (as part of combination therapy).

Contraindications:

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

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

- cardiogenic shock;

- collapse;

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

- sinoatrial blockade;

- syndrome of weakness of the sinus node;

- severe bradycardia (heart rate before treatment less than 50 bpm);

- 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 violations of peripheral circulation;

- Raynaud's syndrome;

- metabolic acidosis;

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

- concomitant use of floktaphenin and sultopride;

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

Carefully:

- Desensitizing therapy;

- hyperthyroidism;

- Type 1 diabetes mellitus and diabetes mellitus with significant fluctuations in blood glucose concentration;

- severe renal failure (creatinine clearance (CK) less than 20 ml / min);

- severe violations of liver function;

- psoriasis;

- AV-blockade of the I degree;

- angina of Prinzmetal;

- restrictive cardiomyopathy;

- Congenital heart disease or heart valve disease with severe hemodynamic disorders;

- chronic heart failure with myocardial infarction during the last 3 months;

- depression (including in the anamnesis);

- pheochromocytoma (with simultaneous use of alpha-blockers);

- strict diet.

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 on the newborn. Usually beta-adrenoblockers reduce placental perfusion, which leads to a slowing of fetal growth, fetal death, miscarriage or premature birth. The fetus and newborn child may experience pathological reactions, such as intrauterine growth retardation, hypoglycemia, bradycardia.

A drug Bisoprolol should not be used during pregnancy, use is possible if the benefit to the mother exceeds the risk of side effects in the fetus and / or the child. In the event that the drug treatment Bisoprolol is considered necessary, blood flow in the placenta and uterus should be monitored, and the growth and development of the unborn child should be monitored, and in the event of undesirable pregnancy and / or fetal events, alternative therapies. You should carefully examine the newborn after delivery. Symptoms of hypoglycemia and bradycardia usually arise during the first 3 days of life.

There is no data on the penetration of bisoprolol into breast milk. Therefore, the drug Bisoprolol is not recommended for women during lactation. If you need to use the drug during lactation, breastfeeding should be discontinued.

Dosing and Administration:

Inside, in the morning on an empty stomach, without chewing, once.

Arterial hypertension and ischemic heart disease: prevention of angina pectoris attacks.

It is recommended to take 5 mg once. If necessary, increase the dose to 10 mg once a day. The maximum daily dose is 20 mg.

In patients with impaired renal function with creatinine clearance (CC) less than 20 ml / min, or with severe impairment of liver function, the maximum daily dose is 10 mg.

Dose adjustments in elderly patients are not required.

Chronic heart failure

Initiation of CHF treatment with a drug Bisoprolol requires mandatory holding of a special period for the selection of doses. The prerequisites for initiating therapy are as follows:

CHF without signs of exacerbation in the previous six weeks,
practically unchanged basic therapy in the previous two weeks,
treatment with optimal doses of angiotensin-converting enzyme (ACE) inhibitors (and vasodilators, in case of intolerance to ACE inhibitors), diuretics and, if necessary, cardiac glycosides.

The treatment is prescribed in accordance with the indicated dose selection scheme:

1st week - 1.25 mg * 1 time per day

2nd week - 2.5 mg once a day

3rd week - 3.75 mg once a day

4th-7th week - 5 mg once a day

8th-11th week - 7.5 mg once a day

12th week and further - 10 mg once a day as maintenance therapy.

* For this dosing regimen, use bisoprolol other manufacturers in dosage form and dosage, allowing a dose of 1.25 mg (for example, ¹/₂ tablets of 2.5 mg).

The maximum recommended dose of the drug Bisoprolol is 10 mg once a day. After starting treatment with the drug at a dose of 1.25 mg the patient should be observed for about 4 hours (heart rate control, blood pressure, conduction disturbances on the ECG, signs of worsening of chronic heart failure).Individual response of the patient to the prescribed therapy is possible, i.e. The dose can be increased only if the previous dose is well tolerated.

During the period of selection of doses or after it there may be a temporary deterioration in the course of CHF, fluid retention in the body, arterial hypotension or aetiology. In this case, it is recommended first of all to pay attention tothe choice of the dose of concomitant basic therapy (to optimize the dose of a diuretic and / or ACE inhibitor), before reducing the dose of the drug Bisoprolol. Treatment with the drug should be discontinued only in case of emergency.

After stabilization of the patient's condition, a repeated dose selection should be performed, or the treatment should be continued.

Special patient groups

Impaired renal or hepatic function

Dysfunction of the liver or kidneys of mild or moderate degree usually does not require dose adjustment. At the expressed infringements of function of kidneys (KK less than 20 ml / mines) and at patients with serious diseases of a liver the maximum daily dose makes 10 mg. Increasing the dose in such patients should be carried out with extreme caution.

To patients of advanced age correction of the dose is not required.

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

Side effects:

The frequency of adverse reactions listed below was determined according to the following (WHO classification): very often (≥ 10%); often (≥1%, but <10%); infrequently (≥ 0.1%, but <1%); rarely (≥ 0.01%, but <0.1%); very rarely (<0.01%, including individual messages).

From the cardiovascular system: very often - a decrease in heart rate (bradycardia, especially in patients with heart failure), a feeling of heartbeat; often marked decrease in blood pressure (especially in patients with CHF), manifestation of angiospasm (increased peripheral circulatory disorders, cold sensation in the extremities (paresthesia), infrequent - violation AV-conductivity (up to the development of complete transverse blockade and cardiac arrest), arrhythmias, orthostatic hypotension,aggravation of the course of CHF with the development of peripheral edema (swelling of the ankles, feet, shortness of breath, chest pain.

From the nervous system: often - dizziness, headache, asthenia; increased fatigue, sleep disorders, depression, anxiety; rarely - confusion or short-term memory loss, nightmares, hallucinations, myasthenia gravis, tremor, muscle cramps. Usually, these phenomena are of an easy nature and usually take place 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; very rarely - dryness and soreness of the eyes, conjunctivitis, taste disorders.

From the respiratory system: infrequently bronchospasm in patients with bronchial asthma or obstructive airway disease; 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 liver enzymes (alanine aminotransferase (ALT), aspartate aminotransferase (ACT)), increasing the concentration of bilirubin.

From the musculoskeletal system: infrequently - arthralgia, back pain.

From the genitourinary system: very rarely - a violation of potency, a weakening of the libido.

From the laboratory indicators: rarely - increased concentration triglycerides in the blood; in some cases - thrombocytopenia, agranulocytosis, and leukopenia.

Allergic reactions: rarely - skin itching, rash, hives.

From the skin: rarely - increased sweating, skin hyperemia, exanthema, psoriasis-like skin reactions; very rarely - alopecia, beta-adrenoblockers can aggravate the course of psoriasis.

Other: a syndrome of "cancellation" (an increase in angina attacks, an increase in blood pressure).

Inform your doctor if you find any of the listed side effects or any other undesirable or unforeseen effects.

Overdose:

Symptoms: arrhythmia, ventricular extrasystole, pronounced bradycardia, AV-blockade, marked decrease in blood pressure, acute heart failure, hypoglycemia, acrocyanosis, difficulty breathing, bronchospasm, dizziness, fainting, convulsions.

Treatment: First of all it is necessary to stop taking the drug, to wash the stomach,should take adsorbent funds, conduct symptomatic therapy.

With pronounced bradycardia - IV injection of atropine. If the effect is insufficient, with caution, you can enter a drug that has a positive chronotropic effect. Sometimes it may be necessary to temporarily set up an artificial pacemaker.

With a pronounced decrease in blood pressure - iv injection of plasma-substituting solutions and vasopressors.

When hypoglycemia can be shown iv injection of glucagon or IV injection of dextrose (glucose).

When AV-blockade: patients should be under constant observation, and receive treatment with beta-adrenomimetics, such as epinephrine. If necessary - staging an artificial pacemaker.

With an exacerbation of the course of CHF - in / in the introduction of diuretics, drugs with a positive inotropic effect, as well as vasodilators.

When bronhospazme - appointment bronhodilatatorov, incl. beta₂adrenomimetics and / or aminophylline.

Interaction:

Uncommon combinations:

In the treatment of CHF

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

All indications for the use of the drug Bisoprolol

Blockers of "slow" calcium channels such as verapamil and to a lesser extent, diltiazem, with simultaneous application with bisoprolol may lead to a decrease in myocardial contractility and disruption AVconductivity. In particular, intravenous administration of verapamil to patients taking beta-blockers can lead to severe arterial hypotension and AV-blockade.

Hypotensive drugs central (such as clonidine, methyldopa, moxonidine, rilmenidine) can lead 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.

Combinations that require caution

Treatment of arterial hypertension (AH) and ischemic heart disease (CHD)

All indications for the use of the drug Bisoprolol

Antiarrhythmic drugs of the III class (for example, amiodarone) can enhance the violation of AV-conduction.

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 use with bisoprolol may increase the disruption AVconductivity and increase the risk of bradycardia.

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

The combination of bisoprolol with adrenomimetics, affecting beta and alpha-adrenergic receptors (for example, norepinephrine, epinephrine), can enhance the vasoconstrictor effects of these agents that arise with the participation of α-adrenergic receptors, leading to an increase in blood pressure. Such interactions are more likely when using nonselective beta-blockers.

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

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.

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

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).

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

The hypotensive effect weakens NSAIDs (sodium ion delay and blockade of prostaglandin synthesis by the kidneys), SCS and estrogens (sodium ion delay).

Cardiac glycosides, reserpine and guanfacine, blockers of "slow" calcium channels, amiodarone and other antiarrhythmic drugs increase the risk of developing or worsening bradycardia, AV-blockade, cardiac arrest and heart failure. Nifedipine can lead to a significant decrease in blood pressure.

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

The effect of nondepolarizing muscle relaxants and the anticoagulant effect of coumarins during treatment with bisoprolol may be prolonged.

Tricyclic and tetracyclic antidepressants, antipsychotics (antipsychotics), ethanol, sedatives and hypnotics increase the depression of the central nervous system.

It should not be used simultaneously with monoamine oxide (MAO) inhibitors due to a significant increase in hypotensive effect. 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.

Sulfasalazine increases the concentration of bisoprolol in the blood plasma.

Rifampicin shortens T_1/2 bisoprolol.

Special instructions:

Do not abruptly discontinue drug treatment Bisoprolol 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 status of patients receiving Bisoprolol, should include a measurement of heart rate and blood pressure (at the beginning of treatment - every day, then - every 3-4 months), ECG, blood glucose in patients with diabetes mellitus (once every 4-5 months).

In elderly patients it is recommended to monitor 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 a heart rate of less than 50 beats per minute.

If elderly patients develop an increasing bradycardia (heart rate less than 50 beats per minute), a marked decrease in blood pressure (systolic blood pressure less than 100 mm Hg), AV blockade, it is necessary to reduce the dose or stop 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 the drug Bisoprolol patients with pheochromocytoma have a risk of developing paradoxical arterial hypertension (unless an effective blockade of alpha-adrenergic receptors is 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.

With diabetes mellitus bisoprolol can mask tachycardia caused by hypoglycemia. In contrast to nonselective 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 may be discontinued only a few days after drug withdrawal Bisoprolol.

It is possible to increase the severity of the reaction of hypersensitivity and the lack of effect from the usual doses of epinephrine (adrenaline) against the background of a weighed allergic anamnesis.

If surgical intervention is necessary, the drug should be withdrawn 48 hours before the start of general anesthesia. If the patient has taken the drug before surgery, he should choose a drug for general anesthesia with a minimally negative inotropic effect.

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

Drugs that reduce catecholamine stocks (incl. reserpine), can enhance the action of beta-blockers, so patients taking such combinations of drugs should be under regular supervision of the doctor for the detection of 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, resistance may increase respiratory tract. If the dose is exceeded Bisoprolol in such patients there is a danger of developing bronchospasm.

It is recommended to stop drug therapy Bisoprolol with the development of depression.

It is necessary to cancel the drug before the study of the concentration in the blood and urine of catecholamines, normetanefrin, vanillylmandelic acid, antinuclear antibody titers.

In smoking patients, the effectiveness of beta-blockers is lower.

Effect on the ability to drive transp. cf. and fur:During the period of drug treatment Bisoprolol Care must be taken when driving vehicles and engaging in other potentially hazardous activities that require increased attention and speed of psychomotor reactions.

Form release / dosage:

Tablets, film-coated, 5 mg and 10 mg.

Packaging:

For 10 or 15 tablets in a contour mesh box made of PVC film and foil of aluminum printed lacquered.

For 1, 2, 3, 5, 6, 9 or 10 contour cell packs, together with instructions for medical use, put in a pack of cardboard.

Storage conditions:

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

Keep out of the reach of children.

Shelf life:

2 years.

Do not use after expiry date.

Terms of leave from pharmacies:On prescription

Registration number:LP-002812

Date of registration:13.01.2015

Expiration Date:13.01.2020

The owner of the registration certificate:IZVARINO PHARMA, LLC IZVARINO PHARMA, LLC Russia

Manufacturer: & nbsp

IZVARINO PHARMA, LLC Russia

Representation: & nbspIZVARIN PHARMA LLC IZVARIN PHARMA LLC Russia

Information update date: & nbsp14.02.2017

Illustrated instructions

Instructions

Bisoprolol (Bisoprolol)