Bisoprolol Alkaloid, 2.5mg 30 pcs.

Pharmacotherapeutic group:
Beta1-adrenoblocker selective
ATC:
C.07.A.B Selective beta1-adrenoblockers
C.07.A.B.07 Bisoprolol
Pharmacodynamics:

Bisoprolol is a selective beta1-adrenoblocker without intrinsic sympathomimetic activity and has no membrane-stabilizing effect. Bisoprolol reduces plasma renin activity, reduces myocardial oxygen demand, and decreases heart rate (HR). It has antihypertensive, antiarrhythmic and anti-angina action.

By blocking in low doses beta1-adrenoceptors of heart, decreases catecholamine-stimulated cyclic adenosine monophosphate (cAMP) formation from adenosine triphosphate (ATP), decreases intracellular calcium ions flow, inhibits all heart functions, decreases atrioventricular (AV) conduction and excitability. If the therapeutic dose is exceeded, it has a beta2-adrenoblocking effect. Overall peripheral vascular resistance increases at the beginning of the drug administration, during the first 24 hours (as a result of reciprocal increase of activity of alpha-adrenoreceptors and elimination of stimulation of beta2-adrenoreceptors), after 1-3 days it returns to its baseline value, and during prolonged use it decreases.

Antihypertensive effect is related to the reduction of the blood minute volume, sympathetic stimulation of peripheral vessels, decrease of the sympathoadrenal system (SAS) activity (of great importance for patients with initial renin hypersecretion), restoration of sensitivity in response to blood pressure (BP) reduction and influence on the central nervous system. In arterial hypertension the effect is developed in 2-5 days, stable effect is observed after 1-2 months.

Antianginal effect is caused by decrease of myocardial oxygen demand due to decrease of contractility and other myocardial functions, prolongation of diastole, improvement of myocardial perfusion. Due to increased end diastolic pressure in the left ventricle and increased stretching of ventricular muscle fibers may increase oxygen demand, especially in patients with chronic heart failure (CHF).

When used in medium therapeutic doses, unlike non-selective beta-adrenoblockers, it has less pronounced effect on the organs containing beta2-adrenoreceptors (pancreas, skeletal muscles, smooth muscle of peripheral arteries, bronchi and uterus) and on carbohydrate metabolism; Does not cause retention of sodium ions in the body; intensity of atherogenic action does not differ from that of propranolol.

Pharmacokinetics:

Bisoprolol is almost completely (over 90%) absorbed in the gastrointestinal tract, eating does not affect absorption. The effect of “primary passage” through the liver is insignificant (at 10-15%), resulting in high bioavailability (90%). Food intake has no effect on the bioavailability of bisoprolol.

Bisoprolol is metabolized by the oxidative pathway without subsequent conjugation. All metabolites are strongly polar and are excreted by the kidneys. The major metabolites detected in plasma and urine have no pharmacological activity. Experiments with human liver microsomes in vitro show that bisoprolol is metabolized primarily by CYP3A4 isoenzyme (about 95%), and CYP2D6 isoenzyme plays only a minor role.

Binding with blood plasma proteins is about 30%. Volume of distribution is 3.5 l/kg. Total clearance is approximately 15 l/h. Maximal concentration in blood plasma is determined after 2-3 hours. The blood plasma half-life (10-12 hours) provides efficacy for 24 hours after a single daily dose.
Bisoprololol is eliminated from the body in two ways, 50% of the dose is metabolized in the liver to form inactive metabolites. About 98% is excreted by the kidneys, of which 50% is excreted unchanged; less than 2% – through the intestine (with bile).

Since excretion takes place in the kidneys and the liver equally, patients with impaired liver function or with renal failure do not require dose adjustment. The pharmacokinetics of bisoprolol are linear and independent of age.
In patients with CHF, the plasma concentrations of bisoprolol are higher and the elimination half-life is longer compared to healthy volunteers.

There is no information on the pharmacokinetics of bisoprolol in patients with CHF and concurrent hepatic or renal impairment.

Indications

Heart palpitations, Cardialgia (pain in the heart), Hypertension (high blood pressure), Heart failure, Arrhythmia, Tachycardia

• Arterial hypertension;
• ischemic heart disease (CHD): Prevention of stable angina attacks;
• Chronic heart failure (CHF).

.

Active ingredient

Bisoprolol

Composition

1 film-coated tablet contains:

active ingredient:

bisoprolol fumarate 2.5 mg.

auxiliary substances:

lactose monohydrate,
microcrystalline cellulose,
colloidal silicon dioxide,
crospovidone,
magnesium stearate.

How to take, the dosage

Bisoprolol is taken orally, in the morning on an empty stomach, once, without chewing, with a small amount of liquid. The tablets should not be chewed or crushed into a powder.

Treatment of arterial hypertension and angina pectoris

In all cases the mode of administration and dosage are chosen by the doctor for each patient individually, in particular taking into account the heart rate and therapeutic response.

In arterial hypertension and coronary heart disease the initial dose is usually 5 mg once a day. If necessary the dose is increased up to 10 mg once a day.

In treatment of arterial hypertension and angina pectoris the maximum daily dose is 20 mg once a day. The daily dose may be divided into two doses.

Treatment of stable chronic heart failure

Standard regimen of CHF treatment includes angiotensin converting enzyme inhibitors (ACE) or angiotensin II receptor antagonists (in case of intolerance to ACE inhibitors), beta-adrenoblockers, diuretics and, optionally, cardiac glycosides. Initiation of CCF treatment with Bisoprolol requires obligatory conduction of special titration phase and regular medical monitoring.
Precondition for Bisoprolol treatment is stable chronic heart failure without aggravation signs.

CCF treatment with Bisoprolol must be started according to the following titration scheme. Individual adaptation may be required depending on how well the patient tolerates the prescribed dose, i.e. the dose may be increased only if the previous dose was well tolerated.

Bisoprolol may be administered in the dosage form as follows: 2.5 mg tablets or 5 mg tablets.

The recommended initial dose is 1.25 mg (1/2 of 2.5 mg tablet) once a day. Depending on individual tolerance, the dose should be gradually increased to 2.5 mg, 3.75 mg (11/2 tablets of 2.5 mg), 7.5 mg (3 tablets of 2.5 mg or 11/2 tablets of Bisoprolol 5 mg) and 10 mg once daily. Each subsequent dose increase should be made at least two weeks later.

If the increased dose of the drug is not well tolerated by the patient, a dose reduction may be possible. The maximum recommended dose in CHF is 10 mg of Bisoprolol once a day.

During titration it is recommended to control BP, HR and severity of CHF symptoms regularly. Worsening of CHF symptoms may occur from the first day of the drug administration.

If the patient poorly tolerates the maximum recommended dose of the drug, a gradual dose reduction is possible.
During or after the titration phase a temporary worsening of CHF course, arterial hypotension or bradycardia may occur. In this case it is recommended first of all to adjust doses of drugs of concomitant therapy. It may also require temporary decrease of Bisoprolol dose or its cancellation.

After the patient’s condition has stabilized, the dose should be titrated again or the treatment may be continued.

Special patient groups
Renal or hepatic impairment:
– In mild to moderate hepatic or renal impairment, the dose usually does not need to be adjusted;
– In severe renal impairment (CK less than 20 ml/min) and in patients with severe liver disease, the maximum daily dose is 10 mg. Increase of the dose in these patients should be performed with caution.

Till now there are not enough data concerning Bisoprolol administration in patients with CHF associated with diabetes mellitus type 1, expressed renal and/or hepatic dysfunction, restrictive cardiomyopathy, congenital heart disease or cardiac valve defect with expressed hemodynamic disturbances. There are also still insufficient data on patients with CHF with myocardial infarction within the last 3 months.

Interaction

Unrecommended combinations

Class I antiarrhythmic agents (e.g., quinidine, disopyramide, lidocaine, phenytoin; flecainide, propafenone) when used simultaneously with bisoprolol may reduce AV conduction and cardiac contractility.

Slow calcium channel blockers (CMBs) such as verapamil and, to a lesser extent, diltiazem, when used simultaneously with bisoprololol, may lead to decreased myocardial contractility and impaired AV conduction. In particular, intravenous administration of verapamil to patients taking beta-adrenoblockers may lead to marked arterial hypotension and AV blockade.
Hypotensive agents of central action (such as clonidine, methyldopa, moxonidine, rilmenidine) may lead to a slowed HR and decreased cardiac output, and also to vasodilation due to a reduction of the central sympathetic tone. Abrupt withdrawal, especially before withdrawal of beta-adrenoblockers, may increase the risk of “ricochet” arterial hypertension.

Combinations requiring caution

Class III antiarrhythmic agents (e.g., amiodarone) may increase AV conduction disturbances.
The action of beta-adrenoblockers for topical use (e.g. eye drops for the treatment of glaucoma) may increase the systemic effects of bisoprolol (BP reduction, heart rate slowing).

Parasympathomimetics concomitantly used with bisoprolol may increase AV conduction disorders and increase the risk of bradycardia.

Simultaneous use of bisoprolol and beta-adrenomimetics (e.g., isoprenaline, dobutamine) may decrease the effect of both drugs.

Combination of bisoprolol with adrenomimetics affecting beta- and alpha-adrenoreceptors (e.g. norepinephrine, epinephrine) may increase vasoconstrictor effects of these drugs with alpha-adrenoreceptors, resulting in increase of BP. Such interaction is more likely with non-selective beta-adrenoblockers.

Mefloquine concomitantly used with bisoprolol may increase the risk of bradycardia.

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

Iodine containing diagnostic X-ray contrast agents for intravenous administration increase the risk of anaphylactic reactions.
Phenytoin when administered intravenously, agents for inhalation anesthesia (hydrocarbon derivatives) increase the severity of the cardiodepressant effect and the risk of BP decrease.

The effectiveness of insulin and hypoglycemic agents for oral administration may change during bisoprolol treatment (masks the symptoms of hypoglycemia developing: tachycardia, BP increase).

Clearance of lidocaine and xanthines (except theophylline) may decrease due to possible increase in their plasma concentrations, especially in patients with initially increased clearance of theophylline due to smoking.

Antihypertensive effect is weakened by nonsteroidal anti-inflammatory drugs (NSAIDs) (sodium ion retention and blockade of prostaglandin synthesis by kidneys), glucocorticosteroids and estrogens (sodium ion retention).

Cardiac glycosides, methyldopa, reserpine and guanfacine, “slow” calcium channel blockers (verapamil, diltiazem), amiodarone and other antiarrhythmic agents increase the risk of developing or worsening bradycardia, AV block, heart failure and heart failure.
Nifedipine can lead to a significant decrease in BP.

Diuretics, clonidine, sympatholytics, hydralazine and other hypotensive agents may lead to excessive BP reduction.
The effects of non-depolarizing myorelaxants and the anticoagulant effect of coumarins may be prolonged during bisoprolol treatment.
Tricyclic and tetracyclic antidepressants, antipsychotic agents (neuroleptics), ethanol, sedatives and hypnotics increase central nervous system depression.

Concomitant use with MAO inhibitors (except for MAO B inhibitors) is not recommended because of significant increase in antihypertensive effect. Concomitant use may also lead to the development of a hypertensive crisis. Treatment interval between MAO inhibitors and bisoprolol should be at least 14 days.

Non-hydrogenated ergot alkaloids increase the risk of peripheral circulatory disorders.

Ergotamine increases the risk of peripheral circulatory disorders.

Sulfasalazine increases the plasma concentration of bisoprolol.

Rifampicin shortens the half-life of bisoprolol.

Special Instructions

Monitoring of patients taking Bisoprolol should include measurement of HR and BP, ECG, determination of blood glucose concentration in patients with diabetes mellitus (once every 4-5 months).

In elderly patients it is recommended to monitor renal function (once every 4-5 months).

The patient should be taught the method of heart rate calculation and instructed to consult a physician if the heart rate is less than 50 bpm.
Before starting treatment, it is recommended to examine external respiratory function in patients with a history of bronchopulmonary complications.
Patients who wear contact lenses should be aware that the drug may decrease tear fluid production.

When using Bisoprolol in patients with pheochromocytoma there is a risk of paradoxical arterial hypertension (if effective blockade of alpha-adrenoreceptors has not been previously achieved).

In thyrotoxicosis bisoprolol may mask certain clinical signs of thyrotoxicosis (e.g., tachycardia). Abrupt withdrawal of the drug in patients with thyrotoxicosis is contraindicated because it may exacerbate the symptoms.

In diabetes mellitus, it may mask the tachycardia caused by hypoglycemia. Unlike non-selective beta-adrenoblockers it does not practically increase insulin-induced hypoglycemia and does not delay recovery of blood glucose concentration to normal values.
With the simultaneous use of clonidine its use may be terminated only after several days after discontinuation of Bisoprolol.
The intensity of hypersensitivity reactions may increase and the lack of effect of usual doses of epinephrine (adrenaline) against the background of a history of aggravated allergy.

If the patient needs a planned surgical treatment the drug should be canceled 48 hours before the general anesthesia. If the patient has taken the drug before surgery, he should choose a general anesthetic drug with a minimally negative lyotropic effect.

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

Medicines that deplete the catecholamine depot (including

Drugs that deplete catecholamine depot (including reserpine) may enhance the effect of beta-adrenoblockers, so patients taking such combinations of drugs should be under constant medical supervision to detect a marked decrease in BP or bradycardia.

Patients with bronchospastic disorders may be treated with caution with cardioselective beta-adrenoblockers in case of intolerance and/or inefficacy of other hypotensive agents. Against the background of taking beta-adrenoblockers in patients with concomitant bronchial asthma, airway resistance may increase. If the dose of the preparation Bisoprolol is exceeded in such patients, there is a risk of bronchospasm development.

In case of detection of increasing bradycardia (HR less than 60 beats/min), marked BP reduction (systolic BP less than 100 mmHg.

It is recommended to stop the therapy with Bisoprolol in case of depression.

The treatment should not be abruptly interrupted due to the risk of severe arrhythmia and myocardial infarction. The drug is withdrawn gradually, reducing the dose for 2 weeks or more (the dose is reduced by 25% every 3 to 4 days).

The drug should be withdrawn before testing the concentration in the blood and urine of catecholamines, normetanephrine, vanillylmindalic acid, antinuclear antibodies titers.

In smokers the effectiveness of beta-adrenoblockers is lower.

Effect on the ability to drive vehicles:

Use of Bisoprolol does not affect the ability to drive vehicles according to the results of studies in patients with CHD. However, due to individual reactions, the ability to drive vehicles or work with technically complex mechanisms may be impaired. Special attention should be paid to this at the beginning of treatment, after changing the dose, as well as in case of concomitant alcohol consumption.

Contraindications

• High sensitivity to bisoprolol, drug components and other beta-adrenoblockers, acute heart failure or decompensated CHF requiring inotropic therapy;
• shock (including cardiogenic);
• pulmonary edema;
• Atrioventricular (AV) block of degree II-III without a pacemaker;
• sinoatrial block;
• syndrome of weak sinus node;
• bradycardia (heart rate less than 60 bpm);
• severe arterial hypotension (systolic blood pressure (BP) 100 mmHg).Hg).
• severe bronchial asthma and a history of chronic obstructive pulmonary disease (COPD);
• explicit peripheral circulatory disorders, Raynaud’s syndrome: metabolic acidosis;
• pheochromocytoma (without concomitant use of alpha-adrenoblockers);
• current use of monoamine oxidase (MAO) inhibitors (except MAO type B inhibitors);
• age less than 18 years (efficacy and safety not established);
• lactose intolerance, lactase deficiency, or glucose-galactose malabsorption syndrome.

With caution:
Carrying out desensitizing therapy, Prinzmetal angina, hyperthyroidism, type 1 diabetes mellitus and diabetes mellitus with significant fluctuations in blood glucose concentration, grade I AV blockade, severe renal failure (creatinine clearance (CK) less than 20 ml/min), severe liver dysfunction, psoriasis, restrictive cardiomyopathy, congenital heart disease or heart valve defect with significant hemodynamic abnormalities, CHF with myocardial infarction within the last 3 months, strict diet, depression (including anamnesis), old age.

Side effects

Frequency of adverse reactions below was determined according to the following (classification of the World Health Organization): very common – at least 10%; common – at least 1%, but less than 10%; infrequent – at least 0.1%, but less than 1%; rare – at least 0.01%, but less than 0.1%: very rare – less than 0.01%, including individual reports.

Heart and vascular disorders: very often – shortening of HR (bradycardia, especially in patients with CHF); sensation of palpitation; often – marked decrease of BP (especially in patients with CHF), manifestation of angiospasm (increase of peripheral circulation disorder, feeling of cold in extremities (paresthesias); infrequent – AV conduction disorders (up to complete transverse blockage and cardiac arrest), arrhythmias, orthostatic hypotension, worsening of CHF course with development of peripheral edema (edema of ankles, groaning; dyspnea), chest pain.

Nervous system disorders: frequently – dizziness, headache, asthenia, fatigability, sleep disturbances, depression, anxiety; rarely – mental confusion or short-term memory loss, “nightmare” dreams, hallucinations, myasthenia, tremor, muscle cramps. Usually these phenomena are mild and disappear usually within 1-2 weeks after the start of treatment.

Senses: rare – visual impairment, decreased tear discharge (should be considered while wearing contact lenses), tinnitus, decreased hearing, ear pain; very rare – dry and sore eyes, conjunctivitis, taste disorders.

Respiratory system: infrequent – bronchospasm in patients with bronchial asthma or obstructive airways diseases; rare – allergic rhinitis, stuffy nose.

The digestive system: frequently – nausea, vomiting, diarrhea, constipation, dry mouth, abdominal pain, rarely – hepatitis, increased liver enzymes activity (alanine aminotransferase, aspartate aminotransferase), increased bilirubin concentration.

Musculoskeletal system: infrequent – arthralgia, back pain.

Urinary system: very rarely – potency disorders, decreased libido.

Laboratory: rare – increase in triglyceride concentration in blood; in some cases – thrombocytopenia, agranulocytosis, leukopenia.

Allergic reactions: rare – skin itching, rash, urticaria.

Skin: rare – increased sweating, skin hyperemia, exanthema, psoriasis-like skin reactions, very rare – alopecia, beta-adrenoblockers can exacerbate psoriasis.
Other: withdrawal syndrome (increased frequency of angina pectoris attacks, increased BP).

Overdose

Symptoms: arrhythmia, ventricular extrasystole, marked bradycardia, AV block, marked BP decrease, acute heart failure, hypoglycemia, acrocyanosis, difficulty in breathing, bronchospasm, dizziness, fainting, convulsions.

Treatment: In case of overdose the drug administration should be suspended, the gastric lavage should be performed, adsorptive agents should be administered, symptomatic therapy should be conducted.

In case of marked bradycardia – intravenous injection of atropine. If the effect is insufficient, a drug with a positive chronotropic effect may be administered with caution. Sometimes a temporary artificial pacer may be necessary.

In a marked decrease in BP – intravenous administration of plasma substitute solutions and vasopressors.

In hypoglycemia intravenous dextrose (glucose) administration may be indicated.

In AV blockade: patients should be constantly monitored and treated with beta-adrenomimetics, such as epinephrine. If necessary – administration of artificial pacemaker.

In exacerbation of CHF – intravenous administration of diuretics, drugs with positive inotropic effect, as well as vasodilators.
In bronchospasm – administration of bronchodilators, including beta2-adrenomimetics and/or aminophylline.

Pregnancy use

Bisoprolol has pharmacological effects that may have adverse effects on the course of pregnancy and/or on the fetus or newborn. Generally, beta-adrenoblockers decrease placental perfusion, which leads to fetal growth retardation, intrauterine fetal death, miscarriage, or preterm birth. The fetus and the newborn child may have pathological reactions (e.g., hypoglycemia, bradycardia, arterial hypotension).