Biol, 5 mg 30 pcs.

A selective beta 1 -adrenoblocker without sympathomimetic activity of its own. It has no membrane stabilizing effect. Reduces blood plasma renin activity, decreases myocardial oxygen demand, reduces heart rate at rest and under load.

It has hypotensive, antiarrhythmic and antianginal action. In low doses it blocks β 1 -adrenoreceptors of heart, decreases catecholamine-stimulated formation of cAMP from ATP, decreases intracellular flow of calcium ions, produces negative chrono-, dromo-, batmo- and inotropic action. It inhibits conduction and excitability, slows down AV conductivity. The total peripheral resistance of vessels increases during the first 24 hours of the drug administration (as a result of reciprocal increase of α-adrenoreceptor activity and elimination of β 2 -adrenoreceptor stimulation) which comes back to the baseline in 1-3 days and decreases with prolonged administration.

Hypotensive effect is related to the decrease of the minute blood volume, sympathetic stimulation of peripheral vessels, decrease of renin-angiotensin system activity (it is more important for patients with initial renin hypersecretion), recovery of aortic arch baroreceptors sensitivity (their activity in response to BP decrease and influence on CNS is not increased). In arterial hypertension the effect comes in 2-5 days, stable hypotensive effect in 1-2 months.

The antianginal effect is caused by decrease of myocardial oxygen demand as a result of shortening of HR and decrease of contractility, prolongation of diastole, improvement of myocardial perfusion. By increasing left ventricular end-diastolic pressure and increasing ventricular muscle fiber stretch can increase oxygen demand, especially in patients with chronic heart failure.

The antiarrhythmic effect is caused by the removal of arrhythmogenic factors (tachycardia, increased activity of the sympathetic nervous system, increased content of CAMF, arterial hypertension), the decrease of spontaneous excitation rate of sinus and ectopic pacemakers and delay of AV conduction (mainly in the antegrade and, to a lesser degree, in the retrograde direction through the AV node) and through additional pathways.

In contrast to non-selective beta-adrenoblockers, when administered in medium therapeutic doses, it has less pronounced effect on the organs containing β 2 -adrenoreceptors (pancreas, skeletal muscles, smooth muscle of peripheral arteries, bronchi and uterus) and on carbohydrate metabolism. It does not cause retention of sodium ions in the body. When increasing the dose above the therapeutic has a beta 2 -adrenoblocking effect.

Pharmacokinetics

Intake

Bisoprolol is almost completely absorbed from the gastrointestinal tract, food intake does not affect absorption. Bioavailability is about 90%. T max in plasma is 2-4 hours after oral administration.

Distribution and metabolism

Binding with plasma proteins is 26-33%. Metabolized in the liver, bisoprolol metabolites have no pharmacological activity. Blood-brain barrier and placental barrier permeability is low; in small amounts it is excreted with breast milk.

T 1/2 is 9-12 hours, which makes it possible to use the drug once a day. It is excreted by the kidneys (50% unchanged), less than 2% – through the intestine.

Indications

Active ingredient

Composition

1 film-coated tablet contains:

The active ingredient:

bisoprolol hemifumarate 5 mg.

Associates:

Microcrystalline cellulose,

calcium hydrophosphate,

corn starch,

croscarmellose sodium,

magnesium stearate,

colloidal anhydrous silica.

Composition of the film coating:

Lactose monohydrate, hypromellose, titanium dioxide, macrogol-4000, iron (III) oxide yellow dye.

How to take, the dosage

Biol® is taken orally, in the morning on an empty stomach, once daily with some liquid, in the morning before, during or after breakfast. The tablets should not be chewed or crushed into a powder.

In all cases, the dosage regimen and the dose are determined by the physician for each patient individually, especially taking into account the heart rate and the patient’s condition.

Hypertension and CHD

In case of arterial hypertension and CHD Biol® is taken in dose of 5 mg 1 time per day. If necessary the dose is increased up to 10 mg 1 time per day.

In the treatment of arterial hypertension and angina pectoris the maximum daily dose is 20 mg once daily.

Chronic heart failure (CHF)

The start of CHF treatment with Biol® requires special titration phase and regular medical monitoring.

The prerequisite for Biol® treatment is stable CHF without aggravation signs. Biol® CHF treatment is 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.

To ensure an appropriate titration process in the initial stages of treatment, it is recommended that the drug be used in lower doses.

The recommended starting dose is 1.25 mg (1/4 tablet of 5 mg) once daily. Depending on individual tolerance, the dose should be gradually increased to 2.5 mg (1/2 tablet of 5 mg), 3.75 mg (3/4 tablet of 5 mg), 5 mg (1 tablet of 5 mg or 1/2 tablet of 10 mg), 7.5 mg (3/4 tablet of 10 mg) and 10 mg once daily at intervals of at least 2 or more weeks. If the increased dose is not well tolerated by the patient, the dose may be reduced.

The maximum daily dose for treatment of CHF is 10 mg once daily.

At the time of titration, regular monitoring of BP, HR and symptoms of CHF increase in severity is recommended. Worsening of CHF symptoms is possible from the first day of using the drug.

A temporary worsening of CHF course, arterial hypotension or bradycardia may occur during or after the titration phase. In this case, first of all, it is recommended to pay attention to the dose selection of concomitant standard therapy. It may also be necessary to temporarily decrease the dose of Biol® 5 mg or discontinue treatment.

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

Hepatic or renal impairment

Mild to moderate hepatic or renal impairment usually does not require dose adjustment. In severe renal impairment (CKD 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.

Dose adjustment is not required in elderly patients.

To date there are not enough data regarding use of Biol® 5 mg in patients with CHF associated with diabetes mellitus type 1, expressed renal and/or hepatic dysfunction, restrictive cardiomyopathy, congenital heart disease or hemodynamically determined heart disease. There are also still insufficient data regarding patients with CHF with myocardial infarction within the last 3 months.

Interaction

Class I antiarrhythmic agents (e.g. quinidine, disopyramide, lidocaine, phenytoin, flecainide, propafenone) when used simultaneously with bisoprololol may decrease AV conduction and myocardial contractility.

The class III antiarrhythmic agents (e.g., amiodarone) may increase AV conduction impairment.

The effects of beta-adrenoblockers for topical use (e.g. eye drops to treat glaucoma) may increase the systemic effects of bisoprololol (BP reduction, heart rate slowing).

Parasympathomimetics when used concomitantly with bisoprololol may increase AV conduction impairment and increase the risk of bradycardia.

The concomitant use of Biol® with beta-adrenomimetics (e.g., isoprenaline, dobutamine) may decrease the effects of both drugs.

Combination of bisoprolol with adrenomimetics affecting beta- and alpha-adrenoreceptors (e.g. norepinephrine, epinephrine) may enhance the vasoconstrictor effects of these drugs arising from α-adrenoreceptors, leading to increased BP. Such interactions are more likely when using non-selective beta-adrenoblockers.

Mefloquine when used concomitantly with bisoprolol may increase the risk of 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 agents for IV administration increase the risk of anaphylactic reactions.

Phenytoin when administered by IV, agents for inhalation anesthesia (hydrocarbon derivatives) increase
the severity of cardiodepressive effects and the likelihood of BP reduction.

The effectiveness of insulin and oral hypoglycemic agents may change with bisoprolol treatment (masks the symptoms of developing hypoglycemia: tachycardia and increased BP).

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

The hypotensive effect is weakened by NSAIDs (retention of sodium ions and blockade of prostaglandin synthesis by kidneys), GCS and estrogens (retention of sodium ions).

The 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 can lead to excessive BP reduction.

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

Tricyclic and tetracyclic antidepressants, antipsychotics (neuroleptics), ethanol, sedatives and hypnotics increase CNS depression.

The concomitant use with MAO inhibitors is not recommended due to a significant increase in hypotensive effect. There should be a break in treatment of at least 14 days between taking MAO inhibitors and bisoprolol.

Unhydrogenated 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 T1/2 of bisoprolol.

Special Instructions

Biol® should not be stopped abruptly because of the danger of severe arrhythmias and myocardial infarction. Withdrawal should be done gradually, reducing the dose by 25% every 3 to 4 days.

Control of patients taking Biol® should include HR and BP measurements (daily at the beginning of therapy and then once every 3-4 months), ECG, determination of blood glucose concentration in diabetic patients (once every 4-5 months).

The patient should be instructed on how to calculate heart rate and instructed to consult a physician if the heart rate is less than 50 bpm.

If elderly patients show increasing bradycardia (HR less than 50 beats/min), markedly decreased BP (systolic BP less than 100 mmHg), AV blockade, the dose should be reduced or the treatment should be stopped.

Before starting treatment, it is recommended to perform an external respiratory function study in patients with a history of poor bronchopulmonary function.

Patients who wear contact lenses should note that there may be a decrease in tear fluid production during treatment with the drug.

In patients with pheochromocytoma, there is a risk of paradoxical arterial hypertension when using Biol® (if effective blockade of the alpha-adrenoreceptors has not been previously achieved).

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

In diabetics with diabetes, bisoprolol may mask the tachycardia caused by hypoglycemia. Unlike non-selective beta-adrenoblockers, it practically does not increase insulin-induced hypoglycemia and does not delay recovery of blood glucose concentration to normal levels.

If clonidine is taken at the same time, its administration can be stopped only after several days after discontinuation of Biol®.

The severity of hypersensitivity reactions may increase and the lack of effect of conventional doses of epinephrine with a history of allergy is possible.

If surgical intervention is necessary, the drug should be withdrawn 48 hours prior to the start of general anesthesia. If the patient has taken the drug prior to surgical intervention, the drug for general anesthesia should be selected with minimal negative inotropic effect.

The reciprocal activation of the vagus nerve can be eliminated by IV atropine (1-2 mg).

Drugs that reduce catecholamine stores (including reserpine) can potentiate the effects of beta-adrenoblockers, so patients taking these combinations of medications should be monitored by a physician for a marked decrease in BP or bradycardia.

Patients with bronchospastic disorders may be prescribed cardioselective beta-
adrenoblockers with caution if other hypotensive agents are intolerant and/or ineffective. Against the background of taking
beta-adrenoblockers in patients with concomitant bronchial asthma, airway resistance may increase. If the dose of Biol® is exceeded in such patients there is a risk of developing bronchospasm.

If patients show increasing bradycardia (HR less than 50 beats/min), significant decrease of BP (systolic BP less than 100 mm Hg), AV blockade, the dose should be reduced or the treatment should be stopped.

It is recommended to discontinue therapy with Biol® if depression develops.

The treatment should not be stopped abruptly because of the risk of severe arrhythmias and myocardial infarction. The drug should be withdrawn gradually, reducing the dose over 2 weeks or more (reduce the dose by 25% every 3 to 4 days).

The drug should be discontinued before blood and urine concentrations of catecholamines, normetanephrine, vanillin acid, and antinuclear antibody titers are tested.

The efficacy of beta-adrenoblockers is lower in smoking patients.

Impact on driving and operating machinery

When treating with Biol® care should be taken when driving vehicles and engaging in other potentially dangerous activities requiring increased concentration and quick psychomotor reactions.

Contraindications

With caution:

Side effects

The frequency of adverse reactions below was determined according to the following (WHO classification): very common (≥10%); common (≥1%, but

Cardiovascular system: very often – decreased HR (bradycardia, especially in patients with CHF), sensation of palpitation; often – marked decrease in BP (especially in patients with CHF), manifestation of angiospasm (increased peripheral circulatory disorders, feeling of cold in extremities (paresthesias); infrequent – AV conduction disorders (up to complete transverse blockade and cardiac arrest), arrhythmias, orthostatic hypotension, worsening of CHF with development of peripheral edema (edema of ankles, feet, dyspnea), chest pain.

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

Senses: rare – visual disturbances, decreased tear production (should be considered when wearing contact lenses), tinnitus, decreased hearing, ear pain; very rare – dry and painful eyes, conjunctivitis, taste disorders.

Respiratory system disorders: infrequent – bronchospasm in patients with bronchial asthma or obstructive airways disease; rare – allergic rhinitis; nasal congestion.

The digestive system: frequently – nausea, vomiting, diarrhea, constipation, dry mouth, abdominal pain; rarely – hepatitis, increased liver enzymes activity (ALT, AST), increased bilirubin concentration, change in taste.

Muscular system disorders: infrequent – arthralgia, back pain.

Urogenital system disorders: very rarely – impaired potency, decreased libido.

Laboratory disorders: rare – increased concentration of triglycerides in the blood; in some cases – thrombocytopenia, agranulocytosis, leukopenia.

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

Skin reactions: rare – increased sweating, skin hyperemia, exanthema, psoriasis-like skin reactions; very rare – alopecia; beta-adrenoblockers may worsen psoriasis.

Others: “withdrawal” syndrome (increased frequency of angina pectoris attacks, increased BP).

Overdose

Symptoms: arrhythmia, ventricular extrasystole, marked bradycardia, AV-blockade, marked BP decrease, acute heart failure, hypoglycemia, acrocyanosis, breathing difficulties, bronchospasm, dizziness, fainting, seizures.

Treatment: first of all the drug administration should be stopped, the stomach should be flushed, adsorptive agents should be taken, symptomatic therapy should be carried out. In marked bradycardia – intravenous injection of atropine. If the effect is insufficient, a drug with positive chronotropic effect may be administered with caution. Sometimes a temporary use of an artificial pacer may be necessary. With a marked decrease in BP – intravenous administration of plasma substitute solutions and vasopressors. In case of hypoglycemia, IV administration of glucagon or IV administration of dextrose (glucose) may be indicated. In AV blockade: patients should be continuously monitored,
and treated with beta-adrenomimetics such as epinephrine.

If necessary, an artificial pacemaker should be inserted. In exacerbation of CHF – intravenous administration of diuretics, drugs with positive inotropic effect, and vasodilators. In bronchospasm – administration of bronchodilators, including beta2-adrenomimetics and/or aminophylline.

Pregnancy use

The use of Biola in pregnancy is possible only if the expected benefits to the mother exceed the potential risk to the fetus.

The drug is excreted with the breast milk, therefore if the drug is taken during lactation, breastfeeding should be stopped.

Similarities