Biol, 2,5mg 30 pcs.

Pharmacodynamics

Bisoprolol is a selective beta₁-adrenoblocker, without its own sympathomimetic activity -, has no membranostabilizing effect. As with other beta₁-adrenoblockers, the mechanism of action in arterial hypertension is unclear. At the same time, it is known that bisoprolol reduces plasma renin activity, decreases myocardial oxygen demand, and slows heart rate. It has hypotensive, antiarrhythmic and antianginal effects.

Blocking in low doses beta₁-adrenoceptors of the heart, reduces catecholamine-stimulated formation of cAMP from ATP, reduces intracellular flow of calcium ions, inhibits all heart functions, reduces AV conduction and excitability. If the therapeutic dose is exceeded, it has beta₂-adrenoblocking effect. HRPP increases at the beginning of drug administration, in the first 24 hours (as a result of reciprocal increase of alpha-adrenoreceptors activity and elimination of beta₂-adrenoreceptors stimulation), after 1-3 days it returns to initial value, and it decreases during prolonged use. The antihypertensive effect is associated with a decrease in the minute blood volume, sympathetic stimulation of peripheral vessels, reduction of sympathoadrenal system (SAS) activity (of great importance for patients with initial renin hypersecretion), restoration of sensitivity in response to BP reduction and influence on CNS. In arterial hypertension the effect develops in 2-5 days, stable effect is noted in 1-2 months.

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

When used at moderate therapeutic doses, unlike non-selective beta-adrenoblockers, it has less pronounced effects 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 in the body; the intensity of atherogenic action does not differ from that of propranololol.

Pharmacokinetics

Bisoprolol is almost completely absorbed from the gastrointestinal tract; absorption is not affected by meals. Bioavailability is about 90%.

T_max is 2-4 h after oral administration. Binding with blood plasma proteins is 26-33%. Metabolized in the liver, bisoprolol metabolites have no pharmacological activity. T_1/2 is 9-12 h, which makes it possible to use the drug once daily.

It is excreted by the kidneys – 50% unchanged, less than 2% – through the intestine.

Permeability through the blood-brain barrier and placental barrier is low; in small amounts it is excreted with the breast milk.

Indications

Active ingredient

Composition

1 tablet contains:

the active ingredient:

bisoprolol hemifumarate 2.5 mg

excipients:

MCC;

calcium hydrophosphate;

corn starch;

croscarmellose sodium;

magnesium stearate;

colloidal anhydrous silicon dioxide

film shell:

Lactose monohydrate; hypromellose; titanium dioxide; macrogol 4000; iron (III) oxide dye yellow; iron (III) oxide dye red (for 10 mg dosage)

How to take, the dosage

In the morning, on an empty stomach (before breakfast), during or after breakfast, once a day with a small amount of liquid. The tablets should not be chewed or crushed into a powder.

In all cases, the dosage and the regimen should be customized for each individual patient, especially based on the patient’s heart rate and their condition.

Art Hypertension and CHD

In case of arterial hypertension and coronary heart disease Biol® is taken in dose of 5 mg once daily. If necessary, the dose is increased to 10 mg once daily.

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

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

The prerequisite for treatment with Biol® is stable CHF without signs of exacerbation.

The treatment of CHF with Biol® starts 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 Biol® 5 mg), 3.75 mg (3/4 tablet 5 mg), 5 mg (1 tablet of Biol® 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 weeks.

If the increased dose is not well tolerated by the patient, the dose may be reduced.

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

At the time of titration, it is recommended that BP, HR and symptoms of CHF increase in severity be monitored regularly. Worsening of CHF symptoms is possible from the first day of using the drug.

A temporary worsening of CHF, arterial hypotension, or bradycardia may occur during or after the titration phase. In this case it is recommended to pay attention to the dose selection of concomitant standard therapy in the first place. It may also be necessary to temporarily decrease the dose of Biol® 5 mg or cancel the treatment. Once the patient’s condition has stabilized, the dose should be re-titrated or treatment should continue.

Hepatic or renal impairment

Mild to moderate hepatic or renal impairment usually does not require dose adjustments. In severe renal impairment (creatinine Cl 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.

Patients in the elderly

There is no need for dose adjustment.

To date there are not enough data regarding use of Biol® 5 mg in patients with CHF associated with diabetes mellitus type 1, severe renal and/or hepatic dysfunction, restrictive cardiomyopathy, congenital heart disease or hemodynamically determined heart defect. 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) in concomitant use with bisoprolol may reduce AV conduction and myocardial contractility. Class III antiarrhythmic agents (e.g. amiodarone) may increase AV conduction disturbance. The action of beta-adrenoblockers for topical use (e.g. eye drops for the treatment of glaucoma) may increase the systemic effects of bisoprololol (BP reduction, heart rate slowing).

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

The concomitant use of Biol® with 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 enhance the vasoconstrictor effects of these drugs occurring with the participation of alpha-adrenoreceptors, leading to an increase in 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 x-ray contrast 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 hypoglycemic agents for oral administration may change when treated with bisoprolol (masks the symptoms of developing hypoglycemia: tachycardia, BP increase).

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. Hypotensive effect is weakened by NSAIDs (retention of sodium ions and blockade of PG synthesis by kidneys), GCS and estrogens (retention of sodium ions).

The cardiac glycosides, methyldopa, reserpine and guanfacine, DMARDs (verapamil, diltiazem), amiodarone and other antiarrhythmic agents increase the risk of developing or worsening bradycardia, AV block, cardiac arrest 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, including ergotamine, increase the risk of peripheral circulatory disorders.

Sulfasalazine increases plasma concentrations 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).

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

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

If elderly patients are found to have increasing bradycardia (HR less than 50 bpm), marked BP decrease (BP less than 100 mmHg), AV block, the dose should be reduced or treatment should be discontinued. Before initiating treatment it is recommended to investigate external respiratory function in patients with a history of complicated bronchopulmonary disease.

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 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 diabetic patients, it 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 values. If clonidine is concomitantly used, its administration may be stopped only after several days after discontinuation of Biol®.

The severity of hypersensitivity reactions and lack of effect of usual doses of epinephrine against a background of a history of allergy may increase.

If planned surgical treatment is necessary, the drug should be discontinued 48 hours before general anesthesia. If the patient has taken the drug prior to surgical intervention, the drug for general anesthesia should be selected with a minimally negative inotropic effect.

Reciprocal activation of the vagus nerve can be eliminated by IV administration of atropine (1-2 mg). Drugs that deplete catecholamine depots (including reserpine) can potentiate the effects of beta-adrenoblockers, so patients taking these combinations of drugs should be under constant medical supervision for marked BP reduction or bradycardia.

Patients with bronchospastic disorders may be treated with caution with cardioselective beta-adrenoblockers 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, such patients are at risk of developing bronchospasm.

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

The therapy with Biol® should be discontinued 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 examined. In smokers, the effectiveness of beta-adrenoblockers is lower.

Impact on the ability to drive vehicles and perform other activities requiring concentration and rapid psychomotor reactions. During the treatment with Biol® care should be taken when driving vehicles and performing other potentially dangerous activities requiring increased concentration and quick psychomotor reactions.

Contraindications

With caution:

Side effects

The incidence of adverse reactions below was defined as follows (WHO classification): 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.

Systems side: very often – decreased HR (bradycardia, especially in patients with CHF), sensation of palpitations; 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 disturbance, 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 impairment, 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.

Motor system disorders: infrequent – arthralgia, back pain.

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

Laboratory measures: rare – increase of triglycerides concentration in blood; in single cases – thrombocytopenia, agranulocytosis, leukopenia.

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

Skin disorders: 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 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, seizures.

Treatment: in case of overdose, the first thing to do is to stop taking the drug, gastric lavage, adsorptive agents should be taken, symptomatic therapy should be carried out.

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 case of a marked decrease in BP – intravenous administration of plasma substitute solutions and vasopressors. In hypoglycemia may be shown by intravenous injection of glucagon or dextrose (glucose). In AV blockade – patients should be constantly monitored and treated with β-adrenomimetics such as epinephrine. If necessary – placement of an artificial pacemaker.

In case of exacerbation of CHF, intravenous administration of diuretics, drugs with positive inotropic effect, and vasodilators.

In case of bronchospasm – administration of bronchodilators, including β-adrenomimetics and/or aminophylline.

Similarities