Expiration date: 02/2026
Clinico-pharmacological group
(Antihypertensive drug)
Release form, composition and packaging
Tablets, coated white or almost white, biconvex.
Excipients: lactose monohydrate - 62 mg, cellulose microcrystalline - 18 mg croscarmellose sodium 2 mg, corn starch - 4.75 mg, povidone - 3.5 mg, magnesium stearate - 1 mg.
The film composition of the shell: hypromellose - 1.65 mg, macrogol 4000 - 0.45 mg, titanium dioxide - 0.9 mg.
Tablets, coated white or almost white, biconvex.
1 tablet contains:
bisoprolol fumarate 2.5 or 5 mg
hydrochlorothiazide 6.25 mg
Excipients: lactose monohydrate - 130.25 mg, microcrystalline cellulose - 36 mg, croscarmellose sodium 4 mg, corn starch - 9.5 mg, povidone - 7 mg, magnesium stearate - 2 mg.
The film composition of the shell: hypromellose - 3.3 mg, macrogol 4000 - 0.9 mg, titanium dioxide - 1.8 mg.
Pharmacological action
Bisoprolol is a selective beta1-blocker without intrinsic sympathomimetic activity. It has antihypertensive, antiarrhythmic and antianginal effects. Blocking in low doses of ?1-adrenergic receptors of the heart, reduces catecholamines stimulated camp formation from ATP, reduces intracellular current of calcium ions, has a negative Chrono-, dromo-, batmo - and inotropic effect (slows heart rate, depresses cardiac conduction, reduces the excitability and contractility of the myocardium). With increasing doses inhibits ?2-adrenoreceptors. The CSO at the beginning of the use of beta-blockers in the first 24 h is increased (as a result of reciprocal increase in activity of ?-adrenergic receptors and eliminate stimulation of ?2-adrenoceptor), through 1-3 day returns to the source, and prolonged assignment is reduced.
The antihypertensive effect associated with a decrease in cardiac output, inhibition of sympathetic stimulation of peripheral vessels, decreased activity of the renin-angiotensin-aldosterone system by inhibiting ?-adrenergic receptors yukstaglomerulyarnogo apparatus of the kidneys (leading to decreased secretion of renin), restoring sensitivity of baroreceptors of the aortic arch (does not enhance their activity in response to decreased blood pressure) and the influence on the Central nervous system. In arterial hypertension effect occurs in 2-5 days, stable effect - in 1-2 months. therapy.
Hydrochlorothiazide is a thiazide diuretic that violates the reabsorption of sodium ions, chlorine, potassium, magnesium in the distal nephron, delays the excretion of calcium, uric acid. Increase renal excretion of these ions is accompanied by an increase in the amount of urine (due to osmotic binding of water). Hydrochlorothiazide reduces plasma volume of blood increases renin activity in plasma and aldosterone secretion. When taken in high doses, hydrochlorothiazide increases excretion of bicarbonate, prolonged use will reduce the excretion of calcium.
Antihypertensive effect develops due to reduction of BCC, the changes in reactivity of the vascular wall, reducing the Pressor effects of vasoconstrictor amines (adrenaline, noradrenaline) and enhance the depressant effect on the ganglia. Does not affect normal blood pressure. The diuretic effect observed after 1-2 h, reaches a maximum after 4 h and lasts 6-12 h. Antihypertensive activity occurs within 3-4 day, but to achieve the optimal therapeutic effect it is necessary 3-4 weeks.
Pharmacokinetics
Bisoprolol
Bisoprolol is almost completely absorbed in the digestive tract, food intake does not affect absorption. The first pass effect through the liver is negligible, which leads to high bioavailability (about 90%).
Bisoprolol is metabolized via the oxidative pathway without subsequent conjugation. All metabolites have a strong polarity and are excreted by the kidneys. The main metabolites detected in plasma and urine, does not exhibit a pharmacological activity. The data obtained in the result of experiments with human liver microsomes in vitro indicate that bisoprolol is metabolized primarily via CYP3A4 (about 95%), and the isoenzyme CYP2D6 plays only a minor role.
Relationship with blood plasma proteins is about 30%. Vd - 3.5 l/kg Total clearance is approximately 15 l/h Cmax in plasma is determined after 2-3 h, the Permeability through the blood-brain barrier and placental barrier - low.
The half-life period from blood plasma (10-12 hours) provides efficiency for 24 hours after administration of a single daily dose.
Bisoprolol is excreted from the body in two ways, 50% of the dose is metabolized in the liver to form inactive metabolites. About 98% excreted by the kidneys, of which 50% is excreted unchanged, less than 2 % - through the intestines (with bile).
Since excretion in the kidney and liver equally, patients with impaired liver or renal insufficiency dose adjustment is not required. The pharmacokinetics of bisoprolol are linear and independent of age.
Hydrochlorothiazide
After oral absorption and bioavailability of hydrochlorothiazide is 70%. Relationship with blood plasma proteins - 60-80%.
When administered 12.5 mg of hydrochlorothiazide Cmax is achieved in 1.5-4 hours and is 70 ng/ml, and when administered 25 mg of hydrochlorothiazide Cmax achieved after 2 - 5 hours and is 142 ng/ml.
In the therapeutic dose range average AUC increases with the increase in dose, the appointment 1 time per day accumulation is negligible. Gematoplatzentarnyi penetrates through the barrier and into breast milk.
T1/2 is 5-6 h. Hydrochlorothiazide is slightly metabolized in the liver. Hydrochlorothiazide is excreted almost entirely (over 95%) by the kidneys in unchanged form. 50-70% of an oral dose is excreted within 24 h.
Dosage
Bismil recommended to be taken in the morning (during the meal). The tablets should be swallowed whole, not liquid, squeezed small amount of liquid 1 times/day.
The dose should be selected individually.
The initial dose of the drug Bismil - 1 tablet 2.5 mg/6.5 mg (bisoprolol 2.5 mg/ hydrochlorothiazide 6.25 mg) 1 times/day.
If the antihypertensive effect is insufficient, increase the dose (after 2 weeks) - 1 tablet 5 mg/6.25 mg (bisoprolol 5 mg/hydrochlorothiazide 6.25 mg) 1 times/day.
Patients with impaired liver function and elderly patients the dosage adjustment is not required.
In patients with impaired renal function (QC over 30 ml/min) the maximum daily dose of bisoprolol must not exceed 10 mg.
Overdose
Bisoprolol
The most frequent symptoms of overdose of beta-blockers: expressed lower AD, aetiology, AV-blockade, bronchospasm, acute cardiac insufficiency and hypoglycaemia.
Hydrochlorothiazide
Clinical manifestations of acute or chronic overdose of hydrochlorothiazide is caused by considerable loss of fluid or electrolytes.
The most frequent symptoms of overdose of hydrochlorothiazide include dizziness, nausea, drowsiness, hypovolemia, marked reduction in blood pressure, hypokalemia.
Treatment: in case of overdose, it is first necessary to discontinue the drug, gastric lavage, assign absorbent means to carry out supportive symptomatic therapy.
When expressed bradikardii: in/in introducing atropine. Sometimes you may need a temporary production of an artificial pacemaker. In marked decrease in blood pressure: in/with the introduction of plasma-substituting solutions. At AV-blockade (II and III degree): patients should be under constant surveillance, you can assign the epinephrine, if necessary -the production of an artificial pacemaker. During exacerbation of chronic heart failure: in/with the introduction of diuretics, drugs with positive inotropic effect, as well as vasodilators. If bronchospasm: appointment of bronchodilators, beta2-sympathomimetics and/or aminophylline. Hypoglycemia: in/appointment of dextrose (glucose).
Drug interactions
Combinations, the use of which is contraindicated
In case of shock or hypotension caused by receiving floctafenine, beta-blockers decrease cardiovascular compensatory reactions.
Bisoprolol should not be used simultaneously with sultopridom, because there is a high risk of ventricular arrhythmias, including type "pirouette".
MAO inhibitors of type A should not be taken simultaneously with bisoprololum, as there is a risk of hypertensive crisis.
Not recommended combinations
Antiarrhythmic agents of class I (e.g., quinidine, disopyramide, lidocaine, phenytoin, flecainid, propafenon) while the use of bisoprololum can reduce AV conduction and contractility of the heart. Blockers of slow calcium channels (bmkk) of the verapamil type and to a lesser extent, diltiazem, while the use of bisoprololum can lead to a decrease in myocardial contractility and impaired AV conduction. In particular, in intravenous verapamil to patients receiving beta-blockers may lead to severe hypotension and AV blockade. Antihypertensive drugs of Central action (such as clonidine, methyldopa, moxonidine, rilmenidine) can lead to slowing the heart rate and decrease cardiac output and to vasodilation due to a decrease in Central sympathetic tone. Abrupt withdrawal of antihypertensives Central action, especially before the abolition of beta-blockers may increase the risk of developing "rebound" hypertension.
Combinations requiring caution
Antiarrhythmic agents of class III (e.g. amiodarone) may increase the violation of AV conduction.
Effect of beta-blockers for topical application (e.g. eye drops for glaucoma treatment) may exacerbate the systemic effects of bisoprolol (decrease in blood pressure, slowing the heart rate).
Parasympathomimetic while the use of bisoprolol may increase the violation of AV conduction and increase the risk of bradycardia. The simultaneous use of the drug Bismil with beta-agonists (e.g., isoprenaline, dobutamine) may cause decreased effect of both drugs. Combination of bisoprolol with agonists affecting beta - and alpha-adrenoceptors (e.g. norepinephrine, epinephrine) may increase the
vasoconstrictor effects of these means that occur with the participation of alpha-adrenergic receptors, leading to increased blood pressure. Such interaction is more likely with use of nonselective beta-blockers.
Mefloquine while the use of bisoprololum can 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/in the introduction increases the risk of anaphylactic reactions.
Phenytoin in the on/in the introduction, means for inhalation anesthesia (derivatives of hydrocarbons) increase the intensity of cardiodepressive actions and reduce the likelihood of AD.
The effectiveness of insulin and hypoglycemic agents for oral administration may vary in the treatment of bisoprololum (masks the symptoms of developing hypoglycemia: tachycardia, the AD).
The clearance of lidocaine and xantinov (except theophylline) may be reduced in connection with a possible increase in their concentration in blood plasma, especially in patients with initially increased clearance of theophylline under the influence of Smoking. Antihypertensive effect of weakening non-steroidal anti-inflammatory drugs (NSAIDs) (delay of sodium ions and blockade of prostaglandin synthesis by the kidney), corticosteroids and estrogens (delays sodium ions).
Cardiac glycosides, methyldopa, reserpine, and guanfacine, blockers slow calcium channels (verapamil, diltiazem), amiodarone and other antiarrhythmic agents increase the risk of developing or exacerbating bradycardia, AV block, cardiac arrest and heart failure.
Antiarrhythmic agents which may cause tachycardia type "pirouette" (the class IA eg, quinidine, gidroxizin, disopyramide and class III, e.g. amiodarone, dofetilide, ibutilide) and sotalol: hypokalemia may provoke the occurrence of tachycardia type "pirouette".
Other arrhythmic agents which may cause tachycardia type "pirouette" (eg, astemizole, erythromycin for I/V administration, halofantrine, pentamidine, sparfloxacin, terfenadine, vincamine has): hypokalemia may provoke the development of tachycardia type "pirouette".
Nifedipine can lead to significant reduction of AD
Diuretics, clonidine, sympatholytic, hydralazine, and other antihypertensive drugs can lead to excessive reduction of AD.
Effects of non-depolarizing muscle relaxants and anticoagulant effect of coumarins during treatment with bisoprolol can be extended.
Tricyclic and tetracyclic antidepressants, antipsychotic means (neuroleptics), ethanol, sedatives and hypnotics drugs increase oppression CNS.
Not recommended simultaneous application with MAO inhibitors because of significant increase in antihypertensive action. The break in treatment between receiving MAO inhibitors and bisoprolol must be not less than 14 days. Non-hydrogenated ergot alkaloids increase the risk of peripheral circulatory disorders.
Ergotamine increases risk of peripheral circulation. Sulfasalazine bisoprolol improves concentration in plasma. Rifampicin shortens the half-life of bisoprolol. Hydrochlorothiazide
With thiazide diuretics drugs such as ethanol, barbiturates and narcotics, may potentiate the risk of orthostatic hypotension.
Hypoglycemic agents (oral and insulin) may require dosage adjustment of hypoglycemic agents.
Other antihypertensive drugs - additive effect.
Cholestyramine and colestipol in the presence of anion exchange resins absorption of hydrochlorothiazide is impaired. Cholestyramine and colestipol dose bind the hydrochlorothiazide and reduce its absorption in the digestive tract of 85% and 43%, respectively.
Corticosteroids, ACTH (adrenocorticotropic hormone) or glycyrrhizin (found in licorice root) - marked reduction of electrolytes, in particular, the risk of hypokalemia.
Pressor amines (e.g. epinephrine, norepinephrine) - lower the intensity of the response to the reception of Pressor amines.
Muscle relaxants non-depolarizing type of action (e.g., tubokurarin) - strengthening effect of the muscle relaxants.
Lithium - diuretics reduce kidney klirens lithium and increase the risk of developing toxic action of lithium concurrent use is not recommended.
Nonsteroidal anti-inflammatory drugs (NSAIDs) (including COX-2 inhibitors) may reduce the diuretic, natriuretic, and antihypertensive effect of diuretics.
Some patients with impaired renal function (e.g. elderly patients or patients with dehydration, including administering diuretics), receiving treatment with NSAIDs, including COX-2 inhibitors, treatment with antagonists of angiotensin II receptors or ACE inhibitors may cause further deterioration of renal function, including acute renal failure. These effects are reversible. The simultaneous use of these drugs should be used with caution in patients with impaired renal function.
In connection with the effect on calcium metabolism it may be able to skew the results of research of function of the parathyroid glands.
He should abruptly stop therapy, especially in patients with coronary artery disease. The dose should be reduced gradually over two weeks. If necessary, simultaneously initiate appropriate anti-anginal therapy.
Special attention is needed in cases of surgery under General anesthesia in patients receiving beta-blockers. Such patients should stop the drug Betangel for 48 h before the surgery to warn the surgeon-anesthesiologist that the patient takes the drug Bismil. As a means for General anesthesia, you should choose the drug with minimal negative inotropic effects.
During therapy with beta-adrenoblokatorami possible worsening of psoriasis. Patients with this disease Bidangil the drug should be administered with caution. When referring to a history of anaphylactic reaction, regardless of their causes, especially when conducting desensitizing therapy, treatment with Betangel (due to the content of bisoprolol) may increase the risk of allergic reactions and contribute to the development of resistance to treatment with epinephrine (adrenaline) in normal doses.
Patients using contact lenses, care should be taken when using the drug Besanger, since beta-blockers can reduce the production of tear fluid.
Patients with hyperuricemia are at increased risk of exacerbation of gout. In this case, the dose of the drug Betangel should be individualized under the control of the concentration of uric acid in the blood serum. Before the study of parathyroid treatment with Betangel should cease, as against the background of its reception may occur transient hypercalcemia.
Athletes should be informed that the drug Bismil contains bisoprolol, which may give false positive results when conducting doping control.
Effects on ability to drive vehicles and management mechanisms
Betangel should be used with caution in the management of vehicles and mechanisms with regard to the possibility of dizziness.
Pregnancy and lactation
The use of the drug Bismil contraindicated in pregnancy.
It is currently not known whether bisoprolol is excreted in breast milk. Diuretics from the group of thiazides are excreted in breast milk and therefore breast-feeding during treatment with the drug Bismil is not recommended. If the use of the drug is necessary during lactation, breastfeeding must cancel
Side effects
Frequency of adverse reactions given below were determined according to the following (classification world health organization): very often - at least 10%, often at least 1% but less than 10%, often not less than 0.1%), but less than 1%, rarely - at least 0.01% but < 0.1 %, very rare - less than 0.01%>, including individual messages.
Of the heart and blood vessels: often - slowing the heart rate (bradycardia, especially in patients with chronic heart failure), palpitations, often - expressed lower AD (especially in patients with chronic heart failure), manifestation of angiospasm (increased peripheral circulatory disorders, cold sensation in the extremities (paresthesia), rare - violation of AV conduction (until the development of a complete transverse blockade and heart failure), arrhythmia, orthostatic hypotension, aggravation of chronic heart failure with the development of peripheral edema (swelling of ankles, feet, shortness of breath), chest pain.
From the nervous system: often - dizziness, headache, asthenia, fatigue, sleep disturbances, depression, anxiety, rarely - confusion or short-term memory loss, nightmares, hallucinations, myasthenia gravis, tremor, muscle cramps. Usually these effects are mild nature and are usually within 1-2 weeks after the start of treatment.
From the sensory organs: rare - impaired vision, reduction of tearing (to consider when wearing contact lenses), tinnitus, hearing loss, ear pain, rarely - dryness and soreness of eyes, conjunctivitis, breach of taste.
The respiratory system: rare - bronchospasm in patients with bronchial asthma or obstructive diseases of the respiratory tract, rarely - allergic rhinitis, nasal congestion.
Co the digestive system: often - nausea, vomiting, diarrhea, constipation, dryness of the mucous membrane of the mouth, abdominal pain, rarely - hepatitis, increased activity of liver enzymes (ALT, AST), increased concentration of bilirubin, a change of taste.
From the side of musculoskeletal system: infrequently - artralgia, pain in the back.
With the genitourinary system: very rarely - violation of potency, weakening of libido.
Laboratory tests: rarely - increased concentration of triglycerides in the blood, in some cases - thrombocytopenia, agranulocytosis, leukopenia.
Allergic reactions: rare - skin itching, rash, hives.
From the skin: rarely - increased sweating, hyperemia of skin, exanthema, psoriasiform skin reactions, very rare - alopecia, beta-blockers can exacerbate psoriasis.
Other: the syndrome (the strokes, the AD).
Hydrochlorothiazide
Violation of water-electrolyte balance: hypokalemia, hypomagnesemia, hypercalcemia and alkalosis gipohloremichesky: dry mucous membranes of the mouth, thirst, irregular heart rhythm, changes in mood or psyche, cramps and muscle aches, nausea, vomiting, unusual tiredness or weakness. Gipohloremichesky alkalosis may cause hepatic encephalopathy or hepatic coma. Hyponatremia: confusion, convulsions, lethargy, slowing of the process of thinking, fatigue, irritability, muscle cramps.
Metabolic disorders: hyperglycemia, glycosuria, hyperuricemia development of gout.
Treatment of thiazide-can disrupt glucose tolerance, and latentperiody diabetes can manifest. With the use of high doses may increase the concentration of lipids in the blood serum.
From the digestive system: cholecystitis or pancreatitis, cholestatic jaundice, diarrhea, sialadenitis, constipation, anorexia.
Of the heart and blood vessels: arrhythmias, orthostatic hypotension, vasculitis.
From the nervous system: dizziness, temporary blurred vision, headache, paresthesia.
Organs of hematopoiesis: rarely - leukopenia, agranulocytosis, thrombocytopenia, hemolytic anemia, aplastic anemia.
Allergic reactions: urticaria, purpura, necrotizing vasculitis, Stevens-Johnson syndrome, respiratory distress (including pneumonitis and necardiogenny pulmonary edema), photosensitivity, anaphylactic reactions up to shock.
Other: low potency, impaired renal function, interstitial nephritis.
Terms and conditions storage
The drug should be stored in a dry, dark, inaccessible to children place at temperature not exceeding 25°C. shelf Life - 3 years. Do not use after the expiry date.
Testimony
— arterial hypertension of mild and moderate severity.
Contraindications
— hypersensitivity to bisoprololu and other components of the drug,
— hypersensitivity to hydrochlorothiazide and other derivatives of sulfonamide,
— severe forms of asthma and chronic obstructive pulmonary disease,
acute heart failure or chronic heart failure decompensation requiring inotropic therapy
— cardiogenic shock,
— syndrome sick sinus (including sinoatrial block),
— AV blockade II and III degree, without an artificial pacemaker,
— severe bradycardia (heart rate less than 50 beats/min),
— pheochromocytoma (without the simultaneous use of alpha-blockers),
— difficult-to-control diabetes,
— late stage human peripheral blood circulation (including Raynaud's syndrome),
— severe hypotension (systolic BP less than 100 mm Hg.St.),
— refractory hypokalemia, hyponatremia, hypercalcemia,
— metabolic acidosis,
— acute renal failure,
— chronic renal failure (creatinine clearance (CC)less than 30 ml/min), anuria,
— severe liver function abnormalities (including coma and precoma),
— simultaneous application with floktafeninom, sultopridom,
— concomitant use of inhibitors of monoamine oxidase (MAO) with the exception of MAO inhibitors type b)
— the age 18 years (effectiveness and safety have not been established),
— lactose intolerance, lactase deficiency or glucose-galactose malabsorption,
— pregnancy,
— lactation.
Caution should be used in heart failure, AV blockade degree I, strokes Prinzmetala, peripheral circulatory disorders, coronary heart disease, liver failure, renal failure (QC more 30 ml/min), hyperthyroidism, pheochromocytoma (treatment alpha-blockers), fluid and electrolyte disorders (hyponatremia, hypokalemia, hypercalcemia), depression (including in history), myasthenia gravis, gout, psoriasis, and in patients of advanced age, hyperuricemia, diabetes, with wide variations in the concentration of glucose in the blood, a strict diet, hypovolemia, asthma, bronchospasm (history), conduct desensitizing therapy.
Special instructions
During the period of drug therapy Bismil necessary to control heart rate and blood pressure (at the beginning of treatment - daily, then 1 once in 3-4 mo), the concentration of blood glucose in patients with diabetes mellitus (1 once in 4-5 mo). In elderly patients it is recommended to monitor kidney function (1 once in 4-5 mo). It is necessary to teach the patient methods of calculating heart rate. During the period of drug therapy Bidangil it is also necessary to control the parameters of acid-base status and the content of electrolytes (potassium, sodium, calcium). More frequent monitoring of potassium in patients at high risk. In patients with impaired peripheral circulation, caution must be exercised in the appointment of Betangel.
Thyrotoxicosis drug Bismil (due to the content of bisoprolol) may mask the clinical signs of disease (e.g., tachycardia).
Patients with pheochromocytoma should not be administered the drug Bidangil until then, until the prescribed treatment alpha-blockers. It is necessary to control the AD.
In patients with mild bronchial asthma or chronic obstructive pulmonary disease treatment starts with the minimum dose.
It is recommended to discontinue treatment with the drug Bismil in the development of depression, caused by taking beta-blocker (due to the content of bisoprolol therein). In elderly patients drug treatment Betangel should start with the dosage form of the preparation containing a low dose of bisoprolol (2.5 mg). This requires regular monitoring of patients ' condition.
Use in impaired renal function
Caution should be used in patients with renal insufficiency (QC more 30 ml/min). Contraindications: chronic renal failure (creatinine clearance (CC)less than 30 ml/min), anuria.
Use in hepatic impairment
Contraindication: severe liver function abnormalities (including coma and precoma).
