COMBISO DUO (Kombiso-Duo)

Composition Pharmacodynamics Indications Carefully Contraindications Dosing and Administration Side effects Form release / dosage
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Active substanceBisoprolol + HydrochlorothiazideBisoprolol + Hydrochlorothiazide
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    • Dosage form: & nbsptabscesses
    Composition:

    Composition per one tablet with a dosage of 2.5 mg + 6.25 mg

    Active substances:

    Bisoprolol fumarate 2.50 mg

    Hydrochlorothiazide 6.25 mg

    Excipients:

    Microcrystalline cellulose granulated, microcrystalline cellulose, crospovidone, magnesium stearate, iron oxide coloring yellow

    Composition per tablet with a dosage of 5 mg + 6.25 mg

    Active substances:

    Bisoprolol fumarate 5.00 mg

    Hydrochlorothiazide 6.25 mg

    Excipients:

    Cellulose microcrystalline granular, microcrystalline cellulose, crospovidone, magnesium stearate, iron dye oxide red, iron oxide dye yellow

    Composition per tablet with a dosage of 10 mg + 6.25 mg

    Active substances:

    Bisoprolol fumarate 10.00 mg

    Hydrochlorothiazide 6.25 mg

    Excipients:

    Microcrystalline cellulose granulated, microcrystalline cellulose, crospovidone, magnesium stearate.
    Description:

    For tablets with a dosage of 2.5 mg + 6.25 mg

    Tablets are yellow, round, biconvex, dark inclusions are allowed.

    For tablets with a dosage of 5 mg + 6.25 mg

    Tablets of light pink color, round, biconcave, it is supposed presence of inclusions of dark color.

    For tablets with a dosage of 10 mg + 6.25 mg

    Tablets are white, round, biconvex.

    Pharmacotherapeutic group:Hypotensive combined agent (beta 1-blocker selective + diuretic)
    ATX: & nbsp

    C.07.B.B.07   Bisoprolol in combination with thiazides

    Pharmacodynamics:

    The drug COMBISO DUO is a combination of a selective beta blocker1-adrenoreceptors - bisoprolol and thiazide diuretic - hydrochlorothiazide.

    Bisoprolol is highly selective beta1adrenoblocker without adrenomimetic and membrane-stabilizing activity. Its hypotensive effect is associated with a decrease in the minute volume of blood, suppression of sympathetic stimulation of peripheral vessels,a decrease in the activity of the renin-angiotensin-aldosterone system by inhibiting beta-adrenoreceptors of the juxtaglomerular renal apparatus, leading to a decrease in renin secretion, restoring the sensitivity of the aortic baroreceptors without increasing their activity in response to lowering blood pressure. The hypotensive effect develops in 2-5 days, the stable effect is manifested after 1-2 months.

    Hydrochlorothiazide - Thiazide diuretic with antihypertensive activity. Reduces the reabsorption of sodium ions in the cortical segment of the Henle loop, without affecting its area passing through the medulla of the kidneys. It blocks carbonic anhydrase in the proximal part of the convoluted renal tubules, enhances the excretion of potassium ions, hydrocarbonates and phosphates by the kidneys. Virtually does not affect the acid-base state. Increases the excretion of magnesium ions by the kidneys; It inhibits calcium ions in the body and slows the excretion of urates. Diuretic effect develops after 1 -2 hours, reaches a maximum after 4 hours and persists for 6-12 hours. The diuretic effect decreases with a decrease in the glomerular filtration rate and ceases with itsless than 30 ml / min.

    The active substances of the COMBISO DUO preparation have an additive antihypertensive effect. Hydrochlorothiazide in a dose of 6.25 mg significantly increases the antihypertensive effect of bisoprolol fumarate in a minimum dose of 2.5 mg, increasing the effectiveness of treatment of mild and moderate arterial hypertension. The combination of active substances reduces the side effects of these components, such as bradycardia, asthenia, headache (bisoprolol), hypokalemia (hydrochlorothiazide), arising in the case of their use as monotherapy.

    Pharmacokinetics:

    When taking the drug inside its components are well sorbed, without affecting the bioavailability of each other. Eating does not affect the absorption of active ingredients. The maximum concentration of bisoprolol in the blood plasma (CmOh) is achieved 3 hours after taking the drug, and hydrochlorothiazide - 2.5 hours. The half-life (T1/2) of bisoprolol is 7-15 hours, hydrochlorothiazide - 4-10 hours.

    Bisoprolol

    Suction. Absorption from the gastrointestinal tract is more than 90%. Time to reach the maximum concentration in the blood plasma (TmOh) ranges from 1 to 4 hours. It has a high bioavailability (88%) with a very low effect of the first passage through the liver. For doses from 5 to 40 mg, the kinetics is linear.

    Distribution. The connection with plasma proteins is 30%. The distribution volume is high (about 3 l / kg).

    Metabolism. 40% of bisoprolol is metabolized in the liver; metabolites are inactive.

    Excretion. The half-life of plasma is 11 hours. Kidney and liver clearance are comparable. 55% of the administered dose is excreted in the urine both in unchanged form and in the form of metabolites. The total ground clearance is about 15 liters per hour.

    Hydrochlorothiazide

    Suction. After oral administration, about 80% of hydrochlorothiazide is absorbed from the gastrointestinal tract. Bioavailability of hydrochlorothiazide ranges from 60 to 80%. TmOh is about 4 hours (from 1.5 to 5 hours).

    Distribution. The connection with plasma proteins is 40%.

    Excretion. Hydrochlorothiazide is not metabolized and almost completely eliminated by glomerular filtration and active tubular secretion. T1/2 is about 8 hours.

    In the case of renal and heart failure in elderly patients the renal clearance of hydrochlorothiazide decreases and the elimination half-life increases.

    In patients of this age group, it is also possible to increase the maximum concentration of hydrochlorothiazide in blood plasma.

    Hydrochlorothiazide penetrates the placental barrier and is excreted in breast milk.

    Indications:Arterial hypertension of mild and moderate severity.
    Contraindications:

    - Hypersensitivity to bisoprolol, hydrochlorothiazide, other thiazides, sulfonamides or other components of the drug;

    - severe forms of bronchial asthma and chronic obstructive pulmonary disease (COPD);

    - acute heart failure or chronic heart failure (CHF) in the stage of decompensation, requiring inotropic therapy;

    - cardiogenic shock;

    - syndrome of weakness of the sinus node, including sinoatrial block;

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

    - pronounced bradycardia (heart rate less than 50 beats per minute);

    - Prinzmetal angina (in pure clinical forms and with monotherapy);

    - arterial hypotension (systolic blood pressure less than 100 mm Hg);

    - severe forms of peripheral circulatory disorders, incl. Raynaud's syndrome;

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

    - metabolic acidosis;

    - severe renal dysfunction (creatinine clearance (CK) less than 30 ml / min);

    - severe violations of liver function;

    - refractory hypokalemia;

    - simultaneous administration with sultopride, floktaphenin;

    - age under 18 years (effectiveness and safety not established);

    - pregnancy and the period of breastfeeding.

    Carefully:

    - Atrioventricular (AV) blockade of the I degree;

    - ischemic heart disease (IHD);

    - compensated chronic heart failure;

    - Prinzmetal angina (in mixed clinical forms and with simultaneous use with vasodilating agents);

    - chronic heart failure (CHF);

    - patients with an elongated interval QT;

    - disorders of peripheral circulation;

    - light and moderate forms of bronchial asthma and COPD;

    - diabetes mellitus with significant fluctuations in the concentration of glucose in the blood;

    - thyrotoxicosis;

    - water-electrolyte disorders (hypokalemia, hyponatremia, hypercalcemia);

    - hypovolemia;

    - hyperuricemia;

    - gout;

    - mild and moderate hepatic impairment;

    - renal failure (creatinine clearance more than 30 ml / min);

    - psoriasis;

    - pheochromocytoma (against the background of treatment with alpha-blockers);

    - depression, incl. in the anamnesis;

    - strict diet;

    - myasthenia gravis;

    - elderly age;

    - Myopia (myopia) and angle-closure glaucoma;

    - in patients with an increased risk of developing anaphylactic reactions;

    - with general anesthesia.

    Pregnancy and lactation:

    Use this combination drug during pregnancy and during breastfeeding is contraindicated.

    Bisoprolol

    In studies carried out on laboratory animals, the teratogenic effect was not revealed. In prospective, controlled trials, beta1- adrenoblokatorov developmental defects in newborns is not revealed. In newborns whose mothers used beta1- adrenoblokatory, the latter can lead to heart failure, bradycardia, respiratory failure, hypoglycemia, which, however, had no clinical consequences.

    In preclinical studies it was found that a small amount of bisoprolol fumarate (<2% dose) falls into the milk of lactating rats.At present, there is no data on the excretion of bisoprolol in breast milk in nursing mothers. The risk of developing bradycardia and hypoglycemia in newborns as a result of breastfeeding was not assessed.

    Hydrochlorothiazide

    Clinical data regarding the use in pregnant women, especially in the first trimester of pregnancy, are limited. Hydrochlorothiazide penetrates the placental barrier. Its use during the second and third trimesters of pregnancy can lead to fetoplacental ischemia with a concomitant risk of fetal hypotrophy, as well as fetal and neonatal symptoms of jaundice, electrolyte balance disorders and thrombocytopenia.

    Hydrochlorothiazide should not be used in the case of gestational edema, gestational hypertension and preeclampsia, since there is a risk of a decrease in the volume of plasma and placental hypoperfusion without a positive effect on the course of the disease. Hydrochlorothiazide in small amounts excreted in breast milk. Thiazides in high doses can cause intense diuresis and, thus, suppress the secretion of breast milk.

    Dosing and Administration:

    Inside, in the morning, once a day.Acceptance of the drug with food.

    The tablet should be swallowed whole, without chewing and washing down with a sufficient amount of water.

    Selection of an effective therapeutic dose should be carried out individually, in accordance with the severity of the disease and under the close supervision of a physician.

    Usually, therapy is started by taking 1 tablet of the drug containing 2.5 mg of bisoprolol and 6.25 mg of hydrochlorothiazide once a day. If the therapeutic effect is inadequate after 1-2 weeks, the dose should be increased to 1 tablet containing 5 mg of bisoprolol and 6.25 mg of hydrochlorothiazide once a day. If in this case hypotensive effect will be insufficient, the dose should be increased to 1 tablet containing 10 mg of bisoprolol and 6.25 mg of hydrochlorothiazide, 1 times a day.

    If the time of taking the drug was missed, the next pill should be taken at the usual time, without increasing the dose in order to compensate for the missed one.

    When deciding whether to cancel the drug, the dose reduction should be carried out gradually, within 2 weeks, under the compulsory supervision of the doctor.

    Elderly patients and patients with mild or moderate hepatic or renal impairment (clearance of creatinine (CC) more than 30 ml / min), do not need a special dose adjustment.

    Application in pediatric practice

    It is not recommended to use the drug in children under the age of 18, since efficacy and safety have not been established.

    Side effects:

    Frequency of occurrence of side effects (number of cases / number of observations): very often (≥ 1/10); often (≥ 1/100 to <1/10); infrequently (≥ 1/1000 to <1/100); rarely (≥ 1/10000 to <1/1000); very rarely, including individual messages (<1/10 000); frequency is not set (can not be calculated from available data).

    Effects caused by the drug COMBISO DUO:

    From the heart: infrequently bradycardia, violation of AV conduction, aggravation of CHF symptoms, very rarely - chest pains.

    From the side of the vessels: often - violation of peripheral circulation (sensation of cold or numbness of limbs); infrequently - orthostatic hypotension, rarely - syncope (syncope).

    From the nervous system: often - fatigue, neurasthenia, dizziness, cephalgia (occur at the beginning of treatment, are mild and disappear within 1 -2 weeks).

    From the side of the psyche: infrequently - sleep disturbance, depression; rarely - nightmares, hallucinations.

    From the respiratory system: infrequently - bronchospasm in patients with bronchial asthma or COPD in anamnesis; rarely allergic rhinitis; frequencynot established - interstitial pulmonary disease.

    From the gastrointestinal tract: often - nausea, vomiting, diarrhea, constipation; infrequently - anorexia, abdominal pain, increased concentration of amylase; very rarely - pancreatitis.

    From the liver and biliary tract: rarely - hepatitis, jaundice, increased activity in the blood of "liver" transaminases: alanine aminotransferase (ALT), aspartic aminotransferase (ACT).

    From the side of the organs of sight: rarely - decreased lacrimal gland production (should be taken into account when wearing contact lenses), visual impairment; very rarely - conjunctivitis.

    On the part of the hearing organs and labyrinthine disorders: rarely - hearing impairment.

    From the musculoskeletal and connective tissue: infrequently - muscle weakness, muscle cramps.

    From the genitals and mammary glands: rarely - a violation of potency.

    From the side of metabolism and nutrition: infrequent loss of appetite, hypertriglyceridemia, hypercholesterolemia, hyperglycemia, glucosuria, hyperuricemia; violation of water-electrolyte balance: hypokalemia, hyponatremia, hypomagnesemia, hypocalcemia, hypochloraemia; very rarely - metabolic alkalosis.

    On the part of the blood and lymphatic system: rarely - leukopenia, thrombocytopenia; very rarely - agranulocytosis.

    From the side of the kidneys and urinary tract: infrequently - a reversible increase in the level of creatinine and urea in the blood serum.

    From the skin and subcutaneous tissues: rarely - hypersensitivity reactions, such as pruritus, redness, skin rash, photosensitivity, purpura, urticaria; very rarely - alopecia, discoid lupus erythematosus. Beta-adrenoblockers can exacerbate psoriasis or cause a psoriasis-like rash.

    Overdose:

    Overdose Symptoms

    The most common symptoms of an overdose beta-blockers: bradycardia, marked decrease in blood pressure (BP), AV-blockade, bronchospasm, acute heart failure and hypoglycemia.

    Children born to mothers who received beta-blocker therapy may develop symptoms of an overdose manifested by cardiac decompensation.

    The sensitivity to a single dose of a high dose of bisoprolol varies widely among individual patients and, probably, patients with CHF have high sensitivity.

    Clinical manifestations of acute and chronic overdose hydrochlorothiazide are caused by a significant loss of fluid or electrolytes and are manifested by dizziness, nausea, drowsiness, hypovolemia, hypotension, hypokalemia.

    Treatment

    There is no specific antidote. It is necessary to stop taking the drug, induce vomiting or rinse the stomach, prescribe adsorption drugs and start supporting symptomatic therapy.

    With arterial hypotension should give the patient a horizontal position, raise their legs and begin replenishing the volume of circulating blood, monitoring the blood pressure level. In the case of excessive reduction in blood pressure or severe bradycardia, the following drugs are injected intravenously:

    - atropine in a dose of 1-2 mg, bolus;

    - glucagon in a dose of 1 mg, slowly bolus, and then, if necessary, in the form of an infusion at a dose of 1-10 mg / h;

    - Further, if necessary, enter either adrenaline at a dose of 15-85 mcg, if necessary, repeatedly (its total amount should not exceed 300 mcg), or dopamine in a dose of 2.5-10 μg / kg / min.

    When treating the symptoms of an overdose in newborns,manifestations of decompensation of cardiac activity, it is necessary to ensure observation of the child in the intensive care unit for newborns, where it is prescribed glucagon at the rate of 0.3 mg / kg; adrenaline and dobutamine (usually in high doses).

    When AV-blockade (II or III degree) patients should be under the constant supervision of a doctor, receive treatment with beta-adrenomimetics, and adrenaline may also be used. In some cases, it may be necessary to install an artificial pacemaker.

    With exacerbation of CHF flow: intravenous injection of diuretics, drugs with a positive inotropic effect, as well as vasodilators.

    When bronhospazme: bronchodilators, betag-adrenomimetics and / or aminophylline.

    With hypoglycemia effective intravenous administration of a solution of dextrose (glucose). There is limited evidence that bisoprolol to a small extent is derived from hemodialysis. The degree of excretion of hydrochlorothiazide by hemodialysis is not established.

    Interaction:

    Contraindicated combinations

    Sultopride: simultaneous use with bisoprolol may increase the risk of ventricular arrhythmia, especially as a pirouette.

    Floktaphenin: in the case of development of shock or arterial hypotension caused by floktaphenin, beta-blockers weaken compensatory cardiovascular reactions.

    Unrecommended combinations

    Lithium salts: hydrochlorothiazide can enhance the cardiotoxic and neurotoxic effect of lithium, reducing the excretion of the latter from the body.

    Drugs that can lead to a polymorphic ventricular tachycardia of the type "pirouette" and do not belong to antiarrhythmics (astemizole, beprideil, erythromycin, halofantrine, pentamidine, sparfloxacin, terfenadine, wincamine, sultopride (cf. Contraindicated combinations): can cause ventricular arrhythmia, including polymorphic ventricular tachycardia of the "pirouette" type. Hypokalemia, bradycardia, prolonged interval of QT are the factors provoking occurrence of ventricular arrhythmias. In case of symptoms of hypokalemia, bradycardia and diagnosed prolonged QT interval, do not use the above medicines.

    Class I antiarrhythmic drugs (quinidine, dihydroquinidine, disopyramide; lidocaine, phenytoin; flecainide, propafenone): with simultaneous application with bisoprolol may lead to a violation of automatism, a decrease in the contractility of the myocardium, a violation of AV conduction.

    Antiarrhythmic agents that can cause a polymorphic ventricular tachycardia of the type "pirouette": IA class (quinidine, hydroquinidine, disopyramide) and class III (amiodarone, sotalol, dofetilide, ibutilide). Hypokalemia, bradycardia, prolonged interval of QT are the factors provoking occurrence of ventricular arrhythmias. In case of symptoms of hypokalemia, bradycardia and diagnosed prolonged QT interval, antiarrhythmics should not be used.

    Class III antiarrhythmic drugs: with simultaneous use with bisoprolol cause a violation AV conductivity.

    Hypotensive means of central action (clonidine, methyldopa, moxonidine, rilmenidine): when combined with COMBISO, DUO can lead to a decrease in the heart rate (heart rate) and a decrease in cardiac output, as well as to vasodilation due to a decrease in the central sympathetic tone.However, do not interrupt treatment without consulting a doctor. Abrupt cancellation, especially before the abolition of beta-blockers, may increase the risk of developing "ricochet" arterial hypertension.

    Combinations that should be used with caution

    Blocks of "slow" calcium channels (verapamil, diltiazem, bepridil): with simultaneous application with bisoprolol may lead to a violation of automatism, a decrease in the contractility of the myocardium, a violation AV conduction and heart failure (synergistic effect). In particular, intravenous administration of verapamil to patients taking beta-blockers can lead to severe arterial hypotension and AV blockade.

    Hypotensive drugs and other means with possible antihypertensive effect (tricyclic antidepressants, barbiturates, phenothiazine derivatives, baclofen): in combination with the COMBISO DUO preparation may increase the risk of developing arterial hypotension.

    Insulin and hypoglycemic agents for oral administration, derivatives of sulfonylureas: beta-adrenoblockers can mask the symptoms of developing hypoglycemia (tachycardia,increase of blood pressure).

    Medicines for general anesthesia and iodine-containing contrast agents: beta-blockers can increase the severity cardiodepressive action and the likelihood of excessive blood pressure lowering.

    Lidocaine: bisoprolol, as well as propranolol, metoprolol and nad, reduces the metabolism of lidocaine in the liver, increasing its level in the blood plasma, which can lead to increased adverse neurological and cardiological effects.

    Cholinesterase inhibitors: while simultaneous application with bisoprolol may inhibit atrial-ventricular conduction and / or enhance bradycardia.

    Cardiac glycosides: with simultaneous application with bisoprolol may increase the time of the impulse, causing the development of bradycardia. Hypokalemia and / or hypomagnesemia can lead to an increase in the toxic effects of cardiac glycosides.

    M-cholinomimetics: with simultaneous use with bisoprolol may increase the violation AV conductivity and increase the risk of developing a bradycardia.

    Beta-blockers for topical use (eye drops for the treatment of glaucoma): may enhance the systemic effects of bisoprolol (lowering blood pressure, Heart rate).

    Adrenomimetics acting on beta and alpha-adrenergic receptors (norepinephrine, epinephrine): with simultaneous application with bisoprolol may increase the vasoconstrictor effects of these drugs that occur with the participation of alpha-adrenoreceptors, which leads to an increase in blood pressure and exacerbation of intermittent claudication.

    Non-steroidal anti-inflammatory drugs (NSAIDs), systemic, high doses of salicylates when used simultaneously with hydrochlorothiazide can cause acute renal failure in patients with hypovolemia, reducing glomerular filtration by inhibiting vasodilating prostaglandins.

    Angiotensin-converting enzyme (ACE) inhibitors (captopril, enalapril, angiotensin II receptor antagonists): when used simultaneously with hydrochlorothiazide may lead to a sudden decrease in blood pressure and / or acute renal failure at the beginning of treatment with ACE inhibitors or angiotensin II receptor antagonists in patients with hyponatremia, especially in patients with renal artery stenosis.If the previous intake of diuretics caused hyponatremia, it is necessary either to stop taking diuretics several days before the start of treatment with ACE inhibitors, or to start treatment with the latter in small doses with a gradual increase in them.

    Drugs that promote the removal of potassium from the body (glucocorticoids, mineralocorticoids (systemic), adrenocorticotropic hormone (ACTH), tetracosactide (cosyntropine), carbenoxolone, amphotericin B, furosemide or stimulant laxatives): with simultaneous use with hydrochlorothiazide may increase the risk of hypokalemia (additive syndrome).

    Potassium-sparing diuretics (amiloride, potassium kanreonate, spironolactone, triamterene): when used simultaneously with hydrochlorothiazide may increase the risk of hypo- or hyperkalemia (most likely for patients with diabetes mellitus or renal insufficiency).

    Metformin: with simultaneous use with diuretics, especially loop, induces lactic acidosis, caused by a possible violation of kidney function.

    Iodine-containing contrast agents: in the case of dehydration caused by taking a diuretic, the risk of developing acute renal failure increases, especially when taking high doses of iodine-containing contrast agents.

    Beta-adrenomimetics (isoprenaline, dobutamine): simultaneous application with the COMBISO DUO preparation leads to a decrease in the effect of both drugs.

    Lipid-lowering drugs (colestramine, colestipol): reduce the absorption of hydrochlorothiazide.

    Methyldopa: described hemolysis due to the formation of antibodies to hydrochlorothiazide.

    Ldrugs that reduce the concentration of uric acid in the blood plasma: when applied simultaneously with hydrochlorothiazide, the therapeutic effect of these drugs can be weakened.

    Combinations that should be considered

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

    Inhibitors of monoamine oxidase (MAO), with the exception of MAO inhibitors B: can enhance the antihypertensive effect of beta-blockers. Simultaneous application can also lead to the development of hypertensive crisis.

    Non-steroidal anti-inflammatory drugs (NSAIDs)): may reduce antihypertensive effect of bisoprolol.

    The blockers of "slow" calcium channels, which are derivatives of dihydropyridine (amlodipine, felodipine, lacidipine, nifedipine, nicardipine, nimodipine, nitrendipine): with simultaneous use with bisoprolol may increase the risk of developing arterial hypotension. In patients with heart failure, the risk of subsequent deterioration in the function of the ventricles of the heart can not be ruled out (both groups of drugs intensify the negative inotropic effect).

    Salts of calcium: the risk of hypercalcemia increases with simultaneous use with hydrochlorothiazide due to a decrease in the excretion of calcium by the kidneys.

    Cyclosporine: with simultaneous application with hydrochlorothiazide is possible increased serum creatinine levels.

    Glucocorticoids, tetracosactide (system): with simultaneous use reduce the antihypertensive effect of the COMBISO DUO preparation due to the delayed water and sodium in the body caused by glucocorticoids.

    Special instructions:

    Precautions associated with bisoprolol

    Discontinuation of therapy

    Do not suddenly stop treatment, especially patients with ischemic heart disease.The dose should be reduced gradually within two weeks. If necessary, simultaneous initiation of alternative antianginal therapy should be initiated.

    Bronchial asthma and chronic obstructive pulmonary disease

    In patients with mild asthma or COPD, treatment is started with a minimal dose of the drug. Preliminary study of respiratory function. Symptomatic manifestations of bronchial asthma or COPD show the simultaneous use of bronchodilator drugs. In patients with bronchial asthma, an increase in airway resistance is possible, which requires the appointment of higher doses of betaa2-adrenomimetics.

    Chronic heart failure

    Patients with compensated CHF who are treated with beta-blockers should begin treatment with minimal doses of the drug, gradually increasing the dose under close supervision of the doctor.

    Bradycardia

    At a heart rate of less than 50-55 bpm at rest and in patients with bradycardia, a dose reduction is necessary.

    Atrioventricular block of degree I

    Given the negative dromotropic effect of beta-blockers, they should be administered with caution to patients with AV blockade of the I degree.

    Angina pectoris

    Beta-adrenoblockers can increase the frequency and duration of vasospastic episodes in patients with Prinzmetal angina. Selective beta1-adreno-blockers can be used for light and mixed manifestations of angina of Prinzmetal with simultaneous application with vasodilating agents.

    Violations of peripheral circulation

    In patients with impaired peripheral circulation or Reynaud's syndrome, beta-blockers may exacerbate the course of the disease.

    Pheochromocytoma

    Patients with pheochromocytoma should not be prescribed a drug until treatment with alpha-blockers has been performed. A thorough control of blood pressure is necessary.

    Elderly patients

    Treatment should be started with a low dose of the drug and carried out under careful control of the water-electrolyte balance (see "Water-electrolyte balance").

    Diabetes

    Patients who are prescribed COMBISO DUO,should be warned about the possibility of hypoglycemia and the need for regular monitoring of blood glucose concentrations at the beginning of treatment. Symptoms of a pronounced decrease in glucose concentration (tachycardia, palpitations, increased blood pressure, or excessive sweating) may be masked.

    Psoriasis

    Therapy with beta-blockers can aggravate the course of psoriasis. Patients suffering from psoriasis, COMBISO DUO preparation should be prescribed in case of acute necessity.

    Allergic reactions

    In patients with anaphylactic reactions in the history, regardless of the cause of their occurrence, especially when using iodine-containing contrast agents, floktaphenin, or with desensitizing therapy, treatment with beta-blockers can aggravate the occurrence of anaphylactic reactions and cause the development of resistance to adrenaline in usual doses.

    General anesthesia

    In general anesthesia, beta-adrenergic blockade reduces the likelihood of arrhythmia, myocardial ischemia, and hypertensive crises during anesthesia and intubation, as well as in the postoperative period.Currently, it is recommended to continue therapy with beta-blockers intraoperatively. An anesthesiologist should consider the risk of blockade of beta-adrenergic receptors because of the potential interaction with other drugs, which can cause bradyarrhythmia, suppression of reflex tachycardia, and a decrease in the reflex capacity to compensate for blood loss. If it is necessary to stop therapy with COMBISO DUO before surgery, it should be done gradually, and completed no later than 48 hours before general anesthesia.

    Thyrotoxicosis

    When treating with COMBISO DUO, the symptoms of thyrotoxicosis can be masked.

    Strict diet

    The drug COMBISO DUO should be used with caution to patients on a strict diet.

    Combination with verapamil, diltiazem or bepridilom

    Such combinations require careful monitoring of patients' condition, ECG, especially in elderly patients and at the beginning of treatment.

    Precautions associated with hydrochlorothiazide

    Water-electrolyte balance and biochemical indicators

    With prolonged use of COMBISO DUO, it is recommended to regularly monitor the content of serum electrolytes, especially potassium, sodium, calcium, creatinine and urea, serum lipids (cholesterol and triglycerides), uric acid and glucose.

    Prolonged use of thiazide diuretics can lead to a violation of the water electrolyte balance, in particular hypokalemia and hyponatremia, as well as hypomagnesemia and hypochloraemia, hypocalcemia.

    The content of sodium in the blood plasma

    Before the start of therapy and further regular monitoring of the sodium content in the blood is necessary. The use of diuretics can provoke hyponatraemia, in some cases with serious consequences.

    Reduction of the sodium content in the blood at the beginning of treatment can be asymptomatic. In this regard, regular monitoring of sodium levels in high-risk patients (elderly and patients with cirrhosis of the liver) is necessary.

    The content of potassium in blood plasma

    The greatest risk associated with taking thiazide and thiazide-like diuretics is loss of potassium, leading to hypokalemia (<3.5 mmol / l).

    More frequent monitoring of the potassium content in the blood in patients at high risk is needed:elderly patients and / or malnourished, and / or taking several medications at the same time, as well as patients with coronary artery disease or with heart failure. In these cases, hypokalemia increases the cardiotoxicity of drugs containing cardiac glycosides, and the risk of developing ventricular arrhythmias.

    Also at risk are patients with prolonged congenital and / or acquired intervals QT. Hypokalemia, as well as bradycardia, potentiates the development of severe arrhythmia, including tachycardias such as "pirouettes."

    The first determination of the potassium content in blood plasma should be carried out during the first week of the beginning of therapy with COMBISO DUO.

    Calcium in the blood plasma

    Thiazide diuretics can reduce the excretion of calcium in the urine, which leads to minor and temporary hypercalcemia. Significant hypercalcemia may be associated with undiagnosed hyperparathyroidism. Before the study of parathyroid function, treatment with thiazides should be discontinued.

    The content of glucose in the blood plasma

    It is necessary to control the concentration of glucose in the blood in patients with diabetes mellitus, especially in the case of hypokalemia.

    Uric acid

    In patients with hyperuricemia, the risk of developing gout attacks is increased: the prescribed dose of the drug should be selected individually.

    Liver function

    In patients with impaired liver function, thiazide diuretics and their derivatives can cause hepatic encephalopathy. In this case, you must immediately stop taking the drug.

    Kidney function

    Thiazide diuretics are effective in normal or slightly reduced renal function (CC less than 25 mg / ml or 220 μmol / L in adults).

    The creatinine clearance is calculated taking into account the age, body weight and sex of the patient according to the Cockcroft-Gault formula:

    ClCr =(140 - age) x body mass / 0.814 x serum creatinine,

    where age is in years; body weight - in kg; serum creatinine - in μmol / l.

    This calculation formula is applicable for elderly male patients. For older female patients, the result is multiplied by 0.85.

    Hypovolemia in addition to the loss of fluid and sodium arising from the use of diuretics at the beginning of therapy,leads to a decrease in glomerular filtration, which in turn leads to an increase in urea and creatinine in the blood serum in patients with normal renal function. In patients without CRF, a temporary impairment of kidney function is leveled without consequences. In patients with initially impaired renal function, exacerbation of existing disorders is possible.

    Combination with other antihypertensive agents

    In case of prescribing COMBISO DUO at the same time as another antihypertensive drug, a dose reduction of the latter, at least at the beginning of treatment, is recommended.

    Photosensitivity

    The use of thiazide diuretics can cause photosensitivity reactions. It is recommended to protect sensitive areas of the skin from sunlight or artificial UV radiation. In severe cases of photosensitivity treatment should be discontinued.

    Myopia (nearsightedness) and angle-closure glaucoma

    Hydrochlorothiazide, as sulfanilamide, can cause idiosyncratic reactions, manifested as acute short-term myopia and acute closed-angle glaucoma. Symptoms include a sharp decrease in visual acuity or pain in the eye and usually occur between a few hours and a few weeks from the start of the drug.The absence of treatment for an angle-closure glaucoma can lead to irreversible loss of vision. The first step in treatment is to stop taking hydrochlorothiazide as soon as possible. If intraocular pressure remains uncontrolled, surgical or surgical treatment may be required. The risk factor for the development of angle-closure glaucoma is the allergic reactions to sulfanylamide derivatives or penicillin in the anamnesis.

    Precautions associated with bisoprolol and hydrochlorothiazide

    Athletes should be informed that the drug contains active substances that can give positive results in doping tests.

    Effect on the ability to drive transp. cf. and fur:

    Because of the risk of hypotension and dizziness during the treatment with COMBISO DUO, especially at the beginning, when adjusting doses or changing the drug, it is necessary to refrain from managing motor vehicles or practicing potentially dangerous activities that require an increased concentration of attention and speed of psychomotor reactions.

    Form release / dosage:

    Tablets, 2.5 mg + 6.25 mg; 5 mg + 6.25 mg; 10 mg + 6.25 mg.

    Packaging:

    For 10 tablets in foil blister OPA / alum / PVC and aluminum foil.

    For 3 or 10 blisters together with the instructions for use are placed in a cardboard box.

    Storage conditions:

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

    Keep out of the reach of children.
    Shelf life:

    5 years.

    Do not use after the expiration date.
    Terms of leave from pharmacies:On prescription
    Registration number:LP-003897
    Date of registration:11.10.2016
    Expiration Date:11.10.2021
    The owner of the registration certificate:PRO.MED.CS Prague as.PRO.MED.CS Prague as. Czech Republic
    Manufacturer: & nbsp
    Representation: & nbspPRO.MED.CS Prague as. PRO.MED.CS Prague as. Czech Republic
    Information update date: & nbsp31.01.2018
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