Kombiso Duo (Tablets) Instructions for Use

Marketing Authorization Holder

PRO.MED.CS Praha, a.s. (Czech Republic)

ATC Code

C07BB07 (Bisoprolol and thiazides)

Active Substances

Hydrochlorothiazide (Rec.INN registered by WHO)

Bisoprolol (Rec.INN registered by WHO)

Dosage Forms

	Kombiso Duo	Tablets 2.5 mg+6.25 mg: 30 or 100 pcs.
		Tablets 5 mg+6.25 mg: 30 or 100 pcs.
		Tablets 10 mg+6.25 mg: 30 or 100 pcs.

Dosage Form, Packaging, and Composition

Tablets yellow, round, biconvex, dark specks may be present.

Excipients: microcrystalline cellulose granular, microcrystalline cellulose, crospovidone, magnesium stearate, iron oxide yellow dye.

10 pcs. – blisters (3) – carton packs.
10 pcs. – blisters (10) – carton packs.

Tablets light pink, round, biconvex, dark specks may be present.

Excipients: microcrystalline cellulose granular, microcrystalline cellulose, crospovidone, magnesium stearate, iron oxide red dye, iron oxide yellow dye.

10 pcs. – blisters (3) – carton packs.
10 pcs. – blisters (10) – carton packs.

Tablets white, round, biconvex.

Excipients: microcrystalline cellulose granular, microcrystalline cellulose, crospovidone, magnesium stearate.

10 pcs. – blisters (3) – carton packs.
10 pcs. – blisters (10) – carton packs.

Clinical-Pharmacological Group

Combined antihypertensive drug

Pharmacotherapeutic Group

Antihypertensive agent, combination (selective beta1-adrenergic blocker + diuretic)

Pharmacological Action

Combined antihypertensive agent.

Bisoprolol is a selective beta₁-adrenergic blocker without intrinsic sympathomimetic and membrane-stabilizing activity. It has antihypertensive, antiarrhythmic, and antianginal effects. By blocking β₁-adrenergic receptors of the heart in low doses, it reduces catecholamine-stimulated formation of cyclic adenosine monophosphate (cAMP) from adenosine triphosphate (ATP), reduces intracellular calcium ion current, and has negative chronotropic, dromotropic, bathmotropic, and inotropic effects (reduces heart rate), inhibits cardiac conduction, and reduces myocardial excitability and contractility. When the dose is increased, it blocks β₂-adrenergic receptors.

Total peripheral vascular resistance at the beginning of beta-blocker use, within the first 24 hours, increases (due to reciprocal increase in alpha-adrenergic receptor activity and elimination of β₂-adrenergic receptor stimulation), returns to the initial level after 1-3 days, and decreases with long-term use.

The antihypertensive effect is associated with a reduction in 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-adrenergic receptors of the juxtaglomerular apparatus of the kidneys (which leads to reduced renin secretion), restoration of the sensitivity of the aortic arch baroreceptors (their activity is not enhanced in response to decreased blood pressure), and an effect on the central nervous system. In arterial hypertension, the effect develops after 2-5 days, stable action – after 1-2 months.

Hydrochlorothiazide is a thiazide diuretic. It reduces the reabsorption of sodium ions in the cortical segment of the loop of Henle, without affecting its part located in the renal medulla. It blocks carbonic anhydrase in the proximal part of the convoluted renal tubules, enhances the renal excretion of potassium, bicarbonate, and phosphate ions. It has almost no effect on the acid-base balance. It enhances the renal excretion of magnesium ions; retains calcium ions in the body and inhibits the excretion of urates. The diuretic effect develops in 1-2 hours, reaches a maximum in 4 hours, the duration of the antihypertensive effect persists for 24 hours. The diuretic effect decreases with a reduction in the glomerular filtration rate and ceases when it is less than 30 ml/min.

Pharmacokinetics

Bisoprolol

Absorption is independent of food intake. After oral administration, absorption from the gastrointestinal tract is 80-90%. C_max in blood plasma is reached in 1-3 hours, plasma protein binding is about 30%. Moderately lipid-soluble, poorly penetrates the blood-brain and placental barriers, excreted in breast milk (about 1%). Metabolized in the liver. Eliminated by two equivalent pathways: approximately 50% of the bisoprolol dose is excreted by the kidneys unchanged and only 1-2% via the intestines. T_1/2 is 10-12 hours.

Hydrochlorothiazide

When taken orally, it is absorbed quickly but incompletely, absorption 80%, plasma protein binding 64%. Bioavailability of hydrochlorothiazide is from 60% to 80%. Time to reach C_max occurs in 2-5 hours, about 4 hours. Penetrates the placental barrier and is excreted in breast milk. T_1/2 is 9-13 hours. Not metabolized. Excreted by the kidneys mainly (more than 95%) unchanged via glomerular filtration and active tubular secretion.

Indications

Mild to moderate arterial hypertension.

ICD codes

Dosage Regimen

Take the tablets orally.

Administer a single dose once daily, preferably in the morning.

Select the appropriate tablet strength based on the patient’s individual therapeutic needs.

Initiate therapy with the 5 mg + 6.25 mg strength for most patients, including the elderly.

For patients requiring further blood pressure control, titrate upwards to the 10 mg + 6.25 mg strength.

Use the 2.5 mg + 6.25 mg strength for dose titration or in patients with specific tolerability concerns.

Do not crush or chew the tablets; swallow them whole with a glass of water.

Monitor heart rate and blood pressure regularly during treatment.

Adjust the dose if the resting heart rate persists below 50-55 beats per minute.

Ensure adequate fluid intake and a diet rich in potassium to mitigate potential electrolyte loss.

Abruptly discontinuing therapy is not recommended; gradually reduce the dose under medical supervision.

Adverse Reactions

Nervous system disorders: frequent – increased fatigue, dizziness, headache, which occur especially often at the beginning of treatment, are mild and disappear during the first 1-2 weeks of treatment; infrequent – sleep disturbance, depression, convulsions; rare – nightmares, hallucinations.

Cardiovascular system disorders: infrequent – bradycardia, AV conduction disturbance, exacerbation of chronic heart failure, ventricular extrasystole, feeling of cold and numbness in the extremities; infrequent – orthostatic hypotension; very rare – chest pain.

Respiratory system disorders: infrequent – bronchospasm in patients with bronchial asthma and bronchospasm (in history).

Digestive system disorders: frequent – nausea, vomiting, diarrhea, constipation, dry oral mucosa; infrequent – loss of appetite, discomfort in the gastrointestinal tract, pancreatitis.

Musculoskeletal system disorders: infrequent – muscle weakness, calf muscle cramps, arthralgia.

Sense organ disorders: rare – hearing and vision impairment, decreased tear production (should be considered by patients using contact lenses); very rare – conjunctivitis.

Reproductive system disorders: very rare – impotence.

Hematopoietic system disorders: rare – leukopenia, thrombocytopenia; very rare – agranulocytosis.

Allergic reactions: rare – skin itching, rash, facial skin redness, allergic rhinitis, increased sweating; very rare – possible exacerbation of psoriasis, alopecia, discoid and systemic lupus erythematosus.

Laboratory parameters: frequent – hypertriglyceridemia, hypercholesterolemia, hyperglycemia and glucosuria, hyperuricemia, water-electrolyte imbalance (especially hypokalemia, hyponatremia, hypomagnesemia, hypochloremia, as well as hypercalcemia), metabolic alkalosis; infrequent – increased amylase activity, reversible increase in serum creatinine and urea concentrations; rare – increased ALT, AST activity.

Liver and biliary tract disorders: rare – hepatitis, jaundice.

Skin and subcutaneous tissue disorders non-melanoma skin cancer (based on available data from epidemiological studies, a cumulative dose-dependent relationship was found between hydrochlorothiazide and NMSC).

Contraindications

Severe forms of bronchial asthma; COPD; cardiogenic shock; SSS (including sinoatrial block); second and third degree AV block without an artificial pacemaker; severe bradycardia (heart rate less than 60 beats/min); pheochromocytoma (without simultaneous use of alpha₁-adrenergic blockers); late stages of peripheral circulatory disorders (including Raynaud’s syndrome); severe arterial hypotension (systolic BP less than 90 mm Hg); refractory hypokalemia, hyponatremia, hypercalcemia; metabolic acidosis; dehydration; acute renal failure; chronic renal failure (creatinine clearance <30 ml/min); simultaneous use with floctafenine, sultopride; simultaneous use with MAO inhibitors (except for MAO type B inhibitors); age under 18 years; severe hepatic failure (including hepatic precoma and coma); gout; hypersensitivity to bisoprolol, hydrochlorothiazide and other sulfonamide derivatives.

With caution

First degree AV block, variant angina (Prinzmetal’s angina), coronary artery disease, diabetes mellitus, water-electrolyte imbalance, hepatic and/or renal (creatinine clearance more than 30 ml/min) insufficiency, thyrotoxicosis, pheochromocytoma (during treatment with alpha-adrenergic blockers), strict diet, reduced blood volume (vomiting, diarrhea, dehydration), bronchospasm (in history), psoriasis, elderly age.

Use in Pregnancy and Lactation

Use during pregnancy and lactation (breastfeeding) is contraindicated.

Use in Hepatic Impairment

Patients with mild to moderate hepatic impairment do not require dose adjustment of the drug.

Use in Renal Impairment

Patients with renal impairment (creatinine clearance more than 30 ml/minute) do not require dose adjustment of the drug.

Pediatric Use

The drug is contraindicated for use in children and adolescents under 18 years of age.

Geriatric Use

Usually, dose adjustment is not required. It is recommended to start with the lowest possible dose.

Special Precautions

During therapy, monitoring of heart rate and blood pressure is necessary (at the beginning of treatment – daily, then – once every 3-4 months), blood glucose concentration in patients with diabetes mellitus (once every 4-5 months). In elderly patients, it is recommended to monitor renal function (once every 4-5 months). The patient should be taught the method of counting heart rate.

The dose (due to the bisoprolol content in the combined preparation) should be reduced from 10 to 5 mg if the resting heart rate does not exceed 50-55 beats/min for 2 weeks.

Special attention should be paid to patients with coronary artery disease, as abrupt withdrawal can lead to sudden deterioration of the patient’s condition. During treatment, it is also necessary to monitor acid-base balance parameters and electrolyte levels (potassium, sodium, calcium).

During treatment with this combination, patients should consume an adequate amount of fluid and potassium-rich foods (e.g., bananas, vegetables, nuts), which is necessary to compensate for potassium losses.

The risk of hypokalemia can be prevented or reduced by the simultaneous administration of potassium-sparing diuretics. Before starting treatment with this combination, blood volume must be compensated.

In thyrotoxicosis, this combination may mask the clinical signs of the disease (e.g., tachycardia).

In patients with pheochromocytoma, it should not be used until treatment with alpha-adrenergic blockers has been initiated. Blood pressure should be monitored in such cases.

It is recommended to discontinue therapy if depression develops caused by the beta-blocker (due to its bisoprolol content).

Special attention is required in cases of surgery under general anesthesia in patients taking beta-blockers. In such patients, this combination should be discontinued 48 hours before surgery, and the anesthesiologist should be informed that the patient is taking this combination. An agent with minimal negative inotropic effect should be chosen for general anesthesia.

During therapy with beta-blockers, exacerbation of psoriasis is possible.

In case of a history of anaphylactic reactions, regardless of their cause, especially during desensitization therapy, treatment with this combination (due to its bisoprolol content) may increase the risk of allergic reactions and contribute to the development of resistance to treatment with epinephrine (adrenaline) in usual doses.

Patients using contact lenses should be cautious when using this combination, as beta-blockers may reduce tear production.

Clonidine – increased risk of “rebound” hypertension, as well as worsening of bradycardia and AV conduction disturbances. First, gradual withdrawal of clonidine must be carried out, and only then can this combination be used.

During long-term therapy, concentrations of creatinine and urea, lipids (cholesterol and triglycerides), and uric acid should be regularly monitored.

In bronchial asthma or other chronic obstructive pulmonary diseases characterized by a risk of deterioration, bronchodilator therapy should be carried out in parallel.

Hypokalemia may contribute to the development of severe arrhythmias, in particular, torsades de pointes arrhythmia.

Exacerbation of metabolic alkalosis due to water-electrolyte imbalance is possible.

This combination contains Hydrochlorothiazide, which may give positive results during doping control.

Effect on ability to drive vehicles and operate machinery

During treatment, caution should be exercised when driving vehicles and engaging in potentially hazardous activities requiring increased concentration and speed of psychomotor reactions due to the possibility of dizziness.

Drug Interactions

Enhancement of the antihypertensive effect of this combination is possible with simultaneous use with tricyclic antidepressants, antipsychotics, slow calcium channel blockers (CCBs) (amlodipine, felodipine, nifedipine, nicardipine, nimodipine, nitrendipine), ACE inhibitors (including captopril, enalapril), irbesartan, diuretics, clonidine, sympatholytics, hydralazine and other antihypertensive agents.

Weakening of the antihypertensive effect of this combination is possible with simultaneous use with systemic corticosteroids, estrogens, NSAIDs (indomethacin, piroxicam, naproxen, phenylbutazone) and tetracosactide.

In the development of hypovolemia, concurrent use of NSAIDs may induce the development of acute renal failure.

The combination of bisoprolol and hydrochlorothiazide with corticosteroids, ACTH, carbenoxolone, amphotericin B, furosemide and laxatives may lead to hypokalemia. When used simultaneously with this combination, the effect of non-depolarizing muscle relaxants and the anticoagulant effect of coumarin derivatives may be enhanced.

Cardiac glycosides, methyldopa, reserpine, guanfacine, CCBs (verapamil, diltiazem, amlodipine, felodipine, nifedipine, nicardipine, nimodipine, nitrendipine), antiarrhythmic agents, as well as agents that can initiate torsades de pointes arrhythmias (astemizole, bepridil, erythromycin (IV), halofantrine, pentamidine, sparfloxacin, terfenadine) increase the risk of development and/or worsening of bradycardia, AV block and chronic heart failure.

When used simultaneously with sotalol, hypokalemia and the development of torsades de pointes ventricular arrhythmia are possible.

Cytostatics (in particular, cyclophosphamide, fluorouracil, methotrexate) – possible enhancement of myelotoxicity.

When this combination is used simultaneously with lithium salts, an increase in their blood concentration to toxic levels is possible.

When this combination is used simultaneously with allergens used for immunotherapy or with allergen extracts for skin tests, as well as with allopurinol or with iodine-containing X-ray contrast diagnostic agents for IV administration, the risk of allergic reactions increases.

When this combination is used simultaneously with carbamazepine, hyponatremia may develop; with cyclosporine – an increase in serum creatinine levels is possible.

Bisoprolol

When this combination is used simultaneously with phenytoin (IV) and agents for inhalation anesthesia (hydrocarbon derivatives), the severity of the cardiodepressive effect and the likelihood of an excessive decrease in blood pressure may increase. The clearance of lidocaine and xanthines (except diphylline) may decrease due to a possible increase in their plasma concentration, especially in patients with initially increased theophylline clearance (due to smoking).

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

Class III antiarrhythmic agents (e.g., amiodarone) may enhance AV conduction disturbance.

CCBs of the verapamil type and, to a lesser extent, diltiazem, when used simultaneously with bisoprolol, may lead to a decrease in myocardial contractility and impairment of AV conduction. In particular, IV administration of verapamil to patients taking beta-blockers may lead to severe arterial hypotension and AV block.

Parasympathomimetics when used simultaneously with bisoprolol may enhance AV conduction disturbance and increase the risk of bradycardia.

The hypoglycemic effect of insulin or oral hypoglycemic agents may be enhanced. Signs of hypoglycemia – in particular tachycardia – may be masked or suppressed. Such interaction is more likely with the use of non-selective beta-blockers.

The action of topical beta-blockers (e.g., eye drops for glaucoma treatment) may enhance the systemic effects of bisoprolol.

Preparations of digitalis when used simultaneously with bisoprolol may lead to an increase in impulse conduction time, and thus, bradycardia.

Antihypertensive agents, as well as other agents with possible antihypertensive effects (for example, tricyclic antidepressants, barbiturates, phenothiazines) may enhance the antihypertensive effect of bisoprolol.

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

The combination of bisoprolol with sympathomimetics affecting α- and β-adrenergic receptors (for example, norepinephrine, epinephrine) may enhance the vasoconstrictor effects of these agents, mediated by α-adrenergic receptors, leading to an increase in blood pressure. Such interactions are more likely with the use of non-selective beta-blockers.

Concomitant use of bisoprolol with beta-sympathomimetics (for example, isoprenaline, dobutamine) may lead to a reduction in the effect of both drugs.

Sulfasalazine increases the plasma concentration of bisoprolol; rifampicin shortens the T_1/2 of bisoprolol.

Hydrochlorothiazide

Concomitant use of calcium and/or vitamin D preparations in high doses may lead to hypercalcemia and increases the risk of metabolic acidosis.

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

Concomitant use of hydrochlorothiazide with lithium salts increases its toxicity, as the renal clearance of lithium is reduced.

Hydrochlorothiazide should be used with caution in combination with the following drugs

• Antihypertensive agents (their effect is potentiated, dose adjustment may be required);
• With cardiac glycosides, as it may increase the possibility of manifestations of digitalis toxicity associated with hypokalemia and hypomagnesemia;
• With non-depolarizing muscle relaxants (enhances their action);
• With amiodarone (increased risk of arrhythmias associated with hypokalemia).
• Oral hypoglycemic agents (their effectiveness is reduced, hyperglycemia may develop);
• With corticosteroids or calcitonin (increased risk of hypokalemia);
• With salicylates (enhances their neurotoxicity);
• With quinidine (reduces its excretion);
• With methyldopa (hemolysis may develop).
• With amantadine (the clearance of amantadine may be reduced by hydrochlorothiazide, leading to an increase in the plasma concentration of amantadine and possible toxicity);

Cholestyramine and colestipol, which reduce the absorption of hydrochlorothiazide;

• Ethanol, barbiturates, and narcotic analgesics, which increase the risk of orthostatic hypotension.

Drugs that are highly protein-bound (indirect anticoagulants, clofibrate), enhance the diuretic effect. Vasodilators, beta-blockers, barbiturates, phenothiazines, tricyclic antidepressants, ethanol enhance the antihypertensive effect.

NSAIDs, especially indomethacin, reduce the antihypertensive and diuretic effect. Concomitant use of diflunisal with hydrochlorothiazide causes a significant increase in the plasma level of the latter and reduces its hyperuricemic effect.

Hydrochlorothiazide weakens the effect of oral contraceptives, norepinephrine, epinephrine, and anti-gout agents.

Thiazides may reduce the level of protein-bound iodine in the blood plasma.

Storage Conditions

Store at 2°C (36°F) to 25°C (77°F). Keep in original packaging, protected from light. Keep out of reach of children.

Dispensing Status

Rx Only

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.