Bisoprolol + Hydrochlorothiazide Canon (Tablets) Instructions for Use

ATC Code

C07BB07 (Bisoprolol and thiazides)

Active Substances

Hydrochlorothiazide (Rec.INN registered by WHO)

Bisoprolol (Rec.INN registered by WHO)

Clinical-Pharmacological Group

Antihypertensive combination drug (selective beta₁-adrenergic blocker + diuretic)

Pharmacotherapeutic Group

Beta-adrenergic blockers; beta-adrenergic blockers in combination with thiazide diuretics; selective beta-adrenergic blockers in combination with thiazide diuretics

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 beta₁-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 exerts negative chronotropic, dromotropic, bathmotropic, and inotropic effects (reduces heart rate), inhibits cardiac conduction, and reduces myocardial excitability and contractility. With increasing dose, it blocks beta₂-adrenergic receptors.

Total peripheral vascular resistance at the beginning of beta-adrenergic blocker use, within the first 24 hours, increases (due to reciprocal increase in alpha-adrenergic receptor activity and elimination of beta₂-adrenergic receptor stimulation), returns to the initial level after 1-3 days, and decreases with long-term administration.

The antihypertensive effect is associated with a reduction in cardiac output, suppression of sympathetic stimulation of peripheral vessels, reduction 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 within 2-5 days, stable action – after 1-2 months.

Hydrochlorothiazide is a thiazide diuretic. It reduces sodium ion reabsorption 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 renal excretion of potassium, bicarbonate, and phosphate ions. It practically does not affect the acid-base balance. It enhances renal excretion of magnesium ions; retains calcium ions in the body and inhibits urate excretion. The diuretic effect develops within 1-2 hours, reaches a maximum after 4 hours, and the duration of the antihypertensive effect persists for 24 hours. The diuretic effect decreases with reduced glomerular filtration rate and ceases when it is less than 30 ml/min.

Pharmacokinetics

Bisoprolol

Absorption does not depend on food intake. After oral administration, absorption from the gastrointestinal tract is 80-90%. C_max in blood plasma is reached after 1-3 hours, plasma protein binding is about 30%. Moderately soluble in lipids, 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% – through the intestines. T_1/2 is 10-12 hours.

Hydrochlorothiazide

When taken orally, it is absorbed quickly but incompletely, absorption is 80%, plasma protein binding is 64%. The bioavailability of hydrochlorothiazide is from 60 to 80%. The time to reach C_max occurs after 2-5 hours, about 4 hours. It penetrates the placental barrier and is excreted in breast milk. T_1/2 is 9-13 hours. It is not metabolized. It is 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.

The dose of this fixed-dose combination must be individualized based on the patient’s previous antihypertensive therapy and clinical response.

Initiate therapy with the lowest available strength containing 5 mg of Bisoprolol. Titrate the dose upward if adequate blood pressure control is not achieved.

For elderly patients, no specific dose adjustment is routinely required; however, begin treatment with the 5 mg Bisoprolol combination due to potential increased sensitivity.

Monitor heart rate and blood pressure regularly. If the resting heart rate persistently falls below 50-55 beats per minute, reduce the dose.

Do not abruptly discontinue therapy, especially in patients with coronary artery disease, due to the risk of rebound hypertension and angina exacerbation.

Ensure adequate hydration and consider dietary potassium intake or potassium-sparing agents to mitigate the risk of hypokalemia from the hydrochlorothiazide component.

Adverse Reactions

Nervous system disorders: frequently – 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; infrequently – sleep disturbance, depression, convulsions; rarely – nightmares, hallucinations.

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

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

Digestive system disorders: frequently – nausea, vomiting, diarrhea, constipation, dry mouth mucosa; infrequently – loss of appetite, discomfort in the gastrointestinal tract, pancreatitis.

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

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

Reproductive system disorders: very rarely – impotence.

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

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

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

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

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

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

In patients with mild to moderate hepatic impairment, no dose adjustment of the drug is required.

Use in Renal Impairment

In patients with renal impairment (creatinine clearance more than 30 ml/minute), no dose adjustment of the drug is required.

Pediatric Use

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

Geriatric Use

Usually, no dose adjustment is 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 drug) 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, acid-base balance parameters and electrolyte levels (potassium, sodium, calcium) should also be monitored.

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 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 this case.

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

Special attention is required in cases of surgical intervention under general anesthesia in patients taking beta-adrenergic 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 action should be chosen as a general anesthetic.

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

In case of a history of anaphylactic reactions, regardless of their cause, especially during desensitizing 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-adrenergic blockers can reduce the production of tear fluid.

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, creatinine and urea concentrations, 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 other potentially hazardous activities that require 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 case of hypovolemia development, concomitant 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. With simultaneous use 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 arrhythmia (astemizole, bepridil, erythromycin (IV), halofantrine, pentamidine, sparfloxacin, terfenadine) increase the risk of development and/or worsening of bradycardia, AV block and chronic heart failure.

With simultaneous use with sotalol, hypokalemia and development of torsades de pointes ventricular arrhythmia are possible.

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

With simultaneous use of this combination with lithium salts, an increase in their blood concentration to toxic levels is possible.

With simultaneous use of this combination 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.

With simultaneous use of this combination with carbamazepine, hyponatremia may develop; with cyclosporine – an increase in serum creatinine content is possible.

Bisoprolol

With simultaneous use of this combination with phenytoin (IV) and agents for inhalation anesthesia (hydrocarbon derivatives), the severity of the cardiodepressive effect and the likelihood of excessive blood pressure reduction 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 decreased myocardial contractility and impaired AV conduction. In particular, IV administration of verapamil to patients taking beta-adrenergic blockers may lead to pronounced 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-adrenergic blockers.

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

Digitalis preparations when used simultaneously with bisoprolol may lead to increased impulse conduction time, and thus, bradycardia.

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

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

The combination of bisoprolol with sympathomimetics affecting alpha- and beta-adrenergic receptors (e.g., norepinephrine, epinephrine) may enhance the vasoconstrictor effects of these agents, occurring via alpha-adrenergic receptors, leading to increased blood pressure. Such interactions are more likely with the use of non-selective beta-adrenergic blockers.

Simultaneous use of bisoprolol with beta-sympathomimetics (e.g., 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

With simultaneous use of calcium preparations and/or vitamin D in high doses, hypercalcemia may develop and the risk of metabolic acidosis increases.

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

With simultaneous use of hydrochlorothiazide with lithium salts, its toxicity increases, as the renal clearance of lithium decreases.

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

• Antihypertensive agents (their effect is potentiated, dose adjustment may be required);
• Cardiac glycosides, because the possibility of manifestations of digitalis toxicity associated with hypokalemia and hypomagnesemia may increase;
• Non-depolarizing muscle relaxants (enhances their effect);
• Amiodarone (increased risk of arrhythmias associated with hypokalemia).
• Oral hypoglycemic agents (their effectiveness is reduced, hyperglycemia may develop);
• Corticosteroids or calcitonin (increased risk of hypokalemia);
• Salicylates (enhances their neurotoxicity);
• Quinidine (reduces its excretion);
• Methyldopa (possible development of hemolysis).
• Amantadine (the clearance of amantadine may be reduced by hydrochlorothiazide, leading to an increase in amantadine plasma concentration and potential 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. Concurrent 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 antigout agents.

Thiazides may reduce the level of iodine in the blood plasma, bound to proteins.

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.