Candecor^® H 16 (Tablets) Instructions for Use

ATC Code

C09DA06 (Candesartan and diuretics)

Active Substances

Hydrochlorothiazide (Rec.INN registered by WHO)

Candesartan (Rec.INN registered by WHO)

Clinical-Pharmacological Group

Antihypertensive drug

Pharmacotherapeutic Group

Antihypertensive combination agent (angiotensin II receptor blocker + diuretic)

Pharmacological Action

Candesartan

Angiotensin II is the main hormone of the renin-angiotensin-aldosterone system (RAAS), which is involved in the pathogenesis of arterial hypertension and other cardiovascular diseases.

Candesartan is a selective angiotensin II receptor antagonist, subtype 1 (AT1 receptors). It does not exhibit agonist properties. It does not affect angiotensin-converting enzyme (ACE) and does not lead to the accumulation of bradykinin or substance P. When comparing candesartan with ACE inhibitors, the development of cough was less common in patients receiving candesartan. It does not bind to receptors of other hormones and does not affect the state of ion channels involved in the regulation of the cardiovascular system. As a result of blocking AT1 receptors of angiotensin II, a compensatory dose-dependent increase in renin activity, concentrations of angiotensin I, angiotensin II, and a decrease in plasma aldosterone concentration occur.

Hydrochlorothiazide

Hydrochlorothiazide suppresses active sodium reabsorption primarily in the distal renal tubules and enhances the excretion of sodium, chloride, and water. It dose-dependently increases the renal excretion of potassium and magnesium; calcium is reabsorbed to a greater extent. It reduces plasma volume and extracellular fluid, decreases cardiac output and blood pressure. With long-term therapy, a reduction in total peripheral vascular resistance develops due to arteriolar dilation. Long-term therapy with hydrochlorothiazide reduces the risk of developing cardiovascular diseases and mortality. Candesartan and Hydrochlorothiazide have an additive hypotensive effect.

Arterial hypertension. In patients with hypertension, candesartan causes a long-term clinically significant reduction in blood pressure without a reflex increase in heart rate. There is no information on the development of marked arterial hypotension after the first dose or the development of a withdrawal syndrome upon discontinuation of the drug. After a single dose of candesartan, the hypotensive effect usually develops within 2 hours. With continued therapy, a stable reduction in blood pressure is achieved within 4 weeks. The achieved blood pressure level is maintained with long-term therapy. When using the drug Candecor^® H 32 once a day, an effective and uniform reduction in blood pressure over 24 hours is ensured.

The incidence of side effects, especially cough, during simultaneous use of the hydrochlorothiazide/candesartan combination is lower than with therapy with the hydrochlorothiazide/ACE inhibitor combination.

The effectiveness of the hydrochlorothiazide/candesartan combination does not depend on the patient’s sex and age.

Pharmacokinetics

Simultaneous use of the hydrochlorothiazide/candesartan combination does not have a clinically significant effect on the pharmacokinetics of hydrochlorothiazide and candesartan.

Absorption and Distribution

Candesartan

Candesartan cilexetil is a prodrug. After oral administration, candesartan cilexetil is rapidly converted to the active substance candesartan via ester hydrolysis. The absolute bioavailability of candesartan is approximately 40% after oral administration of candesartan as a solution. The relative bioavailability of candesartan in the tablet dosage form compared to the oral solution is approximately 34%. The mean C_max is reached 3-4 hours after oral administration of candesartan. The plasma concentration of candesartan increases linearly with increasing doses within the therapeutic range. The pharmacokinetics of candesartan are independent of the patient’s sex. Food intake does not significantly affect the area under the concentration-time curve (AUC).

It is highly bound to plasma proteins (more than 99%). The volume of distribution of candesartan is 0.1 L/kg.

Hydrochlorothiazide

Hydrochlorothiazide is rapidly absorbed from the gastrointestinal tract. Bioavailability is approximately 70%. Concurrent food intake increases absorption by approximately 15%. In patients with chronic heart failure and marked edema, bioavailability may be reduced.

Binding of hydrochlorothiazide to plasma proteins is approximately 60%. The volume of distribution is 0.8 L/kg.

Biotransformation and Elimination

Candesartan

Candesartan is excreted mainly unchanged by the kidneys, via bile through the intestines, and only to a small extent metabolized in the liver (isoenzyme CYP2C9). Study results indicate the absence of clinically significant drug interactions with drugs affecting the CYP2C9 and CYP3A4 isoenzymes. According to in vitro studies, drug interactions with drugs whose metabolism depends on cytochrome P450 isoenzymes: CYP1A2, CYP2A6, CYP2C9, CYP2C19, CYP2D6, CYP2E1, or CYP3A4 are not expected. The T_1/2 of candesartan is approximately 9 hours. It does not accumulate in the body with repeated doses. The T_1/2 of candesartan does not change (approximately 9 hours) after simultaneous use with hydrochlorothiazide.

The total plasma clearance of candesartan is 0.37 ml/min/kg, with renal clearance of about 0.19 ml/min/kg. Candesartan is eliminated by glomerular filtration and active tubular secretion. After oral administration of radioactively labeled candesartan (14C-labeled candesartan), approximately 26% is excreted by the kidneys as candesartan and 7% as an inactive metabolite, and 56% is excreted via bile through the intestines as candesartan and 10% as an inactive metabolite.

Hydrochlorothiazide

Hydrochlorothiazide is not metabolized and is excreted almost completely unchanged by glomerular filtration and active tubular secretion. The T_1/2 of hydrochlorothiazide is approximately 8 hours. Approximately 70% of the orally administered hydrochlorothiazide is excreted by the kidneys within 48 hours. The T_1/2 of hydrochlorothiazide does not change with simultaneous use with candesartan. No additional accumulation of hydrochlorothiazide occurs after multiple administrations in combination with candesartan compared to monotherapy.

Pharmacokinetics in Special Patient Groups

Candesartan

Elderly patients

In patients over 65 years of age, C_max and AUC of candesartan are approximately 50% and 80% higher, respectively, compared to younger patients. However, the hypotensive effect and the incidence of side effects are the same in both age groups.

Renal impairment

In patients with mild or moderate renal impairment, C_max and AUC of candesartan with repeated administration increase by 50% and 70%, respectively; while T_1/2 does not change. The corresponding changes in patients with severe renal impairment are 50% and 110%. The T_1/2 of candesartan in patients with severe renal impairment is approximately doubled.

Pharmacokinetics in patients undergoing hemodialysis are similar to those in patients with severe renal impairment.

Hepatic impairment

In patients with mild or moderate hepatic insufficiency, the mean AUC of candesartan increased by approximately 20% in one study and 80% in another study. There is no experience of use in patients with severe hepatic insufficiency.

Hydrochlorothiazide

The T_1/2 of hydrochlorothiazide is increased in patients with renal impairment.

Indications

• Arterial hypertension (for patients who require combination therapy).

ICD codes

Dosage Regimen

Tablets

Orally, once a day, regardless of meals. The bioavailability of candesartan does not depend on food intake. Food intake does not have a clinically significant effect on the bioavailability of hydrochlorothiazide.

The recommended dose is 1 tablet once a day.

Dose titration of candesartan and hydrochlorothiazide is recommended before switching the patient to therapy with Candecor^® H 32. If necessary, switching the patient from monotherapy with Candecor^® to therapy with Candecor^® H 32 may be considered. When switching a patient from hydrochlorothiazide monotherapy, dose titration of candesartan is recommended.

The drug Candecor^® H 32 can be prescribed to patients whose blood pressure is not optimally controlled by candesartan at a dose of 32 mg (for example, the drug Candecor^® at a dosage of 32 mg) or by a combination of Hydrochlorothiazide/candesartan at a lower dosage (for example, Candecor^® H 8 and Candecor^® H 16).

In most cases, the hypotensive effect is achieved within 4 weeks of starting treatment.

Elderly patients: dose adjustment is not required.

Renal impairment

For patients with renal impairment, the use of loop diuretics is preferable compared to thiazides. For patients with mild or moderate renal impairment (creatinine clearance greater than 30 ml/min), it is recommended to select the dose of candesartan by titration (via monotherapy with Candecor^®), starting with a dose of 4 mg. The drug Candecor^® H 32 is contraindicated in patients with severe renal impairment (creatinine clearance less than 30 ml/min).

Hepatic impairment

For patients with mild or moderate hepatic impairment, it is recommended to select the dose of candesartan by titration (via monotherapy with Candecor^®), starting with a dose of 4 mg.

The drug Candecor^® H 32 is contraindicated in patients with severe hepatic impairment and/or cholestasis.

Patients with reduced blood volume

For patients with reduced blood volume (risk of arterial hypotension), it is recommended to select the dose of candesartan by titration (via monotherapy with Candecor^®), starting with a dose of 4 mg.

Children and adolescents under 18 years

The safety and efficacy of the drug Candecor^® H 32 in children and adolescents under 18 years of age have not been established.

Adverse Reactions

Side effects identified during clinical studies of the Hydrochlorothiazide/candesartan combination were moderate and transient and were comparable (2.3-3.3%) in frequency to the placebo group (2.7%).

The side effects of the Hydrochlorothiazide/candesartan combination are limited to the side effects previously reported separately for candesartan and/or hydrochlorothiazide.

Classification of the frequency of side effects according to the World Health Organization (WHO)

Very common >1/10

Common from >1/100 to <1/10

Uncommon from >1/1000 to <1/100

Rare from >1/10000 to <1/1000

Very rare <1/10000

Frequency unknown cannot be estimated from the available data.

In each group, adverse effects are presented in order of decreasing severity.

Candesartan

Nervous system disorders

Common: dizziness/vertigo, headache.

Urinary system disorders

Very rare: renal impairment, including renal failure in predisposed patients.

Blood and lymphatic system disorders

Very rare: leukopenia, neutropenia and agranulocytosis.

Gastrointestinal disorders

Very rare: nausea, increased activity of “liver” transaminases, liver dysfunction or hepatitis.

Musculoskeletal and connective tissue disorders

Very rare: back pain, arthralgia, myalgia.

Respiratory, thoracic and mediastinal disorders

Common: respiratory tract infections;

Very rare: cough.

Skin and subcutaneous tissue disorders

Very rare: angioedema, skin rash, pruritus, urticaria.

Laboratory parameters

Very rare: hyperkalemia, hyponatremia.

Hydrochlorothiazide

During hydrochlorothiazide monotherapy, usually at a dose of 25 mg or more, the following side effects were noted

Nervous system disorders

Common: mild dizziness, vertigo;

Rare: sleep disorders, depression, anxiety, paresthesia.

Cardiac disorders

Uncommon: orthostatic hypotension;

Rare: arrhythmia, necrotizing angiitis (vasculitis, cutaneous vasculitis).

Respiratory, thoracic and mediastinal disorders

Rare: respiratory distress syndrome (including pneumonitis, pulmonary edema).

Gastrointestinal disorders

Uncommon: anorexia, loss of appetite, gastric irritation, diarrhea, constipation; rare: pancreatitis, intrahepatic cholestatic jaundice.

Blood and lymphatic system disorders

Rare: leukopenia, neutropenia/agranulocytosis, thrombocytopenia, aplastic anemia, bone marrow depression, hemolytic anemia.

Eye disorders

Rare: transient visual impairment;

Frequency unknown: acute myopia, acute angle-closure glaucoma.

Skin and subcutaneous tissue disorders

Uncommon: skin rash, urticaria, photosensitivity reactions;

Rare: toxic epidermal necrolysis, lupus-like skin reactions, exacerbation of skin manifestations of systemic lupus erythematosus.

Renal and urinary disorders

Common: glucosuria;

Rare: renal impairment and interstitial nephritis.

Musculoskeletal and connective tissue disorders

Rare: muscle spasms.

Immune system disorders

Rare: anaphylactic reactions.

Laboratory parameters

Common: hyperglycemia, hyperuricemia, water-electrolyte imbalance (including hyponatremia and hypokalemia), increased concentration of cholesterol and triglycerides;

Rare: increased concentration of blood urea nitrogen and creatinine in plasma.

General disorders and administration site conditions

Common: weakness;

Rare: fever.

Contraindications

• Hypersensitivity to the active substances or auxiliary components of the drug, as well as to sulfonamide derivatives;
• Pregnancy and breastfeeding;
• Severe renal impairment (creatinine clearance less than 30 ml/min), including anuria;
• Severe hepatic impairment and/or cholestasis;
• Refractory hypokalemia or hypercalcemia;
• Gout;
• Age under 18 years (efficacy and safety have not been established);
• Lactose intolerance, lactase deficiency or glucose-galactose malabsorption syndrome.

With caution severe chronic heart failure, bilateral renal artery stenosis, stenosis of the artery of a single kidney, hemodynamically significant stenosis of the aortic and/or mitral valve, cerebrovascular diseases, coronary artery disease, hypertrophic obstructive cardiomyopathy, reduced circulating blood volume, liver cirrhosis, hyponatremia, primary hyperaldosteronism, surgical intervention, condition after recent kidney transplantation, renal failure, hepatic failure, diabetes mellitus.

Use in Pregnancy and Lactation

Pregnancy

The use of angiotensin II receptor antagonists in the first trimester of pregnancy is not recommended. The drug Candecor^® H 32 should not be used during pregnancy, as well as in women planning pregnancy. When planning pregnancy, it is recommended to switch the patient to alternative antihypertensive therapy, taking into account the safety profile. In case of pregnancy, Candecor^® H 32 should be discontinued and, if necessary, switched to alternative antihypertensive therapy.

Candecor^® H 32, like other agents that have a direct effect on the RAAS, is contraindicated in the second and third trimesters of pregnancy, as it can cause fetotoxic effects (impaired renal function, delayed ossification of the fetal skull bones, oligohydramnios) and neonatal toxic effects (renal failure, arterial hypotension, hyperkalemia). If the drug was used in the second and third trimesters of pregnancy, it is necessary to perform an ultrasound examination of the fetal kidneys and skull bones.

Hydrochlorothiazide crosses the placenta. When using thiazide diuretics in the second and third trimesters of pregnancy, a decrease in uteroplacental blood flow, the development of thrombocytopenia, jaundice, and water-electrolyte imbalance in the fetus or newborn are possible.

When planning pregnancy, it is recommended to switch the patient to alternative antihypertensive therapy, taking into account the safety profile. Upon confirmation of pregnancy, Candecor^® H 32 should be discontinued as soon as possible.

Newborns whose mothers took Candecor^® H 32 during pregnancy should be under observation, as arterial hypotension may develop in the newborn.

Breastfeeding period

There are no data on the excretion of candesartan into breast milk. However, candesartan is excreted in the milk of lactating rats.

Hydrochlorothiazide passes into breast milk in small amounts. Thiazide diuretics in high doses cause intense diuresis, thereby suppressing lactation. Candecor^® H 32 is not recommended during breastfeeding.

Use in Hepatic Impairment

For patients with mild or moderate hepatic impairment, it is recommended to select the dose of candesartan by titration (via monotherapy with Candecor^®), starting with a dose of 4 mg.

The drug Candecor^® H 32 is contraindicated in patients with severe hepatic impairment and/or cholestasis.

Use in Renal Impairment

For patients with renal impairment, the use of loop diuretics is preferable compared to thiazides. For patients with mild or moderate renal impairment (creatinine clearance greater than 30 ml/min), it is recommended to select the dose of candesartan by titration (via monotherapy with Candecor^®), starting with a dose of 4 mg. The drug Candecor^® H 32 is contraindicated in patients with severe renal impairment (creatinine clearance less than 30 ml/min).

Pediatric Use

The safety and efficacy of Candecor^® H 32 in children and adolescents under 18 years of age have not been established.

Geriatric Use

Dosage adjustment is not required.

Special Precautions

Renal Impairment

In patients with renal impairment, loop diuretics are preferred. If Candecor^® H 32 is used in patients with renal impairment, periodic monitoring of potassium levels and plasma concentrations of creatinine and uric acid is recommended.

Kidney Transplantation

There is no experience with the use of Candecor^® H 32 in patients who have recently undergone kidney transplantation.

Renal Artery Stenosis

In patients with bilateral renal artery stenosis or stenosis of the artery to a solitary functioning kidney, drugs affecting the RAAS, including angiotensin II receptor antagonists, may increase plasma urea and creatinine concentrations.

Reduced Blood Volume (Hypovolemia) and/or Hyponatremia

In patients with hypovolemia and/or hyponatremia, symptomatic arterial hypotension may develop during treatment with Candecor^® H 32, as with the use of other drugs affecting the RAAS. Therefore, the use of Candecor^® H 32 is not recommended until these conditions are corrected.

General Anesthesia and Surgical Interventions

Before surgical intervention (including dentistry), the anesthesiologist must be informed about the use of Candecor^® H 32.

During surgical interventions under general anesthesia in patients taking angiotensin II receptor antagonists, arterial hypotension may develop due to blockade of the RAAS. Very rarely, arterial hypotension can be severe and require intravenous fluid administration and/or vasopressors.

Hepatic Impairment

Thiazide diuretics should be used with caution in patients with impaired hepatic function or progressive liver disease, as even minor disturbances in water-electrolyte balance may contribute to the development of hepatic coma. There is no experience with the use of Candecor^® H 32 in patients with hepatic impairment.

Aortic and/or Mitral Valve Stenosis, Hypertrophic Obstructive Cardiomyopathy (HOCM)

Candecor^® H 32, like other vasodilators, should be used with caution in patients with hemodynamically significant aortic and/or mitral valve stenosis, or with HOCM.

Primary Hyperaldosteronism

Patients with primary hyperaldosteronism are resistant to antihypertensive drugs affecting the RAAS; therefore, the use of Candecor^® H 32 is not recommended for such patients.

Water-Electrolyte Balance Disorders

In all patients taking diuretics, plasma electrolyte levels should be monitored periodically.

Thiazide diuretics, including Hydrochlorothiazide, can cause water-electrolyte imbalance (hypercalcemia, hypokalemia, hyponatremia, hypomagnesemia, and hypokalemic alkalosis).

Thiazide diuretics can reduce renal calcium excretion and cause a temporary and slight increase in plasma calcium levels.

Marked hypercalcemia may be a sign of latent hyperparathyroidism. Thiazide diuretics should be discontinued before testing parathyroid function.

Hydrochlorothiazide dose-dependently increases potassium excretion and can cause hypokalemia. This effect of hydrochlorothiazide is less pronounced when used concomitantly with candesartan. The risk of hypokalemia is increased in patients with cirrhosis, hypovolemia, or patients taking a low-salt diet, or concurrently taking glucocorticosteroids or ACTH. The use of Candecor^® H 32 may provoke hyperkalemia, especially in patients with heart failure and/or renal failure. Concomitant use with potassium-sparing diuretics, potassium preparations, salt substitutes containing potassium, or other agents that can increase plasma potassium levels (e.g., heparin) may lead to the development of hyperkalemia. Serum potassium levels should be monitored if necessary.

Thiazide diuretics increase renal magnesium excretion, which can lead to hypomagnesemia.

Metabolic and Endocrine Effects

Caution is advised in all patients receiving treatment with oral hypoglycemic agents or insulin, as Hydrochlorothiazide may weaken their effect. During therapy with thiazide diuretics, latent diabetes mellitus may become manifest.

During treatment with thiazide diuretics, an increase in serum cholesterol and triglyceride concentrations is possible. However, with the use of the hydrochlorothiazide/candesartan combination containing Hydrochlorothiazide 12.5 mg, minimal or no such effects were observed.

Thiazide diuretic therapy may exacerbate hyperuricemia and/or precipitate gout in some patients.

Photosensitivity

Cases of photosensitivity have been reported during hydrochlorothiazide administration. If manifestations of photosensitivity occur, it is recommended to discontinue therapy. If therapy continuation is necessary, it is recommended to protect exposed skin areas from sunlight and ultraviolet rays.

General

In patients whose renal function depends on the state of the RAAS (e.g., in chronic heart failure NYHA functional class III-IV, kidney disease, including renal artery stenosis), therapy with drugs affecting the RAAS may be accompanied by sharp arterial hypotension, oliguria and/or progressive azotemia, and in rare cases, acute renal failure. The development of these disorders due to suppression of RAAS activity during angiotensin II receptor antagonist use cannot be ruled out. A sharp decrease in blood pressure in patients with ischemic cardiomyopathy or ischemic cerebrovascular disease, when using any antihypertensive agents, may lead to myocardial infarction or stroke. In patients taking thiazide diuretics, hypersensitivity reactions may occur both in the presence and absence of a history of allergic reactions or bronchial asthma, but are more likely in those with such a history. There are reports of exacerbation of systemic lupus erythematosus with the use of thiazide diuretics.

Concomitant use with other antihypertensive drugs potentiates the hypotensive effect of Candecor^® H 32.

Special Information on Excipients

Candecor^® H 32 contains lactose; therefore, the drug is contraindicated in patients with lactase deficiency, lactose intolerance, glucose-galactose malabsorption syndrome.

Effect on Ability to Drive and Operate Machinery The effect of Candecor^® H 32 on driving vehicles and working with complex technical devices has not been studied, but the pharmacodynamic properties of the drug indicate no such effect. Nevertheless, caution should be exercised when driving vehicles and engaging in other potentially hazardous activities due to the possibility of side effects (dizziness, etc.).

Overdose

Considering the pharmacological properties of the drug, the main manifestation of overdose may be a pronounced decrease in blood pressure and dizziness. Cases of drug overdose (up to 672 mg of candesartan) have been reported, resulting in patient recovery without serious consequences. The main manifestation of hydrochlorothiazide overdose is acute loss of fluid and electrolytes. However, during the use of Candecor^® H 32, the following overdose symptoms are possible: decreased blood pressure, dizziness, thirst, water-electrolyte imbalance, tachycardia, ventricular arrhythmia, depression/loss of consciousness, and muscle cramps.

Treatment Induce vomiting, perform gastric lavage. Then – symptomatic therapy under control of vital functions. The patient should be placed in a horizontal position with legs elevated, and measures aimed at increasing blood volume (intravenous administration of isotonic sodium chloride solution) should be carried out. The state of water-electrolyte and acid-base balance of the blood serum should be monitored and, if necessary, corrected. If necessary, symptomatic agents may be prescribed. Candesartan is not removed by hemodialysis; removal of hydrochlorothiazide is unlikely.

Drug Interactions

No clinically significant drug interaction of candesartan with warfarin, digoxin, oral contraceptives (ethinylestradiol/levonorgestrel), glibenclamide, and nifedipine has been identified.

Diuretics, Laxatives, Amphotericin B and Salicylic Acid Derivatives, Steroids and ACTH

Concomitant use of hydrochlorothiazide with furosemide, amphotericin B, salicylic acid derivatives, steroids and ACTH, or abuse of laxatives may increase potassium ion excretion.

Concomitant use of potassium supplements, potassium-sparing diuretics (triamterene, spironolactone, amiloride, eplerenone) or salt substitutes, or other agents that can increase plasma potassium levels (e.g., heparin) may lead to an increase in serum potassium levels. Serum potassium levels should be monitored if necessary.

Cardiac Glycosides and Antiarrhythmic Agents

Hypokalemia and hypomagnesemia during thiazide diuretic therapy may enhance the cardiotoxicity of cardiac glycosides and antiarrhythmic agents. Periodic monitoring of serum potassium levels is recommended when used concomitantly with cardiac glycosides and drugs that prolong the QT interval (risk of developing torsades de pointes ventricular tachycardia)

• Class I A antiarrhythmic agents (e.g., quinidine, disopyramide);

• Class III antiarrhythmic agents (e.g., amiodarone, sotalol, dofetilide);

• Some antipsychotic agents (e.g., thioridazine, chlorpromazine, levomepromazine, trifluoperazine, sulpiride, amisulpride, tiapride, haloperidol, droperidol);

• Other medicinal products (e.g., cisapride, difemanil methyl sulfate, intravenous erythromycin, halofantrine, ketanserin, mizolastine, sparfloxacin, terfenadine, intravenous vincamine).

Lithium

Cases of transient increases in plasma lithium concentrations and the development of toxic effects have been observed with concomitant use of lithium preparations and ACE inhibitors or hydrochlorothiazide. A similar effect is possible with the concomitant use of lithium preparations and angiotensin II receptor antagonists. Concomitant use of candesartan and hydrochlorothiazide with lithium preparations is not recommended. If concomitant use is necessary, serum lithium concentrations should be carefully monitored.

Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)

Concomitant use of NSAIDs (including selective cyclooxygenase-2 inhibitors, acetylsalicylic acid (more than 3 g/day) and non-selective NSAIDs) may weaken the hypotensive effect of angiotensin II receptor antagonists.

As with ACE inhibitors, concomitant use of angiotensin II receptor antagonists and NSAIDs increases the risk of impaired renal function, up to the development of renal failure, leading to hyperkalemia, especially in patients with pre-existing renal impairment. This combination should be used with caution, especially in elderly patients. All patients should receive adequate fluid intake. Renal function should be monitored at the start of concomitant therapy and periodically throughout the course of treatment.

NSAIDs may reduce the diuretic and hypotensive effects of thiazide diuretics.

Anion Exchange Resins (cholestyramine and colestipol)

The absorption of hydrochlorothiazide is significantly reduced in the presence of anion exchange resins. A single dose of cholestyramine or colestipol reduces the absorption of hydrochlorothiazide in the gastrointestinal tract by 85% and 43%, respectively.

Non-Depolarizing Muscle Relaxants

Thiazide diuretics may enhance the effect of tubocurarine chloride.

Vitamin D and Calcium Salts

Concomitant use of thiazide diuretics with vitamin D or calcium salts increases serum calcium levels because calcium excretion is reduced. If the use of calcium preparations or vitamin D is necessary, serum calcium levels should be monitored and the dose of these drugs may need to be adjusted.

Concomitant use of hydrochlorothiazide with beta-blockers and diazoxide potentiates their hyperglycemic effect.

Anticholinergic agents, e.g., atropine, biperiden increase the bioavailability of thiazide diuretics by reducing gastrointestinal motility.

Concomitant use of amantadine increases the risk of amantadine side effects due to reduced excretion.

Cytostatic drugs, e.g., cyclophosphamide, methotrexate – the myelosuppressive effect is increased due to slowed elimination from the body.

Concomitant use with ethanol, barbiturates, narcotic analgesics may increase the frequency of orthostatic hypotension.

Oral Hypoglycemic Agents and Insulin

Concomitant use of oral hypoglycemic agents and insulin with thiazide diuretics may require dose adjustment.

Metformin

Should be used with caution concomitantly with metformin, as there is a risk of lactic acidosis induced by renal failure during hydrochlorothiazide use.

Sympathomimetics (pressor amines, e.g., epinephrine and norepinephrine)

Thiazide diuretics may reduce the effectiveness of adrenomimetics (epinephrine, norepinephrine).

Hydrochlorothiazide may increase the risk of acute renal failure, especially when used concomitantly with high doses of iodinated contrast agents.

Concomitant use of cyclosporine increases the risk of hyperuricemia and exacerbation of gout).

Baclofen, amifostine, tricyclic antidepressants or neuroleptics enhance the hypotensive effect, risk of arterial hypotension.

Storage Conditions

At a temperature not exceeding 30°C (86°F), in the original packaging. Keep out of reach of children.

Shelf Life

The shelf life is 2 years.

Dispensing Status

Dispensed by prescription.

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.