Hyposart H (Tablets) Instructions for Use

Marketing Authorization Holder

Akrikhin Chemical and Pharmaceutical Plant, JSC (Russia)

Contact Information

AKRIKHIN JSC (Russia)

ATC Code

C09DA06 (Candesartan and diuretics)

Active Substances

Hydrochlorothiazide (Rec.INN registered by WHO)

Candesartan (Rec.INN registered by WHO)

Dosage Forms

	Hyposart H	Tablets 12.5 mg+8 mg: 30, 36, 60 or 90 pcs.
		Tablets 12.5 mg+16 mg: 30, 36, 60 or 90 pcs.
		Tablets 12.5 mg+32 mg: 30, 36, 60 or 90 pcs.

Dosage Form, Packaging, and Composition

Tablets round, flat-cylindrical, from white to white with a grayish or yellowish tint, with a bevel and a score.

Excipients: hypromellose, macrogol, lactose monohydrate – 76 mg, corn starch, calcium carboxymethylcellulose, magnesium stearate.

10 pcs. – blister packs (3) – cardboard packs.
10 pcs. – blister packs (6) – cardboard packs.
10 pcs. – blister packs (9) – cardboard packs.
12 pcs. – blister packs (3) – cardboard packs.

Tablets round, flat-cylindrical, from light pink to pink, with a bevel and a score; minor inclusions are allowed.

Excipients: hypromellose, macrogol, lactose monohydrate – 67.74 mg, corn starch, iron oxide red, iron oxide yellow, calcium carboxymethylcellulose, magnesium stearate.

10 pcs. – blister packs (3) – cardboard packs.
10 pcs. – blister packs (6) – cardboard packs.
10 pcs. – blister packs (9) – cardboard packs.
12 pcs. – blister packs (3) – cardboard packs.

Tablets round, flat-cylindrical, from light yellow to yellow, with a bevel and a score; minor inclusions are allowed.

Excipients: hypromellose, macrogol, lactose monohydrate – 147.98 mg, corn starch, iron oxide yellow, calcium carboxymethylcellulose, magnesium stearate.

10 pcs. – blister packs (3) – cardboard packs.
10 pcs. – blister packs (6) – cardboard packs.
10 pcs. – blister packs (9) – cardboard packs.
12 pcs. – blister packs (3) – cardboard packs.

* calculated as 100% substance.

Clinical-Pharmacological Group

Combined antihypertensive drug (diuretic + angiotensin II receptor antagonist)

Pharmacotherapeutic Group

Antihypertensive combination agent (angiotensin II receptor blocker + diuretic)

Pharmacological Action

Mechanism of action

Angiotensin II is the main hormone of the RAAS, which plays an important role in the pathogenesis of arterial hypertension, heart failure and other cardiovascular diseases. The main physiological effects of angiotensin II are vasoconstriction, stimulation of aldosterone production, regulation of water and electrolyte status and stimulation of cell growth. All these effects are mediated by the interaction of angiotensin II with angiotensin type 1 receptors (AT₁ receptors).

Pharmacodynamic effects

Candesartan is a selective antagonist of angiotensin II type 1 receptors (AT₁ receptors). Candesartan does not inhibit ACE, which converts angiotensin I to angiotensin II and breaks down bradykinin; does not affect 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 cilexetil. Candesartan does not bind to receptors of other hormones and does not block ion channels involved in the regulation of the cardiovascular system. As a result of blocking AT₁ receptors of angiotensin II, a dose-dependent increase in renin activity, concentrations of angiotensin I, angiotensin II and a decrease in plasma aldosterone concentration occur.

Clinical efficacy and safety

The clinical effect of candesartan cilexetil on the indicator of cardiovascular morbidity and mortality when taken at a dose of 8-16 mg (average dose 12 mg) once a day was studied in a randomized clinical trial involving 4937 elderly patients (age from 70 to 89 years, 21% of patients aged 80 years and older) with mild to moderate arterial hypertension, receiving therapy with candesartan cilexetil for an average of 3.7 years (SCOPE study – Study on COgnition and Prognosis in the Elderly).

Patients received Candesartan cilexetil or placebo, if necessary, in combination with other antihypertensive drugs. Both treatment regimens showed effective reduction in systolic and diastolic blood pressure (from 166/90 to 145/80 mm Hg in the group of patients receiving candesartan, and from 167/90 to 149/82 mm Hg in the control group) against the background of good tolerability. Cognitive function and quality of life remained at a good level in both groups of patients.

No statistically significant differences in the frequency of cardiovascular complications for the primary endpoint, including cardiovascular death, development of non-fatal myocardial infarction and non-fatal stroke, were observed between these two groups of patients. However, in the group of patients receiving candesartan, the risk of developing non-fatal stroke was 28% lower than in the control group (relative risk=0.72, 95% confidence interval 0.53-0.99, p=0.04).

Hydrochlorothiazide inhibits active sodium reabsorption, mainly in the distal renal tubules, and enhances the excretion of sodium, chloride and water ions. The excretion of potassium and magnesium by the kidneys increases depending on the dose, while calcium begins to be reabsorbed in larger quantities than before. Hydrochlorothiazide reduces the volume of circulating blood and extracellular fluid and reduces the intensity of blood transport by the heart and blood pressure. During long-term treatment, the hypotensive effect develops due to the expansion of arterioles.

It has been shown that long-term use of hydrochlorothiazide reduces the risk of cardiovascular disease and mortality.

Candesartan and Hydrochlorothiazide have a cumulative hypotensive effect. In patients with arterial hypertension, Hydrochlorothiazide + candesartan causes an effective and prolonged reduction in blood pressure without an increase in heart rate. Orthostatic hypotension is not observed at the first dose of the drug, and arterial hypertension does not increase after the end of treatment. After a single dose of hydrochlorothiazide + candesartan, the main hypotensive effect develops within 2 hours. With prolonged treatment, a stable decrease in blood pressure occurs within 4 weeks after starting the drug and can be maintained during a long course of treatment.

Hydrochlorothiazide + candesartan when taken once a day effectively and gently reduces blood pressure for 24 hours with a slight difference between the maximum and average effect of action. In clinical studies, the incidence of side effects, especially cough, was lower with the use of hydrochlorothiazide + candesartan than with the combination of ACE inhibitors with hydrochlorothiazide.

The effectiveness of the combination of candesartan and hydrochlorothiazide does not depend on the gender and age of the patient. Currently, there are no data on the use of hydrochlorothiazide + candesartan by patients with renal failure/nephropathy, reduced left ventricular function/acute heart failure and patients who have had myocardial infarction.

Pharmacokinetics

Simultaneous use of candesartan cilexetil and hydrochlorothiazide does not have a clinically significant effect on the pharmacokinetics of any of these drugs.

Absorption and distribution

Candesartan cilexetil

Candesartan cilexetil is a prodrug for oral administration. It is rapidly converted into the active substance – candesartan – by ester hydrolysis during absorption from the digestive tract, binds firmly to AT₁ receptors and slowly dissociates, and has no agonist properties.

The absolute bioavailability of candesartan after oral administration of candesartan cilexetil solution is about 40%. The relative bioavailability of the drug in tablet form compared to the oral solution is approximately 34%. Thus, the estimated absolute bioavailability of the drug in tablet form is 14%. C_max in blood serum is reached 3-4 hours after taking the drug in tablet form. When the drug dose is increased within the recommended limits, the concentration of candesartan increases linearly.

The pharmacokinetic parameters of candesartan do not depend on the patient’s gender.

Food intake does not have a significant effect on AUC, i.e., food does not significantly affect the bioavailability of the drug.

Candesartan is actively bound to blood plasma proteins (more than 99%). The plasma V_d of candesartan is 0.1 l/kg.

Hydrochlorothiazide

Hydrochlorothiazide is rapidly absorbed from the gastrointestinal tract, bioavailability is approximately 70%. Concomitant food intake increases absorption by approximately 15%. Bioavailability may be reduced in patients with heart failure and severe edema. Binding to blood plasma proteins is approximately 60%. Apparent V_d is approximately 0.8 l/kg.

Metabolism and excretion

Candesartan

Candesartan is mainly excreted from the body by the kidneys and through the intestines with bile unchanged and only to a small extent metabolized in the liver. T_1/2 of candesartan is approximately 9 hours. No accumulation of the drug in the body is observed.

The total clearance of candesartan is about 0.37 ml/min/kg, with renal clearance being about 0.19 ml/min/kg. Renal excretion of candesartan occurs through glomerular filtration and active tubular secretion. When radioactive-labeled candesartan cilexetil is taken orally, about 26% of the administered amount is excreted by the kidneys in the form of candesartan and 7% in the form of an inactive metabolite, while 56% of the administered amount is found in the feces in the form of candesartan and 10% in the form of an inactive metabolite.

Hydrochlorothiazide

Hydrochlorothiazide is not metabolized and is excreted almost completely in the form of the active form of the drug by glomerular filtration and active tubular secretion in the proximal nephron. T_1/2 is approximately 8 hours. Approximately 70% of the orally administered dose is excreted by the kidneys within 48 hours.

T_1/2 does not change when taken together with candesartan. When using the combination of drugs, no additional accumulation of hydrochlorothiazide was detected compared to monotherapy.

Pharmacokinetics in special patient groups

Candesartan

Age and gender. In elderly patients over 65 years of age, C_max and AUC of candesartan increase by 50% and 80%, respectively, compared with young patients. However, the hypotensive effect and the frequency of side effects when using the drug hydrochlorothiazide + candesartan do not depend on the age of the patients.

Renal failure. In patients with mild to moderate renal impairment, C_max and AUC of candesartan increased by 50% and 70%, respectively, while T_1/2 of the drug did not change compared to patients with normal renal function. In patients with severe renal impairment, C_max and AUC of candesartan increased by 50% and 110%, respectively, and T_1/2 of the drug doubled. In patients on hemodialysis, the same pharmacokinetic parameters of candesartan were found as in patients with severe renal impairment.

Hepatic failure. In 2 studies involving patients with mild or moderate hepatic impairment, an increase in the mean AUC of candesartan of approximately 20% was noted in one study and 80% in the other. There is no experience of use in patients with severe hepatic impairment.

Hydrochlorothiazide

T_1/2 is longer in patients with renal failure.

Indications

• Treatment of arterial hypertension in adult patients for whom combination therapy is indicated.

ICD codes

Dosage Regimen

The drug is taken orally regardless of meals.

The recommended dose is 1 tablet once a day.

It is recommended to titrate the dose of candesartan before transferring a patient from hydrochlorothiazide monotherapy to therapy with Hyposart H.

If necessary, patients are transferred from Hyposart monotherapy to therapy with Hyposart H.

The main hypotensive effect is usually achieved within the first 4 weeks after starting treatment.

In elderly patients, no dose adjustment is required.

In patients with mild or moderate renal impairment (creatinine clearance 30-80 ml/min/1.73 m² body surface area), dose titration is recommended. Hyposart H is contraindicated in patients with severe renal failure (creatinine clearance less than 30 ml/min/1.73 m² body surface area).

In patients with mild or moderate hepatic impairment, dose titration is recommended. Hyposart H is contraindicated in patients with severe hepatic impairment and/or cholestasis.

For patients at risk of arterial hypotension, for example, for patients with reduced circulating blood volume, titration of the candesartan dose (via Hyposart monotherapy) is recommended, starting from 4 mg.

The safety and efficacy of Hyposart H in children under 18 years of age have not been established. No data available.

Adverse Reactions

Side effects identified during clinical studies were moderate and transient and were comparable in frequency to the placebo group. The overall incidence of side effects did not depend on the gender and age of the patient. The frequency of therapy discontinuation due to side effects was similar when using candesartan cilexetil/hydrochlorothiazide (2.3%-3.3%) and placebo (2.7%-4.3%).

The frequency of adverse reactions is presented in the following gradation: 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).

Adverse reactions of candesartan cilexetil/hydrochlorothiazide

Laboratory parameters in general, no clinically significant changes in standard laboratory parameters were noted with the use of candesartan cilexetil/hydrochlorothiazide.

Increased serum uric acid concentration and ALT activity and blood glucose concentration were noted as side effects occurring with the use of candesartan cilexetil/hydrochlorothiazide (approximate frequency 1.1%, 0.9% and 1.0%, respectively) slightly more often than with placebo (0.4%, 0% and 0.2%, respectively). In individual patients taking Candesartan cilexetil/Hydrochlorothiazide, a slight decrease in hemoglobin and an increase in serum AST activity were observed.

An increase in creatinine concentration, urea, hyperkalemia and hyponatremia were also observed.

The table below shows the side effects noted during the use of candesartan in clinical studies and during post-marketing use. In a pooled analysis of data from clinical studies in patients with arterial hypertension, the described side effects were observed with a frequency of at least 1% greater than in the placebo group.

Below are the side effects of hydrochlorothiazide monotherapy, usually at a dose of 25 mg or more.

Contraindications

• Hypersensitivity to the active substances, sulfonamide derivatives or to any of the excipients of the drug;
• Severe hepatic impairment and/or cholestasis;
• Hepatic encephalopathy (risk of hepatic coma);
• Severe renal impairment (CrCl less than 30 ml/min/1.73 m² body surface area);
• Anuria;
• Refractory hypokalemia, hyponatremia, hypercalcemia;
• Gout;
• Pregnancy;
• Breastfeeding period;
• Age under 18 years (efficacy and safety not established);
• Lactose intolerance, lactase deficiency, glucose-galactose malabsorption syndrome;
• Concomitant use with aliskiren and drugs containing aliskiren in patients with diabetes mellitus and/or with moderate or severe renal impairment (GFR less than 60 ml/min/1.73 m² body surface area);
• Concomitant use with ACE inhibitors in patients with diabetic nephropathy.

With caution

Severe chronic heart failure; bilateral renal artery stenosis; stenosis of the artery to a single kidney; hemodynamically significant aortic and mitral valve stenosis; in patients with cerebrovascular diseases and coronary artery disease; hypertrophic obstructive cardiomyopathy; in patients with reduced blood volume; liver cirrhosis; hyponatremia; hypercalcemia; hyperparathyroidism; primary hyperaldosteronism; surgical intervention; in patients after kidney transplantation; renal failure; diabetes mellitus; history of allergic reactions to penicillin; increased QT interval on ECG; concomitant use of drugs that can cause polymorphic ventricular tachycardia of the “torsades de pointes” type or increase the duration of the QT interval on ECG; concomitant use of lithium preparations, drugs that can cause hypokalemia, cardiac glycosides; hyperuricemia; systemic lupus erythematosus; elderly age; history of non-melanoma skin cancer.

Use in Pregnancy and Lactation

Pregnancy

The use of Hyposart H during pregnancy is contraindicated. Female patients taking Hyposart H should be warned about this before planning pregnancy so that they can discuss alternative treatment options with their doctor.

In case of diagnosed pregnancy, therapy with Hyposart H should be discontinued immediately and, if necessary, alternative treatment should be prescribed.

Drugs that have a direct effect on the RAAS can cause fetal development disorders or have a negative effect on the newborn, including death, when the drug is used during pregnancy. It is known that therapy with angiotensin II receptor antagonists can cause fetal development disorders (impaired renal function, oligohydramnios, delayed skull bone ossification) and the development of complications in the newborn (renal failure, arterial hypotension, hyperkalemia).

Experience with the use of hydrochlorothiazide during pregnancy, especially in the first trimester, is limited. Animal study data are also limited. Hydrochlorothiazide crosses the placental barrier. Given the pharmacological mechanism of action of hydrochlorothiazide, its use during pregnancy can cause disturbances in fetoplacental blood flow and adverse effects in the fetus and newborn in the form of jaundice, water-electrolyte imbalance disorders and thrombocytopenia.

Breastfeeding period

It is currently unknown whether candesartan passes into breast milk. However, candesartan is excreted in the milk of lactating rats. Hydrochlorothiazide passes into breast milk.

Due to the possible adverse effects on breastfed infants, Hyposart H should not be used during breastfeeding.

Use in Hepatic Impairment

The use of the drug is contraindicated in hepatic impairment and/or cholestasis.

The drug should be used with caution in liver cirrhosis.

Use in Renal Impairment

The use of the drug is contraindicated in renal impairment.

Pediatric Use

Use in children and adolescents under 18 years of age is contraindicated.

Geriatric Use

In elderly patients, dose adjustment is not required.

Special Precautions

Candesartan cilexetil

Dual blockade of the RAAS

Dual blockade of the RAAS by combining candesartan cilexetil and aliskiren is not recommended due to an increased risk of arterial hypotension, hyperkalemia and changes in renal function.

Concomitant use of angiotensin II receptor antagonists with drugs containing aliskiren is contraindicated in patients with diabetes mellitus and/or with moderate or severe renal impairment (GFR less than 60 ml/min/1.73 m² body surface area) and is not recommended in other patients. Concomitant use of angiotensin II receptor antagonists with ACE inhibitors is contraindicated in patients with diabetic nephropathy and is not recommended in other patients.

Renal impairment

During therapy with Hyposart H, as with the use of other agents that inhibit the RAAS, renal function impairment may occur in susceptible patients.

Kidney transplantation

Clinical experience with hydrochlorothiazide + candesartan in patients who have undergone kidney transplantation is limited.

Renal artery stenosis

Other drugs affecting the RAAS, such as ACE inhibitors, may lead to an increase in blood urea and serum creatinine concentrations in patients with bilateral renal artery stenosis or stenosis of the artery to a single kidney. A similar effect should be expected from angiotensin II receptor antagonists.

Reduced blood volume

In patients with blood volume and/or sodium deficiency, symptomatic arterial hypotension may develop, as described for other drugs affecting the RAAS. Therefore, it is not recommended to use Hyposart H until these disorders are corrected.

General anesthesia and surgery

In patients receiving angiotensin II antagonists, arterial hypotension may develop during general anesthesia and surgery as a result of RAAS blockade. Very rarely, cases of severe arterial hypotension may occur, requiring intravenous administration of plasma-substituting solutions and/or vasopressors.

Aortic and mitral valve stenosis or hypertrophic obstructive cardiomyopathy

When prescribing Hyposart H, as with other vasodilators, caution should be exercised in patients with hypertrophic obstructive cardiomyopathy or hemodynamically significant aortic or mitral valve stenosis.

Primary hyperaldosteronism

Patients with primary hyperaldosteronism are usually resistant to therapy with antihypertensive agents affecting the RAAS. In this regard, it is not recommended to prescribe Hyposart H to such patients.

General

Based on experience with other drugs affecting the RAAS function, concomitant use of Hyposart H with ACE inhibitors, aliskiren, potassium-sparing diuretics, potassium preparations or salt substitutes containing potassium may lead to an increase in serum potassium levels.

Patients in whom vascular tone and renal function predominantly depend on the activity of the RAAS (for example, patients with severe chronic heart failure or kidney disease, including renal artery stenosis) are especially sensitive to drugs acting on the RAAS. The prescription of such drugs in these patients is accompanied by sharp arterial hypotension, azotemia, oliguria and, less frequently, acute renal failure. The possibility of developing the listed effects cannot be excluded when using angiotensin II receptor antagonists. A sharp decrease in blood pressure in patients with coronary artery disease or cerebrovascular diseases of atherosclerotic origin, when using any antihypertensive agents, can lead to the development of myocardial infarction or stroke.

Hydrochlorothiazide

Non-melanoma skin cancer

Two pharmacoepidemiological studies conducted using data from the Danish National Cancer Registry demonstrated an association between hydrochlorothiazide intake and an increased risk of developing non-melanoma skin cancer (NMSC) – basal cell carcinoma and squamous cell carcinoma. The risk of developing NMSC increased with increasing cumulative (accumulated) dose of hydrochlorothiazide. A possible mechanism for the development of NMSC is the photosensitizing effect of hydrochlorothiazide.

Patients taking Hydrochlorothiazide as monotherapy or in combination with other drugs should be informed about the risk of developing NMSC. Such patients are recommended to regularly examine the skin to detect any new suspicious lesions, as well as changes in existing skin lesions.

Any suspicious skin changes should be reported to a doctor immediately. Suspicious skin areas should be examined by a specialist. Histological examination of skin biopsies may be required to clarify the diagnosis.

To minimize the risk of developing NMSC, patients should be advised to take preventive measures, such as limiting exposure to sunlight and UV rays, and using appropriate protective equipment.

In patients with a history of non-melanoma skin cancer, it is recommended to reconsider the advisability of using hydrochlorothiazide.

Acute respiratory toxicity

Very rare cases of severe acute respiratory toxicity, including acute respiratory distress syndrome (ARDS), have been reported after taking hydrochlorothiazide. Pulmonary edema usually develops within minutes or hours after taking hydrochlorothiazide. At the onset of the disease, symptoms include shortness of breath, fever, worsening lung condition and arterial hypotension. If ARDS is suspected, Hyposart H should be discontinued and appropriate treatment should be carried out. Hydrochlorothiazide should not be prescribed to patients who have previously experienced acute respiratory distress syndrome after taking hydrochlorothiazide or another thiazide diuretic.

Hepatic failure

Thiazides should be used with caution in patients with impaired liver function or progressive liver disease, since minor fluctuations in fluid volume and electrolyte composition can cause hepatic coma. There are no data on the use of hydrochlorothiazide + candesartan in patients with hepatic impairment.

Water-electrolyte imbalance

As with all cases of using drugs with diuretic action, plasma electrolyte levels should be monitored. Thiazide-based drugs with diuretic action can reduce the urinary excretion of calcium ions and can cause abrupt changes and a slight increase in plasma calcium ion levels. Thiazides, including Hydrochlorothiazide, can cause water-electrolyte imbalance disorders (hypercalcemia, hypokalemia, hyponatremia, hypomagnesemia and hypochloremic alkalosis). Serum electrolyte levels should be determined periodically.

Detected hypercalcemia may be a sign of latent hyperparathyroidism. Thiazide medications should be discontinued until the results of parathyroid gland tests are obtained.

Hydrochlorothiazide increases potassium excretion in a dose-dependent manner, which can cause hypokalemia. This effect of hydrochlorothiazide is less pronounced when used in combination with candesartan cilexetil. The risk of hypokalemia is increased in patients with liver cirrhosis, in patients with severe diuresis, in patients receiving insufficient electrolytes with food, and in patients simultaneously taking corticosteroids or ACTH.

Based on experience with drugs affecting the RAAS, concomitant use of Hyposart H and potassium-excreting diuretics can be compensated by the use of dietary supplements containing potassium or other drugs that can increase plasma potassium levels.

Thiazides have been shown to increase magnesium excretion, which can cause hypomagnesemia.

Effect on metabolism and endocrine system

Thiazide treatment may impair glucose tolerance. Dose adjustment of hypoglycemic agents, including insulin, may be required. During thiazide therapy, latent diabetes mellitus may manifest. Thiazide treatment is also associated with an increase in cholesterol and triglyceride concentrations. However, when using the drug Hydrochlorothiazide + candesartan, containing Hydrochlorothiazide at a dose of 12.5 mg, a minimal number or absence of such effects was observed. Thiazide diuretics increase plasma uric acid levels and may contribute to the occurrence of gout in predisposed patients.

Choroidal effusion, acute myopia and secondary angle-closure glaucoma

Hydrochlorothiazide, a sulfonamide derivative, can cause an idiosyncratic reaction, leading to the development of choroidal effusion with visual field loss, acute transient myopia and acute angle-closure glaucoma. Symptoms include a sudden decrease in visual acuity or eye pain, and usually occur within hours to weeks after starting the drug. Untreated acute angle-closure glaucoma can lead to permanent vision loss.

Primary treatment involves immediate discontinuation of hydrochlorothiazide. If intraocular pressure is not controlled, urgent medical or surgical treatment may be required. Risk factors for developing acute angle-closure glaucoma may include a history of allergy to sulfonamide or penicillin.

Photosensitivity

Photosensitivity reactions have been reported with the use of thiazide diuretics. If a photosensitivity reaction develops, it is recommended to discontinue the drug. If therapy resumption is necessary, it is recommended to protect areas exposed to sunlight or artificial UV radiation.

General

Manifestation of hypersensitivity reactions to hydrochlorothiazide is possible in patients who did not have previous allergic reactions and bronchial asthma (in history), but it is more likely for patients with a burdened allergic history.

Cases of exacerbation or appearance of symptoms of systemic lupus erythematosus have been noted with the use of thiazide diuretics.

Hydrochlorothiazide is a drug prohibited by the World Anti-Doping Agency when participating in sports competitions. While taking Hyposart H, a positive doping test result may be obtained.

Candesartan cilexetil/Hydrochlorothiazide

Lactose

Hyposart H contains lactose, so it should not be taken by patients with lactose intolerance, lactase deficiency or glucose-galactose malabsorption syndrome.

Effect on ability to drive and operate machinery

The effect on the ability to drive a car or work with machinery has not been studied, but the pharmacodynamic properties of the drug indicate that there is no such effect. Patients should be cautious when driving vehicles or operating machinery, as dizziness and increased fatigue may occur during treatment.

Overdose

Symptoms: analysis of the pharmacological properties of the drug suggests that the main manifestation of overdose may be clinically significant decrease in blood pressure and dizziness. Isolated cases of drug overdose (up to 672 mg of candesartan) have been described, which ended with patient recovery without serious consequences.

The main manifestation of hydrochlorothiazide overdose is acute loss of fluid and electrolytes. Symptoms such as dizziness, decreased blood pressure, dry mouth, tachycardia, ventricular arrhythmia, loss of consciousness and muscle cramps have also been observed.

Treatment in case of clinically significant decrease in blood pressure, symptomatic treatment should be carried out and the patient’s condition should be monitored. Place the patient on their back and elevate their legs. If necessary, the blood volume should be increased, for example, by intravenous administration of 0.9% sodium chloride solution. If necessary, sympathomimetic agents may be prescribed. Candesartan is not removed by hemodialysis. The degree of hydrochlorothiazide removal by hemodialysis is unknown.

Drug Interactions

Interaction with candesartan cilexetil/hydrochlorothiazide

Concomitant use of lithium preparations with ACE inhibitors or hydrochlorothiazide has been reported to cause a reversible increase in serum lithium concentrations and the development of toxic reactions. Similar reactions may also occur with the use of angiotensin II receptor antagonists, therefore, it is recommended to monitor serum lithium concentrations when these drugs are used in combination.

NSAIDs, including selective COX-2 inhibitors and acetylsalicylic acid, may reduce the antihypertensive effect of angiotensin II receptor antagonists, including Hyposart H. The diuretic, natriuretic, and antihypertensive effects of hydrochlorothiazide are reduced by NSAIDs.

Concomitant use of Hyposart H with other antihypertensive agents potentiates the hypotensive effect.

Interaction with candesartan cilexetil

Concomitant use of angiotensin II receptor antagonists with drugs containing aliskiren is contraindicated in patients with diabetes mellitus and/or with moderate or severe renal impairment (GFR less than 60 ml/min/1.73 m² body surface area) and is not recommended in other patients. Concomitant use of angiotensin II receptor antagonists with ACE inhibitors is contraindicated in patients with diabetic nephropathy and is not recommended in other patients.

Pharmacokinetic studies have examined the combined use of candesartan cilexetil with hydrochlorothiazide, warfarin, digoxin, oral contraceptives (ethinylestradiol/levonorgestrel), glibenclamide, nifedipine, and enalapril. No clinically significant pharmacokinetic interaction was identified.

Candesartan is metabolized in the liver to a minor extent (by the CYP2C9 isoenzyme). Conducted interaction studies did not reveal an effect of the drug on the CYP2C9 and CYP3A4 isoenzymes; the effect on other cytochrome P450 system isoenzymes has not been studied.

Experience with other drugs acting on the RAAS shows that concomitant therapy with potassium-sparing diuretics, potassium preparations, salt substitutes containing potassium, and other agents that may increase serum potassium levels (e.g., heparin) may lead to the development of hyperkalemia.

As with the use of ACE inhibitors, concomitant use of angiotensin II receptor antagonists and NSAIDs may increase the risk of impaired renal function, including acute renal failure, and increased serum potassium, especially in patients with pre-existing reduced renal function. Caution should be exercised when these drugs are used concomitantly, especially in elderly patients and in patients with reduced blood volume. Patients should compensate for fluid loss and regularly monitor renal function after initiation of combination therapy and periodically during such therapy. The bioavailability of candesartan is not affected by food intake.

Interaction with hydrochlorothiazide

The effect of hydrochlorothiazide leading to potassium loss can be expected to be enhanced by other agents leading to potassium loss and hypokalemia (e.g., other diuretics, laxatives, amphotericin, carbenoxolone, penicillin G sodium, salicylic acid derivatives).

Diuretic-induced hypokalemia and hypomagnesemia predispose to the potential cardiotoxic effect of cardiac glycosides and antiarrhythmic agents. Periodic monitoring of serum potassium levels is recommended when using Hyposart H with such drugs, as well as with the following drugs that can cause polymorphic ventricular tachycardia of the “torsades de pointes” type

• Class IA antiarrhythmic drugs (e.g., quinidine, hydroquinidine, disopyramide);
• Class III antiarrhythmic drugs (e.g., amiodarone, sotalol, dofetilide, ibutilide);
• Some antipsychotic agents (e.g., thioridazine, chlorpromazine, levomepromazine, trifluoperazine, cyamemazine, sulpiride, sultopride, amisulpride, tiapride, pimozide, haloperidol, droperidol);
• Other drugs (e.g., bepridil, cisapride, difemanil, intravenous erythromycin, halofantrine, ketanserin, mizolastine, pentamidine, sparfloxacin, terfenadine, intravenous vincamine).

Hydrochlorothiazide-induced hypokalemia may increase the risk of arrhythmias when using drugs that increase the QT interval.

Drugs used to treat gout (e.g., probenecid, sulfinpyrazone and allopurinol): dose adjustment of uricosuric drugs may be required because Hydrochlorothiazide may increase serum uric acid concentrations. An increase in the dose of probenecid or sulfinpyrazone may be required. Concomitant use of thiazides may increase the incidence of hypersensitivity reactions to allopurinol.

Cases of immune-mediated intravascular hemolysis have been reported in patients taking Hydrochlorothiazide and methyldopa.

Concomitant use of carbamazepine and hydrochlorothiazide is associated with the risk of symptomatic hyponatremia. Blood electrolyte levels should be monitored when these drugs are used concomitantly. If possible, diuretics of another class should be used.

Concomitant therapy with cyclosporine may increase the risk of hyperuricemia and gout-like complications.

Thiazide diuretics reduce blood volume and may reduce the effect of oral anticoagulants.

The absorption of hydrochlorothiazide is reduced with the use of colestipol or cholestyramine.

The effect of non-depolarizing muscle relaxants (e.g., tubocurarine) may be enhanced by hydrochlorothiazide.

Thiazide diuretics may cause an increase in blood calcium levels due to reduced excretion. If it is necessary to take calcium-containing dietary supplements or vitamin D, serum calcium levels should be monitored and the dose adjusted if necessary.

Thiazides enhance the hyperglycemic effect of beta-blockers and diazoxide.

Anticholinergic agents (e.g., atropine, biperiden) may increase the bioavailability of thiazide-based diuretics due to reduced gastrointestinal motility.

Thiazides may increase the risk of adverse effects of amantadine.

Thiazides may slow the excretion of cytotoxic agents (such as cyclophosphamide, methotrexate) from the body and enhance their myelosuppressive effect.

The risk of hypokalemia may increase with the concomitant use of steroid medicines or ACTH.

While taking the drug, the frequency of orthostatic hypotension may increase when taking ethanol, barbiturates, or general anesthetics.

Treatment with thiazides may reduce glucose tolerance. Dose adjustment of oral hypoglycemic agents and insulin may be required.

Hydrochlorothiazide may reduce the effect of vasoconstrictor amines (e.g., epinephrine (adrenaline)).

Hydrochlorothiazide may increase the risk of acute renal failure, especially in combination with large doses of iodine-containing contrast agents.

No significant interaction of hydrochlorothiazide with food has been found.

Storage Conditions

The drug should be stored out of the reach of children at a temperature not exceeding 30°C (86°F).

Shelf Life

Shelf life – 2 years. Do not use after the expiration date stated on the packaging.

Dispensing Status

The drug is 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.