CANDECYL H

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT Kandecil H (Candecil H)

Composition:

Active substances: candesartan cilexetil, hydrochlorothiazide;

One tablet contains 16 mg of candesartan cilexetil calculated as 100 % substance, 12.5 mg of hydrochlorothiazide calculated as 100 % substance;

Excipients: lactose monohydrate; corn starch; povidone (K-30); calcium carmellose; magnesium stearate; tartrazine (E 102).

Pharmaceutical form. Tablets.

Main physico-chemical characteristics: yellow, oblong, biconvex tablets with a score line on one side.

Pharmacological Properties.

Pharmacodynamics.

Candesartan cilexetil is a prodrug that is rapidly converted into the active substance – candesartan – via complex ester hydrolysis during absorption from the gastrointestinal tract. Candesartan is a selective antagonist of angiotensin II AT1 receptors, exhibiting strong binding and slow dissociation from these receptors. It has no agonist activity. Candesartan does not inhibit angiotensin-converting enzyme (ACE), which converts angiotensin I to angiotensin II and degrades bradykinin. There is no effect on ACE or potentiation of bradykinin or substance P. Compared to ACE inhibitors, cough occurs less frequently in patients receiving candesartan.

Candesartan does not bind to receptors of other hormones and does not block ion channels known to play a role in cardiovascular regulation. Antagonism of AT1 receptors leads to dose-dependent increases in plasma renin levels, levels of angiotensin I and angiotensin II, as well as a reduction in plasma aldosterone levels.

The effect of candesartan cilexetil 16 mg once daily on cardiovascular morbidity and mortality was evaluated in a randomized clinical trial in elderly patients with mild to moderate arterial hypertension. Patients received either candesartan or placebo, with additional antihypertensive agents added as needed. Blood pressure decreased from 166/90 to 145/80 mm Hg in the candesartan group and from 167/90 to 149/82 mm Hg in the control group. No statistically significant difference in the incidence of major cardiovascular events was observed.

Hydrochlorothiazide inhibits sodium reabsorption, primarily in the distal renal tubules, promoting excretion of sodium, chloride, and water. Renal excretion of potassium and magnesium increases in a dose-dependent manner, whereas calcium is reabsorbed to a greater extent. Hydrochlorothiazide reduces plasma volume and extracellular fluid volume and decreases cardiac output and arterial pressure (BP). With prolonged therapy, reduced peripheral resistance contributes to lowering BP.

Candesartan and hydrochlorothiazide have an additive antihypertensive effect. In patients with arterial hypertension, Candexil N provides dose-dependent and sustained reduction in BP. The antihypertensive activity is due to a reduction in systemic peripheral resistance without reflex tachycardia. There is no information regarding severe or excessive hypotension after the first dose or withdrawal syndrome.

After a single dose of Candexil N, the onset of antihypertensive effect typically occurs within 2 hours. With continuous treatment, maximal BP reduction at any dose is achieved within 4 weeks and maintained during long-term therapy. Candexil N, administered once daily, provides effective and consistent 24-hour BP reduction with minimal difference between maximum and minimum effects over the dosing interval. Candexil N is equally effective regardless of patient age or gender.

Based on available epidemiological data, a cumulative dose-dependent association has been established between hydrochlorothiazide use and the risk of non-melanoma skin cancer (NMSC) – basal cell carcinoma (BCC) and squamous cell carcinoma (SCC). In one study, 71,533 cases of BCC and 8,629 cases of SCC were identified from cohorts of 1,430,833 and 172,462 individuals, respectively. The odds ratio (OR) for BCC with high cumulative doses of hydrochlorothiazide – starting from 50,000 mg (≈ 5–6 years of daily 25 mg use) – was 1.29 (95% confidence interval (CI): 1.23–1.35), and for SCC – 3.98 (CI: 3.68–4.31). A clear dose-response relationship was observed for both BCC and SCC. In another study, a possible association between lip cancer (LC, a variant of SCC) and hydrochlorothiazide use was demonstrated: 633 cases of LC were compared with a control group of 63,067 individuals using a risk-set sampling strategy. The OR for LC with long-term hydrochlorothiazide use compared to the general population was 2.1 (CI: 1.7–2.6). At a cumulative dose of 25,000 mg (≈ 3 years of daily 25 mg use), the OR increased to 3.9 (CI: 3.0–4.9), and at the highest cumulative doses of 100,000 mg (≈ 10–12 years of daily 25 mg use), it reached 7.7 (CI: 5.7–10.5) (see also section "Special Warnings and Precautions for Use").

Currently, there are no data on the use of candesartan cilexetil/hydrochlorothiazide in patients with kidney disease/nephropathy, reduced left ventricular function/heart failure, or post-myocardial infarction.

Pharmacokinetics.

Absorption and Distribution.

Candesartan cilexetil.

Candesartan cilexetil is a prodrug suitable for oral administration. It is rapidly converted into the active substance candesartan via complex ester hydrolysis during absorption from the gastrointestinal tract, binds strongly to AT1 receptors, and dissociates slowly. The absolute bioavailability of the tablet is 40%. The mean peak serum concentration (Cmax) is reached within 3–4 hours after tablet intake. Candesartan serum concentrations increase linearly with increasing doses within the therapeutic range.

No gender-related differences in candesartan pharmacokinetics have been observed. Food intake does not have a significant effect on the area under the concentration-time curve (AUC).

Candesartan is highly bound to plasma proteins (>99%). The apparent volume of distribution of candesartan is 0.1 L/kg.

Hydrochlorothiazide.

Hydrochlorothiazide is rapidly absorbed from the gastrointestinal tract with an absolute bioavailability of 70%. Food intake improves hydrochlorothiazide absorption by approximately 15%. Bioavailability may be reduced in patients with heart failure and marked edema. Hydrochlorothiazide binding to plasma proteins is approximately 60%. The apparent volume of distribution is about 0.8 L/kg.

Metabolism and Elimination.

Candesartan cilexetil.

Candesartan is primarily eliminated unchanged via urine and bile, with only minor hepatic metabolism (CYP2C9). Available interaction studies indicate no effect on CYP2C9 or CYP3A4. Based on in vitro data, no in vivo interactions are expected with drugs whose metabolism depends on the cytochrome P450 isoenzymes CYP1A2, CYP2A6, CYP2C9, CYP2C19, CYP2D6, CYP2E1, or CYP3A4.

The elimination half-life of candesartan is approximately 9 hours. After multiple dosing, no drug accumulation occurs. The half-life of candesartan after administration of candesartan cilexetil in combination with hydrochlorothiazide remains unchanged.

An increase in AUC (15–18%) and Cmax (23–24%) of candesartan is observed when administered with hydrochlorothiazide, but this is not clinically significant. Additionally, titration of individual components is recommended before switching to Candexil N. No additional accumulation of candesartan occurs after repeated doses of the combination compared to monotherapy.

Total plasma clearance of candesartan is approximately 0.37 mL/min/kg, and renal clearance is approximately 0.19 mL/min/kg. Renal excretion of candesartan occurs via both glomerular filtration and active tubular secretion. After an oral dose of 14C-labeled candesartan cilexetil, approximately 26% of the dose is excreted in urine as candesartan and 7% as an inactive metabolite, while approximately 56% of the dose is recovered in feces as candesartan and 10% as an inactive metabolite.

Hydrochlorothiazide.

Hydrochlorothiazide is not metabolized and is excreted primarily unchanged via glomerular filtration and active tubular secretion. The terminal elimination half-life is 8 hours. Approximately 70% of the orally administered dose is excreted in urine within 48 hours. The elimination half-life of hydrochlorothiazide remains unchanged when combined with candesartan cilexetil. No additional accumulation of hydrochlorothiazide occurs after repeated doses of the combination compared to monotherapy.

Pharmacokinetics in Special Patient Populations.

Candesartan cilexetil.

In elderly patients (aged 65 years and older), Cmax and AUC of candesartan are increased by approximately 50% and 80%, respectively, compared to younger patients. However, the blood pressure response and incidence of adverse effects are similar after administration of the recommended dose of candesartan in both younger and elderly patients.

In patients with mild to moderate renal impairment compared to those with normal renal function, Cmax and AUC of candesartan increase by approximately 50% and 70%, respectively, after multiple dosing, while the elimination half-life remains unchanged. Corresponding changes in patients with severe renal impairment are approximately 50% and 110%, respectively, and the elimination half-life is doubled.

The AUC of candesartan in patients undergoing hemodialysis is similar to that observed in patients with severe renal impairment.

In patients with mild to moderate hepatic impairment, AUC of candesartan increased by 23% in one study and by 80% in another. Experience with the use of the drug in patients with severe hepatic impairment is lacking.

Hydrochlorothiazide.

The terminal elimination half-life of hydrochlorothiazide is prolonged in patients with renal impairment.

Clinical characteristics.

Indications.

Essential hypertension in adult patients in cases where monotherapy with candesartan cilexetil or hydrochlorothiazide is insufficient.

Contraindications.

Hypersensitivity to the active substances or to any of the excipients, or to sulfonamide derivatives (hydrochlorothiazide is a sulfonamide derivative).

Severe renal impairment (creatinine clearance < 30 mL/min/1.73 m² BSA).

Severe hepatic impairment and/or cholestatic jaundice.

Persistent hypokalemia or hypercalcemia.

Gout.

Pregnancy or breastfeeding.

Children and adolescents under 18 years of age.

Concomitant use of Candecyl N with medicinal products containing aliskiren is contraindicated in patients with diabetes mellitus or renal dysfunction (eGFR <60 mL/min/1.73 m²) (see section "Interaction with other medicinal products and other types of interactions").

Interaction with other medicinal products and other types of interactions.

No clinically significant drug interactions have been observed between candesartan and hydrochlorothiazide-containing compounds, warfarin, digoxin, oral contraceptives (such as ethinylestradiol/levonorgestrel), glyburide, or nifedipine.

Other antihypertensive agents may enhance the antihypertensive effect of Candecyl N.

An additive reduction in potassium levels associated with hydrochlorothiazide may be expected when used concomitantly with other medicinal products associated with potassium loss and hypokalemia (e.g., other potassium-wasting diuretics, laxatives, amphotericin, carbenoxolone, sodium penicillin G, salicylic acid derivatives).

Experience with other medicinal products affecting the renin-angiotensin-aldosterone system (RAAS) suggests that concomitant use of Candecyl N with potassium-sparing diuretics, potassium supplements, potassium-containing salt substitutes, or other medicinal products that may increase serum potassium levels (e.g., heparin) may lead to elevated serum potassium levels.

Hypokalemia and hypomagnesemia induced by diuretics may predispose to potential cardiotoxic effects of digitalis glycosides and antiarrhythmic agents. Periodic monitoring of serum potassium levels is recommended when Candecyl N is used concomitantly with these medicinal products.

Monitoring of serum potassium levels is recommended when Candecyl N is administered concomitantly with the following medicinal products, which may cause torsades de pointes (paroxysmal torsade-type ventricular tachycardia):

• Class Ia antiarrhythmic agents (e.g., quinidine, hydroquinidine, disopyramide);
• Class III antiarrhythmic agents (e.g., amiodarone, sotalol, dofetilide, ibutilide);
• Certain antipsychotic agents (e.g., thioridazine, chlorpromazine, levomepromazine, trifluoperazine, zuclopenthixol, sulpiride, sulpiride, amisulpride, tiapride, pimozide, haloperidol, droperidol);
• Other medicinal products (e.g., bepridil, cisapride, difemanil, intravenous erythromycin, halofantrine, ketanserin, mizolastine, pentamidine, sparfloxacin, terfenadine, intravenous vinca alkaloids).

Reversible increases in serum lithium levels and lithium toxicity may occur during concomitant use of lithium with ACE inhibitors or hydrochlorothiazide. A similar effect may occur with angiotensin II receptor antagonists (ARBs); therefore, careful monitoring of serum lithium levels is recommended when used concomitantly.

Concomitant use of ARBs with nonsteroidal anti-inflammatory drugs (NSAIDs, e.g., selective COX-2 inhibitors, acetylsalicylic acid (> 3 g/day), and nonselective NSAIDs) may result in reduced antihypertensive efficacy.

As with ACE inhibitors, concomitant use of ARBs with NSAIDs may increase the risk of renal impairment, including acute renal failure, and may increase serum potassium levels, particularly in patients with pre-existing renal dysfunction. This combination should be used with caution, especially in elderly patients.

Patients should receive adequate hydration, and renal function should be monitored after initiation of concomitant therapy and periodically thereafter.

NSAIDs reduce the diuretic, natriuretic, and antihypertensive effects of hydrochlorothiazide.

Cholestyramine or colestipol may reduce the absorption of hydrochlorothiazide.

Hydrochlorothiazide may potentiate the effect of non-depolarizing skeletal muscle relaxants (e.g., tubocurarine).

Thiazide diuretics may increase serum calcium levels due to reduced calcium excretion. When calcium supplements or vitamin D are administered, serum calcium levels should be monitored and dosage adjusted accordingly.

Thiazides may enhance the hyperglycemic effect of β-blockers and diazoxide.

Anticholinergic agents (e.g., atropine, biperiden) may increase the bioavailability of thiazide diuretics by reducing gastrointestinal motility and gastric emptying rate.

Thiazides may increase the risk of adverse effects associated with amantadine.

Thiazides may reduce renal excretion of cytotoxic agents (e.g., cyclophosphamide, methotrexate) and potentiate their myelosuppressive effects.

An additive reduction in potassium levels associated with hydrochlorothiazide may be expected when used concomitantly with other medicinal products associated with potassium loss and hypokalemia (e.g., corticosteroids, adrenocorticotropic hormones).

Concomitant intake of alcohol, barbiturates, or anesthetics may cause postural hypotension.

Treatment with thiazide diuretics may impair glucose tolerance. Adjustment of antidiabetic therapy, including insulin, may be required.

Metformin should be used with caution due to an increased risk of lactic acidosis, potentially caused by functional renal impairment associated with hydrochlorothiazide.

Hydrochlorothiazide may reduce arterial responsiveness to pressor amines (e.g., adrenaline), although this effect is not sufficient to preclude their pressor action.

Hydrochlorothiazide, when used concomitantly with high-dose iodinated contrast media, may increase the risk of acute renal failure.

Concomitant use with cyclosporine may increase the risk of hyperuricemia and complications such as gout.

Concomitant use with baclofen, amifostine, tricyclic antidepressants, or neuroleptics may enhance the hypotensive effect and lead to arterial hypotension.

Clinical trial data indicate that dual blockade of the renin-angiotensin-aldosterone system (RAAS), resulting from combined use of ACE inhibitors, angiotensin II receptor blockers, or aliskiren, is associated with a higher incidence of adverse effects such as arterial hypotension, hyperkalemia, and renal dysfunction (including acute renal failure), compared to treatment with a single RAAS-acting agent (see sections "Contraindications" and "Special precautions for use").

Food intake does not affect the bioavailability of candesartan. There is no clinically significant interaction between hydrochlorothiazide and food.

Special precautions for use.

Dual blockade of the renin-angiotensin-aldosterone system (RAAS)

Data indicate that concomitant use of angiotensin-converting enzyme (ACE) inhibitors, angiotensin II receptor antagonists, or aliskiren increases the risk of arterial hypotension, hyperkalemia, and impaired renal function (including acute renal failure). This results in dual blockade of the RAAS; therefore, combined use of ACE inhibitors, angiotensin II receptor blockers, or aliskiren is not recommended (see section "Interaction with other medicinal products and other forms of interaction").

If dual blockade therapy is absolutely necessary, it should be administered only under specialist supervision and with frequent, careful monitoring of renal function, electrolyte levels, and blood pressure. Patients with diabetic nephropathy should not receive concomitant treatment with ACE inhibitors and angiotensin II receptor blockers.

Pregnancy

No specific studies with Kandecyl N during pregnancy or breastfeeding have been conducted. The effects are related to those of the individual components of the drug.

Treatment with angiotensin II receptor antagonists (ARA II) should not be initiated during pregnancy. Except in cases where long-term ARA II therapy is considered essential, women planning pregnancy should switch to alternative antihypertensive agents considered safe during pregnancy. If pregnancy is detected, treatment should be discontinued immediately and alternative therapy initiated if necessary (see sections "Contraindications" and "Use during pregnancy or breastfeeding").

The use of ARA II is contraindicated during pregnancy. If pregnancy is diagnosed, the drug should be discontinued immediately. Alternative therapy should be prescribed if necessary (see section "Use during pregnancy or breastfeeding").

Other antihypertensive medicinal products

The blood pressure-lowering effect of Kandecyl N may be enhanced by concomitant use of other antihypertensive medicinal products.

Renal impairment

Loop diuretics, rather than thiazides, are preferred in this patient population. Periodic monitoring of serum potassium, creatinine, and uric acid levels is recommended in patients with renal impairment receiving Kandecyl N.

Renal transplantation

There is no experience with the use of Kandecyl N in patients who have recently undergone kidney transplantation.

Renal artery stenosis

Other medicinal products affecting the RAAS, such as ACE inhibitors, may increase serum urea and creatinine levels in patients with bilateral or unilateral renal artery stenosis. A similar effect may be expected with the use of ARA II.

Reduced blood volume

Symptomatic hypotension may occur in patients with reduced blood volume and/or hyponatremia, as with other agents affecting the RAAS. Therefore, Kandecyl N is not recommended until blood volume has been corrected.

Anaesthesia and surgery

In patients receiving ARA II therapy, arterial hypotension may develop during anaesthesia and surgical procedures due to RAAS blockade. In isolated cases, arterial hypotension may be so severe that intravenous isotonic saline solutions and/or vasopressors may be required.

Hepatic impairment

Thiazides should be used with caution in patients with hepatic impairment or progressive liver disease, as even minor alterations in fluid and electrolyte balance may precipitate hepatic coma. There is no clinical experience with the use of Kandecyl N in patients with hepatic impairment.

Intestinal angioedema

Cases of intestinal angioedema have been reported in patients taking angiotensin II receptor blockers, including candesartan (see section "Adverse reactions"). These patients experienced abdominal pain, nausea, vomiting, and diarrhea. Symptoms resolved after discontinuation of angiotensin II receptor blockers. If intestinal angioedema is diagnosed, candesartan should be discontinued and appropriate monitoring initiated until symptoms completely resolve.

Aortic or mitral valve stenosis, obstructive hypertrophic cardiomyopathy

As with other vasodilating agents, particular caution is required when treating patients with hemodynamically significant aortic or mitral valve stenosis or obstructive hypertrophic cardiomyopathy.

Primary hyperaldosteronism

Patients with primary hyperaldosteronism generally do not respond to antihypertensive agents acting via suppression of the RAAS. Therefore, use of the drug in such patients is not recommended.

Electrolyte imbalance

As with any patient receiving diuretic therapy, periodic measurement of serum electrolytes should be performed at appropriate intervals.

Thiazides, including hydrochlorothiazide, may cause disturbances in water or electrolyte balance (hypercalcemia, hypokalemia, hyponatremia, hypomagnesemia, and hypochloremic alkalosis).

Thiazide diuretics may reduce urinary calcium excretion and cause transient, slight increases in serum calcium levels.

Marked hypercalcemia may indicate occult hyperparathyroidism. Thiazide use should be discontinued before testing parathyroid function.

Hydrochlorothiazide dose-dependently increases urinary potassium excretion, which may lead to hypokalemia. This effect of hydrochlorothiazide is less pronounced when used in combination with candesartan cilexetil. The risk of hypokalemia may be increased in patients with liver cirrhosis, those with pronounced diuresis, those with inadequate oral electrolyte intake, and those receiving concomitant therapy with corticosteroids or adrenocorticotropic hormone.

Based on experience with other medicinal products affecting the RAAS, concomitant use of Kandecyl N with potassium-sparing diuretics, potassium supplements, salt substitutes, or other agents that may increase serum potassium levels (e.g., heparin) may lead to elevated serum potassium levels.

Treatment with ACE inhibitors or ARA II may cause hyperkalemia, particularly in patients with heart failure and/or renal impairment.

Thiazides increase urinary magnesium excretion, which may lead to hypomagnesemia.

Effects on metabolism and endocrine system

Thiazide diuretic therapy may impair glucose tolerance. Dose adjustments of antidiabetic agents, including insulin, may be required. Latent diabetes mellitus may become apparent during thiazide therapy. Increased cholesterol and triglyceride levels have been associated with thiazide diuretic therapy. However, at the 12.5 mg dose of hydrochlorothiazide contained in the drug, adverse effects are minimal or absent.

Thiazide diuretics increase serum uric acid concentration and may provoke gout in predisposed patients.

Photosensitivity

Photosensitivity reactions have been reported during thiazide diuretic therapy. If photosensitivity reactions occur, discontinuation of therapy is recommended. If diuretics must be reintroduced, protection of vulnerable areas from sunlight or artificial ultraviolet sources is advised.

Choroidal effusion, acute myopia, and secondary angle-closure glaucoma

Medicinal products containing sulfonamide or sulfonamide derivatives may cause an idiosyncratic reaction leading to choroidal effusion with visual field defects, transient myopia, and acute angle-closure glaucoma. Symptoms include acute onset of decreased visual acuity or eye pain and typically occur from several hours to several weeks after initiation of therapy.

Untreated acute angle-closure glaucoma may lead to irreversible vision loss. The primary treatment is prompt discontinuation of the drug. If intraocular pressure remains uncontrolled, medical or surgical intervention may be necessary. A history of allergy to sulfonamides or penicillin may be a risk factor for acute angle-closure glaucoma.

Non-melanoma skin cancer (NMSC)

An increased risk of non-melanoma skin cancer (NMSC) with increasing cumulative dose of hydrochlorothiazide was demonstrated in two epidemiological studies based on data from the Danish National Cancer Registry. The photosensitizing effect of hydrochlorothiazide may be a possible mechanism for NMSC development.

Patients taking hydrochlorothiazide should be informed of the risk of NMSC and should undergo regular skin examinations for new skin lesions. Patients should promptly report any self-detected skin changes to their physician.

Preventive measures to minimize the risk of NMSC include limiting exposure to sunlight and ultraviolet radiation, or, if unavoidable, using appropriate skin protection. Any suspicious skin lesions should be promptly evaluated as potentially malignant, including histological examination of biopsies. The continued use of hydrochlorothiazide should be reconsidered in patients with a history of NMSC (see also section "Adverse reactions").

Acute respiratory toxicity

Very rare, severe cases of acute respiratory toxicity, including acute respiratory distress syndrome (ARDS), have been reported after hydrochlorothiazide administration. Pulmonary edema typically develops within minutes or hours after taking hydrochlorothiazide. Initial symptoms include dyspnea, fever, worsening lung condition, and hypotension. If ARDS is suspected, hydrochlorothiazide should be discontinued and appropriate treatment initiated. Hydrochlorothiazide should not be prescribed to patients who have previously experienced ARDS after taking hydrochlorothiazide.

General information

In patients whose vascular tone and renal function primarily depend on RAAS activity (e.g., patients with severe congestive heart failure or renal diseases, including renal artery stenosis), treatment with other medicinal products affecting this system has been associated with acute arterial hypotension, azotemia, oliguria, or, rarely, acute renal failure. Such effects cannot be excluded with the use of ARA II.

As with any other antihypertensive agents, excessive blood pressure reduction in patients with ischemic heart disease or ischemic cerebrovascular disease may lead to myocardial infarction or stroke.

Hypersensitivity reactions to hydrochlorothiazide may occur in patients with or without a history of allergy or bronchial asthma, although they are more likely in patients with such conditions.

Exacerbation or activation of systemic lupus erythematosus may occur with thiazide diuretic use.

The product contains lactose as an excipient and therefore should not be used in patients with rare hereditary conditions of galactose intolerance, Lapp lactase deficiency, or glucose-galactose malabsorption.

The product contains tartrazine, which may cause allergic reactions.

Use during pregnancy or breastfeeding

Pregnancy

There are very limited data on the use of Kandecyl N in pregnant women. These data are insufficient to draw conclusions regarding potential fetal risk when the drug is used during the first trimester. In humans, fetal renal perfusion, dependent on the development of the renin-angiotensin-aldosterone system, begins in the second trimester. Therefore, fetal risk increases if Kandecyl N is taken during the second or third trimester of pregnancy. Use of medicinal products acting directly on the renin-angiotensin system during the second and third trimesters of pregnancy may cause fetal and neonatal harm (hypotension, renal dysfunction, oliguria and/or anuria, oligohydramnios, cranial hypoplasia, intrauterine growth retardation) and may be fatal. Cases of pulmonary hypoplasia, facial abnormalities, and limb contractures have been reported. Animal studies with candesartan cilexetil demonstrated fetal kidney damage in late pregnancy and in newborns. This mechanism is considered pharmacologically mediated via effects on the renin-angiotensin-aldosterone system.

Angiotensin II receptor antagonists

Kandecyl N is contraindicated in pregnant women or women planning to become pregnant. If pregnancy is confirmed during treatment with the drug, administration must be discontinued immediately and replaced with another medicinal product approved for use in pregnancy.

Hydrochlorothiazide

Hydrochlorothiazide crosses the placental barrier. Based on its pharmacological mechanism of action, use of hydrochlorothiazide during the second and third trimesters of pregnancy may impair fetoplacental circulation and may cause fetal and neonatal complications such as jaundice, electrolyte imbalance, and thrombocytopenia.

Hydrochlorothiazide should not be used for gestational edema, gestational hypertension in pregnant women, or preeclampsia due to the risk of reduced plasma volume and placental hypoperfusion, and lack of any positive effect on disease course.

Hydrochlorothiazide should not be used in pregnant women with essential hypertension except in rare cases where no alternative therapy is available for such patients.

Breastfeeding

It is unknown whether candesartan cilexetil passes into breast milk, but due to the potential for adverse effects on breastfed infants, Kandecyl N should not be used during breastfeeding.

Ability to affect reaction speed when driving or operating machinery

The effect of the drug on the ability to drive or operate machinery has not been studied. However, considering the pharmacodynamic properties of candesartan, such an effect is unlikely. When driving or operating machinery, one should consider the possibility of arterial hypotension during treatment with Kandecyl N, which may be accompanied by dizziness and increased fatigue.

Method of Administration and Dosage.

Dosing.

The recommended initial and usual maintenance dose of Candexil N is 16 mg/12.5 mg (1 tablet) once daily.

Therapy should be adjusted according to blood pressure response.

Maximum antihypertensive effect is achieved within 4 weeks after initiation of treatment.

Before switching a patient to Candexil N, the dose of candesartan cilexetil should be titrated according to blood pressure.

When clinically appropriate, direct transition from monotherapy to the combination drug Candexil N may be considered.

Administration.

Candexil N should be taken once daily, regardless of food intake.

The bioavailability of candesartan is not affected by food.

There are no data regarding clinically significant interactions between hydrochlorothiazide and food intake.

Elderly Patients.

No initial dose adjustment is required for elderly patients.

Patients with Reduced Circulating Blood Volume (CBV).

For patients at risk of arterial hypotension, e.g., those with possible reduced circulating blood volume, an initial dose of candesartan cilexetil 4 mg should be considered. The combination drug in doses of 16 mg/12.5 mg or 32 mg/25 mg is not recommended for such patients. Instead, monotherapy with candesartan cilexetil (Candexil N) at a dose of 4 mg or 8 mg should be initiated, depending on severity and tolerability, with the addition of an appropriate dose of hydrochlorothiazide if necessary.

Patients with Renal Impairment.

Loop diuretics, rather than thiazide diuretics, are preferred in this patient group. Candexil N should not be used for the treatment of patients with severe renal impairment (creatinine clearance < 30 mL/min/1.73 m² BSA). Dose titration of candesartan cilexetil is recommended for patients with renal impairment and creatinine clearance ≥ 30 mL/min/1.73 m² BSA prior to initiating Candexil N (gradual dose titration is recommended for patients with mild to moderate renal impairment).

Patients with Hepatic Impairment.

Dose titration of candesartan cilexetil is recommended for patients with mild to moderate hepatic impairment prior to initiating Candexil N (gradual dose titration is recommended). Dose adjustments should be made based on blood pressure.

Candexil N should not be used for the treatment of patients with severe hepatic impairment and/or cholestasis.

Children.

Safety and efficacy of the drug in children have not been established; therefore, it should not be prescribed to this age group.

Overdose.

Symptoms.

Main manifestations of candesartan cilexetil overdose include symptomatic hypotension and dizziness. In individual reports of overdose (up to 672 mg of candesartan cilexetil), patients recovered without complications.

The main manifestation of hydrochlorothiazide overdose is acute fluid and electrolyte loss. Other possible symptoms include dizziness, arterial hypotension, thirst, tachycardia, ventricular arrhythmia, sedation/loss of consciousness, and muscle cramps.

Treatment.

There is no specific information on the treatment of overdose with this drug. However, the following measures are recommended in case of overdose: induce vomiting or perform gastric lavage. If symptomatic arterial hypotension occurs, symptomatic treatment and monitoring of vital functions should be initiated. The patient should be placed in a supine position with legs elevated. If this is insufficient, blood volume should be expanded by infusion, e.g., with isotonic saline solution. Serum electrolyte and acid-base balance should be monitored and corrected as necessary. If the above measures are inadequate, sympathomimetics may be administered.

Candesartan is not eliminated by hemodialysis. It is also unknown to what extent hydrochlorothiazide is removed by hemodialysis.

Adverse Reactions

According to data from controlled clinical trials, adverse reactions associated with the use of the candesartan cilexetil/hydrochlorothiazide combination were mild and transient. Discontinuation of treatment due to adverse effects during the studies was similar with candesartan cilexetil/hydrochlorothiazide (2.3–3.3%) and placebo (2.7–4.3%).

Clinical trial data indicate that adverse reactions with the fixed-dose combination of candesartan cilexetil/hydrochlorothiazide were consistent with those observed with candesartan cilexetil and/or hydrochlorothiazide when used individually.

Frequency of adverse reactions is defined as follows: very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1,000 to <1/100), rare (≥1/10,000 to <1/1,000), very rare (<1/10,000), and not known (cannot be estimated from available data).

The following commonly observed adverse reactions may occur:

Candesartan cilexetil/hydrochlorothiazide.

Nervous system disorders: common – dizziness/vertigo, headache.

Candesartan cilexetil.

The following adverse reactions have been observed during monotherapy with candesartan cilexetil:

Infections and infestations: common – respiratory tract infections;

Blood and lymphatic system disorders: very rare – leukopenia, neutropenia, agranulocytosis;

Vascular disorders: very rare – arterial hypotension;

Respiratory, thoracic and mediastinal disorders: very rare – cough;

Nervous system disorders: common – dizziness, headache;

Gastrointestinal disorders: very rare – nausea, intestinal angioedema;

Skin and subcutaneous tissue disorders: very rare – angioedema, rash, urticaria, pruritus;

Musculoskeletal and connective tissue disorders: very rare – back pain, arthralgia, myalgia;

Renal and urinary disorders: very rare – renal dysfunction, including renal failure in predisposed patients;

Hepatobiliary disorders: very rare – increased liver enzymes, hepatic dysfunction or hepatitis;

Metabolism and nutrition disorders: very rare – hyperkalemia, hyponatremia.

Hydrochlorothiazide.

The following adverse reactions may occur during monotherapy with hydrochlorothiazide, typically at doses of 25 mg or higher:

Blood and lymphatic system disorders: rare – leukopenia, neutropenia, agranulocytosis, thrombocytopenia, aplastic anemia, bone marrow suppression, hemolytic anemia;

Immune system disorders: rare – anaphylactic reactions;

Metabolism and nutrition disorders: common – hyperglycemia, hyperuricemia, electrolyte imbalance (including hyponatremia and hypokalemia);

Psychiatric disorders: rare – sleep disturbances, depression, restlessness;

Nervous system disorders: common – dizziness, vertigo; rare – paresthesia;

Eye disorders: rare – transient blurred vision, acute myopia, acute angle-closure glaucoma; not known – choroidal effusion;

Cardiac disorders: rare – cardiac arrhythmias;

Vascular disorders: uncommon – postural hypotension; rare – necrotizing angiitis (vasculitis, cutaneous vasculitis);

Respiratory, thoracic and mediastinal disorders: rare – respiratory distress (including pneumonitis and pulmonary edema); very rare – acute respiratory distress syndrome (ARDS) (see section "Special precautions");

Gastrointestinal disorders: uncommon – anorexia, loss of appetite, gastric mucosal irritation, diarrhea, constipation; rare – pancreatitis;

Hepatobiliary disorders: rare – jaundice (intrahepatic cholestatic jaundice);

Skin and subcutaneous tissue disorders: uncommon – rash, urticaria, photosensitivity reactions; rare – toxic epidermal necrolysis, skin reactions resembling systemic lupus erythematosus, reactivation of cutaneous forms of systemic lupus erythematosus;

Musculoskeletal and connective tissue disorders: rare – muscle spasm;

Renal and urinary disorders: common – glucosuria; rare – renal dysfunction and interstitial nephritis;

Benign, malignant and unspecified neoplasms (including cysts and polyps): not known – non-melanoma skin cancer (basal cell carcinoma and squamous cell carcinoma);

General disorders and administration site conditions: common – weakness; rare – fever;

Investigations: common – increased cholesterol and triglyceride levels; uncommon – increased serum urea and creatinine levels; there are reports of increased uric acid, glucose, and ALT levels, slight decrease in hemoglobin, increased AST, increased serum potassium, and decreased serum sodium.

Epidemiological data indicate a cumulative, dose-dependent association between hydrochlorothiazide use and non-melanoma skin cancer.

Reporting of suspected adverse reactions after drug authorization is of great importance. It allows continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals, as well as patients or their legal representatives, are encouraged to report all suspected adverse reactions and lack of efficacy via the automated pharmacovigilance information system at: https://aisf.dec.gov.ua

Shelf life. 1.5 years.

Storage conditions.

Store in the original packaging at a temperature not exceeding 30 °C.

Keep out of the reach and sight of children.

Packaging.

10 tablets in a blister; 1, 3, or 10 blisters in a cardboard box with labeling in Ukrainian.

Prescription status. Prescription only.

Manufacturer.

Evertogen Life Sciences Limited.

Manufacturer's address and location of operations.

Plot No: S-8, S-9, S-13/P & S-14/P TSIIC, Pharma SEZ, Green Industrial Park, Polepally (V), Jadcherla (M), Mahabubnagar, Telangana, IN-509 301, India.