Candecil hd
UkraineTable of Contents
INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT KANDECYL HD (CANDECIL HD)
Composition:
Active substances: candesartani cilexetilum, hydrochlorothiazidum;
One tablet contains 32 mg of candesartan cilexetil, calculated as 100 % substance, and 25 mg of hydrochlorothiazide, calculated as 100 % substance;
Excipients: lactose monohydrate; corn starch; povidone (K-30); calcium carmellose; magnesium stearate; iron oxide red (E 172).
Pharmaceutical form. Tablets.
Main physicochemical properties: pink, oblong, biconvex tablets with a break line on one side.
Pharmacotherapeutic group. ATC code.
Combined angiotensin II inhibitors. ATC code C09DA06.
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, with 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. Cough development was less frequent in patients receiving candesartan compared to patients treated with ACE inhibitors.
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, angiotensin I and angiotensin II levels, as well as a reduction in plasma aldosterone levels.
The effect of candesartan cilexetil 16 mg once daily on morbidity and mortality from cardiovascular diseases was studied 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. There was no statistically significant difference in the incidence of major cardiovascular events.
Hydrochlorothiazide inhibits sodium reabsorption, primarily in the distal renal tubules, promoting excretion of sodium, chlorides, and water. Renal excretion of potassium and magnesium increases in a dose-dependent manner, whereas calcium is more extensively reabsorbed. Hydrochlorothiazide reduces plasma volume and extracellular fluid volume, decreases cardiac output, and lowers arterial blood pressure (BP). With prolonged therapy, reduced peripheral resistance contributes to BP reduction.
Candesartan and hydrochlorothiazide have an additive antihypertensive effect. In patients with arterial hypertension, Candexil HD produces 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 arterial hypotension after the first dose or withdrawal syndrome.
After a single dose of Candexil HD, onset of antihypertensive effect typically occurs within 2 hours. With continuous treatment, maximal BP reduction at any dose is achieved within 4 weeks and is maintained during long-term therapy. Candexil HD, administered once daily, provides effective and consistent BP lowering over 24 hours, with minimal difference between maximum and minimum effects throughout the dosing interval. Candexil HD 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 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 (95% CI 3.68–4.31). A clear dose-response relationship was observed for both BCC and SCC. Another study indicated a possible association between lip cancer (LC, a variant of SCC) and hydrochlorothiazide use: 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 (95% 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 (95% 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 (95% 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 renal 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, strongly binds to AT₁ receptors, and dissociates slowly. The absolute bioavailability of the tablet is 40%. The mean peak plasma concentration (Cmax) is reached within 3–4 hours after tablet intake. Candesartan plasma concentrations increase linearly with increasing doses within the therapeutic range.
No pharmacokinetic differences related to gender have been observed. Food intake has no 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. Plasma protein binding of hydrochlorothiazide is about 60%. The apparent volume of distribution is approximately 0.8 L/kg.
Metabolism and Elimination
Candesartan cilexetil
Candesartan is primarily eliminated unchanged in 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 remains unchanged when candesartan cilexetil is administered in combination with hydrochlorothiazide.
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, dose titration of individual components is recommended before switching to Candexil HD. 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 inactive metabolite, while approximately 56% of the dose is found in feces as candesartan and 10% as inactive metabolite.
Hydrochlorothiazide
Hydrochlorothiazide is not metabolized and is primarily excreted unchanged via glomerular filtration and active tubular secretion. The terminal elimination half-life is 8 hours. Approximately 70% of an orally administered dose is excreted in urine within 48 hours. The 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 (over 65 years of age), Cmax and AUC of candesartan are increased by approximately 50% and 80%, respectively, compared to younger patients. However, blood pressure response and incidence of adverse effects are similar after administration of the same candesartan dose in 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. In patients with severe renal impairment, corresponding increases 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 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 where monotherapy with candesartan cilexetil or hydrochlorothiazide is insufficient.
Contraindications.
Hypersensitivity to the active substances or to any of the excipients of the medicinal product, 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 cholestasis.
Persistent hypokalemia or hypercalcemia.
Gout.
Pregnancy and breastfeeding.
Children and adolescents under 18 years of age.
Concomitant use of Kandecyl HD 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 forms of interaction").
Interaction with other medicinal products and other forms of interaction.
Clinically significant drug interactions between candesartan and compounds containing hydrochlorothiazide, warfarin, digoxin, oral contraceptives (such as ethinylestradiol/levonorgestrel), glyburide, and nifedipine have not been observed.
Other antihypertensive agents may enhance the antihypertensive effect of Kandecyl HD. A reduction in potassium levels, typical of hydrochlorothiazide, may be intensified by 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 RAAS suggests that concomitant use of Kandecyl HD with potassium-sparing diuretics, potassium supplements, potassium-containing salt substitutes, or other medicinal products that may increase potassium levels (e.g. heparin) may lead to elevated serum potassium levels.
Hypokalemia induced by diuretics and hypomagnesemia may predispose to potential cardiotoxic effects of digitalis glycosides and antiarrhythmic agents. When Kandecyl HD is used concomitantly with these medicinal products, periodic monitoring of serum potassium levels is recommended.
Monitoring of serum potassium levels is recommended when Kandecyl HD is administered concomitantly with the following medicinal products, as well as with the following agents that 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, sultopride, amisulpride, tiapride, pimozide, haloperidol, droperidol);
- Other medicinal agents (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.
When ARBs are used concomitantly with non-steroidal anti-inflammatory drugs (NSAIDs, e.g. selective COX-2 inhibitors, acetylsalicylic acid (> 3 g/day), and non-selective NSAIDs), a reduction in antihypertensive effect may occur.
As with ACE inhibitors, concomitant use of ARBs with NSAIDs may increase the risk of renal impairment, including acute renal failure, as well as elevate serum potassium levels, particularly in patients with a history of renal dysfunction. This combination should be used with caution, especially in elderly patients.
Patients should receive adequate fluid intake, and consideration should be given to monitoring renal function after initiation of concomitant therapy and periodically thereafter.
NSAIDs reduce the diuretic, natriuretic, and antihypertensive effects of hydrochlorothiazide.
Cholestyramine or colestipol 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 urinary excretion. When prescribing calcium supplements or vitamin D, 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 caused by amantadine.
Thiazides may reduce renal excretion of cytotoxic agents (e.g. cyclophosphamide, methotrexate) and potentiate their myelosuppressive effects.
The potassium-lowering effect typical of hydrochlorothiazide may be intensified by other medicinal products associated with potassium loss and hypokalemia (e.g. corticosteroids, adrenocorticotropic hormones).
Concomitant intake of alcohol, barbiturates, or anesthetics may lead to postural hypotension.
Treatment with thiazide diuretics may impair glucose tolerance. Adjustment of antidiabetic medication doses, including insulin, may become necessary.
Metformin should be used with caution, as there is an increased risk of lactic acidosis due to possible functional renal impairment associated with hydrochlorothiazide.
Hydrochlorothiazide may reduce arterial responsiveness to pressor amines (e.g. adrenaline), although this is insufficient to preclude their pressor effect.
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.
According to clinical trial data, 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 impaired renal function (including acute renal failure), compared to use of 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 ACE inhibitors, angiotensin II receptor antagonists, or aliskiren increases the risk of hypotension, hyperkalemia, and decreased 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 the medicinal product Kandecyl HD during pregnancy or breastfeeding have been conducted. The effects are related to those of the individual components of the drug.
Initiation of treatment with ARAs II during pregnancy is not recommended. Except in cases where long-term treatment with ARAs II is considered necessary, patients 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 ARAs II is contraindicated during pregnancy. If pregnancy is diagnosed, the drug should be discontinued immediately. Alternative therapy should be initiated if necessary (see section "Use during pregnancy or breastfeeding").
Other antihypertensive medicinal products
The blood pressure-lowering effect of Kandecyl HD may be enhanced by concomitant use of other antihypertensive medicinal products.
Renal impairment
For this category of patients, loop diuretics are preferred over thiazides. In patients with renal impairment receiving Kandecyl HD, periodic monitoring of serum potassium, creatinine, and uric acid levels is recommended.
Kidney transplantation
There is no experience with the use of Kandecyl HD in patients who have recently undergone kidney transplantation.
Renal artery stenosis
Other medicinal products affecting the RAAS, such as ACE inhibitors, may increase blood urea and creatinine levels in patients with bilateral or unilateral renal artery stenosis. A similar effect may be expected with the use of ARAs 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 HD is not recommended until blood volume has been corrected.
Anaesthesia and surgery
In patients receiving treatment with ARAs II, arterial hypotension may develop during anaesthesia and surgical procedures due to blockade of the RAAS. In isolated cases, arterial hypotension may be so severe that intravenous administration of 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 the medicinal product 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, treatment with candesartan should be discontinued and appropriate monitoring initiated until complete resolution of symptoms.
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 medicinal product in such patients is not recommended.
Electrolyte imbalance
As with any patients receiving diuretic therapy, periodic determination 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 and slight elevation of serum calcium levels.
Marked hypercalcemia may indicate occult hyperparathyroidism. Thiazide use should be discontinued before testing parathyroid function.
Hydrochlorothiazide increases potassium excretion in urine in a dose-dependent manner, 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, inadequate oral intake of electrolytes, and those receiving concomitant therapy with corticosteroids or adrenocorticotropic hormone.
Based on experience with other medicinal products affecting the RAAS, concomitant use of Kandecyl HD 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 ARAs II may cause hyperkalemia, particularly in the presence of heart failure and/or renal impairment.
Thiazides increase urinary excretion of magnesium, which may lead to hypomagnesemia.
Effects on metabolism and endocrine system
Treatment with thiazide diuretics may impair glucose tolerance. Dose adjustment of antidiabetic agents, including insulin, may be required. Latent diabetes mellitus may become apparent during thiazide therapy. Increased levels of cholesterol and triglycerides have been associated with thiazide therapy. However, at the hydrochlorothiazide dose of 25 mg contained in the medicinal product, adverse effects are minimal or absent.
Thiazide diuretics increase serum uric acid concentration and may precipitate gout in predisposed patients.
Choroidal effusion, acute myopia, and secondary angle-closure glaucoma
Medicinal products containing sulfonamide or sulfonamide derivatives may cause idiosyncratic reactions 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 usually occur within hours to weeks after starting the medicinal product.
Untreated acute angle-closure glaucoma may lead to irreversible vision loss. The primary treatment is prompt discontinuation of the medicinal product. If intraocular pressure remains uncontrolled, medical or surgical interventions may be necessary. A risk factor for developing acute angle-closure glaucoma may be a history of allergy to sulfonamides or penicillin.
Photosensitivity
Cases of photosensitivity reactions have been reported during thiazide diuretic therapy. If photosensitivity reactions occur, discontinuation of therapy is recommended. If re-administration of diuretics is necessary, protection of vulnerable areas from sunlight or artificial ultraviolet sources is advised.
Non-melanoma skin cancer
An increased risk of non-melanoma skin cancer (NMSC) with increasing cumulative dose of hydrochlorothiazide was observed in two epidemiological studies based on analysis of cases from the Danish National Cancer Registry. The photosensitizing effect of hydrochlorothiazide may be a possible mechanism for the development of NMSC.
Patients taking hydrochlorothiazide should be informed about 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.
To minimize the risk of NMSC, preventive measures such as limiting exposure to sunlight and ultraviolet radiation, or, if unavoidable, using appropriate skin protection, may be considered. 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 intake. Pulmonary edema usually develops within minutes or hours after taking hydrochlorothiazide. Initial symptoms include dyspnea, fever, worsening of lung condition, and hypotension. If ARDS is suspected, hydrochlorothiazide should be discontinued and appropriate treatment initiated. Hydrochlorothiazide should not be prescribed to patients who 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. The possibility of such effects cannot be excluded with the use of ARAs II.
As with any other antihypertensive agents, excessive blood pressure reduction in patients with ischemic heart disease or cerebrovascular ischemic 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, but are more likely in patients with such conditions.
Exacerbation or activation of systemic lupus erythematosus may occur with the use of thiazide diuretics.
The medicinal 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 medicinal product contains tartrazine and may cause allergic reactions.
Use during pregnancy or breastfeeding
Pregnancy
There are very limited data on the use of Kandecyl HD in pregnant women. These data are insufficient to draw conclusions regarding potential fetal risk if the medicinal product 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 HD 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 and neonatal kidney damage in late pregnancy. This mechanism is considered pharmacologically mediated via effects on the renin-angiotensin-aldosterone system.
Angiotensin II receptor antagonists
Kandecyl HD is contraindicated in pregnant women or women planning pregnancy. If pregnancy is confirmed during treatment with the medicinal product, its use must be discontinued immediately and replaced with another medicinal product approved for use during pregnancy.
Hydrochlorothiazide
Hydrochlorothiazide crosses the placental barrier. Based on the pharmacological mechanism of action of hydrochlorothiazide, its use during the second and third trimesters of pregnancy may impair fetoplacental circulation and may cause fetal and neonatal complications such as jaundice, electrolyte imbalances, and thrombocytopenia.
Hydrochlorothiazide should not be used for gestational edema, gestational hypertension in pregnant women, or pre-eclampsia due to the risk of reduced plasma volume and placental hypoperfusion, and lack of any beneficial effects on disease course.
Hydrochlorothiazide should not be used for essential hypertension in pregnant women, except in rare cases where no other alternative treatment 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 HD should not be used during breastfeeding.
Ability to influence the ability to drive and use machines
The effect of the medicinal product 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, the possibility of arterial hypotension occurring during treatment with Kandecyl HD, which may be accompanied by dizziness and increased fatigue, should be taken into account.
Method of Administration and Dosage.
Dosing.
The recommended initial and usual maintenance dose of Candesicil HD is 16 mg/12.5 mg (1/2 tablet of Candesicil HD or 1 tablet of Candesicil HD) once daily. If adequate blood pressure control is not achieved within 4 weeks of treatment with the 16 mg/12.5 mg dose once daily, the dose may be increased to 32 mg/25 mg (1 tablet of Candesicil HD) 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 Candesicil HD, the dose of candesartan cilexetil should be titrated based on blood pressure. When clinically appropriate, a direct switch from monotherapy to the combination drug Candesicil HD is possible.
If adequate blood pressure control is not achieved with Candesicil HD at a dose of 32 mg/25 mg, alternative treatment options should be considered. Doses of candesartan cilexetil exceeding 32 mg do not provide additional blood pressure-lowering effect.
Administration.
Candesicil HD should be taken once daily, regardless of food intake.
The bioavailability of candesartan is not affected by food intake.
There are no data regarding clinically significant interactions between hydrochlorothiazide and food intake.
Use in elderly patients.
No initial dose adjustment is required for elderly patients.
Use in 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 4 mg of candesartan cilexetil should be considered. The combination product in doses of 16 mg/12.5 mg or 32 mg/25 mg is not recommended for such patients. These patients should be treated with monotherapy using candesartan cilexetil (Candesicil HD) at a dose of 4 mg or 8 mg, 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. Candesicil HD should not be used to treat 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 who have a creatinine clearance ≥ 30 mL/min/1.73 m² BSA prior to initiating treatment with Candesicil HD (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 treatment with Candesicil HD (gradual dose titration is recommended). Dose adjustments should be made based on blood pressure response.
Candesicil HD should not be used to treat 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.
The 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 primary 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 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 should be initiated with monitoring of vital functions. The patient should be placed in a supine position with legs elevated. If this is insufficient, blood volume should be expanded by infusion, for example, with isotonic saline solution. As needed, serum electrolyte and acid-base balance should be monitored and corrected. If the above measures are insufficient, sympathomimetics may be administered.
Candesartan is not removed 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 candesartan cilexetil/hydrochlorothiazide combination were mild and transient. Discontinuation of therapy due to adverse effects during the study was similar with candesartan cilexetil/hydrochlorothiazide combination (2.3–3.3%) and placebo (2.7–4.3%).
Based on clinical trial data, adverse reactions with the combined medicinal product candesartan cilexetil/hydrochlorothiazide were consistent with those observed with candesartan cilexetil and/or hydrochlorothiazide.
Frequency of adverse reactions is defined as follows: very common (≥ 1/10), common (≥ 1/100 to <1/10), uncommon (≥ 1/1000 to <1/100), rare (≥ 1/10000 to <1/1000), very rare (<1/10000), and not known (cannot be estimated from available data).
The following commonly occurring adverse reactions may occur:
Candesartan cilexetil/hydrochlorothiazide.
Nervous system disorders: common – dizziness/vertigo, headache.
Candesartan cilexetil.
The following adverse reactions were 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, angioneurotic edema of the intestine;
Skin and subcutaneous tissue disorders: very rare – angioneurotic edema, 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 susceptible 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 arrhythmia;
Vascular disorders: uncommon – postural hypotension; rare – necrotizing angiitis (vasculitis, cutaneous vasculitis);
Respiratory, thoracic and mediastinal disorders: rare – respiratory insufficiency (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 form 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 blood urea nitrogen and serum creatinine; there are reports of increased uric acid and glucose levels, and ALT; slight decrease in hemoglobin level, increased AST, increased serum potassium and decreased serum sodium levels.
Based on available epidemiological data, there is a cumulative, dose-dependent association between hydrochlorothiazide use and non-melanoma skin cancer.
Reporting of adverse reactions after drug registration is of great importance. It enables continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals, pharmacists, patients, or their legal representatives are encouraged to report all suspected adverse reactions and lack of efficacy through 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 reach of children.
Packaging.
10 tablets in a blister; 1, 3, or 10 blisters per cardboard box with labeling in Ukrainian.
Prescription status. Prescription only.
Manufacturer.
Evertogen Life Sciences Limited.
Manufacturer's address and location of its business 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.