Casark hd

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT CASARK® HD (CASARK HD)

Composition:

Active substances: candesartan, hydrochlorothiazide;

One tablet contains candesartan cilexetil, recalculated to 100 % substance – 32 mg, hydrochlorothiazide, recalculated to 100 % substance – 25 mg;

Excipients: lactose monohydrate; maize starch; calcium carmellose; hydroxypropylcellulose; polyethylene glycol (PEG 8000); magnesium stearate; iron oxide red (E 172); iron oxide yellow (E 172).

Pharmaceutical form. Tablets.

Main physicochemical properties: tablets from light pink to pink in color, oval-shaped, biconvex, with a groove on one side and a groove and notch on the other side. The presence of specks of more intense color is permissible.

Pharmacotherapeutic group. Combined angiotensin II inhibitors.

Angiotensin II receptor blockers and diuretics. Candesartan and diuretics.

ATC code C09D A06.

Pharmacological Properties.

Pharmacodynamics.

Angiotensin II is the primary vasoactive hormone of the renin-angiotensin-aldosterone system and plays a role in the pathophysiology of hypertension and other cardiovascular disorders. It also contributes to the pathogenesis of organ hypertrophy and target organ damage. The main physiological effects of angiotensin II, such as vasoconstriction, aldosterone stimulation, regulation of water and electrolyte homeostasis, and stimulation of cell growth, are mediated via type 1 (AT1) receptors.

Candesartan cilexetil is a prodrug that is rapidly converted into the active substance—candesartan—by esterase-mediated 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 affect angiotensin-converting enzyme (ACE) or other enzymatic systems typically associated with ACE inhibitors, as it does not influence the breakdown of kinins or other substances such as substance P. Angiotensin II antagonists do not typically cause cough. Candesartan does not bind to or block receptors of other hormones or ion channels. Blockade of AT1 receptors leads to a dose-dependent increase in plasma renin levels, angiotensin I and angiotensin II levels, and a reduction in plasma aldosterone concentration.

Non-melanoma skin cancer (NMSC).

Available epidemiological data indicate a cumulative dose-dependent association between the use of hydrochlorothiazide and the occurrence of NMSC. One study included 71,533 cases of basal cell carcinoma (BCC) and 8,629 cases of squamous cell carcinoma (SCC), with 1,430,833 and 172,462 control subjects, respectively. High cumulative use of hydrochlorothiazide (total dose ≥50,000 mg) was associated with an adjusted hazard ratio (HR) of 1.29 (95% confidence interval [CI]: 1.23–1.35) for BCC and 3.98 (95% CI: 3.68–4.31) for SCC. A clear dose-response relationship was observed for both BCC and SCC. Another study showed a potential association between lip cancer (SCC) and exposure to hydrochlorothiazide: 633 cases of lip cancer were matched with 63,067 control subjects using a risk-set sampling strategy. A cumulative dose-dependent relationship was demonstrated, with an adjusted HR ranging from 2.1 (95% CI: 1.7–2.6) to HR 3.9 (3.0–4.9) for high cumulative dose (~25,000 mg) and HR 7.7 (5.7–10.5) for the highest cumulative dose (~100,000 mg) (see section "Particular patient groups").

The effect of candesartan cilexetil at a dose of 32 mg once daily resulted in a reduction in blood pressure of 22/15 mm Hg and 21/14 mm Hg, respectively, and was significantly more effective than the corresponding monocomponents. There was no statistically significant difference in the number of major cardiovascular events. Hydrochlorothiazide inhibits sodium reabsorption, primarily in the distal renal tubules, promoting the 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 and extracellular fluid volume and decreases cardiac output and blood pressure. With prolonged therapy, reduced peripheral resistance contributes to lowering blood pressure.

Clinical studies have shown that long-term treatment with hydrochlorothiazide reduces the risk of cardiovascular morbidity and mortality.

Candesartan and hydrochlorothiazide have an additive antihypertensive effect. In patients with arterial hypertension, candesartan in combination with hydrochlorothiazide leads to effective and sustained reduction in blood pressure without reflex tachycardia. No information is available regarding severe or excessive hypotension after the first dose or withdrawal syndrome. After single-dose administration of candesartan in combination with hydrochlorothiazide, onset of antihypertensive effect typically occurs within 2 hours. With continuous treatment, optimal reduction in blood pressure is achieved within four weeks and maintained during long-term therapy. Candesartan in combination with hydrochlorothiazide, administered once daily, provides effective and consistent blood pressure reduction over >24 hours, with a small difference between maximum and minimum effects between doses. The efficacy of candesartan in combination with hydrochlorothiazide does not depend on patient age or sex.

In a study, administration of candesartan in combination with hydrochlorothiazide at doses of 32 mg/12.5 mg and 32 mg/25 mg once daily led to additional blood pressure reduction. The combination of 32 mg candesartan cilexetil with 25 mg hydrochlorothiazide was significantly more effective than the combination of 32 mg candesartan cilexetil with 12.5 mg hydrochlorothiazide, with mean blood pressure reductions of 16/10 mm Hg and 13/9 mm Hg, respectively.

A lower incidence of adverse effects, particularly cough, was observed with candesartan in combination with hydrochlorothiazide compared to treatment with ACE inhibitor/hydrochlorothiazide combinations.

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. After oral administration, candesartan cilexetil is converted into the active substance candesartan. Absolute bioavailability is 40%. The mean peak serum concentration (Cmax) is reached within 3–4 hours after tablet intake. Candesartan serum concentration increases linearly with increasing doses within the therapeutic range. No significant difference in candesartan pharmacokinetics was observed depending on sex. Food intake does not significantly affect the area under the serum 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 is rapidly absorbed from the gastrointestinal tract with an absolute bioavailability of 70%. Food intake improves absorption by approximately 15%. Bioavailability may be reduced in patients with heart failure and marked edema.

The protein binding of hydrochlorothiazide 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 excreted 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. No drug accumulation occurs after repeated multiple dosing. The half-life of candesartan remains unchanged after administration of candesartan cilexetil in combination with hydrochlorothiazide. An increase in AUC (15–18%) and Cmax (23–24%) of candesartan is observed when administered together with hydrochlorothiazide, but this is not clinically significant. Additionally, titration of individual components is recommended before switching to combination therapy with candesartan and hydrochlorothiazide. No additional accumulation of candesartan occurs after repeated doses of the combination compared to monotherapy.

The 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 oral administration of a 14C-labeled candesartan cilexetil dose, approximately 26% of the dose is excreted in urine as candesartan and 7% as an inactive metabolite, while approximately 56% of the dose is found in feces as candesartan and 10% as an inactive metabolite.

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 used in combination 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 subjects (over 65 years), Cmax and AUC of candesartan are increased by approximately 50% and 80%, respectively, compared to younger subjects. However, the blood pressure response and incidence of adverse effects after administration of candesartan in combination with hydrochlorothiazide are similar in young patients and elderly subjects.

In patients with mild to moderate renal impairment, compared to patients with normal renal function, maximum concentration and area under the concentration-time curve (AUC) for candesartan increased by approximately 50% and 70%, respectively, after multiple dosing, although the elimination half-life remained unchanged. Corresponding changes in patients with severe renal impairment were approximately 50% and 110%, respectively. The terminal elimination half-life of candesartan was approximately twice as long in patients with severe renal impairment. Pharmacokinetics in patients undergoing hemodialysis were similar to those in patients with severe renal impairment.

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

In patients with mild to moderate hepatic impairment, an increase in the AUC of candesartan by 23% was observed 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.

For the treatment of essential hypertension in adult patients when blood pressure is not adequately controlled by monotherapy with candesartan cilexetil or hydrochlorothiazide.

Contraindications.

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

Pregnancy and breastfeeding.

Severe renal impairment (creatinine clearance <30 mL/min/1.73 m² body surface area).

Severe hepatic impairment and/or biliary obstruction.

Persistent hypokalemia or hypercalcemia.

Gout.

Concomitant use of candesartan in combination with hydrochlorothiazide and medicinal products containing aliskiren is contraindicated in patients with diabetes mellitus or renal dysfunction (glomerular filtration rate (GFR) <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.

Medicinal products used in clinical pharmacokinetic studies include warfarin, digoxin, oral contraceptives (i.e., ethinylestradiol/levonorgestrel), glipizide, and nifedipine. According to the results of these studies, no clinically significant pharmacokinetic interactions were observed.

The potassium-depleting effect of hydrochlorothiazide may be enhanced by other medicinal products associated with potassium loss and development of hypokalemia (e.g., other potassium-wasting diuretics, laxatives, amphotericin, carbenoxolone, sodium penicillin G, salicylic acid derivatives, steroids, adrenocorticotropic hormone [ACTH]).

Concomitant use of the combination medicinal product Casark® HD with potassium-sparing diuretics, potassium supplements, salt substitutes, or other medicinal products that may increase serum potassium levels (e.g., sodium heparin) may lead to increased serum potassium levels. Monitoring of potassium levels should be performed if necessary (see section "Special precautions for use").

Hypokalemia caused by diuretics and hypomagnesemia create conditions for possible cardiotoxic effects of digitalis glycosides and antiarrhythmic agents. Therefore, periodic determination of serum potassium levels is recommended when Casark® HD is used concomitantly with such medicinal products, as well as with agents that may provoke torsades de pointes:

• Class Ia antiarrhythmics (e.g., quinidine, hydroquinidine, disopyramide);
• Class III antiarrhythmics (e.g., amiodarone, sotalol, dofetilide, ibutilide);
• Certain neuroleptics (e.g., thioridazine, chlorpromazine, levomepromazine, trifluoperazine, zuclopenthixol, sulpiride, sultopride, amisulpride, tiapride, pimozide, haloperidol, droperidol);
• Other medicinal products (e.g., bepridil, cisapride, disopyramide, intravenous erythromycin, halofantrine, ketanserin, mesoridazine, pentamidine, sparfloxacin, terfenadine, intravenous vincamine).

Cases of reversible increases in serum lithium concentrations and toxicity have been reported when lithium is used concomitantly with angiotensin-converting enzyme (ACE) inhibitors or hydrochlorothiazide. A similar effect has also been observed with angiotensin II receptor antagonists (ARBs). The use of candesartan and hydrochlorothiazide with lithium is not recommended. If such a combination is necessary, careful monitoring of serum lithium levels is recommended.

When ARBs are used concomitantly with nonsteroidal anti-inflammatory drugs (NSAIDs) (i.e., selective COX-2 inhibitors, acetylsalicylic acid (> 3 g/day), and nonselective NSAIDs), a reduction in antihypertensive effect may occur.

As with ACE inhibitors, concomitant use of ARBs and NSAIDs may lead to an increased risk of worsening renal function, including possible development of acute renal failure, as well as increased serum potassium levels, particularly in patients with chronically reduced renal function. This combination of medicinal products should be prescribed 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.

Colestipol or cholestyramine reduce the absorption of hydrochlorothiazide.

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

Thiazide diuretics may increase serum calcium levels by reducing its excretion. If calcium or vitamin D supplements are necessary, serum calcium levels should be monitored and the dose adjusted accordingly.

Thiazide diuretics may enhance the hyperglycemic effect of beta-blockers and diazoxide.

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

Thiazide diuretics may increase the risk of adverse effects of amantadine.

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

Concomitant intake of alcohol, barbiturates, or anesthetics may exacerbate orthostatic hypotension.

The use of thiazide diuretics may lead to impaired glucose tolerance. Dose adjustment of antidiabetic medicinal products, including insulin, may be necessary. Metformin should be used with caution due to the risk of lactic acidosis caused by possible functional renal impairment associated with hydrochlorothiazide.

Hydrochlorothiazide may cause reduced arterial response to pressor amines (such as adrenaline), but this effect is insufficient to abolish the pressor effect.

Hydrochlorothiazide may increase the risk of acute renal failure, especially when high doses of iodinated contrast agents are administered.

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

Concomitant use of baclofen, amifostine, tricyclic antidepressants, or neuroleptics may enhance the antihypertensive effect and may provoke the development of arterial hypotension.

According to clinical trial data, dual blockade of the renin-angiotensin-aldosterone system (RAAS), resulting from the 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 treatment with a single medicinal product affecting the RAAS (see sections "Contraindications", "Special precautions for use").

Special precautions for use.

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

Data are available indicating that concomitant use of 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 is absolutely necessary, it should be performed 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.

Renal impairment

As with other drugs that inhibit the renin-angiotensin-aldosterone system, changes in renal function may be expected in susceptible patients receiving the combined medicinal product Casark® HD (see section "Contraindications").

Kidney transplantation

There is insufficient clinical data on the use of Casark® HD in patients who have undergone kidney transplantation.

Renal artery stenosis

In patients with bilateral renal artery stenosis or stenosis of the artery of a single kidney, administration of medicinal products affecting the renin-angiotensin-aldosterone system, including angiotensin II receptor antagonists (ARBs), may increase blood urea and serum creatinine levels.

Reduced circulating blood volume (CBV)

Symptomatic arterial hypotension may develop in patients with reduced CBV and/or hypovolemia, as with other drugs affecting the renin-angiotensin-aldosterone system. Therefore, use of Casark® HD is not recommended until this condition has been corrected.

Anaesthesia and surgery

During anaesthesia and surgical procedures in patients receiving ARBs, arterial hypotension may occur due to blockade of the renin-angiotensin system. In rare cases of severe arterial hypotension, intravenous fluids and/or vasopressors may be required.

Hepatic impairment

Thiazide diuretics should be used with caution in patients with hepatic impairment or progressive liver disease, as minor disturbances in fluid and electrolyte balance may precipitate hepatic coma. There are no clinical data on the use of Casark® HD in patients with hepatic impairment.

Aortic and mitral valve stenosis (obstructive hypertrophic cardiomyopathy)

As with other vasodilators, particular caution should be exercised when administering to 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 drugs acting via suppression of the renin-angiotensin-aldosterone system. Therefore, use of the combined medicinal product Casark® HD is not recommended in this patient group.

Electrolyte imbalance

Serum electrolyte levels should be periodically monitored at appropriate intervals. Use of thiazide diuretics, including hydrochlorothiazide, may lead to fluid or electrolyte imbalance (hypercalcemia, hypokalemia, hyponatremia, hypomagnesemia, and hypochloremic alkalosis).

Thiazide diuretics may reduce urinary excretion of calcium and may lead to occasional and slightly elevated serum calcium concentrations. Marked hypercalcemia may be a sign of occult hyperparathyroidism. In such cases, thiazide diuretics should be discontinued until parathyroid function has been evaluated.

Hydrochlorothiazide increases potassium excretion in urine in a dose-dependent manner, which may lead to hypokalemia. In combination with candesartan cilexetil, this effect of hydrochlorothiazide is less pronounced. The risk of hypokalemia may be higher in patients with liver cirrhosis, those with increased diuresis, those with inadequate oral electrolyte intake, and those receiving concomitant therapy with corticosteroids or adrenocorticotropic hormone (ACTH).

Acute respiratory toxicity

Very rare severe cases of acute respiratory toxicity, including acute respiratory distress syndrome (ARDS), have been reported. After administration of hydrochlorothiazide, very rare severe cases of acute respiratory toxicity, including acute respiratory distress syndrome (ARDS), have been reported. 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.

Use of candesartan cilexetil may lead to hyperkalemia, particularly in the presence of heart failure and/or renal impairment. Concomitant use of the combined medicinal product Casark® HD with ACE inhibitors, aliskiren, potassium-sparing diuretics, potassium supplements, salt substitutes, or other medicinal products that may increase serum potassium levels (e.g., sodium heparin) may result in increased serum potassium levels. Serum potassium levels should be monitored when necessary.

Thiazide diuretics also increase urinary excretion of magnesium, which may lead to hypomagnesemia.

Effects on metabolism and endocrine system

Use of thiazide diuretics may impair glucose tolerance. Dose adjustment of antidiabetic medicinal products, including insulin, may be required. Latent diabetes mellitus may become manifest during treatment with thiazide diuretics. Increased cholesterol and triglyceride levels have been associated with thiazide diuretic use. However, only minor effects have been observed when doses contained in the combined medicinal product Casark® HD are used. Thiazide diuretics increase serum uric acid concentration and may trigger gout attacks in predisposed patients.

Photosensitization

Cases of photosensitization reactions have been reported during use of thiazide diuretics (see section "Adverse reactions"). If a photosensitivity reaction occurs, treatment should be discontinued. If re-treatment is necessary, protection of skin areas exposed to sunlight or artificial UV radiation is recommended.

Non-melanoma skin cancer

In two epidemiological studies based on data from the Danish National Cancer Registry, an increased risk of non-melanoma skin cancer (NMSC) [basal cell carcinoma (BCC) and squamous cell carcinoma (SCC)] was observed with higher cumulative doses of hydrochlorothiazide.

The photosensitizing effect of hydrochlorothiazide may be a likely mechanism for the development of NMSC.

Patients taking hydrochlorothiazide should be informed about the risk of non-melanoma skin cancer and advised to regularly check their skin for new lesions and promptly report any suspicious skin changes. To minimize the risk of skin cancer, patients should be advised to take preventive measures such as limiting exposure to sunlight and UV radiation, and, when exposure occurs, to ensure adequate skin protection. Any suspicious skin lesions should be promptly evaluated, including histological examination of biopsy material. Consideration should be given to reviewing the use of hydrochlorothiazide in patients with a history of NMSC (see section "Adverse reactions").

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

Sulfonamides 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 within hours or weeks of starting the drug. Untreated acute angle-closure glaucoma may lead to permanent vision loss. The primary treatment is prompt discontinuation of the drug. If intraocular pressure remains uncontrolled, emergency medical or surgical treatment may be required. Risk factors for developing acute angle-closure glaucoma may include a history of sulfonamide or penicillin allergy.

General conditions

In patients in whom vascular tone and renal function depend predominantly on the activity of the renin-angiotensin-aldosterone system (e.g., patients with severe congestive heart failure or primary renal failure, including renal artery stenosis), treatment with drugs affecting this system, including ARBs, has been associated with acute arterial hypotension, azotemia, oliguria, or, rarely, acute renal failure. As with any antihypertensive drug, excessive reduction in blood pressure in patients with ischemic heart disease or ischemic cerebrovascular disease may lead to myocardial infarction or stroke.

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

Cases of exacerbation or development of systemic lupus erythematosus have been reported during treatment with thiazide diuretics.

The antihypertensive effect of Casark® HD may be enhanced by concomitant use of other antihypertensive agents.

Casark® HD contains lactose as an excipient; therefore, patients with rare hereditary forms of galactose intolerance, congenital lactase deficiency, or glucose-galactose malabsorption should not take this medicinal product.

Pregnancy

Angiotensin II receptor antagonists should not be taken during pregnancy. Except in cases where ARB therapy is essential, patients planning pregnancy should switch to alternative antihypertensive medicinal products with an established safety profile in pregnancy. Upon diagnosis of pregnancy, ARBs should be discontinued immediately and alternative therapy initiated if needed (see sections "Contraindications" and "Use during pregnancy and breastfeeding").

Use during pregnancy and breastfeeding

Available data on the use of Casark® HD in pregnant women are very limited. These data are insufficient to draw conclusions about the potential risk to the fetus if 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, the risk to the fetus increases if Casark® HD is taken during the second or third trimester of pregnancy. Use of drugs acting directly on the renin-angiotensin system during the second and third trimesters of pregnancy may harm the fetus and newborn (hypotension, renal dysfunction, oliguria and/or anuria, oligohydramnios, cranial hypoplasia, intrauterine growth retardation) up to and including fatal outcomes. Cases of pulmonary hypoplasia, facial abnormalities, and limb contractures have been described. Animal studies with candesartan cilexetil have demonstrated fetal kidney damage in late pregnancy and in newborns. This mechanism is considered pharmacologically mediated via effects on the renin-angiotensin-aldosterone system.

Hydrochlorothiazide may reduce plasma volume as well as uteroplacental blood flow. It may also cause neonatal thrombocytopenia. Due to the pharmacological mechanism of action of hydrochlorothiazide, its use during the second and third trimesters may worsen fetoplacental perfusion and lead to fetal and neonatal effects such as jaundice, electrolyte imbalance, and thrombocytopenia.

Hydrochlorothiazide should not be used to treat gestational edema, gestational hypertension, or preeclampsia due to the risk of reduced plasma volume and placental hypoperfusion without beneficial effects on disease course.

Hydrochlorothiazide should not be used to treat essential hypertension in pregnant women, except in rare cases where no other treatment is possible.

Given the above, Casark® HD is contraindicated during pregnancy. If pregnancy is diagnosed during treatment, use of Casark® HD should be discontinued.

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

Ability to affect reaction speed when driving or operating machinery

No studies have been conducted on the effect on the ability to drive or operate machinery. When driving or operating machinery, it should be considered that dizziness or fatigue may occasionally occur during treatment with Casark® HD.

Method of Administration and Dosage

Dosage for the Treatment of Hypertension

The recommended dose of the combined medicinal product Casark® HD is 1 tablet per day.

It is recommended to titrate the doses of individual components (candesartan cilexetil and hydrochlorothiazide). In clinical practice, a direct transition from monotherapy to treatment with the combined medicinal product Casark® HD may be considered. When switching from hydrochlorothiazide monotherapy, gradual dose titration of candesartan cilexetil is recommended. The combined medicinal product Casark® HD may be prescribed to patients whose blood pressure is not adequately controlled with monotherapy using either candesartan cilexetil or hydrochlorothiazide, or with combination therapy of candesartan and hydrochlorothiazide at lower doses.

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

Special Patient Groups

Elderly Patients

Dose adjustment is not required in elderly patients.

Patients with Reduced Circulating Blood Volume

In patients at risk of developing arterial hypotension, such as those with possible reduction in circulating blood volume, gradual dose titration of candesartan cilexetil is recommended (in such patients, the initial dose of candesartan cilexetil may be 4 mg).

Patients with Renal Impairment

Gradual dose titration of the drug is recommended in patients with mild to moderate renal impairment (creatinine clearance 30–80 mL/min/1.73 m² body surface area).

The combined medicinal product Casark® HD is contraindicated in patients with severe renal impairment (creatinine clearance <30 mL/min/1.73 m² body surface area) (see section "Contraindications").

Patients with Hepatic Impairment

Gradual dose titration of candesartan cilexetil is recommended in patients with mild to moderate chronic liver disease. The combined medicinal product Casark® HD is contraindicated in patients with severe hepatic impairment and/or cholestasis (see section "Contraindications").

Method of Administration

Oral use.

The combined medicinal product Casark® HD can be taken independently of food intake.

The bioavailability of candesartan is not affected by food.

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

Children

Safety and efficacy of Casark® HD in pediatric patients (from birth to 18 years of age) have not been established. Data are lacking.

Overdose

Symptoms

Based on pharmacological analysis, the main manifestation of overdose with candesartan cilexetil may be symptomatic arterial hypotension and dizziness. In individual reports of overdose cases (up to 672 mg of candesartan cilexetil), recovery occurred without complications.

The main manifestation of hydrochlorothiazide overdose is acute fluid and electrolyte loss. Other possible symptoms include dizziness, arterial hypotension, thirst, tachycardia, ventricular arrhythmias, lethargy/mental status changes, and muscle cramps.

Treatment

There is no specific information on the management of patients in case of overdose with the combined medicinal product Casark® HD. However, the following measures are recommended in case of overdose.

If clinically indicated, induce vomiting or perform gastric lavage. If symptomatic arterial hypotension occurs, symptomatic treatment should be initiated and vital signs should be monitored. The patient should be placed in a supine position with legs slightly elevated. If this is insufficient, plasma volume should be expanded by infusion of isotonic saline solution. Serum electrolyte levels and acid-base balance should be monitored and corrected if necessary. If the above measures are inadequate, sympathomimetic agents may be administered.

Candesartan cannot be removed from the body by hemodialysis. It is also unknown what portion of hydrochlorothiazide is removed by hemodialysis.

Adverse reactions

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

Clinical trial data indicate that adverse reactions with the combined medicinal product candesartan cilexetil/hydrochlorothiazide were consistent with those observed with candesartan cilexetil and/or hydrochlorothiazide.

Table 1 lists adverse reactions observed with candesartan cilexetil, based on data from clinical studies and post-marketing experience. The reactions were identified from a pooled analysis of clinical trial data in patients with hypertension, defined as those occurring at a frequency at least 1% higher with candesartan cilexetil than with placebo.

The following frequency classification is used: 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), not known (cannot be estimated from available data).

Table 1.

System organ class	Frequency	Adverse reactions
Infections and infestations	Common	Respiratory tract infections
Blood and lymphatic system disorders	Very rare	Leukopenia, neutropenia and agranulocytosis
Metabolism and nutrition disorders	Very rare	Hyperkalaemia, hyponatraemia
Nervous system disorders	Common	Dizziness/vertigo, headache
Respiratory, thoracic and mediastinal disorders	Very rare	Cough
Gastrointestinal disorders	Very rare	Nausea
Hepatobiliary disorders	Very rare	Elevated liver enzymes, liver function abnormalities or hepatitis
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 failure, including renal failure in predisposed patients (see section "Dosage and administration")

Table 2 presents adverse reactions observed during monotherapy with hydrochlorothiazide, usually at doses of 25 mg or higher.

Table 2.

System Organ Class	Frequency	Adverse Reactions
Benign, malignant and unspecified neoplasms (including cysts and polyps)	Unknown	Non-melanoma skin cancer (basal cell and squamous cell carcinomas)
Blood and lymphatic system disorders	Uncommon	Leukopenia, neutropenia/agranulocytosis, thrombocytopenia, aplastic anemia, bone marrow suppression, hemolytic anemia
Immune system disorders	Uncommon	Anaphylactic reactions
Metabolism and nutrition disorders	Common	Hyperglycemia, hyperuricemia, electrolyte imbalance (including hyponatremia and hypokalemia)
Psychiatric disorders	Uncommon	Sleep disturbances, depression, excited state
Nervous system disorders	Common	Dizziness, vertigo
	Uncommon	Paresthesia
Eye disorders	Uncommon	Transient blurred vision
	Unknown	Acute myopia, acute angle-closure glaucoma, choroidal effusion
Cardiac disorders	Uncommon	Cardiac rhythm disorders
Vascular disorders	Uncommon	Orthostatic hypotension
	Uncommon	Necrotizing angiitis (vasculitis, cutaneous vasculitis)
Respiratory, thoracic and mediastinal disorders	Uncommon	Respiratory distress (including pneumonitis and pulmonary edema)
Gastrointestinal disorders	Uncommon	Anorexia, loss of appetite, gastric irritation, diarrhea, constipation
	Uncommon	Pancreatitis
Hepatobiliary disorders	Uncommon	Jaundice (intrahepatic cholestatic jaundice)
Skin and subcutaneous tissue disorders	Uncommon	Rash, urticaria, photosensitivity reactions
	Uncommon	Toxic epidermal necrolysis
	Unknown	Systemic lupus erythematosus, cutaneous lupus erythematosus
Musculoskeletal and connective tissue disorders	Uncommon	Muscle spasm
Renal and urinary disorders	Common	Glucosuria
	Uncommon	Renal dysfunction and interstitial nephritis
General disorders and administration site conditions	Common	Weakness
	Uncommon	Fever
Investigations	Common	Elevated cholesterol and triglyceride levels
	Uncommon	Elevated serum urea and creatinine levels

Description of individual adverse reactions

Non-melanoma skin cancer: epidemiological data indicate a cumulative dose-dependent association between the use of hydrochlorothiazide and the development of NMSC (see sections "Particular precautions for use" and "Pharmacological properties").
Respiratory, thoracic and mediastinal disorders: very rare: Acute respiratory distress syndrome (ARDS) (see section "Particular precautions for use").

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorization of the medicinal product is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals and pharmacists, as well as patients or their legal representatives, should report any suspected adverse reactions and lack of efficacy of the medicinal product via the automated pharmacovigilance information system at the following link: https://aisf.dec.gov.ua.

Shelf life.

3 years.

Storage conditions.

Store in the original packaging at a temperature not exceeding 25 °C. Keep out of reach of children.

Packaging. 10 tablets per blister, 3 blisters per carton.

Prescription status. Prescription only.

Manufacturer. JSC "Kievmedpreparat".

Manufacturer's address and place of business.

139 Saksaganskogo Street, Kyiv, 01032, Ukraine.