Casark®n

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

Composition:

Active substances: candesartan, hydrochlorothiazide;

One tablet contains candesartan cilexetil, recalculated to 100% substance — 16 mg, hydrochlorothiazide, recalculated to 100% substance — 12.5 mg;

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

Pharmaceutical form. Tablets.

Main physico-chemical properties: tablets from light pink to pink in color, round-shaped, biconvex. Presence of specks of more intense color is allowed.

Pharmacotherapeutic group. Combined angiotensin II inhibitors.

Angiotensin II receptor blockers and diuretics. Candesartan and diuretics.

ATC code C09DA06.

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 ester hydrolysis during absorption from the gastrointestinal tract. Candesartan is a selective angiotensin II AT1-receptor antagonist 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, as well as a reduction in plasma aldosterone concentration.

Non-melanoma skin cancer (NMSC).

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 patients, respectively. High cumulative use of hydrochlorothiazide (total dose ≥50,000 mg) was associated with an adjusted risk ratio (RR) of 1.29 (95% confidence interval (CI): range 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 indicated a possible association between lip cancer (SCC) and hydrochlorothiazide exposure: 633 cases of lip cancer were matched with 63,067 controls using a risk-set sampling strategy. A cumulative dose-dependent relationship was demonstrated, with an adjusted RR of 2.1 (95% CI: 1.7–2.6) increasing to an RR of 3.9 (3.0–4.9) for high cumulative dose (~25,000 mg) and an RR of 7.7 (5.7–10.5) for the highest cumulative dose (~100,000 mg) (see section "Special warnings and precautions for use").

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 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, chlorides, and water. Renal excretion of potassium and magnesium increases in a dose-dependent manner, while calcium is more extensively reabsorbed. Hydrochlorothiazide reduces plasma volume and extracellular fluid volume, decreases cardiac output, and lowers blood pressure. With prolonged therapy, reduced peripheral resistance contributes to blood pressure reduction.

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

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

In a study, candesartan in combination with hydrochlorothiazide at a dose of 16 mg/12.5 mg once daily resulted in greater blood pressure reduction and achievement of control in a significantly higher number of patients compared to the combination of losartan/hydrochlorothiazide at a dose of 50 mg/12.5 mg once daily.

A lower incidence of adverse events, particularly cough, has been observed with candesartan in combination with hydrochlorothiazide compared to treatment with combinations of ACE inhibitors and hydrochlorothiazide.

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 gender. 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.

Protein binding of hydrochlorothiazide to plasma proteins is about 60%. The apparent volume of distribution is approximately 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 elimination 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.

Total plasma clearance of candesartan is approximately 0.37 mL/min/kg, and renal clearance is approximately 0.19 mL/min/kg. Candesartan is eliminated by the kidneys via both glomerular filtration and active tubular secretion. After oral administration 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 is not metabolized and is excreted primarily unchanged by 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 individuals (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 individuals.

In patients with mild to moderate renal impairment compared to those with normal renal function, maximum concentration and AUC of candesartan increased by approximately 50% and 70%, respectively, after multiple dosing, while 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 was similar to that 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 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 increases 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 cholestatic jaundice.

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), glyburide, 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-losing diuretics, laxatives, amphotericin, carbenoxolone, sodium penicillin G, salicylic acid derivatives, steroids, adrenocorticotropic hormone [ACTH]).

Concomitant use of the combined medicinal product Casark® Nta 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 serum potassium levels should be performed if necessary (see section "Special precautions for use").

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

• Class Ia antiarrhythmic agents (e.g., quinidine, hydroquinidine, disopyramide);
• Class III antiarrhythmic agents (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, mizolastine, pentamidine, sparfloxacin, terfenadine, intravenous vincamine).

Cases of reversible increases in serum lithium concentrations and lithium 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 chronic 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.

Cholestyramine or colestipol 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 due to reduced calcium excretion. When calcium or vitamin D supplements are necessary, serum calcium levels should be monitored and dosage 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 reducing 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 medicinal products (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 required. 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 not sufficient to abolish the pressor effect.

Hydrochlorothiazide may increase the risk of acute renal failure, particularly when high doses of iodine-containing contrast agents are used.

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 data from clinical trials, 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 use of 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 indicate that concomitant use of angiotensin-converting enzyme (ACE) inhibitors, angiotensin II receptor antagonists, or aliskiren increases the risk of 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.

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 combination medicinal product Casark® N (see section "Contraindications").

Kidney transplantation

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

Renal artery stenosis

In patients with bilateral renal artery stenosis or stenosis of the artery of a solitary kidney, treatment with drugs affecting the renin-angiotensin-aldosterone system, including angiotensin II receptor antagonists (AIIAs), may increase blood urea and serum creatinine levels.

Reduced circulating blood volume (CBV)

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

Anaesthesia and surgery

During anaesthesia and surgical procedures, arterial hypotension may develop in patients receiving AIIAs 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 even minor disturbances in fluid and electrolyte balance may precipitate hepatic coma. There are no clinical data on the use of Casark® N in patients with hepatic impairment.

Aortic and mitral valve stenosis (obstructive hypertrophic cardiomyopathy)

As with other vasodilators, 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 agents acting via inhibition of the renin-angiotensin-aldosterone system. Therefore, use of the combination medicinal product Casark® N is not recommended in these patients.

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 calcium excretion in urine and may cause occasional and slightly elevated serum calcium concentrations. Marked hypercalcemia may indicate occult hyperparathyroidism. In such cases, thiazide diuretics should be discontinued until parathyroid function is evaluated.

Hydrochlorothiazide increases urinary potassium excretion in a dose-dependent manner, potentially leading to hypokalemia. When combined with candesartan cilexetil, this effect of hydrochlorothiazide is less pronounced. The risk of hypokalemia may be higher in patients with hepatic 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. Very rare severe cases of acute respiratory toxicity, including ARDS, have been reported following hydrochlorothiazide administration. Pulmonary edema usually develops within minutes or hours after hydrochlorothiazide intake. 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.

Candesartan cilexetil may cause hyperkalemia, particularly in patients with heart failure and/or renal impairment. Concomitant use of the combination medicinal product Casark® N 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 lead to increased serum potassium levels. Serum potassium levels should be monitored when necessary.

Thiazide diuretics also increase urinary magnesium excretion, potentially leading 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 apparent during treatment with thiazide diuretics. Increased cholesterol and triglyceride levels have been associated with thiazide diuretic use. However, only minor effects have been observed with doses contained in the combination medicinal product Casark® N. Thiazide diuretics increase serum uric acid concentration and may precipitate gout in susceptible 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

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

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

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 sudden onset of decreased visual acuity or eye pain and typically occur within hours or weeks after 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, urgent medical or surgical treatment may be required. Risk factors for acute angle-closure glaucoma may include a history of sulfonamide or penicillin allergy.

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 immediately 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 is unavoidable, to ensure adequate skin protection. Any suspicious skin lesions should be promptly evaluated, including histological examination of biopsy specimens. In patients with a history of NMSC, reconsideration of hydrochlorothiazide use may be appropriate (see section "Adverse reactions").

General conditions

In patients whose vascular tone and renal function primarily depend on the activity of the renin-angiotensin-aldosterone system (e.g., patients with severe congestive heart failure or primary renal insufficiency, including renal artery stenosis), treatment with drugs affecting this system, including AIIAs, has been associated with acute hypotension, azotemia, oliguria, or, less frequently, acute renal failure. As with any antihypertensive agent, excessive reduction in blood pressure in patients with ischemic heart disease or 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.

Exacerbation or development of systemic lupus erythematosus has been reported during treatment with thiazide diuretics.

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

This medicinal product 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 AIIA therapy is essential, patients planning pregnancy should switch to alternative antihypertensive medicinal products with an established safety profile during pregnancy. Upon diagnosis of pregnancy, AIIAs should be discontinued immediately and alternative therapy initiated if needed (see sections "Contraindications" and "Use during pregnancy and breastfeeding").

Use during pregnancy and breastfeeding

Clinical data on the use of Casark® N in pregnant women are very limited. These data are insufficient to draw conclusions about 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 Casark® N 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 cause fetal and neonatal harm (hypotension, renal dysfunction, oliguria and/or anuria, oligohydramnios, cranial hypoplasia, intrauterine growth retardation) up to and including fetal death. Cases of pulmonary hypoplasia, facial abnormalities, and limb contractures have been described. Animal studies with candesartan cilexetil have demonstrated fetal renal 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 and uteroplacental blood flow. It may also cause neonatal thrombocytopenia. Given the pharmacological mechanism 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® N is contraindicated during pregnancy. If pregnancy is diagnosed during treatment, use of Casark® N should be discontinued.

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

Ability to influence reaction speed while 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® N.

Dosage and Administration

Dosage for the treatment of hypertension

The recommended dose of the combination medicinal product Casark® H is 1 tablet per day.

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

Patients at risk of developing arterial hypotension, such as those with possible reduced CBV, should have a gradual dose titration of candesartan cilexetil (the initial dose of candesartan cilexetil for such patients 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).

Casark® H combination medicinal product 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. Casark® H combination medicinal product is contraindicated in patients with severe hepatic impairment and/or cholestasis (see section "Contraindications").

Administration

Oral use.

The combination medicinal product Casark® H can be taken independently of food intake.

The bioavailability of candesartan is not affected by food intake.

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

Children

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

Overdose.

Symptoms

Based on pharmacological analysis, the main manifestation of candesartan cilexetil overdose may be symptomatic arterial hypotension and dizziness. In individual reports of overdose cases (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 arrhythmias, lethargy/mental status changes, and muscle cramps.

Treatment

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

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 the lower limbs 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 as 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 combination of candesartan cilexetil/hydrochlorothiazide were mild and transient. Discontinuation of therapy due to adverse effects during the studies was similar with the candesartan cilexetil/hydrochlorothiazide combination (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 are consistent with those observed with candesartan cilexetil and/or hydrochlorothiazide administered alone.

Table 1 lists adverse reactions observed with candesartan cilexetil based on clinical trial data and post-marketing experience. The reactions were identified from a pooled analysis of clinical trials in patients with hypertension, in which adverse reactions occurred 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), and not known (cannot be estimated from available data).

Table 1.

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

Table 2.

Description of individual adverse reactions

Non-melanoma skin cancer: available data from epidemiological studies indicate a cumulative dose-dependent association between hydrochlorothiazide use and the occurrence of NMSC (see sections "Particular patient populations" and "Pharmacological properties").

Respiratory, thoracic and mediastinal disorders: very rare: Acute respiratory distress syndrome (ARDS) (see section "Particular patient populations").

Reporting suspected adverse reactions

Reporting of suspected adverse reactions after authorization of the medicinal product is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Medical and pharmaceutical personnel, as well as patients or their legal representatives, should report all suspected adverse reactions and lack of efficacy through 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 in a blister pack, 3 blisters in a carton.

Prescription status. Prescription only.

Manufacturer. JSC "Kyivmedpreparat".

Address of the manufacturer and location of its business activities.

139 Saksaganskoho Street, Kyiv, 01032, Ukraine.