Instructions for Kasark HD tablets 32/25 mg No. 30
Composition
active ingredients: candesartan, hydrochlorothiazide;
1 tablet contains candesartan cilexetil in terms of 100% substance - 32 mg, hydrochlorothiazide in terms of 100% substance - 25 mg;
Excipients: lactose monohydrate; corn starch; carmellose calcium; hydroxypropylcellulose; polyethylene glycol (PEG 8000); magnesium stearate; red iron oxide (E 172); yellow iron oxide (E 172).
Dosage form
Pills.
Main physicochemical properties: tablets from light pink to pink, oval, biconvex with a score on one side and a score and notch on the other side. The presence of inclusions of a more intense color is allowed.
Pharmacotherapeutic group
Combination drugs of angiotensin II inhibitors.
Angiotensin II receptor blockers and diuretics. Candesartan and diuretics.
ATX code C09D A06.
Pharmacological properties
Pharmacodynamics.
Angiotensin II is the main vasoactive hormone of the renin-angiotensin-aldosterone system and plays a role in the pathophysiology of hypertension and other cardiovascular disorders. It also plays a role in the pathogenesis of organ hypertrophy and target organ damage. The main physiological effects of angiotensin II, such as vasoconstriction, stimulation of aldosterone, regulation of water-salt homeostasis, and stimulation of cell growth, are mediated through type 1 (AT1) receptors.
Candesartan cilexetil is a prodrug that is rapidly converted to the active substance, candesartan, by ester hydrolysis during absorption from the gastrointestinal tract. Candesartan is a selective antagonist of the angiotensin II AT1 receptor with tight binding and slow dissociation from it. It has no agonist activity.
Candesartan does not affect the angiotensin-converting enzyme (ACE) and other enzyme systems, which is usually associated with the use of ACE inhibitors, since there is no effect on the breakdown of kinins to other substances, such as substance P. Angiotensin II antagonists do not actually cause cough. Candesartan does not bind to or block receptors for other hormones and ion channels. Antagonism of AT1 receptors leads to a dose-dependent increase in plasma renin levels, angiotensin I and angiotensin II levels, and a decrease in plasma aldosterone concentrations.
Non-melanoma skin cancer (NMSC).
Available epidemiological data suggest that there is a cumulative dose-dependent relationship between hydrochlorothiazide use and the occurrence of NSCLC. 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 controls, respectively. High-dose hydrochlorothiazide use (≥50,000 mg) was associated with an adjusted hazard ratio (HR) 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 relationship between cumulative dose and outcome was observed for both BCC and SCC. Another study showed a possible association between lip cancer (LC) and hydrochlorothiazide exposure: 633 cases of lip cancer were matched to 63,067 controls using a randomised risk-matching strategy. A cumulative dose-dependent association was demonstrated with an adjusted HR of 2.1 (95% CI: 1.7–2.6) to HR of 3.9 (3.0–4.9) for the high total dose (25,000 mg) and HR of 7.7 (5.7–10.5) for the highest total dose (100,000 mg) (see section 4.4).
Candesartan cilexetil 32 mg once daily resulted in blood pressure reductions of 22/15 mmHg and 21/14 mmHg, respectively, and were significantly more effective than the respective monocomponents. There was no statistically significant difference in the number of major cardiovascular events. Hydrochlorothiazide blocks sodium reabsorption, mainly in the distal renal tubules, and promotes the excretion of sodium, chloride, and water. Renal excretion of potassium and magnesium increases in a dose-dependent manner, while calcium is reabsorbed to a greater extent. Hydrochlorothiazide reduces plasma and extracellular fluid volume and reduces cardiac output and blood pressure. With prolonged therapy, the reduced peripheral resistance contributes to the reduction in blood pressure.
Candesartan and hydrochlorothiazide have an additive antihypertensive effect. In patients with hypertension, candesartan in combination with hydrochlorothiazide provides effective and sustained blood pressure reduction without a reflex increase in heart rate. There is no information on serious or excessive hypotension after the first dose or on withdrawal syndrome. After a single dose of candesartan in combination with hydrochlorothiazide, the onset of the antihypertensive effect usually occurs within 2 hours. With continuous treatment, optimal blood pressure reduction is achieved within four weeks and is maintained with long-term treatment. Candesartan in combination with hydrochlorothiazide, when administered once daily, provides effective and consistent blood pressure reduction for > 24 hours with little difference between peak and trough effects between doses. The effectiveness of candesartan in combination with hydrochlorothiazide is independent of the age and gender of the patients.
In the study, candesartan cilexetil 32 mg/12.5 mg and 32 mg/25 mg once daily resulted in additional reductions in blood pressure. 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 overall mean blood pressure reductions of 16/10 mmHg and 13/9 mmHg, respectively.
It was noted that the incidence of adverse events, especially cough, was lower when candesartan was used in combination with hydrochlorothiazide than when treated with a combination of ACE inhibitors and hydrochlorothiazide.
There are currently no data on the use of candesartan cilexetil/hydrochlorothiazide in patients with renal disease/nephropathy, decreased left ventricular function/congestive heart failure, and post-myocardial infarction.
Pharmacokinetics.
Absorption and distribution
Candesartan cilexetil. After oral administration of candesartan cilexetil is converted to the active substance candesartan. Absolute bioavailability is 40%. The mean peak serum concentration (Cmax) is reached 3–4 hours after taking the tablet. The concentration of candesartan in serum increases linearly with increasing doses within the therapeutic range. No significant difference in the pharmacokinetics of candesartan 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 (more than 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 significant edema.
The binding of hydrochlorothiazide to plasma proteins is about 60%. The apparent volume of distribution is about 0.8 l/kg.
Metabolism and excretion
Candesartan cilexetil. Candesartan is mainly excreted unchanged in the urine and bile and is only slightly metabolised by the liver (CYP2C9). Available interaction studies indicate no effect on CYP2C9 and CYP3A4. Based on in vitro data, no in vivo interactions are expected with medicinal products metabolised by the cytochrome P450 isoenzymes CYP1A2, CYP2A6, CYP2C9, CYP2C19, CYP2D6, CYP2E1 or CYP3A4. The elimination half-life of candesartan is approximately 9 hours. There is no accumulation of the drug after repeated dosing. The elimination half-life of candesartan is unchanged after administration of candesartan cilexetil in combination with hydrochlorothiazide. An increase in AUC (15-18%) and Cmax (23-24%) of candesartan was observed when administered with hydrochlorothiazide, but this is not clinically significant. In addition, titration of the individual components is recommended before switching to the use of candesartan in combination with hydrochlorothiazide. There is no additional accumulation of candesartan after repeated doses of the combination compared to monotherapy.
The total plasma clearance of candesartan is approximately 0.37 ml/min/kg and the renal clearance is approximately 0.19 ml/min/kg. Renal elimination of candesartan occurs by both glomerular filtration and active tubular secretion. Following an oral dose of 14C-labeled candesartan cilexetil, approximately 26% of the dose is excreted in the urine as candesartan and 7% as an inactive metabolite, while approximately 56% of the dose is recovered in the feces as candesartan and 10% as an inactive metabolite.
Hydrochlorothiazide is not metabolized and is excreted primarily unchanged by glomerular filtration and active tubular secretion. The terminal half-life is 8 hours. Approximately 70% of an oral dose is excreted in the urine within 48 hours. The half-life of hydrochlorothiazide is unchanged when used in combination with candesartan cilexetil. There is no additional accumulation of hydrochlorothiazide after repeated doses of the combination compared to monotherapy.
Candesartan cilexetil. In elderly subjects (over 65 years of age), Cmax and AUC of candesartan are increased by approximately 50% and 80%, respectively, compared with younger subjects. However, the blood pressure response and the incidence of adverse events following a single dose of candesartan in combination with hydrochlorothiazide are similar in young and elderly subjects.
In patients with mild to moderate renal impairment, the maximum concentration and area under the concentration-time curve of candesartan increased after multiple dosing by approximately 50% and 70%, respectively, compared with patients with normal renal function, but the elimination half-life remained unchanged. The corresponding changes in patients with severe renal impairment were approximately 50% and 110%, respectively. The terminal elimination half-life of candesartan was approximately doubled in patients with severe renal impairment. The pharmacokinetics in patients on haemodialysis 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 candesartan AUC was observed by 23% in one study and by 80% in another study. There is no experience in patients with severe hepatic impairment.
Hydrochlorothiazide
The terminal half-life of hydrochlorothiazide is increased in patients with renal insufficiency.
Indication
For the treatment of essential hypertension in adult patients whose blood pressure is not adequately controlled by candesartan cilexetil or hydrochlorothiazide monotherapy.
Contraindication
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 liver failure and/or bile stasis.
Persistent hypokalemia or hypercalcemia.
Gout.
In patients with diabetes mellitus or renal impairment (glomerular filtration rate (GFR) <60 ml/min/1.73 m2), the concomitant use of candesartan in combination with hydrochlorothiazide with medicinal products containing aliskiren is contraindicated (see section 4.5).
Interaction with other medicinal products and other types of interactions
Medicinal products used in clinical pharmacokinetic studies include warfarin, digoxin, oral contraceptives (i.e. ethinyl estradiol/levonorgestrel), glibenclamide and nifedipine. No clinically significant pharmacokinetic interactions were identified in these studies.
The potassium-depleting effect of hydrochlorothiazide may be potentiated by other drugs associated with potassium loss and the development of hypokalemia (e.g., other kaliuretic diuretics, laxatives, amphotericin, carbenoxolone, penicillin G sodium, salicylic acid derivatives, steroids, adrenocorticotropic hormone [ACTH]).
Concomitant use of the combined drug Kasark® HD and potassium-sparing diuretics, potassium supplements or salt substitutes, or other drugs that may increase serum potassium levels (e.g. heparin sodium) may lead to an increase in serum potassium levels. If necessary, potassium levels should be monitored (see section "Special instructions").
Diuretic-induced hypokalemia and hypomagnesemia create conditions for the development of possible cardiotoxic effects of digitalis glycosides and antiarrhythmic drugs. Therefore, it is recommended to periodically determine the level of potassium in the blood serum when using Kasark® HD with the following drugs, as well as with drugs that can provoke torsades de pointes:
Class Ia antiarrhythmics (e.g. quinidine, hydroquinidine, disopyramide);
class III antiarrhythmics (e.g. amiodarone, sotalol, dofetilide, ibutilide);
some neuroleptics (e.g. thioridazine, chlorpromazine, levomepromazine, trifluoroperazine, cyamemazine, sulpiride, sultopride, amisulpride, tiapride, pimozide, haloperidol, droperidol);
other medicines (e.g. bepridil, cisapride, diphenamyl, erythromycin IV, halofantrine, ketanserin, mizolastine, pentamidine, sparfloxacin, terfenadine, vincamine IV).
When ARVIs are used concomitantly with non-steroidal anti-inflammatory drugs (NSAIDs) (i.e. selective COX-2 inhibitors, acetylsalicylic acid (> 3 g/day) and non-selective NSAIDs), a reduction in the antihypertensive effect may be observed.
As with ACE inhibitors, concomitant use of ARBs and NSAIDs may lead to an increased risk of worsening of renal function, including possible acute renal failure, and an increase in serum potassium, especially in patients with chronic renal impairment. This combination should be administered with caution, especially in the elderly. Patients should be adequately hydrated 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 enhance the non-depolarizing effect of muscle relaxants (e.g. tubocurarine).
Thiazide diuretics may increase serum calcium levels by decreasing its excretion. If calcium or vitamin D supplements are required, 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 reducing gastrointestinal motility and gastric emptying rate.
Thiazide diuretics may increase the risk of side effects of amantadine.
Thiazide diuretics may reduce the renal excretion of cytotoxic drugs (e.g. cyclophosphamide, methotrexate) and potentiate their myelosuppressive effects.
Orthostatic hypotension may be exacerbated by concomitant use of alcohol, barbiturates, or anesthetics.
The use of thiazide diuretics may lead to impaired glucose tolerance. It is necessary to adjust the dose of antidiabetic drugs, including insulin. Metformin should be used with caution due to the risk of lactic acidosis caused by possible functional renal failure associated with the action of hydrochlorothiazide.
Hydrochlorothiazide may cause a decrease in the response of the arteries to pressor amines (such as adrenaline), but is insufficient to eliminate the pressor effect.
Hydrochlorothiazide may increase the risk of acute renal failure, especially when using high doses of iodinated contrast media.
Concomitant use of cyclosporine may increase the risk of developing hyperuricemia and gout-like complications.
Concomitant use of baclofen, amifostine, tricyclic antidepressants or neuroleptics may lead to an increase in the antihypertensive effect and may provoke the development of arterial hypotension.
According to clinical studies, 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 events such as hypotension, hyperkalemia and decreased renal function (including acute renal failure) compared to the use of a single drug that affects the RAAS (see sections "Contraindications", "Special instructions for use").
Application features
Dual blockade of the renin-angiotensin-aldosterone system (RAAS)
There is evidence that the 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, which is why the 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 used only under specialist supervision and with frequent and careful monitoring of renal function, electrolytes and blood pressure. ACE inhibitors and angiotensin II receptor blockers should not be used concomitantly in patients with diabetic nephropathy.
Kidney dysfunction
As with other drugs that inhibit the renin-angiotensin-aldosterone system, changes in renal function may be expected in susceptible patients taking the combination drug Kasark® HD (see section "Contraindications").
Kidney transplantation
There is insufficient clinical data on the use of the drug Kasark® HD in patients who have undergone kidney transplantation.
Renal artery stenosis
In patients with bilateral renal artery stenosis or stenosis of the artery to a solitary kidney, the use of medicinal products that affect the renin-angiotensin-aldosterone system, including angiotensin II receptor antagonists (ARBs), may increase blood urea and serum creatinine.
Patients with reduced BCC and/or hypovolemia may develop symptomatic hypotension, as with the use of drugs that affect the renin-angiotensin-aldosterone system. Therefore, the use of Kasark® HD is not recommended until this condition is corrected.
Anesthesia and surgical interventions
During anesthesia and surgery, patients receiving ARBs may develop hypotension due to blockade of the renin-angiotensin system. Very rarely, severe hypotension may require the use of intravenous fluids and/or vasopressors.
Liver dysfunction
Thiazide diuretics should be used with caution in patients with impaired hepatic function or progressive liver disease, as minor changes in fluid and electrolyte balance may precipitate hepatic coma. There is no clinical experience with Kasark® HD in patients with impaired hepatic function.
Aortic and mitral valve stenosis (obstructive hypertrophic cardiomyopathy)
As with other vasodilators, special caution should be exercised when used in 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 that act by inhibiting the renin-angiotensin-aldosterone system. Therefore, the combination drug Kasark® HD is not recommended for this group of patients.
Electrolyte imbalance
Serum electrolytes should be determined periodically at appropriate intervals. Thiazide diuretics, including hydrochlorothiazide, may lead to fluid or electrolyte imbalance (hypercalcemia, hypokalemia, hyponatremia, hypomagnesemia, and hypochloremic alkalosis).
Thiazide diuretics may reduce urinary calcium excretion and may lead to occasional and slightly elevated serum calcium concentrations. Marked hypercalcemia may be a sign of latent hyperparathyroidism. In such cases, thiazide diuretics should be discontinued until parathyroid function is measured.
Hydrochlorothiazide dose-dependently increases urinary potassium excretion, 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 cirrhosis of the liver, in patients with increased diuresis, in patients with inadequate oral electrolyte intake, and in patients 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. Very rare severe cases of acute respiratory toxicity, including acute respiratory distress syndrome (ARDS), have been reported following the administration of hydrochlorothiazide. Pulmonary oedema usually develops within minutes to hours of taking hydrochlorothiazide. Early symptoms include dyspnoea, fever, worsening of pulmonary function and hypotension. If ARDS is suspected, hydrochlorothiazide should be discontinued and appropriate treatment initiated. Hydrochlorothiazide should not be given to patients who have previously experienced ARDS after taking hydrochlorothiazide.
The use of candesartan cilexetil may lead to the development of hyperkalemia, especially in the presence of heart failure and/or impaired renal function. The simultaneous use of the combined drug Kasark® HD and ACE inhibitors, aliskiren, potassium-sparing diuretics, potassium supplements or salt substitutes or other drugs that may increase serum potassium levels (e.g. heparin sodium) may lead to an increase in serum potassium levels. If necessary, potassium levels should be monitored.
Thiazide diuretics also increase urinary magnesium excretion, which can lead to the development of hypomagnesemia.
Effects on metabolism and endocrine system
The use of thiazide diuretics may lead to impaired glucose tolerance. It is necessary to adjust the dose of antidiabetic drugs, including insulin. Latent diabetes mellitus may manifest during treatment with thiazide diuretics. An increase in cholesterol and triglyceride levels is associated with the use of thiazide diuretics. However, only minor effects have been observed when using the doses contained in the combined drug Kasark® HD. Thiazide diuretics increase the concentration of uric acid in the blood serum and may provoke the development of gout in patients prone to it.
Photosensitization
Photosensitivity reactions have been reported with thiazide diuretics (see section 4.8). If a photosensitivity reaction occurs, it is recommended to discontinue treatment. If a second course of treatment is necessary, it is recommended to protect areas of the body exposed to sunlight or artificial UV radiation.
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 total doses of hydrochlorothiazide.
The photosensitizing effect of hydrochlorothiazide may be a likely mechanism for the development of NMR.
Patients taking hydrochlorothiazide should be informed of the risk of non-melanoma skin cancer; they should also be advised to periodically check their skin for new lesions and to report any suspicious skin lesions immediately. 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 to use adequate skin protection if exposed. Any suspicious skin lesion should be promptly investigated, including histological examination of biopsy material. Patients with a history of NMSC may wish to reconsider the use of hydrochlorothiazide (see section 4.8).
Choroidal effusion, acute myopia, and secondary angle-closure glaucoma
Sulfonamides or sulfonamide derivatives may cause an idiosyncratic reaction resulting in choroidal effusion with visual field defect, 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 of starting the drug. Untreated acute angle-closure glaucoma may result in permanent vision loss. The primary treatment is to discontinue the drug as soon as possible. If intraocular pressure remains uncontrolled, urgent medical or surgical treatment may be necessary. Risk factors for acute angle-closure glaucoma may include a history of allergy to sulfonamides or penicillin.
General conditions
In patients whose 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 insufficiency, including renal artery stenosis), treatment with medicinal products that affect this system, including ARBs, has been associated with the development of acute hypotension, azotemia, oliguria or, rarely, acute renal failure. As with any antihypertensive agent, excessive blood pressure reduction in patients with ischemic cardiopathy or ischemic cerebrovascular disease may result in myocardial infarction or stroke.
Hypersensitivity reactions to hydrochlorothiazide can occur with or without a history of allergy or bronchial asthma, but are more likely in patients with such conditions.
Cases of exacerbation or development of systemic lupus erythematosus have been reported with the use of thiazide diuretics.
The antihypertensive effect of the drug Kasark® HD can be enhanced by the use of other antihypertensive agents.
Kasark® 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 medicine.
Pregnancy
Angiotensin II receptor antagonists should not be used during pregnancy. Unless continued ARB therapy is considered essential, patients planning pregnancy should be changed to alternative antihypertensive treatments which have an established safety profile for use in pregnancy. When pregnancy is diagnosed, ARB therapy should be stopped immediately, and, if appropriate, alternative therapy should be started (see sections 4.3 and 4.8).
Use during pregnancy and breastfeeding
Hydrochlorothiazide may reduce plasma volume and uteroplacental blood flow. It may also cause neonatal thrombocytopenia. Given the pharmacological mechanism of action of hydrochlorothiazide, its use during the second and third trimesters may impair feto-placental perfusion and cause 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 decreased plasma volume and placental hypoperfusion without a beneficial effect on the course of the disease.
Hydrochlorothiazide should not be used to treat essential hypertension in pregnant women, except in rare cases where other treatment is not possible.
Considering the above, Kasark® HD is contraindicated during pregnancy. If pregnancy is detected during treatment, the use of the drug Kasark® HD should be discontinued.
It is not known whether candesartan cilexetil passes into breast milk, but due to the potential for adverse effects on nursing infants, Candesartan cilexetil should not be used during breastfeeding.
Ability to influence reaction speed when driving vehicles or other mechanisms
No studies on the effects on the ability to drive and use machines have been conducted. When driving and using machines, it should be taken into account that dizziness or fatigue may occasionally occur when using Kasark® HD.
Method of administration and doses
Dosage for the treatment of hypertension
The recommended dose of the combined drug Kasark® HD is 1 tablet per day.
It is recommended to titrate the dose of the individual components (candesartan cilexetil and hydrochlorothiazide). In clinical practice, direct transfer from monotherapy to the combined drug Kasark® HD may be considered. When transferring from monotherapy with hydrochlorothiazide, it is recommended to gradually adjust the dose of candesartan cilexetil. The combined drug Kasark® HD may be prescribed to patients whose blood pressure is not adequately controlled with monotherapy with candesartan cilexetil or hydrochlorothiazide or with the combination of candesartan and hydrochlorothiazide at lower doses.
The antihypertensive effect is usually achieved within 4 weeks after the start of treatment.
Special patient groups
Elderly patients
Elderly patients do not need to adjust the dose.
Patients with reduced circulating blood volume (CVB)
In patients at risk of developing arterial hypotension, for example, patients with possible reduction in BCC, it is recommended to gradually adjust the dose of candesartan cilexetil (for such patients, the initial dose of candesartan cilexetil may be 4 mg).
Patients with renal impairment
For patients with mild to moderate renal impairment (creatinine clearance 30–80 mL/min/1.73 m2 body surface area), gradual dose titration is recommended.
The combined drug Kasark® HD is contraindicated in patients with severe renal insufficiency (creatinine clearance <30 ml/min/1.73 m2 body surface area) (see section “Contraindications”).
Patients with hepatic impairment
In patients with chronic liver disease of mild to moderate severity, gradual dose titration of candesartan cilexetil is recommended. The combined drug Kasark® HD is contraindicated in patients with severe hepatic insufficiency and/or cholestasis (see section "Contraindications").
Method of application
Oral use.
The combined drug Kasark® HD can be taken regardless of meals.
The bioavailability of candesartan is not affected by food intake.
There are no data on a clinically significant relationship between hydrochlorothiazide and food intake.
Children
The safety and efficacy of Kasark® HD in children (from birth to 18 years of age) have not been established. Data are not available.
Overdose
Symptoms
Based on pharmacological analysis, the main manifestation of candesartan cilexetil overdose may be symptomatic arterial hypotension.
