Casark®
Ukraine
Table of Contents
INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT KASARK® (CASARK)
Composition:
Active substance: candesartan cilexetil;
1 tablet contains candesartan cilexetil, calculated as 100 % substance, 8 mg or 16 mg or 32 mg;
Excipients: calcium carmellose; corn starch; hydroxypropylcellulose; lactose monohydrate; magnesium stearate; polyethylene glycol (PEG 8000).
Pharmaceutical form. Tablets.
Main physicochemical properties:
Kasark®, 8 mg or 16 mg tablets: white or almost white, round-shaped, biconvex tablets. Marbling on the tablet surface may occur.
Kasark®, 32 mg tablets: white or almost white, round-shaped, biconvex tablets with a score line on one side of the tablet. Marbling on the tablet surface may occur.
Pharmacotherapeutic group. Angiotensin II receptor antagonists.
ATC code C09CA06.
Pharmacological Properties
Pharmacodynamics
Angiotensin II is the principal vasoactive hormone of the renin-angiotensin-aldosterone system (RAAS), playing a key role in the pathophysiological mechanism of hypertension, heart failure, and other cardiovascular diseases. It is also involved in the pathogenesis of end-organ hypertrophy and damage. The main physiological effects of angiotensin II, such as vasoconstriction, stimulation of aldosterone secretion, regulation of salt and water homeostasis, and stimulation of cell growth, are mediated via type 1 (AT1) receptors.
Pharmacodynamic Effects
Candesartan cilexetil is a prodrug suitable for oral administration. It is rapidly converted into the active substance, candesartan, by ester hydrolysis during absorption from the gastrointestinal tract. Candesartan is a selective angiotensin II receptor antagonist (ARA-II) with high affinity for AT1 receptors, exhibiting tight binding and slow dissociation from the receptor. It has no agonistic activity.
Candesartan does not inhibit angiotensin-converting enzyme (ACE), which converts angiotensin I to angiotensin II and degrades bradykinin. No influence on ACE or potentiation of bradykinin or substance P has been observed. In controlled clinical trials comparing candesartan with ACE inhibitors, the incidence of cough was lower in patients receiving candesartan cilexetil. Candesartan does not bind to receptors of other hormones and does not block them or ion channels known to be important in cardiovascular regulation. Antagonism of angiotensin II receptors (AT1) leads to a dose-dependent increase in plasma levels of renin, angiotensin I, and angiotensin II, as well as a reduction in plasma aldosterone concentration.
Clinical Efficacy and Safety
Arterial Hypertension
In arterial hypertension, candesartan induces a dose-dependent, long-lasting reduction in arterial pressure (AP). The antihypertensive effect results from a reduction in systemic peripheral resistance without reflex tachycardia. There is no evidence of severe or excessive hypotension after the first dose or of a withdrawal syndrome upon discontinuation of treatment.
After a single dose of candesartan cilexetil, the onset of antihypertensive effect typically occurs within 2 hours. With long-term treatment, the maximum reduction in AP is usually achieved within 4 weeks and is maintained during prolonged therapy. According to meta-analysis data, the average additional effect of increasing the dose from 16 mg to 32 mg once daily was minimal. However, due to inter-individual variability, a more pronounced effect than average may be expected in some patients. When administered once daily, candesartan cilexetil provides effective and smooth reduction of AP over 24 hours, with only a small difference between maximum and minimum effects within the dosing interval.
When candesartan cilexetil is used concomitantly with hydrochlorothiazide, an additional reduction in AP is observed. An enhanced antihypertensive effect is also noted when candesartan cilexetil is combined with amlodipine or felodipine.
Medicinal products that block the renin-angiotensin-aldosterone system have a less pronounced antihypertensive effect in patients of black race (typically a population with low renin levels) compared to patients of other races. This also applies to candesartan.
Candesartan increases renal blood flow and either does not affect or increases glomerular filtration rate, while renal vascular resistance and filtration fraction decrease. In a 3-month clinical study involving patients with arterial hypertension, type 2 diabetes, and microalbuminuria, antihypertensive treatment with candesartan cilexetil reduced urinary albumin excretion. Currently, there are no data on the effect of candesartan on the progression of diabetic nephropathy.
The effect of candesartan cilexetil, administered at doses of 8–16 mg (mean dose 12 mg) once daily, on cardiovascular morbidity and mortality was evaluated in a randomized, placebo-controlled clinical trial involving elderly patients with mild to moderate hypertension, with a mean duration of 3.7 years.
No statistically significant difference was observed in the primary endpoint—the number of major cardiovascular events (cardiovascular mortality, non-fatal stroke, and non-fatal myocardial infarction)—between the candesartan treatment group and the control group.
In the randomized, controlled clinical trials ONTARGET and VA NEPHRON-D, the benefits of combining an ACE inhibitor with an angiotensin II receptor blocker were investigated. The ONTARGET trial included patients with a history of cardiovascular or cerebrovascular disease or type 2 diabetes with evidence of target organ damage. The VA NEPHRON-D trial included patients with type 2 diabetes and diabetic nephropathy.
These trials did not demonstrate a significant favorable effect on renal and/or cardiovascular outcomes or mortality. Instead, an increased risk of hyperkalemia, acute kidney injury, and/or arterial hypotension was observed compared to monotherapy. Due to the similar pharmacodynamic properties of these medicinal products, these findings are relevant for other ACE inhibitors and angiotensin II receptor antagonists.
Therefore, concomitant use of ACE inhibitors and angiotensin II receptor antagonists is not recommended in patients with diabetic nephropathy.
The ALTITUDE trial included patients with type 2 diabetes and chronic kidney disease and/or cardiovascular disease to evaluate the benefits of adding aliskiren to standard therapy with an ACE inhibitor or angiotensin II receptor blocker.
Due to an increased risk of adverse reactions, this trial was terminated prematurely. Cardiovascular death and stroke occurred more frequently in the aliskiren group than in the placebo group. The incidence of adverse reactions, including serious adverse reactions (hyperkalemia, arterial hypotension, and renal failure), was higher in the aliskiren group than in the placebo group.
Heart Failure
Treatment with candesartan cilexetil reduces mortality, decreases hospitalizations due to heart failure, and alleviates symptoms in patients with left ventricular systolic dysfunction, as demonstrated in the "Candesartan in Heart failure – Assessment of Reduction in Mortality and Morbidity" (CHARM) program.
The beneficial effect of candesartan on reducing cardiovascular mortality or the rate of first hospitalization due to chronic heart failure (CHF) was consistent regardless of age, sex, or concomitant therapy. Candesartan was also effective in patients receiving both beta-blockers and ACE inhibitors, with a positive effect observed independently of whether patients were receiving target-dose ACE inhibitors as recommended by treatment guidelines.
In patients with CHF and reduced left ventricular systolic function (left ventricular ejection fraction ≤40%), candesartan reduces systemic vascular resistance and pulmonary capillary wedge pressure, increases plasma renin activity and angiotensin II concentration, and reduces aldosterone levels.
Pharmacokinetics
Absorption and Distribution
After oral administration, candesartan cilexetil is converted into the active substance candesartan. The absolute bioavailability of candesartan is approximately 40% following oral administration of a candesartan cilexetil solution. The relative bioavailability of the tablet formulation compared to the same oral solution is about 34% with very low variability. Thus, the calculated absolute bioavailability of the tablet is 14%. The mean peak serum concentration (Cmax) is reached 3–4 hours after tablet administration. Serum concentrations of candesartan increase linearly with increasing doses within the therapeutic dose range. No gender differences in candesartan pharmacokinetics have been observed. The area under the serum concentration-time curve (AUC) of candesartan is not significantly affected by food.
Candesartan is highly bound to plasma proteins (>99%). The apparent volume of distribution of candesartan is 0.1 L/kg.
The bioavailability of candesartan is not altered by food.
Metabolism and Elimination
Candesartan is primarily excreted unchanged in urine and bile, with only minor hepatic metabolism (CYP2C9). Available interaction studies indicate no effect on CYP2C9 and CYP3A4.
Based on in vitro studies, 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 terminal half-life of candesartan is approximately 9 hours. There is no accumulation of the drug after repeated administration.
The total plasma clearance of candesartan is approximately 0.37 mL/min/kg, with renal clearance of about 0.19 mL/min/kg. Renal excretion of candesartan occurs via both glomerular filtration and active tubular secretion. After oral administration of a radiolabeled (14C) dose of 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 excreted in feces as candesartan and 10% as inactive metabolite.
Pharmacokinetics in Special Patient Populations
In elderly individuals (aged 65 years and older), Cmax and AUC of candesartan are increased by approximately 50% and 80%, respectively, compared to younger individuals. However, the antihypertensive response and incidence of adverse events were similar after administration of Casark® to younger patients and elderly patients.
In patients with mild to moderate renal impairment, Cmax and AUC of candesartan increase by approximately 50% and 70%, respectively, upon repeated dosing, while t½ remains unchanged compared to patients with normal renal function. Corresponding changes in patients with severe renal impairment are approximately 50% and 110%, respectively.
The terminal t½ of candesartan is approximately doubled in patients with severe renal impairment. AUC of candesartan in patients undergoing hemodialysis is close to that observed in patients with severe renal impairment.
In two studies involving patients with mild to moderate hepatic impairment, an increase in mean AUC of candesartan of approximately 20% was observed in one study and 80% in another. Experience with the use of the drug in patients with severe hepatic impairment is lacking.
Clinical characteristics
Indications
Treatment of essential hypertension in adults.
Treatment of adult patients with heart failure and impaired systolic function of the left ventricle (left ventricular ejection fraction ≤40%) who are intolerant to angiotensin-converting enzyme (ACE) inhibitors, or as add-on therapy to ACE inhibitor treatment in patients with symptoms of heart failure despite optimal therapy, and who are intolerant to mineralocorticoid receptor antagonists (see sections "Pharmacodynamics", "Interaction with other medicinal products and other forms of interaction", "Special warnings and precautions for use", and "Dosage and administration").
Contraindications
Hypersensitivity to candesartan cilexetil or to any of the excipients.
Severe hepatic impairment and/or cholestasis.
Concomitant use of candesartan cilexetil and aliskiren-containing medicinal products is contraindicated in patients with diabetes mellitus or renal dysfunction (GFR <60 ml/min/1.73 m²).
Pregnancy or women who are planning to become pregnant (see section "Use in pregnancy or lactation").
Interaction with other medicinal products and other forms of interaction
Medicinal products studied in clinical pharmacokinetic studies include hydrochlorothiazide, warfarin, digoxin, oral contraceptives (i.e. ethinylestradiol/levonorgestrel), glyburide, nifedipine, and enalapril. No clinically significant pharmacokinetic interactions with these medicinal products have been observed.
Concomitant use of potassium-sparing diuretics, potassium supplements, potassium-containing salt substitutes, or other medicinal products (e.g. heparin) may increase potassium levels. Monitoring of potassium levels should be performed appropriately (see section "Special warnings and precautions for use").
Reversible increases in serum lithium concentrations and toxicity have been reported during concomitant use of lithium and ACE inhibitors.
A similar effect may occur with angiotensin II receptor antagonists (ARBs). Concomitant use of candesartan with lithium is not recommended. If combination therapy is deemed necessary, careful monitoring of serum lithium levels is recommended.
When angiotensin II receptor antagonists (ARBs) are administered concomitantly with non-steroidal anti-inflammatory drugs (NSAIDs) (e.g. selective COX-2 inhibitors, acetylsalicylic acid (> 3 g/day), and non-selective NSAIDs), a reduction in antihypertensive effect may occur.
As with ACE inhibitors, concomitant use of ARBs and NSAIDs may lead to an increased risk of worsening renal function, including possible acute renal failure, and increased serum potassium levels, particularly in patients with pre-existing impaired renal function. This combination should be used with caution, especially in elderly patients. Adequate hydration should be ensured, and renal function should be monitored appropriately after initiation of concomitant therapy and periodically thereafter.
Clinical trial data indicate that dual blockade of the renin-angiotensin-aldosterone system (RAAS) by combined use of ACE inhibitors and angiotensin II blockers or aliskiren is associated with a higher incidence of adverse events such as hypotension, hyperkalaemia, and worsening of renal function (including acute renal failure), compared to monotherapy affecting the RAAS.
Special precautions for use
Double blockade of the renin-angiotensin-aldosterone system (RAAS)
Evidence exists that concomitant use of ACE inhibitors, angiotensin II receptor blockers (ARBs), or aliskiren increases the risk of hypotension, hyperkalemia, and deterioration of renal function (including acute renal failure). Therefore, dual blockade of RAAS by combining ACE inhibitors with ARBs or aliskiren is not recommended. If dual blockade therapy is considered absolutely necessary, it should be administered only under specialist supervision and with frequent, 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.
Renal impairment
As with other agents that inhibit the renin-angiotensin-aldosterone system, changes in renal function may be expected in sensitive patients receiving candesartan cilexetil.
In patients with arterial hypertension and impaired renal function receiving candesartan cilexetil, periodic monitoring of serum potassium and creatinine levels is recommended.
Experience with the use of the drug in patients with severe or end-stage renal failure (creatinine clearance < 15 mL/min) is limited. In such patients, the dose of Casarc® should be carefully adjusted with close monitoring of blood pressure (BP). Evaluation of patients with heart failure should include periodic assessment of renal function, particularly in elderly patients (aged 75 years and older) and in patients with impaired renal function. During dose titration of candesartan cilexetil, monitoring of serum creatinine and potassium levels is recommended. Clinical trials in heart failure did not include patients with serum creatinine levels > 265 µmol/L (> 3 mg/dL).
Concomitant therapy with ACE inhibitors in heart failure
The risk of adverse reactions, particularly hypotension, hyperkalemia, and worsening renal function (including acute renal failure), may increase when candesartan cilexetil is used in combination with ACE inhibitors. Triple combination therapy with an ACE inhibitor, a mineralocorticoid receptor antagonist, and candesartan cilexetil is also not recommended. The use of these combinations should only be carried out under specialist supervision and with frequent, careful monitoring of renal function, electrolytes, and blood pressure.
ACE inhibitors should not be used concomitantly with angiotensin II receptor blockers in patients with diabetic nephropathy.
Hemodialysis
During dialysis, blood pressure may be particularly sensitive to blockade of AT1 receptors due to reduced plasma volume and activation of the renin-angiotensin-aldosterone system. Therefore, the dose of candesartan cilexetil in patients undergoing hemodialysis should be carefully adjusted with monitoring of blood pressure.
Renal artery stenosis
Medicinal products affecting the renin-angiotensin-aldosterone system, including angiotensin II receptor antagonists (ARBs), may increase blood urea nitrogen and serum creatinine levels in patients with bilateral renal artery stenosis or stenosis of the artery of a single kidney.
Kidney transplantation
Experience with the use of Casarc® in patients who have recently undergone kidney transplantation is limited.
Arterial hypotension
In patients with heart failure, hypotension may occur during treatment with Casarc®. It may also develop in patients with arterial hypertension and intravascular volume depletion due to high-dose diuretic therapy. Therapy should be initiated cautiously, and measures should be taken to correct hypovolemia.
Anesthesia and surgery
In patients taking angiotensin II antagonists, hypotension may occur during anesthesia and surgical procedures due to blockade of the renin-angiotensin system. Rarely, hypotension may be profound and require intravenous fluid administration and/or vasopressor therapy.
Stenosis of aortic and mitral valves (obstructive hypertrophic cardiomyopathy)
As with other vasodilators, particular caution is advised in patients with hemodynamically significant stenosis of the aortic or mitral valve or obstructive hypertrophic cardiomyopathy.
Primary hyperaldosteronism
Patients with primary hyperaldosteronism generally do not respond to antihypertensive drugs acting through inhibition of the renin-angiotensin-aldosterone system. Therefore, the use of candesartan cilexetil in this population is not recommended.
Hyperkalemia
Concomitant use of Casarc® with potassium-sparing diuretics, potassium supplements, potassium-containing salt substitutes, or other medicinal products capable of increasing potassium levels (e.g., heparin) may lead to elevated serum potassium levels in patients with arterial hypertension. Appropriate monitoring of potassium levels is required.
Hyperkalemia may occur in patients with heart failure receiving Casarc®. Periodic monitoring of serum potassium levels is recommended. Triple combination therapy with ACE inhibitors, potassium-sparing diuretics (e.g., spironolactone), and candesartan cilexetil is not recommended and should be used only after careful assessment of potential benefits and risks.
Intestinal angioedema
Cases of intestinal angioedema have been reported in patients taking angiotensin II receptor blockers (including candesartan cilexetil) (see section "Adverse reactions"). These patients experienced abdominal pain, nausea, vomiting, and diarrhea. Symptoms resolved after discontinuation of angiotensin II receptor blockers. If intestinal angioedema is diagnosed, candesartan cilexetil should be discontinued and appropriate monitoring initiated until symptoms completely resolve.
General
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 underlying renal disease, including renal artery stenosis), treatment with other medicinal products affecting this system has been associated with acute hypotension, azotemia, oliguria, or rarely, acute renal failure. Such effects cannot be excluded with the use of ARBs. 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.
The antihypertensive effect of candesartan may be enhanced by other medicinal products that have blood pressure-lowering properties, regardless of whether they are prescribed as antihypertensive agents or used for other indications.
Casarc® contains lactose. Patients with rare hereditary forms of galactose intolerance, Lapp lactase deficiency, or glucose-galactose malabsorption should not take this medicinal product.
Pregnancy
Initiation of ARB therapy during pregnancy is not recommended. Except in cases where continuation of ARB therapy is considered absolutely necessary, alternative antihypertensive treatment with an established safety profile during pregnancy should be prescribed to women planning pregnancy. If pregnancy is diagnosed, ARB therapy should be discontinued immediately and, if necessary, alternative therapy initiated.
In postmenarchal women, the possibility of pregnancy should be assessed on a general basis. Appropriate information and/or measures to prevent fetal exposure to the drug should be provided (see sections "Contraindications", "Use during pregnancy or breastfeeding").
Use during pregnancy or breastfeeding
The use of candesartan cilexetil during pregnancy is contraindicated. Candesartan cilexetil is not recommended during breastfeeding.
Pregnancy
Epidemiological data on teratogenic risk following exposure to ACE inhibitors during the first trimester of pregnancy do not allow definitive conclusions, but a small increased risk cannot be excluded. Since controlled epidemiological data on the risk of ARBs are lacking, similar risks may exist for this class of medicinal products. Except in cases where continuation of ARB therapy is considered absolutely necessary, alternative antihypertensive treatment with an established safety profile during pregnancy should be prescribed to women planning pregnancy. If pregnancy is diagnosed, ARB therapy should be discontinued immediately and, if necessary, alternative therapy initiated.
It is known that use of ARBs by humans during the second and third trimesters of pregnancy can lead to fetal toxicity (impaired renal function, oligohydramnios, delayed skull ossification) and neonatal toxicity (renal failure, hypotension, hyperkalemia). If ARB exposure has occurred during the second trimester of pregnancy, ultrasound examination of pregnant women is recommended to assess fetal renal function and skull condition.
Newborns whose mothers received ARBs require careful monitoring for arterial hypotension.
Breastfeeding
As there is no information on the use of Casarc® during breastfeeding, the drug is not recommended. Alternative treatments with better-established safety profiles during breastfeeding should be preferred, especially during breastfeeding of newborns or preterm infants.
Effect on ability to drive and use machines
Studies on the effect of candesartan on the ability to drive vehicles or operate machinery have not been conducted. However, it should be noted that dizziness or increased fatigue may occur during treatment with Casarc®.
Dosage and Administration
Take orally.
Casark® should be taken once daily, independent of food intake.
Food intake does not affect the bioavailability of candesartan.
Tablets of 8 mg, 16 mg, and 32 mg cannot be divided; therefore, if administration of candesartan cilexetil at a dose of 4 mg is required, a medicinal product allowing dosing of candesartan cilexetil at 4 mg should be used.
Dosing in arterial hypertension
The recommended initial and usual maintenance dose of Casark® is 8 mg once daily. The maximum antihypertensive effect is achieved within 4 weeks. In some patients whose blood pressure is not adequately controlled, the dose may be increased to 16 mg once daily and up to a maximum of 32 mg once daily. Therapy should be adjusted according to the blood pressure response to treatment. Casark® may also be used in combination with other antihypertensive agents (see sections "Pharmacodynamics", "Contraindications", "Interaction with other medicinal products and other forms of interaction", and "Special warnings and precautions for use"). It has been shown that adding hydrochlorothiazide provides additional antihypertensive effects with various doses of Casark®.
Use in elderly patients
No initial dose adjustment is required for elderly patients.
Use in patients with reduced intravascular volume
An initial dose of 4 mg may be considered in patients at risk of developing arterial hypotension, such as those with possible dehydration (see section "Special warnings and precautions for use").
Use in renal impairment
The initial dose for patients with renal impairment, including those on hemodialysis, is 4 mg. The dose should be titrated according to the treatment response. Experience with the use of the drug in patients with very severe or end-stage renal failure (creatinine clearance < 15 mL/min) is limited (see section "Special warnings and precautions for use").
Use in hepatic impairment
In patients with mild to moderate hepatic impairment, an initial dose of 4 mg once daily is recommended. The dose may be adjusted according to the treatment response. Casark® is contraindicated in patients with severe hepatic impairment and/or cholestasis (see sections "Pharmacokinetics" and "Contraindications").
Use in patients of non-Caucasian race
The antihypertensive effect of candesartan in patients of non-Caucasian race is less pronounced than in patients of other races. Therefore, the need for increasing the dose of Casark® and concomitant therapy to control blood pressure may occur more frequently in patients of non-Caucasian race than in patients of other races (see section "Pharmacodynamics").
Dosing in heart failure
The usual recommended initial dose of candesartan cilexetil is 4 mg once daily. Titration to the target dose of 32 mg once daily (maximum dose) or to the highest tolerated dose is achieved by doubling the dose at intervals of at least 2 weeks (see section "Special warnings and precautions for use"). Evaluation of patients with heart failure should always include assessment of renal function, including monitoring of serum creatinine and potassium.
Casark® may be used concomitantly with other heart failure treatments, including ACE inhibitors, beta-blockers, diuretics, and digoxin, or combinations of these agents.
Casark® may be prescribed together with ACE inhibitors in patients with symptoms of heart failure despite optimal standard heart failure therapy, particularly in cases of intolerance to mineralocorticoid receptor antagonists.
Combination of ACE inhibitors, potassium-sparing diuretics (e.g., spironolactone), and Casark® is not recommended and should be used only after careful assessment of potential benefits and risks (see sections "Pharmacodynamics", "Special warnings and precautions for use", and "Undesirable effects").
Special patient populations
There is no need to adjust the initial dose in elderly patients or in patients with reduced intravascular volume, renal impairment, or mild to moderate hepatic impairment.
Children
The safety and efficacy of Casark® in children from birth to 18 years of age for the treatment of heart failure have not been established. Data are lacking.
Children
The safety and efficacy of Casark® in children have not been established.
Overdose
Symptoms: Given the pharmacological properties of the drug, the main manifestation of overdose is likely to be symptomatic hypotension and dizziness. In individual cases of overdose (up to 672 mg of candesartan cilexetil), recovery without consequences has been reported.
Treatment: If symptomatic hypotension develops, symptomatic treatment should be administered and vital signs monitored. The patient should be placed in a supine position with legs elevated. If this is insufficient, plasma volume should be increased by infusion, for example, 0.9% sodium chloride solution. If the above measures are inadequate, sympathomimetic agents may be used. Candesartan is not removed by hemodialysis.
Adverse Reactions
Treatment of arterial hypertension
Adverse reactions observed during controlled clinical studies with candesartan cilexetil were mild and transient. No correlation between the overall frequency of adverse events and dose or age was observed. The number of cases of treatment discontinuation due to adverse events was similar in patients treated with candesartan cilexetil (3.1%) and those receiving placebo (3.2%).
In a pooled analysis of clinical trial data in patients with hypertension, adverse reactions associated with candesartan cilexetil were defined as those occurring at least 1% more frequently than with placebo. The most common adverse reactions were dizziness/vertigo, headache, and respiratory tract infections.
The following frequency definitions were used: very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1000 to <1/100), rare (≥1/10000 to <1/1000), and very rare (<1/10000).
The following adverse reactions may occur during treatment with candesartan cilexetil:
Infections and infestations: common – respiratory tract infections.
Blood and lymphatic system disorders: very rare – leukopenia, neutropenia, agranulocytosis.
Metabolism and nutrition disorders: very rare – hyperkalemia, hyponatremia.
Nervous system disorders: common – dizziness/vertigo, headache.
Respiratory, thoracic and mediastinal disorders: very rare – cough.
Gastrointestinal disorders: very rare – nausea, very rare – intestinal angioedema, unknown – diarrhea.
Hepatobiliary disorders: very rare – increased liver enzymes, liver function abnormalities, 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 – worsening of renal function, including acute renal failure in susceptible patients.
Laboratory findings: In most cases, Casark® did not show clinically significant effects on routine laboratory parameters. As with other inhibitors of the renin-angiotensin-aldosterone system, a slight decrease in hemoglobin levels was observed. Generally, routine laboratory monitoring is not required for patients taking Casark®. However, in patients with impaired renal function, periodic monitoring of serum potassium and creatinine levels is recommended.
Treatment of heart failure
The adverse reaction profile of Casark® in patients with heart failure was consistent with the pharmacological properties of the drug and the underlying health status of these patients. In the CHARM clinical program comparing candesartan cilexetil at doses up to 32 mg (n=3803) with placebo (n=3796), 21.0% of the candesartan cilexetil group and 16.1% of the placebo group discontinued treatment due to adverse effects. Adverse events such as hyperkalemia, hypotension, and renal failure were most frequently observed in patients aged 70 years or older, patients with diabetes mellitus, or those receiving other drugs affecting the renin-angiotensin-aldosterone system, including ACE inhibitors and/or spironolactone.
The following adverse reactions may occur during treatment with candesartan cilexetil:
Blood and lymphatic system disorders: very rare – leukopenia, neutropenia, agranulocytosis.
Metabolism and nutrition disorders: common – hyperkalemia, very rare – hyponatremia.
Nervous system disorders: very rare – dizziness, headache.
Vascular disorders: common – hypotension.
Respiratory, thoracic and mediastinal disorders: very rare – cough.
Gastrointestinal disorders: very rare – nausea, very rare – intestinal angioedema, unknown – diarrhea.
Hepatobiliary disorders: very rare – increased liver enzymes, liver function abnormalities, 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: common – renal function impairment, including renal failure in susceptible patients.
Laboratory findings: In patients receiving candesartan cilexetil for heart failure, hyperkalemia and renal function impairment occur commonly. Periodic monitoring of serum creatinine and potassium levels is recommended (see section "Special precautions for use").
Reporting suspected adverse reactions
Reporting of suspected adverse reactions after drug authorization 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 all suspected adverse reactions and lack of efficacy via the automated pharmacovigilance information system at: https://aisf.dec.gov.ua
Shelf life. 2 years.
Storage conditions. Store in the original packaging at a temperature not exceeding 25 °C. Keep out of reach of children.
Packaging. For 16 mg and 32 mg – 10 tablets per blister, 3 blisters per carton; for 8 mg – 10 tablets per blister, 3 or 9 blisters per carton.
Prescription status. Prescription only.
Manufacturer. JSC "Kyivmedpreparat".
Manufacturer's address and location of operations
139 Saksaganskogo Street, Kyiv, 01032, Ukraine.