Candesartan-SZ (Tablets) Instructions for Use

Marketing Authorization Holder

Severnaya Zvezda NAO (Russia)

Contact Information

SEVERNAYA ZVEZDA NAO (Russia)

ATC Code

C09CA06 (Candesartan)

Active Substance

Candesartan (Rec.INN registered by WHO)

Dosage Forms

	Candesartan-SZ	Tablets 8 mg: 20, 28, 30, 56 or 60 pcs.
		Tablets 16 mg: 20, 28, 30, 56 or 60 pcs.
		Tablets 32 mg: 20, 28, 30, 56 or 60 pcs.

Dosage Form, Packaging, and Composition

Tablets white or almost white, round, flat-cylindrical with a bevel and a score.

Excipients: lactose monohydrate (milk sugar) – 39.1 mg, microcrystalline cellulose 102, pregelatinized starch (starch 1500), croscarmellose sodium (primellose), povidone K30 (medium molecular weight polyvinylpyrrolidone), colloidal silicon dioxide (aerosil), sodium stearyl fumarate.

10 pcs. – contour cell packs (3) – cardboard packs.
10 pcs. – contour cell packs (6) – cardboard packs.
14 pcs. – contour cell packs (2) – cardboard packs.
14 pcs. – contour cell packs (4) – cardboard packs.
30 pcs. – contour cell packs (1) – cardboard packs.
30 pcs. – contour cell packs (2) – cardboard packs.
20 pcs. – polymer jars (1) – cardboard packs.
20 pcs. – polymer bottles (1) – cardboard packs.

Tablets white or almost white, round, flat-cylindrical with a bevel and a score.

Excipients: lactose monohydrate (milk sugar) – 64.8 mg, microcrystalline cellulose 102, pregelatinized starch (starch 1500), croscarmellose sodium (primellose), povidone K30 (medium molecular weight polyvinylpyrrolidone), colloidal silicon dioxide (aerosil), sodium stearyl fumarate.

10 pcs. – contour cell packs (3) – cardboard packs.
10 pcs. – contour cell packs (6) – cardboard packs.
14 pcs. – contour cell packs (2) – cardboard packs.
14 pcs. – contour cell packs (4) – cardboard packs.
30 pcs. – contour cell packs (1) – cardboard packs.
30 pcs. – contour cell packs (2) – cardboard packs.
20 pcs. – polymer jars (1) – cardboard packs.
20 pcs. – polymer bottles (1) – cardboard packs.

Tablets white or almost white, round, flat-cylindrical with a bevel and a score.

Excipients: lactose monohydrate (milk sugar) – 78 mg, microcrystalline cellulose 102, pregelatinized starch (starch 1500), croscarmellose sodium (primellose), povidone K30 (medium molecular weight polyvinylpyrrolidone), colloidal silicon dioxide (aerosil), sodium stearyl fumarate.

10 pcs. – contour cell packs (3) – cardboard packs.
10 pcs. – contour cell packs (6) – cardboard packs.
14 pcs. – contour cell packs (2) – cardboard packs.
14 pcs. – contour cell packs (4) – cardboard packs.
30 pcs. – contour cell packs (1) – cardboard packs.
30 pcs. – contour cell packs (2) – cardboard packs.
20 pcs. – polymer jars (1) – cardboard packs.
20 pcs. – polymer bottles (1) – cardboard packs.

Clinical-Pharmacological Group

Angiotensin II receptor antagonist

Pharmacotherapeutic Group

Angiotensin II receptor antagonist

Pharmacological Action

Mechanism of action and pharmacodynamic effects

Angiotensin II is the main hormone of the RAAS, which plays an important role in the pathogenesis of arterial hypertension, heart failure and other cardiovascular diseases. The main physiological effects of angiotensin II are vasoconstriction, stimulation of aldosterone production, regulation of water-electrolyte homeostasis and stimulation of cell growth. All these effects are mediated by the interaction of angiotensin II with angiotensin type 1 receptors (AT₁ receptors).

Candesartan is a selective antagonist of angiotensin II type 1 receptors (AT₁ receptors). Candesartan does not inhibit ACE, which converts angiotensin I to angiotensin II and breaks down bradykinin; does not affect ACE and does not lead to the accumulation of bradykinin or substance P. When comparing candesartan with ACE inhibitors, the development of cough was less common in patients receiving candesartan cilexetil. Candesartan does not bind to receptors of other hormones and does not block ion channels involved in the regulation of the cardiovascular system functions. As a result of blocking AT₁ receptors of angiotensin II, a dose-dependent increase in the activity of renin, angiotensin I, angiotensin II and a decrease in the concentration of aldosterone in the blood plasma occurs.

Arterial hypertension

In arterial hypertension, Candesartan causes a dose-dependent long-term decrease in blood pressure. The antihypertensive effect of the drug is due to a decrease in total peripheral vascular resistance, without changing the heart rate. There were no cases of marked arterial hypotension after taking the first dose of the drug, as well as withdrawal syndrome (rebound syndrome) after discontinuation of therapy.

The onset of the antihypertensive effect after taking the first dose of candesartan cilexetil usually develops within 2 hours. Against the background of ongoing therapy with the drug at a fixed dose, the maximum decrease in blood pressure is usually achieved within 4 weeks and is maintained throughout the treatment. Candesartan cilexetil, prescribed once a day, provides an effective and smooth reduction in blood pressure over 24 hours with minor fluctuations in blood pressure in the intervals between taking the next dose of the drug. The use of candesartan cilexetil together with hydrochlorothiazide leads to an enhancement of the antihypertensive effect. The combined use of candesartan cilexetil and hydrochlorothiazide (or amlodipine) is well tolerated.

The effectiveness of the drug does not depend on the age and gender of the patients. Candesartan cilexetil increases renal blood flow and does not change or increases the glomerular filtration rate, while renal vascular resistance and filtration fraction decrease. Taking candesartan cilexetil at a dose of 8-16 mg for 12 weeks does not have a negative effect on blood glucose concentration and lipid profile in patients with arterial hypertension and type 2 diabetes mellitus.

Clinical efficacy and safety

The clinical effect of candesartan cilexetil on the indicator of cardiovascular morbidity and mortality when taken at a dose of 8-16 mg (average dose 12 mg) once a day was studied in a randomized clinical trial involving 4937 elderly patients (aged 70 to 89 years, 21% of patients aged 80 years and older) with mild to moderate arterial hypertension, receiving therapy with candesartan cilexetil for an average of 3.7 years (SCOPE study – Study on COgnition and Prognosis in the Elderly). Patients received candesartan cilexetil or placebo, if necessary in combination with other antihypertensive drugs. Both treatment regimens showed effective reduction in systolic and diastolic blood pressure (from 166/90 to 145/80 mm Hg in the group of patients receiving Candesartan, and from 167/90 to 149/82 mm Hg in the control group) against the background of good tolerability. Cognitive function and quality of life remained at a good level in both groups of patients. There were no statistically significant differences in the frequency of cardiovascular complications according to the primary endpoint, which included cardiovascular death, the development of non-fatal myocardial infarction and non-fatal stroke, between these two groups of patients. However, in the group of patients receiving Candesartan, the risk of developing non-fatal stroke was 28% lower than in the control group (relative risk=0.72, 95% confidence interval (CI) 0.53-0.99, p=0.04).

Chronic heart failure

According to the results of the CHARM clinical trial program (Candesartan in Heart failure – Assessment of Reduction in Mortality and Morbidity) involving 7599 patients, the use of candesartan cilexetil (the average dose was 24 mg/day) led to a reduction in the frequency of fatal outcomes and the need for hospitalization due to chronic heart failure and to an improvement in the systolic function of the left ventricle. The median follow-up duration was 37.7 months.

In the CHARM-Alternative study (n=2028) in patients with reduced left ventricular ejection fraction (LVEF) ≤40%, who did not receive an ACE inhibitor due to intolerance (mainly due to cough – 72%), the combined criterion, which included death from cardiovascular diseases or the first hospitalization for chronic heart failure, was significantly lower in the group of patients receiving Candesartan compared to the placebo group (hazard ratio=0.77, 95% CI 0.67-0.89, p <0.001). The relative risk reduction was 23%. At the same time, a positive effect of candesartan was noted on each of the components of this combined criterion. The use of candesartan cilexetil led to an improvement in the functional class of chronic heart failure according to the NYHA classification (p=0.008).

In the CHARM-Added study (n=2548) in patients with reduced LVEF ≤40% receiving ACE inhibitors, the combined criterion, which included death from cardiovascular diseases or the first hospitalization for chronic heart failure, was significantly lower in the group of patients receiving Candesartan compared to the placebo group (hazard ratio=0.85, 95% CI 0.75-0.96, p=0.011), which corresponded to a 15% reduction in relative risk. The use of candesartan cilexetil led to an improvement in the functional class of chronic heart failure according to the NYHA classification (p=0.020).

In the CHARM-Preserved study (n=3023) in patients with preserved systolic function (LVEF >40%), no statistically significant differences were found in the value of the combined efficacy criterion, which included the frequency of fatal outcomes from cardiovascular diseases or the frequency of the first hospitalization for chronic heart failure, in the candesartan and placebo groups (hazard ratio=0.89, 95% CI 0.77-1.03, p=0.118). At the same time, a positive effect of candesartan was noted on one of the components of this combined criterion – a reduction in the frequency of hospitalizations for chronic heart failure.

In the combined analysis of all 3 studies of the CHARM program, no reliable differences in the frequency of fatal outcomes from all causes were obtained in the candesartan and placebo groups (hazard ratio=0.91, 95% CI 0.83-1.00, p=0.055).

The reduction in the frequency of fatal outcomes or the frequency of hospitalizations for chronic heart failure during therapy with candesartan did not depend on age, gender and concomitant therapy. Candesartan was also effective in patients taking beta-blockers in combination with ACE inhibitors, and the effectiveness of candesartan did not depend on whether the patient was taking the optimal dose of an ACE inhibitor or not.

In patients with chronic heart failure and reduced systolic function of the left ventricle (LVEF ≤40%), taking candesartan contributed to a decrease in total peripheral vascular resistance and capillary pressure in the lungs, an increase in the activity of renin and the concentration of angiotensin II in the blood plasma, as well as a decrease in the level of aldosterone.

Pharmacokinetics

Absorption and distribution

Candesartan cilexetil is a prodrug for oral administration. It is rapidly converted into the active substance – Candesartan by ester hydrolysis during absorption from the digestive tract, binds firmly to AT₁ receptors and dissociates slowly, and has no agonist properties. The absolute bioavailability of candesartan after oral administration of candesartan cilexetil solution is about 40%. The relative bioavailability of the drug in the form of tablets compared to the oral solution is approximately 34%. Thus, the estimated absolute bioavailability of the drug in the form of tablets is 14%. C_max in blood serum is reached 3-4 hours after taking the drug in the form of tablets. When the drug dose is increased within the recommended limits, the concentration of candesartan increases linearly. Food intake does not have a significant effect on AUC, i.e., simultaneous food intake does not significantly affect the bioavailability of the drug.

Candesartan is actively bound to blood plasma proteins (>99%). V_d of candesartan is 0.1 l/kg. No accumulation in the body is observed.

Metabolism and excretion

Candesartan is mainly excreted from the body by the kidneys and bile unchanged and only to a small extent metabolized in the liver. T_1/2 of candesartan is approximately 9 hours. The total clearance of candesartan is about 0.37 ml/min/kg, while renal clearance is about 0.19 ml/min/kg. Renal excretion of candesartan is carried out by glomerular filtration and active tubular secretion. When radioactive-labeled candesartan cilexetil is taken orally, about 26% of the administered amount is excreted by the kidneys in the form of candesartan and 7% in the form of an inactive metabolite, while 56% of the administered amount is found in the feces in the form of candesartan and 10% in the form of an inactive metabolite.

Linearity (non-linearity)

When the drug dose is increased within the recommended limits, the concentration of candesartan increases linearly.

Pharmacokinetics in special patient groups

Elderly patients. In elderly patients (over 65 years old), C_max and AUC of candesartan increase by 50% and 80%, respectively, compared to young patients. However, the hypotensive effect and the frequency of side effects when using the drug Candesartan-SZ do not depend on the age of the patients.

Patients with impaired renal function. In patients with mild to moderate renal impairment, C_max and AUC of candesartan increased by 50% and 70%, respectively, while T_1/2 of the drug did not change compared to patients with normal renal function. In patients with severe renal impairment, C_max and AUC of candesartan increased by 50% and 110%, respectively, and T_1/2 of the drug doubled. In patients on hemodialysis, the same pharmacokinetic parameters of candesartan were found as in patients with severe renal impairment.

Patients with impaired liver function. In 2 studies involving patients with mild or moderate liver impairment, an increase in the mean AUC of candesartan by about 20% in one study and by 80% in the other was noted (see section “Dosage Regimen”). There is no experience of use in patients with severe liver impairment.

Gender. The pharmacokinetic parameters of candesartan do not depend on the patient’s gender.

Indications

The drug Candesartan-SZ is indicated for use in adults aged 18 years and older

• Arterial hypertension;
• Chronic heart failure and impaired systolic function of the left ventricle (LVEF ≤40%) as an additional therapy to ACE inhibitors or in case of intolerance to ACE inhibitors.

ICD codes

Dosage Regimen

The drug is taken orally, once a day, regardless of food intake.

Arterial hypertension

The recommended initial and maintenance dose of the drug Candesartan-SZ is 8 mg once a day. For patients who require a further decrease in blood pressure, it is recommended to increase the dose to 16 mg once a day. For patients who failed to sufficiently reduce blood pressure after 4 weeks of taking the drug Candesartan-SZ at a dose of 16 mg/day, it is recommended to increase the dose to 32 mg once a day.

In case therapy with the drug Candesartan-SZ does not lead to a decrease in blood pressure to an optimal level, it is recommended to add a thiazide diuretic to the therapy.

Therapy should be adjusted according to the blood pressure level. The maximum antihypertensive effect is achieved within 4 weeks from the start of treatment.

Chronic heart failure

The recommended initial dose of the drug Candesartan-SZ is 4 mg (1/2 tab. of 8 mg) once a day. Increasing the dose to 32 mg once a day or to the maximum tolerated dose is carried out by doubling it at intervals of at least 2 weeks (see section “Special Instructions”).

Special patient groups

In elderly patients, there is no need to adjust the initial dose of the drug.

In patients with mild or moderate renal impairment (CC 30-80 ml/min), including patients on hemodialysis, the initial dose of the drug is 4 mg (1/2 tab. of 8 mg). The dose should be titrated depending on the therapeutic effect of the drug. Clinical experience with the drug in patients with severe renal impairment or end-stage renal failure (CC less than 15 ml/min) is limited (see section “Special Instructions”). Chronic heart failure dose adjustment is not required.

In patients with mild to moderate hepatic impairment, it is recommended to start treatment with a daily dose of 4 mg once a day (1/2 tab. of 8 mg). The dose may be increased if necessary. Candesartan-SZ is contraindicated in patients with severe hepatic impairment and/or cholestasis(see section “Contraindications”). Chronic heart failure dose adjustment is not required.

Concomitant therapy

Arterial hypertension the use of the drug Candesartan-SZ together with thiazide-type diuretics (for example, hydrochlorothiazide) may enhance the antihypertensive effect of the drug Candesartan-SZ.

Chronic heart failure the drug Candesartan-SZ can be prescribed together with other agents used in the therapy of CHF, for example, ACE inhibitors, beta-blockers, diuretics and cardiac glycosides.

Children

The safety and efficacy of the drug Candesartan-SZ in children aged 0 to 18 years have not been established to date. The drug Candesartan-SZ is contraindicated in children aged 0 to 18 years.

Adverse Reactions

Arterial hypertension

Adverse reactions in clinical trials were moderate and transient and were comparable in frequency to the placebo group. The overall incidence of adverse reactions during candesartan cilexetil administration did not depend on the drug dose, patient’s sex, or age. The frequency of therapy discontinuation due to side effects was similar for candesartan cilexetil (3.1%) and placebo (3.2%).

During a pooled analysis of data from conducted studies, the following adverse reactions were reported, occurring frequently (>1/100) during candesartan cilexetil administration. The described adverse reactions were observed with a frequency at least 1% greater than in the placebo group. By this definition, dizziness/vertigo, headache, and respiratory infections were most frequently noted.

Chronic heart failure

Side effects identified during the use of candesartan cilexetil in patients with chronic heart failure corresponded to the pharmacological properties of the drug and depended on the patient’s condition.

In the CHARM clinical trials, candesartan cilexetil in doses up to 32 mg (n=3803) was compared with placebo (n=3796); 21% of patients in the candesartan cilexetil group and 16.1% of patients in the placebo group discontinued treatment due to adverse reactions. The most frequently encountered side effects were hyperkalemia, marked decrease in blood pressure, and impaired renal function. These phenomena were more frequent in patients over 70 years of age, patients with diabetes mellitus, or those receiving other drugs affecting the RAAS, in particular, an ACE inhibitor and/or spironolactone.

Summary of adverse reactions

Tables 1 and 2 present adverse reactions noted in clinical trials and post-marketing use. Adverse reactions are distributed by system-organ classes in descending order of their severity, indicating the frequency of their occurrence according to WHO classification: very common (≥1/10), common (≥1/100, <1/10), uncommon (≥1/1000, <1/100), rare (≥1/10000, <1/1000), and very rare (<1/10000).

Table 1. Adverse reactions in arterial hypertension

Laboratory parameters in general, no clinically significant changes in standard laboratory parameters were noted with the use of candesartan cilexetil. As with the use of other agents affecting or acting on the RAAS, a slight decrease in hemoglobin may be observed. An increase in creatinine and urea concentration, an increase in potassium content, and a decrease in sodium content were observed. Increased ALT activity was noted somewhat more frequently with candesartan cilexetil compared to placebo (1.3% vs. 0.5%). Regular monitoring of laboratory parameters is usually not required with candesartan cilexetil use. However, in patients with impaired renal function, periodic monitoring of serum potassium and creatinine concentration is recommended.

Table 2. Adverse reactions in chronic heart failure

Laboratory parameters increase in creatinine and urea concentration, increase in potassium content. Monitoring of serum creatinine concentration and potassium content is recommended.

Contraindications

• Hypersensitivity to candesartan cilexetil or other components included in the drug;
• Severe liver dysfunction and/or cholestasis;
• Concomitant use with aliskiren and drugs containing aliskiren in patients with diabetes mellitus and/or with moderate and severe renal impairment (GFR less than 60 ml/min/1.73 m² body surface area);
• Concomitant use with ACE inhibitors in patients with diabetic nephropathy;
• Lactose intolerance, lactase deficiency and glucose-galactose malabsorption syndrome;
• Pregnancy (see section “Pregnancy and Lactation”);
• Breastfeeding period (see section “Pregnancy and Lactation”);
• Age under 18 years (efficacy and safety not established).

With caution

In patients

• With severe renal failure (CrCl <30 ml/min);
• With bilateral renal artery stenosis or stenosis of the artery of a single kidney;
• With hemodynamically significant aortic and mitral valve stenosis;
• With a history of kidney transplantation;
• With cerebrovascular diseases and coronary artery disease;
• With hyperkalemia;
• With reduced circulating blood volume;
• With primary hyperaldosteronism (insufficient data from clinical studies);
• With hypertrophic obstructive cardiomyopathy.

Use in Pregnancy and Lactation

Pregnancy

The use of Candesartan-SZ during pregnancy is contraindicated (see section “Contraindications”). Patients taking Candesartan-SZ should be warned about this before planning pregnancy so that they can discuss alternative treatment options with their doctor. If pregnancy is diagnosed, therapy with Candesartan-SZ should be discontinued immediately and, if necessary, alternative treatment should be prescribed.

Drugs that have a direct effect on the RAAS can cause fetal development disorders or have a negative effect on the newborn, including death, when the drug is used during pregnancy.

It is known that therapy with angiotensin II receptor antagonists can cause fetal development disorders (impaired renal function, oligohydramnios, delayed skull bone ossification) and the development of complications in the newborn (renal failure, arterial hypotension, hyperkalemia).

Breastfeeding period

It is not known whether Candesartan is excreted in human breast milk. However, Candesartan is excreted in the milk of lactating rats. Due to the possible adverse effects on infants, Candesartan-SZ is contraindicated during breastfeeding.

Fertility

There are no data on the effect of candesartan on human fertility.

Use in Hepatic Impairment

The use of the drug is contraindicated in severe liver dysfunction.

Use in Renal Impairment

With caution in patients with severe renal failure (CrCl <30 ml/min), bilateral renal artery stenosis or stenosis of the artery of a single kidney, with a history of kidney transplantation.

Pediatric Use

The use of the drug is contraindicated under the age of 18 years.

Geriatric Use

In elderly patients, there is no need to adjust the initial dose of the drug.

Special Precautions

Renal impairment

During therapy with Candesartan-SZ, as with the use of other agents affecting the RAAS, some patients may experience impaired renal function.

When using Candesartan-SZ in patients with arterial hypertension and severe renal failure (CrCl <30 ml/min), periodic monitoring of serum potassium and creatinine concentration is recommended. Clinical experience with the drug in patients with severe renal impairment or end-stage renal disease is limited (CrCl <15 ml/min). Such patients should be carefully titrated with the dose of Candesartan-SZ under careful blood pressure control.

In patients with chronic heart failure, renal function should be monitored periodically, especially in patients aged 75 years and older, as well as in patients with impaired renal function.

When increasing the dose of Candesartan-SZ, monitoring of potassium and creatinine concentration is also recommended.

Clinical trials of candesartan cilexetil in chronic heart failure did not include patients with creatinine concentration >265 µmol/l (>3 mg/dl).

Concomitant use with ACE inhibitors in chronic heart failure

When using candesartan in combination with ACE inhibitors, the risk of side effects, especially impaired renal function and hyperkalemia, may increase (see section “Adverse Reactions”). In these cases, careful observation and monitoring of laboratory parameters is necessary.

Hemodialysis

During hemodialysis, blood pressure may be particularly sensitive to blocking AT₁ receptors due to a decrease in plasma volume and activation of the RAAS. In this regard, patients on hemodialysis should be carefully titrated with Candesartan-SZ under careful blood pressure control.

Renal artery stenosis

In patients with bilateral renal artery stenosis or stenosis of the artery of a single kidney, drugs affecting the RAAS, in particular ACE inhibitors, can cause an increase in serum urea and creatinine concentration. Similar effects can be expected with the use of angiotensin II receptor antagonists.

Kidney transplantation

Clinical experience with candesartan cilexetil in patients who have undergone kidney transplantation is limited.

Arterial hypotension

In patients with chronic heart failure, arterial hypotension may develop during therapy with Candesartan-SZ. As with the use of other drugs affecting the RAAS, the cause of arterial hypotension in patients with arterial hypertension may be a decrease in circulating blood volume, as observed in patients receiving high doses of diuretics. Therefore, caution should be exercised at the beginning of therapy and, if necessary, hypovolemia should be corrected.

Dual blockade of the RAAS

Dual blockade of the RAAS by combining candesartan cilexetil and aliskiren is not recommended due to an increased risk of arterial hypotension, hyperkalemia, and changes in renal function.

Concomitant use of angiotensin II receptor antagonists with drugs containing aliskiren is contraindicated in patients with diabetes mellitus and/or with moderate or severe renal impairment (GFR <60 ml/min/1.73 m² body surface area) and is not recommended in other patients. Concomitant use of angiotensin II receptor antagonists with ACE inhibitors is contraindicated in patients with diabetic nephropathy and is not recommended in other patients (see section “Contraindications”).

General anesthesia and surgery

In patients receiving angiotensin II antagonists, arterial hypotension may develop during general anesthesia and surgery as a result of RAAS blockade. Very rarely, cases of severe arterial hypotension may occur, requiring intravenous administration of plasma substitutes and/or vasopressors.

Aortic and mitral valve stenosis or hypertrophic obstructive cardiomyopathy

When prescribing Candesartan-SZ, as well as other vasodilators, caution should be exercised in patients with hypertrophic obstructive cardiomyopathy or hemodynamically significant aortic or mitral valve stenosis.

Primary hyperaldosteronism

Patients with primary hyperaldosteronism are usually resistant to antihypertensive therapy affecting the RAAS. Therefore, Candesartan-SZ is not recommended for such patients.

Hyperkalemia

Clinical experience with other drugs affecting the RAAS shows that concomitant administration of Candesartan-SZ with potassium-sparing diuretics, potassium preparations or salt substitutes containing potassium, or other drugs that may increase blood potassium levels (e.g., heparin) can lead to the development of hyperkalemia in patients with arterial hypertension.

In patients with chronic heart failure, hyperkalemia may develop during therapy with Candesartan-SZ. When prescribing Candesartan-SZ to patients with chronic heart failure, regular monitoring of blood potassium levels is recommended, especially when co-administered with ACE inhibitors and potassium-sparing diuretics.

General

Patients in whom vascular tone and renal function predominantly depend on the activity of the RAAS (e.g., patients with severe chronic heart failure or kidney disease, including renal artery stenosis) are particularly sensitive to drugs acting on the RAAS. The prescription of such agents in these patients is accompanied by a sharp arterial hypotension, azotemia, oliguria and, less frequently, acute renal failure. The possibility of developing the listed effects cannot be excluded when using angiotensin II receptor antagonists. A sharp decrease in blood pressure in patients with coronary artery disease or cerebrovascular diseases of atherosclerotic origin, when using any antihypertensive agents, can lead to the development of myocardial infarction or stroke.

Excipients

Candesartan-SZ contains lactose monohydrate (milk sugar). Patients with rare hereditary galactose intolerance, lactase deficiency or glucose-galactose malabsorption should not take this drug.

Effect on ability to drive vehicles and mechanisms

Candesartan-SZ has no or negligible influence on the ability to drive vehicles and operate machinery. When driving vehicles and engaging in potentially hazardous activities requiring increased concentration and speed of psychomotor reactions, it should be taken into account that dizziness and increased fatigue may be observed when using the drug.

Overdose

Symptoms analysis of the pharmacological properties of the drug suggests that the main manifestation of overdose may be a clinically significant decrease in blood pressure and dizziness. Isolated cases of drug overdose (up to 672 mg of candesartan cilexetil) have been described, which ended with patient recovery without serious consequences.

Treatment if clinically significant arterial hypotension develops, symptomatic treatment should be carried out and the patient’s condition should be monitored. Lay the patient down, raise the foot end of the bed. If necessary, the volume of circulating plasma should be increased, for example, by intravenous administration of 0.9% sodium chloride solution. If necessary, sympathomimetic drugs may be prescribed. Candesartan is not removed by hemodialysis.

Drug Interactions

Contraindicated combinations

Concomitant use of angiotensin II receptor antagonists with drugs containing aliskiren is contraindicated in patients with diabetes mellitus and/or with moderate or severe renal impairment (GFR less than 60 ml/min/1.73 m² body surface area) and is not recommended in other patients.

Concomitant use of angiotensin II receptor antagonists with ACE inhibitors is contraindicated in patients with diabetic nephropathy and is not recommended in other patients (see sections “Contraindications” and “Special Precautions”).

Combinations requiring caution

Concomitant use of Candesartan-SZ with other antihypertensive agents potentiates the antihypertensive effect.

Experience with other drugs acting on the RAAS shows that concomitant therapy with potassium-sparing diuretics, potassium preparations, salt substitutes containing potassium, and other agents that may increase serum potassium concentration (e.g., heparin) can lead to the development of hyperkalemia.

When lithium preparations are co-administered with ACE inhibitors, reversible increases in serum lithium concentration and the development of toxic reactions have been reported. Similar reactions may occur with the use of angiotensin II receptor antagonists, therefore monitoring of serum lithium concentration is recommended when these drugs are used in combination.

When angiotensin II receptor antagonists and NSAIDs, including selective COX-2 inhibitors, acetylsalicylic acid (more than 3 g/day), are used concomitantly, a decrease in the antihypertensive effect may be observed.

As with the use of ACE inhibitors, the concomitant use of angiotensin II receptor antagonists and NSAIDs may increase the risk of impaired renal function, including acute renal failure, and increased serum potassium concentration, especially in patients with pre-existing reduced renal function. Caution should be exercised when these drugs are used concomitantly, especially in elderly patients and in patients with reduced circulating blood volume. Patients should compensate for fluid loss and regularly monitor renal function after initiation of combination therapy and periodically during such therapy.

Combinations to be considered

Pharmacokinetic studies have examined the combined use of candesartan cilexetil with hydrochlorothiazide, warfarin, digoxin, oral contraceptives (ethinyl estradiol/levonorgestrel), glibenclamide, nifedipine, and enalapril. No clinically significant pharmacokinetic interaction was identified.

Candesartan is metabolized in the liver to a minor extent (by the CYP2C9 isoenzyme). Conducted interaction studies have not revealed an effect of the drug on the CYP2C9 and CYP3A4 isoenzymes; the effect on other cytochrome P450 system isoenzymes has not been studied.

Storage Conditions

The drug should be stored out of the reach of children, protected from light, at a temperature not exceeding 25°C (77°F).

Shelf Life

The shelf life is 3 years. Do not use after the expiration date.

Dispensing Status

The drug is dispensed by prescription.

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.