Atacand, 8 mg, tablets, 28 pcs.

Pharmacological properties of the drug Atacand

Angiotensin II is the primary vasoactive hormone of the renin-angiotensin-aldosterone system and is involved in the pathophysiology of hypertension (arterial hypertension), heart failure and other cardiovascular disorders. The major 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 through the type 1 (AT1) receptor. Candesartan cilexetil is a prodrug suitable for oral administration. Candesartan is rapidly converted into the active substance by ester hydrolysis during absorption in the gastrointestinal tract. Candesartan is an angiotensin II receptor antagonist, selective for AT1 receptors, with strong binding to the receptor and slow dissociation from it. Candesartan does not inhibit ACE, which converts angiotensin I to angiotensin II and destroys bradykinin. There is no effect on ACE and potentiation of bradykinin or substance P. In controlled clinical trials in which candesartan was compared with ACE inhibitors, the incidence of cough was lower in patients receiving candesartan cilexetil. Candesartan does not bind to or block other hormone receptors or ion channels that play an important role in cardiovascular regulation. Antagonism of angiotensin II receptors (AT1) leads to a dose-dependent increase in the levels of plasma renin, angiotensin I and II, as well as a decrease in the concentration of aldosterone in the blood plasma. Arterial hypertension (AH) In hypertension (arterial hypertension), candesartan leads to a dose-dependent long-term decrease in blood pressure. Antihypertensive activity is due to a decrease in systemic peripheral resistance, which is not accompanied by a reflex increase in heart rate. There is nothing to indicate severe or increased hypotension after the first dose or a reactive effect after discontinuation of treatment. After taking a single dose of candesartan cilexetil, the onset of the antihypertensive effect occurs within 2 hours. With continuous therapy, the maximum reduction in blood pressure with any dose is achieved within 4 weeks and is maintained during long-term treatment. According to the meta-analysis, the average additional effect of increasing the dose from 16 to 32 mg once daily was insignificant. Given interindividual variability, greater than average effects may occur in some patients. When using candesartan cilexetil once a day, an effective and uniform reduction in blood pressure is ensured over 24 hours with a slight difference between the effects of the maximum and minimum doses. Candesartan increases renal blood flow and/or does not affect the glomerular filtration rate, or increases it, while vascular resistance and filtration fraction are reduced. In patients with hypertension (arterial hypertension) and type II diabetes mellitus, therapy with candesartan cilexetil 8–16 mg for 12 weeks did not cause side effects regarding blood glucose levels or lipid profile. Heart failure Treatment with candesartan cilexetil reduces mortality and hospitalization due to heart failure and improves symptoms in patients with impaired left ventricular systolic function. The beneficial effect of candesartan on reducing cardiovascular mortality or the incidence of first hospitalization due to chronic heart failure (CHF) was consistent regardless of age, sex and concomitant treatment. Candesartan was also effective in patients taking both beta-blockers and ACE inhibitors concomitantly, and the positive effect was achieved regardless of whether the patient was taking ACE inhibitors at the recommended dose. In patients with CHF and impaired left ventricular systolic function (left ventricular ejection fraction ≤40%), candesartan reduces systemic vascular resistance and pulmonary capillary pressure, increases renin activity and the concentration of angiotensin II in the blood plasma, and also reduces aldosterone levels. Absorption and distribution After oral administration, candesartan cilexetil is converted to the active substance candesartan. Absolute bioavailability - 40%. The average maximum concentration in the blood serum (Cmax) is reached 3–4 hours after taking the drug, increasing linearly with increasing doses within the therapeutic dose. No gender-related differences in pharmacokinetics were noted. Food intake does not have a significant effect on candesartan AUC. Candesartan is highly (99%) bound to plasma proteins. The apparent volume of distribution is 0.1 l/kg body weight. Metabolism and excretion Excreted unchanged in urine and bile and only in small amounts by hepatic metabolism. The terminal half-life is approximately 9 hours. No accumulation was noted after repeated doses. Total plasma clearance is approximately 0.37 ml/min/kg, and renal clearance is approximately 0.19 ml/min/kg. Candesartan is excreted by the kidneys both by 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, although approximately 56% of the dose is excreted in the feces as candesartan and 10% as an inactive metabolite. In elderly patients (65 years), the Cmax and AUC of candesartan are increased by approximately 50 and 80%, respectively, compared to young patients. However, the blood pressure response and the incidence of side effects are the same after taking the drug at the prescribed dose in young and elderly patients. In patients with mild to moderate renal impairment, compared with patients with normal renal function, the Cmax and AUC of candesartan increased during multiple doses by approximately 50% and 70%, respectively, but the elimination half-life remained unchanged. The corresponding changes in patients with severe renal impairment were approximately 50 and 110%, respectively. The terminal half-life of candesartan was approximately doubled in patients with severe renal impairment. The AUC in hemodialysis patients was similar to that in patients with severe renal impairment. In patients with mild to moderate hepatic impairment, an increase in AUC of 23% was detected.

Atacand®

Angiotensin II is the main hormone of the renin-angiotensin-aldosterone system, 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 angiotensin-converting enzyme (ACE), which converts angiotensin I to angiotensin II and destroys 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 the receptors of other hormones and does not block ion channels involved in the regulation of the functions of the cardiovascular system. As a result of blocking the AT1 receptors of angiotensin II, there is a dose-dependent increase in renin activity, the concentration of angiotensin I, angiotensin II and a decrease in the concentration of aldosterone in the blood plasma.

Arterial hypertension

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

The onset of the hypotensive effect after taking the first dose of candesartan cilexetil usually develops within 2 hours. With continued therapy with the drug at a fixed dose, the maximum reduction in blood pressure is usually achieved within 4 weeks and is maintained throughout 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 doses of the drug. The use of candesartan cilexetil in combination with hydrochlorothiazide leads to an increased hypotensive 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 patients.

Candesartan cilexetil increases renal blood flow and does not change or increases glomerular filtration rate, while renal vascular resistance and filtration fraction are reduced. Taking candesartan cilexetil at a dose of 8-16 mg for 12 weeks does not have a negative effect on glucose concentrations and lipid profiles in patients with arterial hypertension and type 2 diabetes mellitus.

The clinical effects of candesartan cilexetil on cardiovascular morbidity and mortality when administered at a dose of 8-16 mg (mean dose 12 mg) once daily were investigated in a randomized clinical trial involving 4937 elderly patients (age range 70 to 89 years, 21 % of patients aged 80 years and older) with mild to moderate hypertension treated with candesartan cilexetil for an average of 3.7 years (SCOPE Study - Study of Cognitive Function and Prognosis in Elderly Patients). Patients received candesartan cilexetil or placebo, if necessary in combination with other antihypertensive agents. Both treatment regimens showed an effective reduction in systolic and diastolic blood pressure (from 166/90 to 145/80 mmHg in the group of patients receiving candesartan, and from 167/90 to 149/82 mmHg in the control group) by 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 incidence of cardiovascular events among the two groups of patients for the primary endpoint of cardiovascular death, nonfatal myocardial infarction, and nonfatal stroke. However, in the group of patients receiving candesartan, the risk of nonfatal stroke was 28% lower than in the control group (relative risk = 0.72, 95% confidence interval 0.53-0.99, p = 0.04).

Heart failure

According to the results of the CHARM (Candesartan in Heart Failure - Mortality and Morbidity Reduction Assessment) clinical trial program involving 7599 patients, the use of candesartan cilexetil (average dose was 24 mg/day) led to a reduction in the incidence of deaths and hospitalization for chronic heart failure, as well as improving left ventricular systolic function. The median follow-up duration was 37.7 months.

In the CHARM-Altemative study (n=2028), in patients with reduced left ventricular ejection fraction (LVEF) ≤ 40% who did not receive ACE inhibitors due to poor tolerability (mainly due to cough - 72%), a combined criterion that included Death from cardiovascular disease or first hospitalization for chronic heart failure was significantly lower in the group of patients receiving candesartan. compared with the placebo group (hazard ratio = 0.77, 95% confidence interval 0.67-0.89, p < 0.001). The relative risk reduction was 23%. At the same time, a positive effect of candesartan on each of the components of this combined criterion was noted. 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 composite endpoint of cardiovascular death or first hospitalization for chronic heart failure was significantly lower in the group receiving candesartan compared with placebo (hazard ratio = 0.85, 95% confidence interval 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 LVEF > 40%, there were no statistically significant differences in the value of the combined effectiveness criterion, which included the frequency of deaths from cardiovascular diseases or the frequency of first hospitalization for chronic heart failure, between groups candesartan and placebo (hazard ratio = 0.89, 95% confidence interval 0.77-1.03, p = 0.118). At the same time, a positive effect of candesartan on one of the components of this combined criterion was noted - a decrease in the frequency of hospitalizations for chronic heart failure.

In a pooled analysis of all 3 CHARM studies, there was no significant difference in the incidence of deaths from all causes in the candesartan and placebo groups (hazard ratio = 0.91, 95% confidence interval 0.83-1.00, p = 0.055) .

The reduction in the incidence of death or hospitalization for chronic heart failure during therapy with candsartan 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 was independent of whether the patient was taking the optimal dose of the ACE inhibitor or not.

In patients with chronic heart failure and LVEF ≤ 40%, taking candesartan reduced total peripheral vascular resistance and capillary pressure in the lungs, increased renin activity and plasma angiotensin II concentrations, and decreased aldosterone levels.

Use of the drug Atacand

Arterial hypertension (AH) The recommended initial and usual maintenance dose is 8 mg 1 time per day. The dose can be increased to 16 mg 1 time per day. If sufficient blood pressure control is not achieved after 4 weeks of treatment with a dose of 16 mg once daily, it can be increased to a maximum dose of 32 mg once daily. If blood pressure control is not achieved using the drug at this dose, alternative treatment methods should be considered. Therapy must be adjusted based on blood pressure. The maximum antihypertensive effect is achieved within 4 weeks from the start of treatment. Elderly persons The initial dose does not require adjustment. Patients with reduced blood volume For patients at risk of developing arterial hypotension, for example for patients with a possible decrease in blood volume, an initial dose of 4 mg should be considered. Renal failure In patients with renal failure, including those on hemodialysis, the initial dose is 4 mg. The dose must be adjusted taking into account blood pressure. Experience in patients with severe renal failure or end-stage renal failure (creatinine clearance ≤15 ml/min) is limited. Liver failure For patients with mild to moderate liver failure, an initial dose of 2 mg once daily is recommended. The dose can be adjusted based on blood pressure. There is no experience with use in patients with severe liver failure. Concomitant therapy It has been established that the additional use of hydrochlorothiazide in combination with Atacand causes an additive antihypertensive effect. Patients of the Negroid race The antihypertensive effect of candesartan is less pronounced than in patients of the Caucasian race. Upward titration of Atacand and concomitant therapy to control blood pressure are more often necessary in black patients than in Caucasians. Heart failure The recommended starting dose of Atacand is 4 mg once daily. Titration upward to the target dose of 32 mg once daily or the maximum tolerated dose is carried out by doubling the dose over a period of at least 2 weeks. Special categories of patients For elderly patients or with a decrease in blood volume, mild to moderate renal or hepatic insufficiency, no adjustment of the initial dose is required. Concomitant therapy Atacand can be prescribed in combination with other drugs for the treatment of heart failure, including ACE inhibitors, beta-blockers, diuretics and digitalis drugs, or a combination of these drugs. Application. Atacand is taken once a day with or without food. Children and adolescents The safety and effectiveness of Atacanda in children and adolescents (under 18 years of age) have not been established.

Atacand, 8 mg, tablets, 28 pcs.

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 angiotensin II type 1 receptor antagonist. Candesartan does not inhibit ACE, which converts angiotensin I to angiotensin II and destroys 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 the receptors of other hormones and does not block ion channels involved in the regulation of cardiovascular functions. As a result of blocking the AT1 receptors of angiotensin II, there is a dose-dependent increase in the levels of renin, angiotensin I, angiotensin II and a decrease in the concentration of aldosterone in the blood plasma.

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 peripheral vascular resistance, without changing heart rate. There were no cases of severe arterial hypotension after taking the first dose of the drug, as well as o) syndrome after cessation of therapy.

The onset of the hypotensive effect after taking the first dose of candesartan cilexetil usually develops within 2 hours. With continued therapy with the drug at a fixed dose, the maximum reduction in blood pressure is usually achieved within 4 weeks and is maintained throughout treatment. Candesartan cilexetil, prescribed once a day, provides an effective and smooth decrease in blood pressure over 24 hours with minor fluctuations in blood pressure in the intervals between doses of the drug. The use of candesartan cilexetil in combination with hydrochlorothiazide leads to an increased hypotensive 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 patients.

Candesartan cilexetil increases renal blood flow and does not change or increases glomerular filtration rate, while renal vascular resistance and filtration fraction are reduced. Taking candesartan cilexetil at a dose of 8–16 mg for 12 weeks does not have a negative effect on glucose levels and lipid profiles in patients with arterial hypertension and type 2 diabetes mellitus.

The clinical effects of candesartan cilexetil on morbidity and mortality when administered at a dose of 8–16 mg (mean dose 12 mg) once daily were studied in a randomized clinical trial involving 4937 elderly patients (age 70 to 89 years, 21% of patients in aged 80 years and older) with mild to moderate hypertension treated with candesartan cilexetil for an average of 3.7 years ( COPE

- study of cognitive functions and prognosis in elderly patients). Patients received candesartan or placebo, if necessary, in combination with other antihypertensive agents. In the group of patients receiving candesartan, there was a decrease in blood pressure from 166/90 to 145/80 mm Hg. Art. and in the control group - from 167/90 to 149/82 mm Hg. Art. There were no statistically significant differences in the incidence of cardiovascular complications (cardiovascular mortality, myocardial infarction and non-fatal stroke) between the two groups of patients.

In the candesartan group, there were 26.7 incident cardiovascular events per 1000 patient-years compared with 30 per 1000 patient-years in the control group (hazard ratio = 0.89; 95% confidence interval 0. 75–1.06; p=0.19).

Chronic heart failure

According to the results of the CHARM

(Candesartan in Chronic Heart Failure—Evaluation of Mortality and Morbidity Reductions) use of candesartan cilexetil resulted in a reduction in the incidence of death and the need for hospitalization for chronic heart failure and an improvement in left ventricular systolic function.

Patients with chronic heart failure, in addition to the main therapy, received candesartan cilexetil at a dose of 4–8 mg/day with a dose increase to 32 mg/day or to the maximum tolerated therapeutic dose (the average dose of candesartan was 24 mg). The median follow-up duration was 37.7 months. After 6 months of therapy, 63% of patients who continued to take candesartan cilexetil (89%) received a therapeutic dose of 32 mg.

In another study, CHARM-Alternative

(n=2028) included patients with reduced (≤40%) left ventricular ejection fraction (LVEF) who did not receive an ACE inhibitor due to intolerance (mainly due to cough - 72%);
The rates of cardiovascular death and first hospitalization for chronic heart failure were significantly lower in the candesartan group compared with the placebo group (hazard ratio = 0.77; 95% confidence interval 0.67–0.89 ; p<0.001). The relative risk reduction was 23%. In this study, to prevent one cardiovascular death or hospitalization for chronic heart failure, it was necessary to treat 14 patients throughout the study period. The combined criterion, which included the incidence of deaths regardless of their cause and the rate of first hospitalization for chronic heart failure, was also significantly lower in the group of patients receiving candesartan (hazard ratio = 0.80; 95% confidence interval 0.7– 0.92; p=0.001). At the same time, a positive effect of candesartan was noted on each of the components of this combined criterion - the frequency of deaths and morbidity (an indicator of the frequency of hospitalizations for chronic heart failure). The use of candesartan cilexetil led to an improvement in the functional class of chronic heart failure according to the NYHA
(p = 0.008).

In the CHARM-Added

(n=2548) in patients with reduced LVEF ≤40% receiving ACE inhibitors, the composite criterion of cardiovascular mortality and first hospitalization for chronic heart failure was significantly lower in the group of patients receiving candesartan, according to compared with the placebo group (risk ratio = 0.85; 95% confidence interval 0.75–0.96; p = 0.011), which corresponded to a 15% reduction in relative risk.
In this study, to prevent one cardiovascular death or hospitalization for chronic heart failure, it was necessary to treat 23 patients throughout the study period. The value of the combined effectiveness criterion, which included an assessment of the incidence of deaths regardless of their cause or the frequency of the first hospitalization for chronic heart failure, was significantly lower in the group of patients receiving candesartan (hazard ratio = 0.87; 95% confidence interval 0. 78–0.98; p=0.021), which also indicated a positive effect when using candesartan. The use of candesartan cilexetil led to an improvement in the functional class of chronic heart failure according to the NYHA
(p = 0.02).

In the CHARM-Preserve

(n=3023) in patients with preserved systolic function (LVEF >40%), there were no statistically significant differences in the value of the combined effectiveness criterion, which included the incidence of deaths and the incidence of first hospitalization for chronic heart failure, in the candesartan and placebo groups (risk ratio =0.89; 95% confidence interval 0.77–1.03; p=0.118). The small numerical decrease in this criterion was due to a decrease in the frequency of hospitalizations for chronic heart failure. This study did not show the effect of candesartan on the incidence of deaths.

When separately analyzing the results of 3 studies of the CHARM

There were no significant differences in the incidence of deaths in the candesartan and placebo groups.
However, the incidence of death was estimated in the combined population of the CHARM-Alternative
and
CHARM-Added
and in all 3 studies (hazard ratio = 0.91; 95% confidence interval 0.83–1.0; p = 0.055). The reduction in the incidence of death and hospitalization for chronic heart failure during therapy with candesartan was independent of age, gender and concomitant therapy. Candesartan was also effective in patients taking beta-blockers in combination with ACE inhibitors, and the effectiveness of candesartan was independent of whether the patient was taking the optimal dose of the ACE inhibitor or not.

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

Side effects of the drug Atacand

For the treatment of arterial hypertension (HTN) During controlled clinical trials, side effects were mild, temporary and comparable to placebo. The overall incidence of side effects did not appear to be dose or age related. The rate of treatment discontinuation due to adverse reactions was similar for candesartan cilexetil (3.1%) and placebo (3.2%). The following common (1/100) adverse reactions were reported (the incidence of side effects that was at least 1% higher than the incidence of such effects when using placebo): from the nervous system: dizziness, headache. infections and infestations: respiratory tract infections. Results of laboratory studies No clinically significant effect of Atacand on laboratory parameters was noted. When using other inhibitors of the renin-angiotensin-aldosterone system, a slight decrease in hemoglobin was detected. Creatinine, urea, or potassium levels increased and sodium levels decreased. Increases in ALT, considered an adverse event, were not significantly more frequently reported with Atacand than with placebo (1.3 vs. 0.5%). For patients receiving Atacand, continuous monitoring of laboratory parameters is not necessary. However, periodic monitoring of serum potassium and creatinine levels is recommended in patients with renal impairment. For heart failure: the side effect profile of Atacanda in patients with heart failure is consistent with the pharmacological properties of this drug and the health status of the patients. Common adverse reactions (≥1/100, ≤1/10) identified during clinical trials included: From the cardiovascular system: arterial hypotension. Metabolic and nutritional disorders: hyperkalemia. From the urinary system: renal failure. Laboratory test indicators: increased levels of creatinine, urea and potassium. Periodic monitoring of serum creatinine and potassium levels is recommended. Post-marketing study: the following side effects were reported very rarely (≤1/10,000): from the blood system: leukopenia, neutropenia and agranulocytosis; metabolic and nutritional disorders: hyperkalemia, hyponatremia; from the nervous system: dizziness, headache; from the gastrointestinal tract: nausea; from the hepatobiliary system: increased levels of liver enzymes, abnormal liver function or hepatitis; from the skin and subcutaneous tissue: angioedema, rash, urticaria, itching; from the musculoskeletal system, connective tissue: back pain, arthralgia, myalgia; from the urinary system: impaired renal function, including renal failure in predisposed patients.

Special instructions for the use of the drug Atacand

Renal impairment As with other drugs that inhibit the renin-angiotensin-aldosterone system, changes in renal function can be expected in predisposed patients taking Atacand. When using Atacand in patients with hypertension (arterial hypertension) and renal failure, periodic monitoring of potassium and creatinine levels in the blood serum is recommended. Experience in patients with severe renal failure or end-stage renal failure (creatinine clearance ≤15 ml/min) is limited. In these patients, Atacand should be titrated in combination with blood pressure monitoring. Evaluation of patients with heart failure should include periodic assessment of renal function, especially in elderly patients over 75 years of age and in patients with renal insufficiency. Monitoring serum creatinine and potassium levels is recommended during Atacand dose titration. Clinical studies in patients with heart failure did not include subjects with a serum creatinine level of 265 mmol/L (3 mg/dL). Concomitant therapy with an ACE inhibitor in heart failure The risk of side effects, especially in renal failure and hyperkalemia, may be increased when candesartan is used in combination with an ACE inhibitor. These patients require regular and careful monitoring. Hemodialysis During dialysis, blood pressure may be particularly sensitive to AT1 receptor blockade due to a decrease in blood plasma volume and activation of the renin-angiotensin-aldosterone system. For patients on hemodialysis, Atacand should be carefully titrated and blood pressure monitored closely. Renal artery stenosis Other drugs that affect the renin-angiotensin-aldosterone system, such as ACE inhibitors, may increase blood urea and serum creatinine levels in patients with bilateral renal artery stenosis or stenosis of the artery leading to one kidney. A similar effect can be expected with the use of angiotensin II receptor antagonists. Kidney transplantation There is no experience with the use of Atacand in patients who have recently undergone kidney transplantation. Hypotension Hypotension may occur during use of Atacand in patients with heart failure. As described for other drugs that affect the renin-angiotensin-aldosterone system, hypotension can also occur in patients with hypertension (arterial hypertension) and reduced blood volume, such as those taking high doses of diuretics. When initiating therapy, caution should be exercised and attempts should be made to correct hypovolemia. Anesthesia and surgery In patients treated with angiotensin II receptor antagonists, hypotension may develop during anesthesia and surgery due to blockade of the renin-angiotensin-aldosterone system. In very rare cases, hypotension may be so severe that the use of IV fluids and/or vasopressors is required. Aortic and mitral valve stenosis (obstructive hypertrophic cardiomyopathy) As with other vasodilators, special caution should be used when treating patients with hemodynamically significant aortic or mitral valve stenosis, or obstructive hypertrophic cardiomyopathy. Primary hyperaldosteronism Patients with primary hyperaldosteronism usually do not respond to antihypertensive drugs that act by inhibiting the renin-angiotensin-aldosterone system. Therefore, the use of Atacand is not recommended. Hyperkalemia Experience with other drugs that affect the renin-angiotensin-aldosterone system suggests that concomitant use of Atacand with potassium-sparing diuretics, potassium supplements, potassium-containing salt substitutes, or other drugs that may increase potassium levels (eg, heparin) , may lead to increased serum potassium levels in patients with hypertension (arterial hypertension). Hyperkalemia may occur in patients with heart failure taking Atacand. During treatment with Atacand in patients with heart failure, it is recommended to periodically monitor serum potassium levels, especially if this drug is taken concomitantly with ACE inhibitors and potassium-sparing diuretics, such as spironolactone. General information: In patients whose vascular tone and renal function depend primarily on the activity of the renin-angiotensin-aldosterone system (for example, patients with severe congestive heart failure or kidney disease, including renal artery stenosis), treatment with other drugs that affect this system. has been associated with acute hypotension, azotemia, oliguria, or in rare cases, acute renal failure. The possibility of similar effects cannot be excluded when using angiotensin II receptor antagonists. As with any antihypertensive drug, excessive reduction of blood pressure in patients with ischemic cardiopathy or ischemic cerebrovascular disease can lead to myocardial infarction or stroke. Atacand should not be taken by patients with rare hereditary problems of galactose intolerance, Lapp lactase deficiency or glucose-galactose malabsorption. Pregnancy and lactation There is limited data regarding the use of Atacand during pregnancy, which is not sufficient to draw conclusions about the potential risk to the fetus when using the drug in the first trimester. Fetal renal perfusion, which develops in the second trimester, depends on the development of the renin-angiotensin-aldosterone system. The risk to the fetus increases if Atacand is taken during the second or third trimester of pregnancy. The use of drugs acting directly on the renin-angiotensin-aldosterone system during this period can cause harm to the fetus and newborn (hypotension, renal dysfunction, oliguria and/or anuria, oligohydramnios, cranial hypoplasia, intrauterine growth retardation) and lead to death. Cases of pulmonary hypoplasia, facial anomalies and contractures of the limbs have been described. An animal study using candesartan cilexetil showed renal damage in late pregnancy fetuses and newborns. This mechanism is considered to be pharmacologically mediated due to its effect on the renin-angiotensin-aldosterone system. Taking into account the above information, Atacand is not recommended for use during pregnancy. If pregnancy is detected during treatment, Atacand should be discontinued. It has not been established whether candesartan passes into breast milk, but due to potential adverse effects in breast-fed infants, Atacand should not be used during breastfeeding. The drug is unlikely to affect the ability to drive vehicles and operate machinery. When driving or operating machinery, dizziness and fatigue that may occur during treatment should be taken into account.

Atacand tablets 8 mg No. 28

Compound

Active substance: candesartan cilexetil 8 mg. Excipients: carmellose calcium (carmellose calcium salt) - 5.6 mg, hyprolose (hydroxypropylcellulose) - 4 mg, red iron oxide dye (E172) - 0.065 mg, lactose monohydrate - 89.4 mg, magnesium stearate - 0.4 mg, corn starch - 20 mg , macrogol - 2.6 mg.

Pharmacokinetics

Suction and distribution

Candesartan cilexetil is an oral prodrug. It quickly turns into the active substance - candesartan through ether hydrolysis when absorbed from the digestive tract, binds strongly to AT1 receptors and slowly dissociates, and does not have agonist properties. The absolute bioavailability of candesartan after oral administration of candesartan cilexetil solution is about 40%. The relative bioavailability of the tablet preparation compared to the oral solution is approximately 34%. Thus, the calculated absolute bioavailability of the tablet form of the drug is 14%. The maximum concentration in the blood serum (Cmax) is achieved 3-4 hours after taking the tablet form of the drug. With an increase in the dose of the drug within the recommended limits, the concentration of candesartan increases linearly. The pharmacokinetic parameters of candesartan do not depend on the gender of the patient. A meal does not have a significant effect on the area under the concentration-time curve (AUC), i.e. simultaneous food intake does not significantly affect the bioavailability of the drug. Candesartan actively binds to plasma proteins (>.99%). The volume of distribution of candesartan is 0.1 l/kg.

Metabolism and excretion from the body

Candesartan is mainly excreted unchanged from the body by the kidneys and bile and is only slightly metabolized in the liver. The half-life of candesartan is approximately 9 hours. Cumulation in the body is not observed.

The total clearance of candesartan is about 0.37 ml/min/kg, while the renal clearance is about 0.19 ml/min/kg. Renal excretion of candesartan is carried out by glomerular filtration and active tubular secretion. When radiolabeled candesartan cilexetil is administered orally, approximately 26% of the administered amount is excreted by the kidneys as candesartan and 7% as an inactive metabolite, whereas 56% of the administered amount is found in the feces as candesartan and 10% as an inactive metabolite.

In elderly patients (over 65 years of age), the Cmax and AUC of candesartan increase by 50% and 80%, respectively, compared with young patients. However, the hypotensive effect and the incidence of side effects when using Atacand do not depend on the age of the patients.

In patients with mild and moderate renal impairment, the Cmax and AUC of candesartan increased by 50% and 70%, respectively, while the half-life of the drug did not change compared to patients with normal renal function. In patients with severe renal impairment, the Cmax and AUC of candesartan increased by 50% and 110%, respectively, and the half-life of the drug increased by 2 times. In patients on hemodialysis, the same pharmacokinetic parameters of candesartan were found as in patients with severe renal impairment.

In patients with mild to moderate hepatic impairment, the AUC of candesartan increased by 23%.

Indications for use

• Arterial hypertension.
• Chronic heart failure and impaired left ventricular systolic function (decrease in LVEF 40%) as an additional therapy to angiotensin-converting enzyme (ACE) inhibitors or in case of intolerance to ACE inhibitors (see Pharmacodynamics section).

Contraindications

• Severe liver dysfunction and/or cholestasis;
• pregnancy;
• lactation period (breastfeeding);
• age under 18 years (efficacy and safety have not been established);
• lactose intolerance, lactase deficiency and glucose-galactose malabsorption syndrome;
• the use of candesartan cilexetil in combination with drugs containing aliskiren in patients with diabetes mellitus (type 1 or 2) or with moderate or severe renal failure (GFR <60 ml/min/1.73 m2);
• hypersensitivity to candesartan cilexetil or other components of the drug.

Directions for use and doses

Atacand® should be taken 1 time/day, regardless of meals.

Arterial hypertension

The recommended initial and maintenance dose of Atacand® is 8 mg 1 time/day. For patients who require further reduction in blood pressure, it is recommended to increase the dose to 16 mg 1 time / day. If therapy with Atacand® does not reduce blood pressure to the optimal level, it is recommended to add a thiazide diuretic to therapy.

The maximum antihypertensive effect is achieved within 4 weeks from the start of treatment.

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

In patients with mild or moderate renal impairment (creatinine clearance 30-80 ml/min), including patients on hemodialysis, the initial dose of the drug is 4 mg (1/2 tablet 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 (CrCl <15 ml/min) is limited.

In patients with mild to moderate liver dysfunction, it is recommended to start treatment with a daily dose of 4 mg (1/2 tablet of 8 mg). It is possible to increase the dose if necessary. Atacand® is contraindicated in patients with severe liver dysfunction and/or cholestasis.

The use of Atacand® in combination with thiazide diuretics (for example, hydrochlorothiazide) may enhance the antihypertensive effect of Atacand®.

Chronic heart failure

The recommended initial dose of Atacand® is 4 mg (1/2 tablet of 8 mg) 1 time/day. The dose is increased to 32 mg 1 time / day or to the maximum tolerated dose by doubling it at intervals of at least 2 weeks.

Elderly patients and patients with impaired renal or liver function do not require a change in the initial dose of the drug.

The safety and effectiveness of Atacand® in children and adolescents under 18 years of age have not been established.

Atacand® can be prescribed in conjunction with other drugs used for chronic heart failure, for example, ACE inhibitors, beta-blockers, diuretics and cardiac glycosides.

Storage conditions

The drug should be stored out of the reach of children at a temperature not exceeding 30°C.

Best before date

3 years. Do not use after the expiration date.

special instructions

Renal dysfunction

During therapy with Atacand, as with the use of other drugs that affect or act on the renin-angiotensin-aldosterone system, some patients may experience impaired renal function.

When using the drug Atacand in patients with arterial hypertension and severe renal failure (creatinine clearance less than 30 ml/min), it is recommended to periodically monitor the potassium content and creatinine concentration in the blood serum. Clinical experience with the drug in patients with severe renal impairment or end-stage renal failure is limited (creatinine clearance less than 15 ml/min). In such patients, the dose of Atacand should be titrated carefully under close blood pressure monitoring.

In patients with chronic heart failure, renal function should be periodically monitored, especially in patients aged 75 years and older, as well as in patients with impaired renal function. When increasing the dose of Atacand, it is also recommended to monitor potassium levels and creatinine concentrations.

Clinical studies of the drug Atacand for chronic heart failure did not include patients with a creatinine concentration of more than 265 µmol/l (> 3 mg/dl).

Combined use with ACE inhibitors in chronic heart failure

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

Renal artery stenosis

In patients with bilateral renal artery stenosis or stenosis of the artery of a solitary kidney, drugs that affect the renin-angiotensin-aldosterone system, in particular ACE inhibitors, may cause an increase in serum urea and creatinine concentrations. Similar effects can be expected when prescribing angiotensin II receptor antagonists.

Kidney transplant

Clinical experience with the use of Atacand in patients who have undergone a kidney transplant is limited.

Arterial hypotension

In patients with chronic heart failure during therapy with Atacand, arterial hypotension may develop. As with other drugs that affect the renin-angiotensin-aldosterone system, 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, at the beginning of therapy, caution should be exercised and, if necessary, correction of hypovolemia should be carried out.

Double blockade of the renin-angiotensin-aldosterone system when using drugs containing aliskiren

Dual blockade of the renin-angiotensin-aldosterone system by combining candesartan cilexetil and aliskiren is not recommended due to the increased risk of arterial hypotension, hyperkalemia and changes in renal function.

The use of candesartan cilexetil in combination with aliskiren is contraindicated in patients with diabetes mellitus (type 1 or 2) or with moderate or severe renal impairment (GFR < 60 ml/min/1.73 m2) (see Contraindications section).

General anesthesia and surgery

In patients receiving angiotensin II antagonists, arterial hypotension may develop during general anesthesia and surgical procedures as a result of blockade of the renin-angiotensin-aldosterone system. Very rarely, cases of severe arterial hypotension may occur, requiring intravenous administration of plasma replacement solutions and/or vasopressors.

Aortic and mitral valve stenosis or hypertrophic obstructive cardiomyopathy

When prescribing Atacand, like other vasodilators, patients with hypertrophic obstructive cardiomyopathy or hemodynamically significant stenosis of the aortic or mitral valve should be careful.

Primary hyperaldosteronism

Patients with primary hyperaldosteronism are usually resistant to treatment with antihypertensive drugs that affect the renin-angiotensin-aldosterone system. In this regard, Atacand is not recommended for such patients.

Hyperkalemia

Clinical experience with other drugs that affect the renin-angiotensin-aldosterone system shows that the simultaneous administration of Atacand with potassium-sparing diuretics, potassium supplements or salt substitutes containing potassium, or other drugs that can increase potassium levels in the blood (for example, heparin ), may lead to the development of hyperkalemia in patients with arterial hypertension.

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

Are common

Patients whose vascular tone and renal function are primarily dependent on the activity of the renin-angiotensin-aldosterone system (for example, patients with severe chronic heart failure or kidney disease, including renal artery stenosis) are especially sensitive to drugs that act on the renin-angiotensin-aldosterone system. system. The prescription of such drugs is accompanied in these patients by severe arterial hypotension, azotemia, oliguria and, less commonly, 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 heart disease or cerebrovascular diseases of atherosclerotic origin when using any antihypertensive drugs can lead to the development of myocardial infarction or stroke.

Conditions for dispensing from pharmacies

On prescription.

Dosage form

Pills.

Use in children

The effectiveness and safety of the drug in children and adolescents under 18 years of age have not been established.

Pharmacodynamics

Angiotensin II is the main hormone of the renin-angiotensin-aldosterone system, 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 angiotensin-converting enzyme (ACE), which converts angiotensin I to angiotensin II and destroys 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 the receptors of other hormones and does not block ion channels involved in the regulation of the functions of the cardiovascular system. As a result of blocking the AT1 receptors of angiotensin II, there is a dose-dependent increase in renin activity, the concentration of angiotensin I, angiotensin II and a decrease in the concentration of aldosterone in the blood plasma.

Arterial hypertension

In arterial hypertension, candesartan causes a dose-dependent, long-term decrease in blood pressure (BP). The antihypertensive effect of the drug is due to a decrease in general peripheral vascular resistance, without changing heart rate (HR). There were no cases of severe arterial hypotension after taking the first dose of the drug, as well as withdrawal syndrome (rebound syndrome) after cessation of therapy. The onset of antihypertensive effect after taking the first dose of candesartan cilexetil usually develops within 2 hours. With continued therapy with the drug at a fixed dose, the maximum reduction in blood pressure is usually achieved within 4 weeks and is maintained throughout 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 doses of the drug. The use of candesartan cilexetil in combination with hydrochlorothiazide leads to an enhanced 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 patients.

Candesartan cilexetil increases renal blood flow and does not change or increases glomerular filtration rate, while renal vascular resistance and filtration fraction are reduced. Taking candesartan cilexetil at a dose of 8-16 mg for 12 weeks does not have a negative effect on glucose concentrations and lipid profiles in patients with arterial hypertension and type 2 diabetes mellitus. The clinical effects of candesartan cilexetil on morbidity and mortality when administered at a dose of 8-16 mg (mean dose 12 mg) once daily were investigated in a randomized clinical trial involving 4937 elderly patients (age 70 to 89 years, 21% of patients in aged 80 years and older) with mild to moderate hypertension receiving candesartan cilexetil therapy for an average of 3.7 years (SCOPE study - a study of cognitive function and prognosis in elderly patients). Patients received candesartan cilexetil or placebo, if necessary, in combination with other antihypertensive agents. Both treatment regimens showed an 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 good tolerance. Cognitive function and quality of life remained at a good level in both groups of patients. There were no statistically significant differences in the incidence of cardiovascular events (cardiovascular mortality, nonfatal myocardial infarction, and nonfatal stroke) between the two groups of patients.

There were 26.7 incident cardiovascular events per 1,000 patient-years in the candesartan group compared with 30.0 per 1,000 patient-years in the control group (relative risk = 0.89, 95% confidence interval 0.75 - 1.06, p=0.19).

The table below presents the results of the assessment of the primary end point (cardiovascular complications) and its components.

*Before randomization, any previous antihypertensive therapy was standardized to hydrochlorothiazide at a dose of 12.5 mg once daily.

Another antihypertensive agent was added to the double-blind study drug (candesartan cilexetil 8–16 mg or placebo once daily) if systolic BP remained 160 mmHg and/or diastolic BP 90 mmHg. 49% and 66% of patients in the candesartan cilexetil group and control group, respectively, received such additional therapy.

Heart failure

According to the results of the CHARM (Candesartan in Chronic Heart Failure - Mortality and Morbidity Reduction Assessment) study, the use of candesartan cilexetil led to a reduction in the incidence of death and the need for hospitalization for chronic heart failure and to an improvement in left ventricular systolic function.

Patients with chronic heart failure, in addition to the main therapy, received candesartan cilexetil at a dose of 4 - 8 mg per day with a dose increase to 32 mg per day or to the maximum tolerated therapeutic dose (the average dose of candesartan was 24 mg). The median follow-up duration was 37.7 months. After 6 months of therapy, 63% of patients continuing to take candesartan cilexetil (89%) received a therapeutic dose of 32 mg.

Another study, the CHARM-Alternative study (n=2028), included patients with a reduced left ventricular ejection fraction (LVEF) of 40% who did not receive an ACE inhibitor due to intolerance (mainly due to cough - 72%), mortality rates from cardiovascular disease and first hospitalization for chronic heart failure were significantly lower in the group of patients receiving candesartan compared with the placebo group (hazard ratio = 0.77, 95% confidence interval 0.67 - 0.89, p < 0.001). The relative risk reduction was 23%. Statistically, in this study, to prevent one cardiovascular death or hospitalization for chronic heart failure, it was necessary to treat 14 patients throughout the study period. The combined rate of death regardless of cause and the rate of first hospitalization for chronic heart failure was also significantly lower in the group of patients receiving candesartan (hazard ratio = 0.80, 95% confidence interval 0.70 - 0 .92, p = .001). At the same time, a positive effect of candesartan was noted on each of the components of this combined criterion - the frequency of deaths and morbidity (an indicator of the frequency of hospitalizations for chronic heart failure). 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 a reduced LVEF of 40% receiving ACE inhibitors, the composite criterion of cardiovascular mortality and first hospitalization for chronic heart failure was significantly lower in the group of patients receiving candesartan , compared with the placebo group (hazard ratio = 0.85, 95% confidence interval 0.75 - 0.96, p = 0.011), which corresponded to a 15% reduction in relative risk. In this study, to prevent one cardiovascular death or hospitalization for chronic heart failure, it was necessary to treat 23 patients throughout the study period. The composite efficacy measure, which included an estimate of the incidence of death regardless of cause or incidence of first hospitalization for chronic heart failure, was significantly lower in the group of patients receiving candesartan (hazard ratio = 0.87, 95% confidence interval 0. 78 - 0.98, p = 0.021), which also indicated a positive effect when using candesartan. 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-Preserve study (n = 3023), in patients with preserved systolic function (LVEF > 40%), there were no statistically significant differences in the value of the combined effectiveness indicator, which included the rate of death and the rate of first hospitalization for chronic heart failure , in the candesartan and placebo groups (risk ratio = 0.89, 95%, confidence interval 0.77 - 1.03, p = 0.118). The small numerical decrease in this criterion was due to a decrease in the frequency of hospitalizations for chronic heart failure. This study did not show the effect of candesartan on the incidence of deaths.

When separately analyzing the results of 3 studies of the CHARM program, there were no significant differences in the incidence of deaths in the candesartan and placebo groups. However, the incidence of death was estimated in the combined population of the CHARM-Alternative and CHARM-Added studies and in all 3 studies (hazard ratio = 0.91, 95% confidence interval 0.83 - 1.00, p = 0.055). The reduction in the incidence of deaths and hospitalizations for chronic heart failure during candesartan therapy was independent of age, gender and concomitant therapy. Candesartan was also effective in patients taking beta-blockers in combination with ACE inhibitors, and the effectiveness of candesartan was independent of whether the patient was taking the optimal dose of the 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 renin activity and the concentration of angiotensin II in the blood plasma, as well as a decrease in aldosterone levels

Side effects

Arterial hypertension

Side effects during clinical trials were moderate and transient and were comparable in frequency to the placebo group. The overall incidence of adverse reactions while taking Atacand® did not depend on the dose of the drug, gender or age of the patient. Discontinuation rates due to side effects were similar between candesartan cilexetil (3.1%) and placebo (3.2%).

During the analysis of data from studies, the following side effects were reported, which were often (> 1/100) encountered while taking candesartan cilexetil. The described adverse reactions were observed with a frequency of at least 1% greater than in the placebo group.

From the side of the central nervous system: dizziness, weakness, headache.

From the musculoskeletal system: back pain.

From the laboratory parameters: in general, when using the drug Atacand®, no clinically significant changes in standard laboratory parameters were noted. As with the use of other drugs that affect the RAAS, a slight decrease in hemoglobin may be observed. An increase in creatinine and urea concentrations, an increase in potassium content and a decrease in sodium content were observed. Increases in ALT levels were observed slightly more frequently with Atacand® compared to placebo (1.3% instead of 0.5%). When using the drug Atacand®, regular monitoring of laboratory parameters is usually not required. However, in patients with impaired renal function, it is recommended to periodically monitor potassium levels and serum creatinine concentrations.

Other: respiratory infections.

Chronic heart failure

Adverse reactions identified during the use of the drug Atacand® in patients with chronic heart failure corresponded to the pharmacological properties of the drug and depended on the patient’s condition. The CHARM clinical trial compared Atacand® at doses up to 32 mg (n=3803) with placebo (n=3796), with 21% of patients receiving candesartan cilexetil and 16.1% of patients receiving placebo receiving stopped treatment due to adverse reactions.

The most common adverse reactions (≥1/100, <1/10).

From the cardiovascular system: marked decrease in blood pressure.

From the urinary system: impaired renal function.

From laboratory parameters: increased concentrations of creatinine and urea, increased potassium content.

It is recommended to monitor the concentration of creatinine and potassium levels in the blood serum.

The following adverse reactions have been reported very rarely (<1/10,000) during post-marketing use of the drug:

From the hematopoietic system: leukopenia, neutropenia and agranulocytosis.

Metabolism: hyperkalemia, hyponatremia.

From the nervous system: dizziness, headache, weakness.

From the respiratory system: cough.

From the gastrointestinal tract: nausea.

From the liver and biliary tract: increased activity of liver enzymes, impaired liver function or hepatitis.

Dermatological and allergic reactions: angioedema, rash, urticaria, itching.

From the musculoskeletal system: back pain, arthralgia, myalgia.

From the urinary system: impaired renal function, including renal failure in predisposed patients.

Use during pregnancy and breastfeeding

Pregnancy

The use of Atacand during pregnancy is contraindicated (see section Contraindications). Patients taking Atacand should be warned about this before planning pregnancy so that they can discuss alternative treatment options with their doctor. If pregnancy occurs, therapy with Atacand should be stopped immediately and, if necessary, alternative treatment should be prescribed. Drugs that have a direct effect on the renin-angiotensin-aldosterone system can cause developmental disorders in the fetus or have a negative effect on the newborn, including death, if the drug is used during pregnancy. It is known that therapy with angiotensin II receptor antagonists can cause fetal developmental disorders (impaired renal function, oligohydramnios, delayed ossification of the skull bones) and the development of complications in the newborn (renal failure, arterial hypotension, hyperkalemia).

Breastfeeding period

It is currently not known whether candesartan passes into breast milk. Due to possible undesirable effects on infants, Atacand should not be used during breastfeeding.

Interaction

The use of candesartan cilexetil in combination with drugs containing aliskiren is contraindicated in patients with diabetes mellitus (type 1 or 2) or moderate or severe renal impairment (glomerular filtration rate <60 ml/min/1.73 m2) and is not recommended in other patients ( see sections Contraindications and Special instructions).

Pharmacokinetic studies examined the combined use of Atacand with hydrochlorothiazide, warfarin, digoxin, oral contraceptives (ethinyl estradiol/levonorgestrel), glibenclamide, nifedipine and enalapril. No clinically significant pharmacokinetic interactions were identified.

Candesartan is metabolized in the liver to a small extent (by the CYP2C9 isoenzyme). Interaction studies have not revealed any effect of the drug on the CYP2C9 and CYP3A4 isoenzymes; the effect on other isoenzymes of the cytochrome P450 system has not been studied. Concomitant use of Atacand with other antihypertensive drugs potentiates the antihypertensive effect.

Experience with other drugs acting on the renin-angiotensin-aldosterone system shows that concomitant therapy with potassium-sparing diuretics, potassium supplements, salt substitutes containing potassium, and other drugs that can increase serum potassium levels (for example, heparin) may lead to the development of hyperkalemia.

When combined with lithium preparations and ACE inhibitors, a reversible increase in the concentration of lithium in the blood serum and the development of toxic reactions were reported. Similar reactions can also occur when using angiotensin II receptor antagonists, and therefore it is recommended to monitor the concentration of lithium in the blood serum when using these drugs in combination.

When combined with angiotensin II receptor antagonists and nonsteroidal anti-inflammatory drugs (NSAIDs), including selective cyclooxygenase-2 inhibitors, acetylsalicylic acid, a decrease in the hypotensive effect may be observed.

As with the use of ACE inhibitors, the combined use of angiotensin II receptor antagonists and NSAIDs may increase the risk of renal dysfunction, including acute renal failure, increased serum potassium, especially in patients with reduced renal function.

Caution should be exercised when using these drugs together, especially in elderly patients and in patients with reduced circulating blood volume. Patients need to compensate for fluid loss and regularly monitor renal function after starting combination therapy and periodically during such therapy.

The bioavailability of candesartan is independent of food intake.

Overdose

Symptoms: analysis of the pharmacological data of the drug suggests that the main manifestation of an overdose may be clinically significant arterial hypotension and dizziness. Isolated cases of drug overdose (up to 672 mg of candesartan cilexetil) have been described, resulting in the recovery of patients without serious consequences.

Treatment: with the development of clinically significant arterial hypotension, it is necessary to carry out symptomatic treatment and monitor the patient's condition. The patient should be placed on his back, with the head of the bed lowered. If necessary, the volume of blood volume should be increased, for example, by intravenous administration of 0.9% sodium chloride solution. If necessary, sympathomimetic drugs can be prescribed. Candesartan is not eliminated by hemodialysis.

Impact on the ability to drive vehicles and operate machinery

The effect on the ability to drive a car or operate machinery has not been studied, but the pharmacodynamic properties of the drug indicate that there is no such effect. Patients should be informed that dizziness and increased fatigue may occur during treatment, which should be taken into account before operating equipment or driving vehicles.

Drug interactions Atacand

No clinically significant interaction was identified. Compounds that were studied in clinical pharmacokinetic studies included hydrochlorothiazide, warfarin, digoxin, oral contraceptives (i.e., ethinyl estradiol/levonorgestrel), glibenclamide, nifedipine, and enalapril. Candesartan is excreted to a small extent by hepatic metabolism (CYP 2C9). Data from interaction studies indicate no effect on CYP 2C9 and CYP 3A4, however, the effect on other cytochrome P450 isoenzymes is not known. The antihypertensive effect of candesartan may be enhanced by other medicinal products that can lower blood pressure, whether prescribed as an antihypertensive agent or for other indications. Experience with other drugs that affect the renin-angiotensin-aldosterone system suggests that concomitant use of potassium-sparing diuretics, potassium supplements, potassium-containing salt substitutes, or other drugs that may increase potassium levels (eg, heparin) may result in increased potassium levels in the blood serum. There are reports of an inverse increase in serum lithium concentrations and toxicity during concomitant use of lithium with ACE inhibitors. A similar effect may occur with angiotensin II receptor antagonists. Therefore, careful monitoring of serum lithium levels is recommended during concurrent use. When combined with angiotensin II receptor antagonists and NSAIDs (for example, selective COX-2 inhibitors, acetylsalicylic acid (3 g/day) and non-selective NSAIDs), a weakening of the antihypertensive effect may occur. As with ACE inhibitors, concomitant use of angiotensin II receptor antagonists and NSAIDs may increase the risk of worsening renal function, including possible acute renal failure and increased serum potassium levels, especially in patients with impaired renal function. This combination is used with caution, especially in the elderly. Patients should receive sufficient fluids and consideration should be given to monitoring renal function at the initiation of concomitant therapy and periodically throughout the course of treatment. Food intake does not affect the bioavailability of candesartan.

Overdose of the drug Atacand, symptoms and treatment

Symptoms: hypotension and dizziness. Information on an individual case of overdose (up to 672 mg of candesartan cilexetil) reported that the patient recovered without consequences. Treatment: symptomatic, monitoring vital functions. The patient should be placed on his back with his lower limbs elevated. If this is not enough, it is necessary to increase the volume of blood plasma by infusion, for example, an isotonic saline solution. Candesartan is not eliminated by hemodialysis.