Atacand

Active material: Candesartan cïleksetïl
When ATH: C09CA06
CCF: Angiotensin II receptor antagonists
ICD-10 codes (testimony): I10, I50.0
When CSF: 01.04.02
Manufacturer: ASTRAZENECA AB (Sweden)

PHARMACEUTICAL FORM, COMPOSITION AND PACKAGING

Pills light pink, round, lenticular, with risk and engraving in the form of a letter “A” above the line and letters “CG” – below the line on one side of the tablet and “008” – on the other side.

Excipients: carmellose calcium (carmellose calcium salt), giproloza (hydroksypropyltsellyuloza), iron dioxide red dye (E172), lactose monohydrate, magnesium stearate, corn starch, macrogol.

14 PC. – blisters (2) – packs cardboard.

Pills Pink colour, round, lenticular, with risk and engraving in the form of a letter “A” above the line and letters “CN” – below the line on one side of the tablet and “016” – on the other side.

Excipients: carmellose calcium (carmellose calcium salt), giproloza (hydroksypropyltsellyuloza), iron dioxide red dye (E172), lactose monohydrate, magnesium stearate, corn starch, macrogol.

14 PC. – blisters (2) – packs cardboard.

Pills Pink colour, round, lenticular, with a notch and engraving in the form of letters “CL” on one side and “032” – another.

Excipients: carmellose calcium (carmellose calcium salt), giproloza (hydroksypropyltsellyuloza), iron oxide red dye (IS 172), lactose monohydrate, magnesium stearate, corn starch, macrogol.

14 PC. – blisters (2) – packs cardboard.

Pharmacological action

Antihypertensive drugs, antagonist retseptorov angiotensin II, selectively acting on AT receptors₁. Angiotensin II – 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 products, regulation of water-electrolyte homeostasis and stimulation of cell growth. All these effects are mediated by the interaction of angiotensin II with angiotensin receptors 1 type (AT₁-receptors).

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, The cigarette tanks receiving Candesartan. Candesartan is not associated with receptors of other hormones and does not block ion channels, involved in the regulation of cardiovascular functions. As a result of blocking AT₁ Angiotensin II receptors are in a dose -dependent increase in renin levels, Angiotensina and, Angiotensin II and a decrease in the concentration of aldosterone in 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 OPSS, no change in heart rate. There were no cases of severe arterial hypotension after taking the first dose of the drug, as well as the withdrawal effect (syndrome “Ricochet”) after cessation of therapy.

The onset of antihypertensive action after the first dose of candesartan cilexetil usually develops within 2 no. With continued therapy with the drug at a fixed dose, the maximum reduction in blood pressure is usually achieved within 4 weeks and persists throughout treatment. Candessartan Tsiglexil, appointed 1 time / day, provides an effective and smooth reduction in blood pressure during 24 h 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 increased hypotensive effect. Combined use of candesartan cilexetil and hydrochlorothiazide (or amlodipine) 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, whereas renal vascular resistance and filtration fraction decrease. Taking candesartan cilexetil dose 8-16 mg for 12 weeks does not have a negative effect on glucose levels and lipid profiles in patients with arterial hypertension and diabetes mellitus 2.

Clinical effect of candesartan cilexetil on morbidity and mortality when taken at a dose 8-16 mg (the average dose 12 mg) 1 once/day was studied during a randomized clinical study with the participation 4.937 elderly patients (age from 70 to 89 years, 21% patients aged 80 and older) with mild to moderate arterial hypertension, receiving therapy with candesartan cilexetil for an average of 3.7 years (SCORE study – study of cognitive functions and forecasting in elderly patients). Patients received candesartan or placebo, if necessary, in combination with other antihypertensive drugs. In the group of patients, receiving a candesartan, a decrease in blood pressure was noted 166/90 to 145/80 mmHg and in the control group with 167/90 to 149/82 mmHg. Statistically significant differences in the frequency of cardiovascular complications (mortality as a result of cardiovascular diseases, myocardial and stroke heart attack frequency, did not lead to death) There were no patients noted between the two groups of patients.

In the group of patients, receiving a candesartan, It was observed 26.7 cases of cardiovascular complications in 1000 patient-years compared to 30.0 cases on 1000 patient-years in the control group (risk ratio = 0.89, 95% confidence interval 0.75-1.06, p=0.19).

Heart failure

According to the results of the CHARM study (Candesartan for heart failure – Assessing Mortality and Morbidity Reductions) the use of candesartan cilexetil led to a decrease in the incidence of deaths 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 4-8 mg/day with increasing dose to 32 mg/day or up to the maximum tolerated therapeutic dose (The average dose of candesartan was 24 mg). The median follow-up duration was 37.7 months. Through 6 months of therapy 63% patients, who continued to take candesartan cilexetil (89%), received a therapeutic dose 32 mg.

In another study, CHARM-Alternative (n=2.028) included patients with reduced left ventricular ejection fraction (FVLJ ≤ 40%), not receiving an ACE inhibitor due to intolerance (mainly due to cough – 72%); Rates of death from cardiovascular disease and first hospitalization for chronic heart failure were significantly lower in the patient group, treated with candesartan compared with the placebo group (risk ratio = 0.77, 95% confidence interval 0.67- 0.89, p<0.001). The relative risk reduction was 23%. Statistically, in this study, treatment was necessary to prevent one case of cardiovascular death or hospitalization for chronic heart failure. 14 patients throughout the study period. Combined criterion, which included the incidence of deaths, regardless of their causes, and the rate of first hospitalization for chronic heart failure, was also significantly lower in the patient group, receiving a candesartan (risk ratio = 0.80, 95% confidence interval 0.70-0.92, p = 0.001). At the same time, a positive effect of candesartan on each of the components of this combined criterion was noted – mortality rate and morbidity (rate of hospitalization for 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=2.548) in patients with reduced LVEF (≤ 40%), ACE inhibitor, combined criterion, which included mortality rates from cardiovascular diseases and first hospitalization for chronic heart failure, was significantly lower in the patient group, receiving a candesartan, compared with the placebo group (risk ratio = 0.85, 95% confidence interval 0.75-0.96, p=0.011), which corresponded to a reduction in relative risk by 15%. In this study, treatment was required to prevent one case of cardiovascular death or hospitalization for chronic heart failure. 23 patients throughout the study period. The value of the combined performance criterion, which included an assessment of the frequency of deaths, regardless of their causes or the frequency of first hospitalization for chronic heart failure, was significantly lower in the patient group, receiving a candesartan (risk 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=3.023) 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). A 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 analyzing the results separately 3 CHARM program studies did not show 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 research (risk 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 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, however, the effectiveness of candesartan did not depend on whether, whether the patient is taking the optimal dose of ACE inhibitor or not.

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

Pharmacokinetics

Absorption and distribution

Candesartan cilexetil is an oral prodrug. After taking the drug orally, candesartan cilexetil is quickly converted into the active substance candesartan through ether hydrolysis. Strongly binds to AT₁-receptors and slowly dissociates, does not have the properties of an agonist. The absolute bioavailability of Candesartan after taking a ziglesectal of the piclexyle of the plywood is about 40%. The relative bioavailability of the tablet drug compared to the solution for oral administration is approximately 34%. Thus, The calculated absolute bioavailability of the tablet form is 14%.

C_max reached on average through 3-4 h after taking the tablet form of the drug. As the dose of the drug increases within the recommended doses, the concentration of candesartan increases linearly.

Pharmacokinetic parameters of Kandesartan are not dependent on the patient's gender. Food intake has no significant effect on AUC, ie. food does not significantly affect the bioavailability of the drug.

Candesartan actively binds to plasma proteins (>99%). V_d Candessartan is 0.1 l / kg.

Metabolism and excretion

Kandhedanskant, primarily, It is excreted from the body with urine and bile in unchanged form and only in a slight degree is metabolized in the liver. T_1/2 Kandesartan is approximately 9 no. There is no accumulation of the drug in the body.

The general clearance of Pandesartan is about 0.37 ml / min / kg, At the same time, renal clearance – about 0.19 ml / min / kg. The renal excretion of Kandesartan is carried out by glomerular filtration and active tubular secretion. With oral administration of radiolabeled candesartan cilexetil, approximately 26% From the introduced amount is removed with urine in the form 7% Vide in neaktivnogo metabolite, Whereas in Kala is detected 56% from the entered number in the form 10% Vide in neaktivnogo metabolite.

Pharmacokinetics in special clinical situations

Elderly patients over 65 years p_max and AUC of candesartan increase by 50% and 80%, respectively, compared to younger patients. But, hypotensive effect and incidence of side effects when using Atacand^® do not depend on the age of the patients.

In patients with a mild and moderate impaired renal function C_max and AUC of candesartan increased by 50% and 70% respectively, Whereas t_1/2 the drug does 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, a T_1/2 the drug increased in 2 times. Patients, hemodialysis, the same pharmacokinetic parameters of candesartan were identified, as in patients with severe renal impairment.

In patients with a mild and moderate impaired liver function, an increase in Pandesartan AUC was observed by 23%.

Testimony

- Arterial hypertension;

- heart failure and impaired left ventricular systolic function (decrease in LVEF ≤ 40%) (as adjunctive therapy to ACE inhibitors or intolerance to ACE inhibitors).

Dosage regimen

Atakand^® should be taken 1 time / day regardless of the meal.

Recommended initial and maintenance dose of Atacanda^® at hypertension is 8 mg 1 time / day. Patients, who require further reduction in blood pressure, it is recommended to increase the dose to 16 mg 1 time / day. When, if therapy with Atacand^® does not lead to a decrease in blood pressure to the optimal level, It is recommended to add a thiazide diuretic to therapy.

The maximum antihypertensive effect is reached 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 mild to moderate impaired renal function (CC≥30 ml/min) no change in the initial dose of the drug is required.

Clinical experience with the drug in patients severe renal impairment or end-stage renal failure (CC<30 ml / min) limited. In these cases, consideration should be given to starting treatment with a daily dose 4 mg.

In patients impaired liver function mild to moderate severity starting dose is 2 mg 1 time / day. If necessary, the dose can be increased. Clinical experience with the drug in patients with severely impaired hepatic function limited.

Atakand^® can be prescribed in conjunction with thiazide diuretics (eg, gidroxlorotiazid), which leads to increased hypotensive effect.

Recommended starting dose of Atacanda^® at Heart Failure is 4 mg 1 time / day. Increasing the dose to 32 mg 1 once a day or up to the maximum tolerated dose is carried out by doubling it at intervals of at least 2 weeks.

Atakand^® can be prescribed together with other drugs, used for chronic heart failure, eg, with ACE inhibitors, beta blockers, diuretics and cardiac glycosides.

Elderly patients and patients with impaired renal or liver function no change in the initial dose of the drug is required.

Side effect

Arterial hypertension

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

The following side effects were reported in studies reviewed:, often (>1/100) encountered while taking candesartan cilexetil. The described adverse reactions were observed with a frequency of at least 1% better, than placebo.

CNS Co: dizziness, weakness, headache.

On the part of the musculoskeletal system: backache.

From the laboratory parameters: in general when using Atacanda^® no clinically significant changes in standard laboratory parameters were noted. As with the use of other inhibitors of the renin-angiotensin-aldosterone system, There may be a slight decrease in hemoglobin levels. There was an increase in creatinine levels, urea or calcium and sodium reduction. Increases in ALT levels were noted slightly more frequently with Atacand.^® vs placebo (1.3% instead 0.5%). When using Atacanda^® routine laboratory monitoring is usually not required. But, in patients with impaired renal function, it is recommended to periodically monitor serum potassium and creatinine levels.

Other: respiratory infections.

Congestive heart failure

Adverse Reactions, identified during the use of Atacand^® in patients with heart failure, corresponded to the pharmacological properties of the drug and depended on the patient’s condition. CHARM clinical trials compared Atacanda^® at doses up to 32 mg (n=3.803) with placebo (n=3.796), 21% patients from the patient group, The cigarette tanks receiving Candesartan, and 16.1% patients from the patient group, placebo, stopped treatment due to adverse reactions.

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

Cardio-vascular system: marked reduction in blood pressure.

From the urinary system: impairment of renal function.

From the laboratory parameters: increased creatinine, urea and potassium.

It is recommended to monitor serum creatinine and potassium levels.

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

From the hematopoietic system: leukopenia, neutropenia and agranulocytosis.

Metabolism: hyperkalemia, giponatriemiya.

From the nervous system: dizziness, headache, weakness.

On the part of the digestive tract: nausea.

Liver and biliary tract: elevated liver enzymes, liver dysfunction or hepatitis.

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

On the part of the musculoskeletal system: backache, arthralgia, myalgia.

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

Contraindications

- impaired liver function and/or cholestasis;

- Pregnancy;

- Lactation (breast-feeding);

- hypersensitivity to candesartan cilexetil or other components of the drug.

FROM caution the drug should be prescribed to patients with severe renal failure (CC<30 ml / min), bilateral renal artery stenosis or stenosis of the artery of a solitary kidney, with hemodynamically significant stenosis of the aortic and mitral valve, history of kidney transplantation, patients with cerebrovascular disease and ischemic heart disease, with reduced BCC, with hyperkalemia, with primary hyperaldosteronism (lack of sufficient clinical trial data), with hypertrophic cardiomyopathy, as well as patients under the age of 18 years (efficacy and safety have not been established).

Pregnancy and lactation

The drug is contraindicated during pregnancy and lactation.

The human embryo has a blood supply system, which depends on the development of the renin-angiotensin-aldosterone system, begins to form in the II trimester of pregnancy. Thus, The risk for the fetus increases with the appointment of Atacand^® in the II and III trimesters of pregnancy. Preparations, having a direct effect on the renin-angiotensin-aldosterone system, can cause fetal development or a negative effect on the newborn, until death, when used in II and III trimesters of pregnancy.

IN experimental studies In animals, kidney damage was detected in the embryonic and neonatal periods when using candesartan cilexetil. Expected, that the damage mechanism is due to the pharmacological effect of the drug on the renin-angiotensin-aldosterone system. Based on the information received, Atacand should not be used^® Pregnancy. If pregnancy has occurred during the treatment for Atacande^®, therapy should be discontinued.

It is currently unknown, whether candesartan penetrates into breast milk. Due to possible adverse effects on nursing infants, Atakand^® should not be used during lactation (breast-feeding).

Cautions

Impaired renal function

During therapy with Atacand^®, as with the use of other drugs, inhibiting the renin-angiotensin-aldosterone system, Some patients may experience impaired renal function.

When using Atacanda^® in patients with arterial hypertension and severe renal failure, it is recommended to periodically monitor the level of potassium and creatinine in the blood serum. Clinical experience with the drug in patients with severe renal impairment or end-stage renal failure is limited. (CC<15 ml / min).

In patients with chronic heart failure, renal function should be periodically monitored, especially in older patients 75 and older, as well as in patients with impaired renal function. When increasing the dose of Atacanda^® It is also recommended to monitor potassium and creatinine levels.

In clinical trials Atacanda^® for chronic heart failure, patients with a creatinine level of more than 265 mmol / 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. In these cases, careful observation and monitoring of laboratory parameters is necessary..

Renal artery stenosis

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

Kidney transplant

Data on the use of Atacand^® patients, recently transferred kidney transplantation, no.

Hypotension

In patients with chronic heart failure during therapy with Atacand^® arterial hypotension may develop. As with other medications, vliyayushtih renin-angiotensin-alydosteronovuyu sistemu, the cause of the development of arterial hypotension in patients with arterial hypertension may be a decrease in blood volume, as observed in patients, receiving high doses of diuretics. Therefore, caution should be exercised when starting therapy, if necessary, correct hypovolemia.

General anesthesia and surgery

Patients, receiving angiotensin II receptor antagonists, During anesthesia and surgical interventions, arterial hypotension may develop as a result of the blockade of the renin-angiotensin system. Cases of severe arterial hypotension can be very rarely noted, requiring IV fluids and/or vasopressors.

Aortic and mitral valve stenosis (obstruktivnaya gipertroficheskaya cardiomyopathy)

When appointing Atacand^®, like other vasodilators, Caution should be exercised in patients with obstructive hypertrophic cardiomyopathy or hemodynamically significant aortic or mitral valve stenosis.

Primary hyperaldosteronism

Patients with primary hyperaldosteronism are usually resistant to antihypertensive drug therapy, influencing renin-angiotensin-aldosterone system. In this regard, Atakand^® it is not recommended to prescribe to such patients.

Hyperkalemia

Clinical experience with other drugs, vliyayushtih sistemu of the renin-angiotensin-alydosteron, shows, that the simultaneous administration of Atacand^® with potassium-sparing diuretics, potassium supplements or salt substitutes, containing potassium, or other drugs, which can increase potassium levels in the blood (eg, Heparin), may lead to the development of hyperkalemia in patients with arterial hypertension.

In patients with heart failure during therapy with Atacand^®, hyperkalemia may develop. When appointing Atacand^® Patients with heart failure are advised to regularly monitor potassium levels in the blood, especially when co-administered with ACE inhibitors and potassium-sparing diuretics.

General

Patients, In which vascular tone and kidney function mainly depend on the activity of the renin-angiotensin-aldosterone system (eg, patients with severe chronic heart failure or kidney disease, including renal artery stenosis), Particularly sensitive to drugs, operating on renin-angiotensin-aldosterone system. The prescription of such drugs is accompanied by severe arterial hypotension in these patients., azotemia, oliguria and less often – acute renal failure. The possibility of developing these effects cannot be excluded when using angiotensin II receptor antagonists.. A sharp decrease in blood pressure in patients with ischemic cardiopathy or cerebrovascular diseases of ischemic origin when using any antihypertensive drugs can lead to the development of myocardial infarction or stroke.

Use in Pediatrics

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

Effects on ability to drive vehicles and management mechanisms

Influence on the ability to drive a car or work with equipment was not studied, but the pharmacodynamic properties of the drug indicate, that such an influence is absent. Patients should be informed about, that during treatment dizziness and increased fatigue may occur, what should be taken into account before starting to work with equipment or drive vehicles.

Overdose

Symptoms: analysis of the pharmacological data of the drug suggests, что основным проявлением передозировки может быть клинически выраженная артериальная гипотензия и головокружение. Certain cases of an overdose of the drug were described (to 672 мг кандесартана цилексетила), ending with recovery of patients without severe consequences.

Treatment: при развитии клинически выраженной артериальной гипотензии необходимо проводить симптоматическое лечение и контролировать состояние пациента. Следует уложить пациента на спину, опустить голову вниз. If necessary, it should be increased by the BCC, eg, путем в/в введения изотонического раствора натрия хлорида. В случае необходимости могут быть назначены симпатомиметические препараты. Elimination of candesartan by hemodialysis is unlikely.

Drug Interactions

In pharmacokinetic studies, the combined use of Atacand was studied^® hydrochlorothiazide, varfarinom, digoksinom, oral contraceptives (ethinyl estradiol / levonorgestrel), glibenclamide, Nifedipin and enalapril. Clinically significant drug interactions were not revealed.

Candesartan is metabolized in the liver to a small extent by the CYP2C9 isoenzyme.. Interaction studies did not reveal the effect of the drug on CYP2C9 and CYP3A4, action on other isoenzyme systems of the cytochrome P450 has not been studied.

Joint application of Atacakd^® with other antihypertensive drugs potentiates the hypotensive effect.

Experience in the use of other drugs, acting on renin-angiotensin-aldosterone system, shows, what is the accompanying therapy with potassium -saving diuretics, potassium supplements, potassium-containing salt substitutes and other means, which may increase serum potassium levels (eg, Heparin), can 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 be found when using antagonists of angiotensin II receptors, therefore, it is recommended to monitor the level of lithium in the blood serum when using these drugs in combination.

Conditions of supply of pharmacies

The drug is released under the prescription.

Conditions and terms

List B. The drug should be stored out of reach of children at or above 30 ° C. Shelf life – 3 year. Do not use beyond the expiration date.