Atacand, pills 16mg, 28pcs

Composition

Active ingredient:

candesartan cilexetil 16 mg.

Auxiliary substances:

Carmellose calcium (carmellose calcium salt) 5.6 mg,

hyprolose (hydroxypropyl cellulose) 4.0 mg,

iron oxide red dye E 172 0.26 mg;

lactose monohydrate 81.4 mg,

magnesium stearate 0.4 mg,

corn starch 20.0 mg,

macrogol 2.6 mg

Pharmacological action

Pharmacotherapy group: angiotensin II receptor antagonist. ATX Code: C09CA06 Pharmacological properties

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 type 1 angiotensin receptors (AT1 receptors).

Candesartan is a selective angiotensin II type 1 receptor (AT1 receptor) antagonist. Candesartan does not inhibit the angiotensin-converting enzyme (ACE), which converts angiotensin I to angiotensin II and destroys bradykinin; it 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 regulating the functions of the cardiovascular system. As a result of blocking the AT1 receptors of angiotensin II, there is a dose-dependent increase in the activity of renin, the concentration of angiotensin I, 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 (BP).

The antihypertensive effect of the drug is due to a decrease in total peripheral vascular resistance, without changing the heart rate (HR). There were no cases of severe hypotension after taking the first dose of the drug, as well as withdrawal syndrome (rebound syndrome) after discontinuation of therapy. The onset of antihypertensive effects after taking the first dose of candesartan cilexetil usually develops within 2 hours. With continued treatment with the drug in a fixed dose, the maximum reduction in blood pressure is usually achieved within 4 weeks and persists throughout treatment.

Candesartan cilexetil, administered once a day, provides an effective and smooth reduction in blood pressure for 24 hours with slight fluctuations in blood pressure in the intervals between taking the next dose of the drug. The use of candesartan cilexetil together with hydrochlorothiazide leads to an increased antihypertensive effect. Concomitant 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 alter or increase 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 concentration and lipid profile in patients with arterial hypertension and type 2 diabetes mellitus.

The clinical effect of candesartan cilexetil on morbidity and mortality at a dose of 8-16 mg (average dose 12 mg) once a day was investigated in a randomized clinical trial involving 4,937 elderly patients (aged 70 to 89 years,21% of patients aged 80 years and older) with mild to moderate arterial 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 treated with candesartan, and from 167/90 to 149/82 mm Hg in the control group) on the background of good tolerability.

Cognitive function and quality of life were maintained at a good level in both groups of patients. There were no statistically significant differences in the incidence of cardiovascular events (cardiovascular mortality, non-fatal myocardial infarction and non-fatal stroke) between these two groups of patients.

In the group of patients treated with candesartan, there were 26.7 cases of cardiovascular complications per 1000 patient-years, compared with 30.0 cases per 1000 patient-years in the control group (relative risk = 0.89,95% confidence interval 0.75-1.06, p=0.19).

The table below shows the results of the assessment of the primary endpoint (cardiovascular complications) and its components.

* Prior to randomization, any previous antihypertensive therapy was standardized to 12.5 mg hydrochlorothiazide once daily.

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

Chronic heart failure

According to the results of the CHARM study (Candesartan for chronic heart failure-Assessment of the Reduction in Mortality and Morbidity), the use of candesartan cilexetil led to a decrease in the frequency 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 of 4-8 mg per day with an increase in the dose to 32 mg per day or to the maximum tolerated therapeutic dose (the average dose of candesartan was 24 mg). The median follow-up period 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.

Another CHARM-Alternative study (n=2028) included patients with reduced left ventricular ejection fraction (LVEF) < 40% who did not receive an ACE inhibitor due to intolerance (mainly due to cough-72%); the incidence of cardiovascular deaths and first hospitalization for chronic heart failure was significantly lower in the candesartan-treated group compared to the placebo group (risk ratio = 0.77,95% confidence interval 0.67 – 0.89, p In the CHARM-Added study (n = 2548) in patients with reduced LVEF < 40% treated with ACE inhibitors, the combined criterion that included the mortality rate from cardiovascular diseases and first hospitalization for chronic heart failure was significantly lower in the candesartan group compared to the placebo group (risk ratio = 0.85,95% confidence interval 0.75 – 0.96, p = 0.011), which corresponded to a decrease in the relative risk by 15%.

In this study,23 patients were treated throughout the entire study period to prevent one case of death from cardiovascular complications or hospitalization for chronic heart failure. The value of the combined efficacy 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 group of patients receiving 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 resulted in an improvement in the NYHA functional class of chronic heart failure (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 efficacy criterion, which included the frequency of deaths and the frequency 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.

In a separate analysis of the results of 3 CHARM trials, there were no significant differences in the frequency of deaths in the candesartan and placebo groups. However, the mortality rate was estimated in the combined population of CHARM-Alternative and CHARM-Added studies and in all 3 studies (risk ratio = 0.91,95% confidence interval 0.83-1.00, p = 0.055). The reduction in the number of deaths and hospitalizations for chronic heart failure during candesartan therapy did not depend on age, gender, or concomitant therapy. Candesartan was also effective in patients taking beta-blockers in combination with ACE inhibitors, and the effectiveness of candesartan did not depend on whether the patient was taking the optimal dose of an ACE inhibitor or not.

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

Pharmacokinetics

Suction and distribution

Candesartan cilexetil is an oral prodrug. It is rapidly converted to the Active ingredient candesartan by ether hydrolysis upon absorption from the digestive tract, binds strongly to AT-1 receptors and slowly dissociates, and has no agonist properties.

The absolute bioavailability of candesartan after oral use of candesartan cilexetil solution is about 40%.

The relative bioavailability of the tablet preparation compared to the oral solution is approximately 34%. Thus, the estimated absolute bioavailability of the tablet form of the drug is 14%. The maximum concentration in the blood serum (Cmax) is reached 3-4 hours after taking the tablet form of the drug. When the dose of the drug is increased within the recommended limits, the concentration of candesartan increases linearly.

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

Food intake does not significantly affect 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 elimination from the body

Candesartan is mainly eliminated from the body by the kidneys and bile in unchanged form and is only slightly metabolized in the liver. The elimination half-life of candesartan is approximately 9 hours. Accumulation 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 taken orally, about 26% of the administered amount is excreted by the kidneys as candesartan and 7% as an inactive metabolite, while 56% of the administered amount is detected 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 increased by 50% and 80%, respectively, compared with younger patients. However, the antihypertensive effect and frequency of side effects when using Atacand® do not depend on the age of 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 undergoing hemodialysis, the same pharmacokinetic parameters of candesartan were detected as in patients with severe renal impairment.

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

Indications

Arterial hypertensionchronic heart failure and impaired left ventricular systolic function (reduced LVEF < 40%) as adjunctive therapy to angiotensin converting enzyme (ACE) inhibitors or in case of intolerance to ACE inhibitors

Use during pregnancy and lactation

Pregnancy

The use of Atacand® during pregnancy is contraindicated (see section “Contraindications”). Patients taking Atacand should be advised of this prior to pregnancy planning so that they can discuss alternative treatment options with their healthcare provider.

If pregnancy is diagnosed, 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 fetal developmental disorders or have a negative effect on the newborn, up to a fatal outcome, when 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, slowing of ossification of the skull bones) and the development of complications in the newborn (renal failure, hypotension, hyperkalemia).

Breast-feeding period

It is currently unknown whether candesartan passes into breast milk. However, candesartan is excreted in the milk of lactating rats. Due to possible adverse effects on infants, Atacand® should not be used during breastfeeding.

Contraindications

• Hypersensitivity to candesartan cilexetil or other components of the drug.
• Pregnancy and lactation (see the section “Use during pregnancy and lactation”).
• Severe hepatic impairment and / or cholestasis.
• Age up to 18 years (efficacy and safety have not been established).
• Lactose intolerance, lactase deficiency, and glucose-galactose malabsorption syndrome.
• 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 insufficiency (glomerular filtration rate

With caution: in patients with severe renal insufficiency (creatinine clearance less than 30 ml/min), bilateral renal artery stenosis or stenosis of the artery of a single kidney, with hemodynamically significant aortic and mitral valve stenosis, after a history of kidney transplantation, in patients with cerebrovascular diseases and coronary heart disease (CHD), hyperkalemia, in patients with reduced circulating blood volume, with primary hyperaldosteronism (there is not enough data from clinical studies), hypertrophic obstructive cardiomyopathy.

Side effects

From the central nervous system: often ( more than 2%) – headache, dizziness.

From the side of laboratory parameters: increased AST activity (slightly higher than in the placebo groups). In general, there were no clinically significant changes in laboratory parameters when taking Atacand.

Other services: often ( more than 2%) – back pain.

Clinical trials showed good tolerability of the drug, the frequency of side effects was comparable to placebo, did not depend on the dose of the drug, as well as on the age and gender of the patient. In general, side effects were moderate and temporary. The number of cases of discontinuation of the drug due to side effects was similar to the number in the group of patients taking candesartan cilexetil and placebo.

A causal relationship between Atakand and the described side effects has not been established.

Interaction

Interaction with other drugs and other forms of drug interaction

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

Candesartan is only slightly metabolized in the liver (CYP2C9). Interaction studies have not revealed the effect of the drug on CYP2C9 and CYP3A4, and the effect on other cytochrome P450 isoenzymes has not been studied.

The combined use of Atacand with other antihypertensive agents potentiates the hypotensive effect.

Experience with other drugs that affect the renin-angiotensin-aldosterone system shows that concomitant therapy with potassium-sparing diuretics, potassium preparations, salt substitutes containing potassium, and other agents that can increase the level of potassium in the blood serum (for example, heparin) may lead to the development of hyperkalemia.

Reversible increases in serum lithium concentrations and the development of toxic reactions have been reported when lithium preparations are co-administered with ACE inhibitors. Similar reactions can also occur with the use of angiotensin II receptor antagonists, and therefore, it is recommended to monitor the level of lithium in the blood serum with the combined use of these drugs.

The bioavailability of candesartan is independent of food intake.

How to take, course of use and dosage

Atacand® should be taken once a day, regardless of food intake.

Arterial hypertension

The recommended starting and maintenance dose of Atacand® is 8 mg once daily.

Patients who need a further reduction in blood pressure are recommended to increase the dose to 16 mg once a day.

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

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.

Elderly patients

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

Patients with impaired renal function

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 (creatinine clearance less than 15 ml / min) is limited.

Patients with impaired liver function

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

Concomitant therapy

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

Chronic heart failure

The recommended starting dose of Atacand® is 4 mg (‘L tablets of 8 mg) once a day. Increasing the dose to 32 mg once a day or to the maximum tolerated dose is carried out by doubling it at intervals of at least 2 weeks.

Special patient groups

Elderly patients and patients with impaired renal or hepatic function do not need to change the initial dose of the drug.

Use in children and adolescents

Safety and efficacy of Atacand® in children and adolescents (under 18 years of age) not installed

Concomitant therapy

Atacand® can be co-administered with other agents used in the treatment of chronic heart failure, such as ACE inhibitors, beta-blockers, diuretics and cardiac glycosides.

Overdose

Analysis of the pharmacological properties of the drug suggests that the main manifestation of overdose may be a clinically pronounced decrease in blood pressure and dizziness. Individual cases of overdose of the drug (up to 672 mg of candesartan cilexetil) were described, which resulted in recovery of patients without serious consequences. Treatment If a clinically pronounced decrease in blood pressure develops, it is necessary to conduct symptomatic treatment and monitor the patient’s condition. Lay the patient down, lift the foot end of the bed. If necessary, increase the volume of circulating blood plasma, for example, by intravenous use of 0.9% sodium chloride solution. If necessary, sympathomimetic drugs may be prescribed. Candesartan is not eliminated by hemodialysis.

Special instructions

Impaired renal function

Some patients may experience impaired renal function during Atacand therapy, as with other agents that affect or act on the renin-angiotensin-aldosterone system.

When using Atacand® in patients with arterial hypertension and severe renal insufficiency (creatinine clearance less than 30 ml/min), it is recommended to periodically monitor the potassium content and serum creatinine concentration. 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). Such patients should carefully titrate the dose of Atacand® under careful blood pressure monitoring.

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

Patients with creatinine concentrations > 265 mmol/l (>3 mg/dl) were excluded from clinical trials of Atacand® in chronic heart failure.

Concomitant use with ACE inhibitors in chronic heart failure When candesartan is used in combination with ACE inhibitors, the risk of side effects may increase, especially impaired renal function and hyperkalemia. In these cases, careful monitoring and monitoring of laboratory parameters is necessary.

Renal artery stenosis

In patients with bilateral renal artery stenosis or stenosis of the artery of a single kidney, drugs that affect the renin-angiotensin-aldosterone system, in particular ACE inhibitors, can cause an increase in serum urea and creatinine concentrations.

Similar effects can be expected with angiotensin P receptor antagonists.

Kidney transplant

Clinical experience with Atacand® in kidney transplant patients is limited.

Arterial hypotension

Patients with chronic heart failure may develop hypotension during Atacand therapy. As with other drugs that affect the renin-angiotensin-aldosterone system, hypotension in patients with hypertension may be caused by a decrease in the volume of circulating blood, as is observed in patients receiving high doses of diuretics. Therefore, at the beginning of therapy, care should be taken and, if necessary, correction of hypovolemia should be carried out.

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

Double blockade of the renin-angiotensin-aldosterone system by combining candesartan cilexetil and aliskiren is not recommended, due to the increased risk of 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 insufficiency (GFR General anesthesia and surgery

Patients receiving angiotensin II antagonists may develop hypotension during general anesthesia and surgery as a result of blockade of the renin-angiotensin-aldosterone system. Very rarely, cases of severe hypotension may occur, requiring intravenous use of plasma-substituting solutions and / or vasopressors.

Aortic and mitral valve stenosis or hypertrophic obstructive cardiomyopathy

Caution should be exercised when prescribing Atacand®, as with other vasodilators, to patients with hypertrophic obstructive cardiomyopathy or hemodynamically significant aortic or mitral valve stenosis.

Primary hyperaldosteronism

Patients with primary hyperaldosteronism are usually resistant to therapy with antihypertensive drugs that affect the renin-angiotensin-aldosterone system. Therefore, Atacand® is not recommended for such patients.

Hyperkalemia

Clinical experience with other drugs that affect the renin-angiotensin-aldosterone system shows that concomitant use of Atacand® with potassium-sparing diuretics, potassium preparations or salt substitutes containing potassium, or other drugs that can increase the potassium content in the blood (for example, heparin) may lead to the development of hyperkalemia in patients with arterial hypertension. Hyperkalaemia may occur in patients with chronic heart failure treated with Atacand®. When prescribing Atacand® to patients with chronic heart failure, regular monitoring of blood potassium levels is recommended, especially when co-administered with ACE inhibitors and potassium-sparing diuretics.

General information

Patients whose vascular tone and renal function are predominantly dependent on the activity of the renin-angiotensin-aldosterone system (for example, patients with severe chronic heart failure or kidney diseases, including renal artery stenosis) are particularly sensitive to drugs acting on the renin-angiotensin-aldosterone system.The use of such drugs is accompanied in these patients by severe hypotension, azotemia, oliguria and, less often, acute renal failure.

The possibility of developing these effects cannot be excluded even with the use of angiotensin II receptor antagonists. A sharp decrease in blood pressure in patients with coronary heart disease or cerebrovascular diseases of atherosclerotic origin with the use of any antihypertensive agents can lead to the development of myocardial infarction or stroke.

Impact on the ability to drive a car or work with machinery

The effect on the ability to drive a car or work with machinery has not been studied, but the pharmacodynamic properties of the drug indicate that there is no such effect.

When driving vehicles and engaging in potentially dangerous activities that require increased concentration of attention and speed of psychomotor reactions, it should be borne in mind that dizziness and increased fatigue may occur when using the drug.

Form of production

Pills.

Storage conditions

At temperatures below 30 °C

Shelf life

3 years

Active ingredient

Candesartan

Conditions of release from pharmacies

By prescription

Dosage form

Tablets

Purpose

For adults as directed by your doctor

Indications

Heart Failure, Hypertension