Atakand, tablets 8 mg 28 pcs.

Pharmacotherapeutic 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 interaction of angiotensin II with angiotensin type 1 receptors (AT1 receptors).

Candesartan is a selective angiotensin II type 1 receptor (AT1 receptor) antagonist. Candesartan does not inhibit angiotensin-converting enzyme (ACE), which converts angiotensin I to angiotensin II and degrades bradykinin; it does not affect ACE and does not lead to accumulation of bradykinin or substance P. When comparing candesartan with ACE inhibitors, cough development was less common in patients treated with candesartan cylexetil. Candesartan does not bind to other hormone receptors and does not block ion channels involved in the regulation of cardiovascular function. As a result of blocking of AT1 angiotensin II receptors, there is a dose-dependent increase of renin activity, angiotensin I and angiotensin II concentration and decrease of plasma aldosterone concentration.

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, with no change in heart rate (HR). There have been no cases of marked arterial hypotension after the first dose of the drug, and no cases of withdrawal syndrome (ricochet syndrome) after discontinuation of therapy.
The beginning of antihypertensive effect after the first dose of candesartan cilexetil usually develops within 2 hours. On continued fixed-dose therapy with the drug, maximum BP reduction is usually achieved within 4 weeks and persists for the duration of treatment.

Candesartan cilexetil, administered once daily, provides an effective and gradual decrease in BP over 24 hours with little variation in BP between doses of the drug. The use of candesartan cilexetil together with hydrochlorothiazide leads to increased antihypertensive effect. Concomitant use of candesartan cilexetil and hydrochlorothiazide (or amlodipine) is well tolerated.

The efficacy of the drug is independent of the age and sex of patients.

Candesartan cilexetil increases renal blood flow and does not alter or increase glomerular filtration rate, whereas renal vascular resistance and filtration fraction decrease. Administration of candesartan cilexetil at a dose of 8-16 mg for 12 weeks has no adverse effect on glucose concentration and lipid profile in patients with arterial hypertension and type 2 diabetes.

. 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 examined in a randomized clinical trial involving 4,937 elderly patients (age 70 to 89 years, 21% of patients aged 80 years or older) with mild to moderate arterial hypertension receiving therapy with candesartan cilexetil for an average of 3.7 years (the SCOPE Study of Cognitive Function and Prognosis in Elderly Patients). Patients received candesartan cilexetil or placebo, if necessary, in combination with other hypotensive agents. Both regimens demonstrated efficacious reduction of systolic and diastolic BP (from 166/90 to 145/80 mmHg in candesartan-treated patients and from 167/90 to 149/82 mmHg in the control group) with good tolerability.

Cognitive function and quality of life were maintained at good levels in both patient groups. There were no statistically significant differences in the incidence of cardiovascular complications (cardiovascular mortality, rate of non-fatal myocardial infarction and non-fatal stroke) between the two patient groups.

In the group of patients receiving candesartan, there were 26.7 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 to 1.06, p=0.19).

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

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

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

Cronic Heart Failure

The CHARM trial (Candesartan in Chronic Heart Failure – Assessment of Reduced Mortality and Morbidity) reported that use of candesartan cilexetil was associated with lower rates of death and need for hospitalization for chronic heart failure and improved left ventricular systolic function.

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

The other CHARM-Alternative study (n=2028) included patients with reduced left ventricular ejection fraction (LVEF) ≤40% who were not receiving an ACE inhibitor due to intolerance (mainly due to coughing – 72%); rates of cardiovascular mortality and first hospitalization for chronic heart failure were significantly lower in patients receiving candesartan compared with the placebo group (hazard ratio = 0.77, 95% confidence interval 0.67 – 0.89, p In the CHARM-Added study (n = 2548), patients with decreased PVLD ≤40% receiving ACE inhibitors combined criterion, which included mortality from cardiovascular disease 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 to 0.96, p = 0.011), corresponding to a 15% reduction in relative risk.

In this study, 23 patients had to be treated throughout the study period to prevent one death from cardiovascular complications or hospitalization for chronic heart failure. The value of the combined efficacy criterion, which included an assessment of the incidence of death regardless of cause or the 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 to 0.98, p = 0.021), which also indicated a positive effect with candesartan.

The use of candesartan cilexetil led to an improvement in the NYHA functional class of chronic heart failure (p=0.020).

In the CHARM-Preserve study (n=3023), patients with preserved systolic function (LVEF >40%), there were no statistically significant differences in the value of the combined efficacy criterion, which included the rate of death and the rate of first hospitalization for chronic heart failure, between the candesartan and placebo groups (hazard ratio = 0.89, 95% confidence interval 0.77 to 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 showed no effect of candesartan on mortality rates.

In a separate analysis of the 3 CHARM trials, there were no significant differences in mortality between the candesartan and placebo groups. However, mortality rates were estimated in the pooled population of the CHARM-Alternative and CHARM-Added trials and in all 3 trials (hazard ratio = 0.91, 95% confidence interval 0.83 to 1.00, p = 0.055). Reduced rates of death and hospitalizations for chronic heart failure on candesartan therapy were independent of age, sex, and concomitant therapy. Candesartan was also effective in patients taking beta-adreno-blockers in combination with ACE inhibitors, and the effectiveness of candesartan was independent of whether or not the patient was taking the optimal dose of ACE inhibitor.

In patients with chronic heart failure and reduced left ventricular systolic function (LVEF ≤40%), taking candesartan contributed to a decrease in total peripheral vascular resistance and pulmonary capillary pressure, increased renin activity and plasma angiotensin II concentration, and decreased aldosterone levels.

Pharmacokinetics

Intake and distribution

Candesartan cilexetil is a prodrug for oral administration. It rapidly converts to the active ingredient, candesartan, by ester hydrolysis upon absorption from the digestive tract, binds firmly to AT1 receptors and dissociates slowly, has no agonist properties.

The absolute bioavailability of candesartan after oral administration of candesartan cilexetil solution is approximately 40%.

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

The pharmacokinetic parameters of candesartan are independent of patient gender.

Eating has no significant effect on the area under the “concentration-time curve” (AUC), i.e. simultaneous eating does not significantly affect the bioavailability of the drug. Candesartan is actively bound to plasma proteins (>99%). The volume of distribution of candesartan is 0.1 l/kg.

Metabolism and excretion

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

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

In elderly patients (older than 65 years), the Cmax and AUC of candesartan are increased by 50% and 80%, respectively, compared to younger patients. However, the hypotensive effect and the incidence of side effects with Atacand^® do not depend on the age of patients.

In patients with mild to moderate renal impairment, the Cmax and AUC of candesartan were increased by 50% and 70%, respectively, while the half-life of the drug was unchanged 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, while the half-life of the drug was doubled. Patients on hemodialysis showed similar pharmacokinetic parameters for candesartan as patients with severe renal impairment.

In patients with mild to moderate hepatic impairment, there was a 23% increase in the AUC of candesartan.

Indications

Active ingredient

Composition

Active ingredient:

candesartan cilexetil 8 mg.

Auxiliary substances:

Calcium carmellose (carmellose calcium salt) 5.6 mg,

hyprolose (hydroxypropyl cellulose) 4.0 mg,

Iron oxide red dye E 172 0.065 mg;

Lactose monohydrate 89.4 mg,

Magnesium stearate 0.4 mg,

Corn starch 20.0 mg,

Macrogol 2.6 mg.

.

How to take, the dosage

Atacand® should be taken once daily regardless of meals.

Hypertension

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

Patients who require further reduction of BP are recommended to increase the dose to 16 mg once daily.

The maximum antihypertensive effect is achieved within 4 weeks of starting treatment.

If therapy with Atacand® does not lower BP to optimal levels, it is recommended to add a thiazide diuretic to therapy.

Patients in the elderly

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

Patients with impaired renal function

In patients with mild to moderate renal impairment (creatinine clearance 30-80 ml/min), including patients on hemodialysis, the starting 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.

The clinical experience with the drug in patients with severe renal dysfunction or terminal renal failure (creatinine clearance less than 15 ml/min) is limited.

Patients with hepatic impairment

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

Companion therapy

The use of Atacand® together with thiazide-type diuretics (e.g. hydrochlorothiazide) may increase the antihypertensive effect of Atacand®.

Chronic heart failure

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

Patients in special groups

Patients who are elderly and those with impaired renal or hepatic function do not need to change the starting dose of the drug.

Periatric and adolescent use

The safety and effectiveness of Atacand® in children and adolescents (

Interaction

In interaction with other medicinal products and other forms of drug interactions

In pharmacokinetic studies, co-administration of Atacand with hydrochlorothiazide, warfarin, digoxin, oral contraceptives (ethinylestradiol/levonorgestrel), glibenclamide, nifedipine and enalapril has been studied. No clinically significant drug interactions have been identified.

Candesartan is slightly metabolized in the liver (CYP2C9). The conducted studies on interaction showed no effect of the drug on CYP2C9 and CYP3A4, the effect on other isoenzymes of cytochrome P450 system has not been studied.

The co-administration of Atacand with other antihypertensive agents potentiates the hypotensive effect.

The experience with other drugs acting on the renin-angiotensin-aldosterone system shows that concomitant therapy with potassium-saving diuretics, potassium preparations, salt substitutes containing potassium, and other agents that may increase serum potassium levels (e.g., heparin) may lead to hyperkalemia.

When lithium preparations are coadministered with ACE inhibitors, reversible increase in serum lithium concentration and development of toxic reactions have been reported. Similar reactions can occur when using angiotensin II receptor antagonists, therefore, it is recommended to monitor serum lithium levels when combining use of these drugs.

The bioavailability of candesartan is not dependent on food intake.

Special Instructions

When prescribing Atacand to patients with renal artery stenosis (bilateral or single artery stenosis), it should be taken into account that drugs affecting the renin-angiotensin-aldosterone system (ACE inhibitors) may increase serum urea and creatinine concentrations. There is a possibility (unconfirmed) that similar effects may be observed with angiotensin II antagonists.

Patients treated with 12.5 mg hydrochlorothiazide tolerate well the subsequent use of Atacand at a dose of 8 mg. Patients also tolerate concomitant therapy with hydrochlorothiazide at a dose of up to 25 mg and Atacand at a dose of 8-16 mg for 8 weeks well. However, with a pronounced decrease of the RBC (when using diuretics in high doses), symptomatic hypotension may occur, which is also typical for other drugs affecting the renin-angiotensin-aldosterone system. Obviously, this condition needs to be corrected before using Atacand.

The concomitant use of Atacand with potassium-saving diuretics that do not eliminate potassium from the body can theoretically lead to increased serum potassium concentrations. Caution should be exercised if such a combination is necessary.

Pediatric use

The clinical efficacy and safety of Atacand in children has not been established.

Contraindications

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

Side effects

CNS disorders: often (more than 2%) – headache, dizziness.

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

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

The clinical trials showed good tolerability of the drug, the incidence of side effects was comparable to placebo, it did not depend on the dose of the drug, as well as on the age and sex of the patient. In general, the side effects were moderate and temporary. The number of drug discontinuation cases due to side effects was similar to that of the candesartan cilexetil and placebo groups.

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

Overdose

Symptoms

An analysis of the pharmacological properties of the drug suggests that the main manifestation of overdose may be clinically pronounced decreased BP and dizziness. Individual cases of overdose of the drug (up to 672 mg of candesartan cilexetil) have been described, ending in the recovery of patients without serious consequences.

Treatment

If clinically significant arterial hypotension develops, symptomatic treatment should be administered and the patient’s condition monitored. Place the patient in bed with the head end of the bed elevated. If necessary, increase the volume of circulating plasma, e.g., by intravenous administration of isotonic sodium chloride solution. Sympathomimetic drugs may be administered if necessary. Excretion of candesartan by hemodialysis is unlikely.

Pregnancy use

The drug is contraindicated in pregnancy.

In experimental studies it was found that the use of candesartan leads to impaired renal function in the fetus in the late developmental period, as well as in the neonatal period. The mechanism of this action is probably due to the effect of the drug on the renin-angiotensin-aldosterone system.

In humans, fetal renal perfusion, which depends on the renin-angiotensin-aldosterone system, begins in the second trimester of pregnancy. Thus, the risk to the fetus increases when the drug is taken in the second trimester.

It has not been established whether candesartan is excreted with breast milk. If it is necessary to use the drug during lactation, breastfeeding should be stopped due to the potential for negative side effects in the baby.

Candesartan has been found in the milk of lactating rats in experimental studies.

Similarities