ATTENTO 5MG + 40MG PILLS 10MG

Active substance

Amlodipine, Olmesartan Medoxomil

Amount in a package

28

Dosage Form

pills

Release form

Tablets, film coated, 5 mg + 20 mg, 5 mg + 40 mg, 10 mg + 40 mg.

Composition

Core:

Active ingredients: olmesartan medoxomil - 40.00 mg, Amlodipine besilate - 13.888 mg (in terms of amlodipine base - 10.00 mg).

Excipients: pregelatinized starch - 70,000 mg, microcrystalline silicized cellulose * - 65.312 mg, croscarmellose sodium - 10.0 mg, Magnesium stearate - 0.800 mg.

Film shell:

Opadry II red 85F25467, consisting of: polyvinyl alcohol - 3.2000 mg, titanium dioxide (E 171) - 1.4920 mg, macrogol - 1.6160 mg, talc - 1.1840 mg, dye iron oxide yellow (E 172) - 0.1080 mg, dye iron oxide red (E 172) - 0.4000 mg.

* consists of 98% microcrystalline cellulose and 2% colloidal silicon dioxide.

pharmachologic effect

Pharmacotherapeutic group:

combined antihypertensive agent (BMCC + angiotensin II receptor antagonist)

ATH:

Olmesartan medoxomil and amlodipine

Pharmacodynamics:

The drug Attento&№174; is a combined antihypertensive drug, which consists of angiotensin II receptor antagonist (ARA II) - olmesartan medoxomil and the slow Calcium channel blocker (BMCC) - amlodipine. The combination of the two active substances has a synergistic antihypertensive effect, as a result of which the arterial pressure (BP) decreases to a greater extent than when each one is taken separately.

In an 8-week double-blind, randomized, placebo-controlled study involving 1940 patients, it was shown that the antihypertensive effect of Attento&№174; develops, as a rule, during the first 2 weeks of therapy. As was shown in three studies, when using the drug 1 time per day, the antihypertensive effect of Attento&№174; is maintained for 24 hours, while the residual / peak ratio for systolic blood pressure (MAP) and diastolic blood pressure (DAD) ranged from 71% to 82%.. The antihypertensive effect was confirmed during outpatient monitoring of blood pressure and was not dependent on age and gender, as well as on the presence of diabetes in patients.In two open non-randomized extended studies, the sustained efficacy of Attento&№174; at a dosage of 5 mg + 40 mg was shown for 49-67% of patients within one year of use.

In a double-blind, randomized, placebo-controlled study, the addition of amlodipine at a dose of 5 mg with insufficient effectiveness of previous (within 8 weeks) monotherapy of olmesartan medoxomil at a dose of 20 mg resulted in 8.2 and a decrease in GARDENE and DAD by 16.2 and 10.6 mm Hg. st. (p = 0.0006), respectively. The proportion of patients in whom target blood pressure values ​​were achieved (<140/90 mmHg for patients without diabetes and <130/80 mmHg for patients with diabetes) was 44.5% in combination therapy olmesartan medoxomil at a dose of 20 mg and amlodipine at a dose of 5 mg compared to 28.5% with monotherapy with 20 mg of olmesartan medoxomil.

In another study, the addition of 20 mg (40 mg) of olmesartan medoxomil with insufficient effectiveness of the previous monotherapy with amlodipine at a dose of 5 mg (over 8 weeks) resulted in 8 weeks to decrease GARDEN and DBP by 15.3 and 9.3 mm Hg. Art., respectively (the addition of 40 mg of olmesartan medoxomil - 16.7 and 9.5 mm Hg. Art.). In patients who continued to receive monotherapy with amlodipine at a dose of 5 mg, GARDEN and DBP decreased by 9.9 and 5.7 mm Hg after 8 weeks. st. respectively.

The proportion of patients in whom target BP values ​​were achieved (<140/90 mmHg for patients without diabetes and <130/80 mmHg for patients with diabetes) was 29.9% in the monotherapy group amlodipine at a dose of 5 mg, 53.5% in the Attento&№174; group at a dosage of 5 mg + 20 mg and 50.5% in the Attento&№174; group at a dosage of 5 mg + 40 mg.

In the 8-week double-blind, randomized, placebo-controlled study involving 1940 patients (71% of the Europoid race and 29% of the other races), Attento&№174; (with any combination of doses of its components) resulted in a significantly more pronounced decrease in CAD and DBP compared to monotherapy. The degree of reduction in CAD / DAD depended on the doses of amlodipine / olmesartan medoxomil used: -24 / -14 mm Hg. st. (5 mg + 20 mg), -25 / -16 mm Hg. st. (5 mg + 40 mg) and -30 / -19 mm. Hg st. (10 mg + 40 mg).

At use of the drug Attento&№174; in a dosage of 5 mg + 40 mg, an additional decrease in SBP / DBP in the sitting position by 2.5 / 1.7 mm of mercury was noted. st. in comparison with use of the drug Attento&№174; in a dosage of 5 mg + 20 mg. Similarly, the use of Attento&№174; at a dosage of 10 mg + 40 mg resulted in an additional decrease in SBP / DBP in the sitting position by 4.7 / 3.5 mmHg.st. in comparison with the use of Attento&№174; at a dosage of 5 mg + 40 mg. The proportion of patients who managed to achieve target blood pressure values ​​(<140/90 mmHg for patients without diabetes and <130/80 mmHg for patients with diabetes) was 42.5%, 51, 0% and 49.1% for Attento&№174; drugs at a dosage of 5 mg + 20 mg, 5 mg + 40 mg and 10 mg + 40 mg, respectively.

Olmesartan medoxomil, which is a part of Attento&№174;, is a powerful specific APA II (AT1 type). Angiotensin II is the primary vasoactive component of the renin-angiotensin-aldosterone system and plays a significant role in the pathophysiology of arterial hypertension by acting on AT1 receptors. Olmesartan, preventing the binding of angiotensin II to AT1 receptors in tissues (including vascular smooth muscle and adrenal glands), blocks its vasoconstrictor action, as well as the effects associated with the effect of angiotensin II on the secretion of aldosterone. The specific antagonism of olmesartan in relation to AT1 receptors leads to an increase in the activity of renin, angiotensin I and II in the blood plasma, and also contributes to a decrease in the plasma concentration of aldosterone.

In case of arterial hypertension of olmesartan, medoxomil causes a dose-dependent, prolonged decrease in blood pressure. There is no data on the development of arterial hypotension after taking the first dose of olmesartan medoxomil, on tachyphylaxis during long-term treatment, or on the "withdrawal" syndrome (a sharp increase in blood pressure after discontinuation of olmesartan medoxomil).

Taking olmesartan medoxomil once a day provides an effective and mild decrease in blood pressure over 24 hours. Dividing the daily dose into two doses has an antihypertensive effect similar to that seen when taking the same daily dose at a time. The antihypertensive effect of olmesartan medoxomil occurs, as a rule, already after 2 weeks, and the maximum effect develops approximately 8 weeks after the start of therapy.

To date, data on the effect of olmesartan medoxomil on mortality and morbidity are not available.

In a randomized ROADMAP study involving 4447 patients with type 2 diabetes mellitus, normoalbuminuria and at least one additional cardiovascular risk factor, the ability of olmesartan to increase the time until microalbuminuria appeared.During the study period (median follow-up was 3.2 g), patients took olmesartan or placebo in addition to other antihypertensive drugs (with the exception of angiotensin-converting enzyme inhibitors (APF) or other ARA II). The study showed a 23% reduction in risk with respect to the primary endpoint (time before microalbuminuria appeared) in favor of olmesartan (ODF 0.770; 95.1% CI: 0.630-0.941; p = 0.0104). Cardiovascular complications (secondary endpoints) were reported in 96 patients (4.3%) in the olmesartan group and in 94 patients (4.2%) in the placebo group.

In a randomized ORIENT study conducted in Japan and China, the effect of olmesartan on renal and cardiovascular outcomes was studied in 577 patients with type 2 diabetes and severe nephropathy. During the study (median follow-up was 3.1 years), patients received olmesartan or placebo in addition to other antihypertensive drugs, including ACE inhibitors.

The primary combined endpoint (time to the event that will occur first: a doubling of plasma creatinine concentration, development of end-stage chronic kidney disease, death from all causes) was recorded in 116 patients in the olmesartan group (41.1%) and in 129 patients in the placebo group (45.4%) (FIR 0.97; 95% CI: 0.75-1.24; p = 0.791).

Amlodipine, which is a part of Attento&№174;, is BMCA, blocking the incoming transmembrane current of calcium ions into cardiomyocytes and vascular smooth muscle cells through potential-dependent L-type channels. Experimental data suggest that amlodipine interacts with both the dihydropyridine and non-dihydropyridine binding sites. Amlodipine has a relative vasoselectivity and has a greater effect on vascular smooth muscle cells than on cardiomyocytes. The mechanism of antihypertensive action of amlodipine is associated with a direct relaxing effect on vascular smooth muscle, causing a decrease in peripheral vascular resistance and a decrease in blood pressure.

Amlodipine causes a dose-dependent, prolonged decrease in blood pressure in patients with arterial hypertension. There is no data on the development of arterial hypotension after taking the first dose of amlodipine, on tachyphylaxis during long-term treatment or on the "withdrawal" syndrome.

When used in therapeutic doses in patients with arterial hypertension, amlodipine causes dilation of blood vessels, leading to a decrease in blood pressure (in the patient&№39;s position "lying", "sitting" and "standing"). With prolonged use, a decrease in blood pressure is not accompanied by a significant change in heart rate (HR) and catecholamine concentration in plasma. In hypertension in patients with normal renal function, the use of amlodipine in therapeutic doses leads to a decrease in renal vascular resistance, an increase in glomerular filtration rate and an increase in effective renal blood flow without changing the filtration fraction and the level of proteinuria.

In hemodynamic studies in patients with heart failure , as well as in clinical studies involving patients with heart failure (NYHA Class II-IV functional class) when performing a stress test, amlodipine did not worsen the patient&№39;s condition, which was assessed by exercise tolerance, ejection fraction left ventricular, as well as on clinical signs and symptoms.

In a placebo-controlled study (PRAISE) involving patients with heart failure (III-IV functional class according to the NYHA classification) who received Digoxin , diuretics and ACE inhibitors, it was shown that amlodipine does not increase the risk of complications and / or mortality (total and from cardiovascular causes) in patients with heart failure.

In a long-term placebo-controlled study (PRAISE-II) involving patients with heart failure (NYHA Class III-IV functional class) without clinical symptoms or objective evidence of coronary heart disease, taking ACE inhibitors, digoxin and diuretics, that the use of amlodipine did not affect the overall mortality and mortality from cardiovascular causes.

In a double-blind, randomized study (ALLHAT), we compared the efficacy of amlodipine at a dose of 2.5–10 mg / day or lisinopril at a dose of 10–40 mg / day as the first choice therapy and the use of thiazide diuretic chlortalidone at a dose of 12.5 - 25 mg / day for mild to moderate hypertension.A total of 33,357 patients with hypertension aged 55 years and older were included in the study and were followed up for an average of 4.9 years. The combined primary endpoint included death in patients with ischemic heart disease or non-fatal myocardial infarction. There were no statistically significant differences in the effect on the primary endpoint of the study in the amlodipine and chlorthalidone groups. There was also no significant difference in all-cause mortality between these groups.

Pharmacokinetics:

After oral administration of Attento&№174;, the maximum concentration (Cmax) of olmesartan and amlodipine in the blood plasma is reached in 1.5–2 h and 6–8 h, respectively. The rate and extent of absorption of olmesartan medoxomil and amlodipine in the composition of the drug Attento&№174; correspond to the speed and extent of absorption of these components in the form of monodrugs. A simultaneous meal does not affect the bioavailability of olmesartan medoxomil and amlodipine.

Olmesartana Medoxomil

Absorption and distribution: olmesartan medoxomil is a prodrug. It quickly turns into a pharmacologically active metabolite of olmesartan under the action of enzymes (esterases) in the intestinal mucosa and in the portal blood during absorption from the gastrointestinal tract. Olmesartan medoxomil in unchanged form or with an intact fragment of medoxomil is not detected in the blood plasma and / or feces. The bioavailability of olmesartan is on average 25.6%. Simultaneous ingestion of food does not have a significant effect on the bioavailability of olmesartan, therefore, olmesartan medoxomil can be taken regardless of the meal.

Cmax of olmesartan in plasma is, on average, achieved 2 hours after taking olmesartan medoxomil by mouth and increases approximately linearly with an increase in a single dose to 80 mg.

Olmesartan is characterized by a high degree of binding to plasma proteins (99.7%), however, the potential for a clinically significant shift in protein binding when olmesartan interacts with other highly binding and simultaneously used drugs is low (a confirmation of this is the absence of clinically significant interaction between olmesartan and warfarin). Communication olmesartan with blood cells is negligible.The average volume of distribution after intravenous administration is low (16–29 l).

Metabolism and excretion: total plasma clearance is usually 1.3 l / h (coefficient of variation - 19%) and is relatively low compared with hepatic blood flow (approximately 90 l / h).

Removal of olmesartan is carried out in two ways. After a single intake of olmesartan medoxomil labeled with an 14C isotope, 10–16% of the radioactive substance was excreted by the kidneys (most within 24 hours after taking olmesartan medoxomil), and the remaining radioactive substance was secreted through the intestine. Taking into account the systemic bioavailability of 25.6%, it can be calculated that approximately 40% of the absorbed olmesartan is excreted through the kidneys, and about 60% through the hepatobiliary system. The released radioactive substance was represented by olmesartan. No other metabolites were detected. The enterohepatic recirculation of olmesartan is minimal. Since most of olmesartan is excreted through the hepatobiliary system, its use in patients with obstruction of the biliary tract is contraindicated (see section "Contraindications"). The elimination half-life of olmesartan (T1 / 2) is 10-15 h after repeated ingestion. The equilibrium state is achieved after taking the first few doses of the drug, after 14 days of repeated use, further cumulation is not observed. Renal clearance is approximately 0.5-0.7 l / h and does not depend on the dose of the drug.

There were no clinically significant differences in pharmacokinetic parameters of olmesartan depending on gender.

Amlodipine

Absorption and distribution: after oral administration in therapeutic doses, amlodipine is well absorbed, the time to reach the maximum concentration (TCmax) is 6-12 hours after administration. Absolute bioavailability is about 64-80%. The volume of distribution is about 21 l / kg. In vitro plasma protein binding for circulating amlodipine is approximately 97.5%. A simultaneous meal does not have a significant effect on the absorption of amlodipine.

Metabolism and excretion: after a single dose of T1 / 2 from plasma in the terminal phase is about 35-50 hours. Amlodipine is largely metabolized in the liver to form inactive metabolites, 10% of the original substance and 60% of metabolites excreted by the kidneys.

Pharmacokinetics in patients aged 65 and over

In patients of elderly (65-75 years) and senile age (75 years and older) with arterial hypertension, the area under the concentration-time curve (AUC) (in equilibrium) for olmesartan is 35% more and approximately 44% more, compared with the AUC of olmesartan in younger patients, which may be partly due to the age-related decline in renal function.

The time to achieve Cmax amlodipine in plasma does not differ in elderly patients and in young patients. In elderly patients, there is a tendency to a decrease in the clearance of amlodipine, which leads to an increase in AUC and a prolongation of T1 / 2.

Pharmacokinetics in Patients with Renal Insufficiency

Compared with healthy volunteers, patients with mild, moderate, and severe severity of renal insufficiency have increased the AUC of olmesartan by approximately 62%, 82%, and 179%, respectively.

Renal failure has no significant effect on the pharmacokinetics of amlodipine. Changes in the concentration of amlodipine in the blood plasma do not correlate with the degree of renal dysfunction. Amlodipine is not excreted during dialysis.

Pharmacokinetics in Patients with Hepatic Insufficiency

After a single oral administration, the AUC values ​​of olmesartan were 6% and 65% higher in patients with mild to moderate hepatic insufficiency, respectively, compared with healthy volunteers. The unbound fraction of olmesartan 2 hours after ingestion of a single dose of the drug in healthy volunteers, in patients with mild and moderate hepatic insufficiency was 0.26