Attento, 10 mg+40 mg 28 pcs

Pharmacotherapeutic group:

Hypertensive combined (BMCC+angiotensin II receptor antagonist)

ATC:

Olmesartan medoxomil and amlodipine

Pharmacodynamics:

The drug Attento® is a combined hypotensive drug that contains the angiotensin II receptor antagonist (ARA II), olmesartan medoxomil, and the “slow” calcium channel blocker (SCB), amlodipine. The combination of the two active substances has a synergistic antihypertensive effect, resulting in a greater reduction of blood pressure (BP) than when taking each of them separately.

In an 8-week, double-blind, randomized, placebo-controlled study involving 1,940 patients, the antihypertensive effects of Attento® were shown to develop generally within the first 2 weeks of therapy. As shown in three studies, when administered once daily, the antihypertensive effect of Attento® was maintained for 24 hours, with a residual/peak ratio for systolic BP (BP) and diastolic BP (BP) ranging from 71% to 82%. The antihypertensive effect was confirmed by ambulatory BP monitoring and was independent of age and sex, as well as of the presence of diabetes mellitus in patients. In two open-label, non-randomized, expanded studies, sustained efficacy of Attento® at 5 mg + 40 mg was demonstrated in 49-67% of patients at one year of use.

In a double-blind, randomized, placebo-controlled trial, the addition of amlodipine at a dose of 5 mg when the prior (for 8 weeks) monotherapy of olmesartan medoxomil at a dose of 20 mg was not effective led to a decrease in BP and BP by 16.2 and 10.6 mm Hg after 8 weeks (p = 0.0006), respectively. The proportion of patients who achieved target BP values (< 140/90 mm Hg for patients without diabetes and < 130/80 mm Hg for patients with diabetes) was 44.5% with combined therapy with olmesartan medoxomil at 20 mg and amlodipine at 5 mg, compared with 28.5% with monotherapy with 20 mg olmesartan medoxomil.

In another study, the addition of 20 mg (40 mg) olmesartan medoxomil when the previous 5-mg amlodipine monotherapy was not effective (for 8 weeks) resulted in a decrease in BP and BP by 15.3 and 9.3 mm Hg, respectively, after 8 weeks (adding 40 mg olmesartan medoxomil by 16.7 and 9.5 mm Hg). In patients who continued to receive amlodipine monotherapy at a dose of 5 mg, BP and BP decreased by 9.9 and 5.7 mm Hg, respectively, after 8 weeks.

The proportion of patients in whom target BP values were achieved (< 140/90 mm Hg for patients without diabetes and < 130/80 mm Hg. for patients with diabetes mellitus), was 29.9% in the amlodipine 5 mg monotherapy group, 53.5% in the Attento® 5 mg + 20 mg group, and 50.5% in the Attento® 5 mg + 40 mg group.

In an 8-week, double-blind, randomized, placebo-controlled study involving 1940 patients (71% Caucasian race and 29% other races), use of Attento® (with any combination of doses of its components) resulted in a significantly greater reduction in BP and BPD compared to monotherapy. The degree of BP/DPH reduction depended on the doses of amlodipine/olmesartan medoxomil used: -24/-14 mm Hg (5 mg + 20 mg), -25/-16 mm Hg (5 mg + 40 mg) and -30/-19 mm Hg (10 mg + 40 mg).

Atento® 5 mg + 40 mg resulted in an additional 2.5/1.7 mm Hg decrease in sitting BP/DP compared to Atento® 5 mg + 20 mg. Similarly, the use of Attento® 10 mg + 40 mg resulted in an additional 4.7/3.5 mm Hg decrease in BP/DD at the sitting position compared to the use of Attento® 5 mg + 40 mg. The percentages of patients who were able to achieve target BP values (< 140/90 mm Hg for patients without diabetes and < 130/80 mm Hg for patients with diabetes) were 42.5%, 51.0% and 49.1% for Attento® in the 5 mg + 20 mg, 5 mg + 40 mg and 10 mg + 40 mg doses, respectively.

Olmesartan medoxomil in Attento® is a potent, specific ARA II (type AT1). 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, by preventing angiotensin II binding to AT1 receptors in tissues (including vascular smooth muscle and adrenal glands), blocks its vasoconstrictor effects as well as effects related to the effect of angiotensin II on aldosterone secretion. The specific antagonism of olmesartan against AT1-receptors leads to an increase in plasma renin, angiotensin I and II activity and also contributes to a decrease in plasma aldosterone concentration.

In arterial hypertension, olmesartan medoxomil causes a dose-dependent prolonged reduction of blood pressure. There are no data on the development of arterial hypotension after the first dose of olmesartan medoxomil, on tachyphylaxis during long-term treatment, or on “withdrawal” syndrome (a sharp increase in BP after withdrawal of olmesartan medoxomil).

The administration of olmesartan medoxomil once daily provides effective and gentle BP reduction within 24 hours. Dividing the daily dose into two doses has an antihypertensive effect similar to that produced by taking the same daily dose alone. The antihypertensive effect of olmesartan medoxomil usually occurs after 2 weeks, and the maximum effect develops approximately 8 weeks after initiation of therapy.

There are currently no data on the effect of olmesartan medoxomil on mortality and morbidity.

The randomized ROADMAP trial involving 4,447 patients with type 2 diabetes, normoalbuminuria, and at least one additional cardiovascular risk factor evaluated the ability of olmesartan to increase time to microalbuminuria. During the study period (median follow-up was 3.2 d), patients were taking olmesartan or placebo in addition to other hypotensive agents (excluding angiotensin-converting enzyme (ACE) inhibitors or other ARA II). The study showed a 23% reduction in risk for the primary endpoint (time to microalbuminuria) in favor of olmesartan (ORR 0.770; 95.1% CI: 0.630-0.941; p=0.0104). Cardiovascular complications (secondary end points) were reported in 96 patients (4.3%) in the olmesartan group and 94 patients (4.2%) in the placebo group.

The ORIENT randomized trial, conducted in Japan and China, studied the effect of olmesartan on renal and cardiovascular outcomes 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 hypotensive drugs, including ACE inhibitors.

The primary combined endpoint (time to the event that occurs first: doubling of plasma creatinine concentration, development of terminal chronic kidney disease, all-cause death) was reported in 116 patients in the olmesartan group (41.1%) and in 129 patients in the placebo group (45.4%) (ORR 0.97; 95% CI: 0.75-1.24; p = 0.791).

Amlodipine, a component of Attento®, is a BMCC that blocks the incoming transmembrane flow of calcium ions into cardiomyocytes and vascular smooth muscle cells through L-type potential-dependent channels. Experimental data indicate that amlodipine interacts with both dihydropyridine and non-dihydropyridine binding sites. Amlodipine has 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 relaxant effect on vascular smooth muscle, causing reduction of peripheral vascular resistance and BP.

Amlodipine causes dose-dependent prolonged BP reduction in patients with arterial hypertension. There are no data on the development of arterial hypotension after the first dose of amlodipine, on tachyphylaxis during long-term treatment or on “withdrawal” syndrome.

When used in therapeutic doses in patients with arterial hypertension, amlodipine causes vasodilation leading to a decrease in BP (in the position of the patient “lying”, “sitting” and “standing”). With long-term use, the BP reduction is not accompanied by significant changes in heart rate (HR) and plasma catecholamine concentrations. In hypertensive patients with normal renal function the use of amlodipine in therapeutic doses leads to decrease of renal vascular resistance, increase of glomerular filtration rate and strengthening of effective renal blood flow without changing filtration fraction and proteinuria level.

In studies of hemodynamics in patients with heart failure and in clinical studies with patients with heart failure (functional class II-IV according to NYHA classification) during stress test amlodipine did not worsen condition of patients, which was assessed by tolerance of physical activity, left ventricular ejection fraction, and by clinical signs and symptoms.

In a placebo-controlled study (PRAISE) involving patients with heart failure (NYHA functional class III-IV) receiving digoxin, diuretics, and ACE inhibitors, amlodipine was shown not to increase the risk of complications and/or mortality (total and cardiovascular causes) in patients with heart failure.

In a long-term placebo-controlled study (PRAISE-II) involving patients with heart failure (NYHA functional class III-IV) without clinical symptoms or objective evidence of coronary heart disease taking ACE inhibitors, digoxin and diuretics, amlodipine was shown to have no effect on overall mortality and mortality from cardiovascular causes.

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

Pharmacokinetics:

After oral administration of Attento® the maximum concentration (Cmax) of olmesartan and amlodipine in blood plasma is reached after 1.5-2 h and 6-8 h respectively. The speed and degree of absorption of olmesartan medoxomil and amlodipine in the formulation of Attento® correspond to the speed and degree of absorption of these components in the form of monotherapy. The bioavailability of olmesartan medoxomil and amlodipine is not affected by concomitant ingestion.

Olmesartan medoxomil

Absorption and distribution: Olmesartan medoxomil is a prodrug. It is rapidly converted to the pharmacologically active metabolite olmesartan by enzymes (esterases) in the intestinal mucosa and in the portal blood during absorption from the gastrointestinal tract. Olmesartan medoxomil in unchanged form or with intact medoxomil fragment is not detected in plasma and/or feces. The bioavailability of olmesartan averages 25.6%. Concurrent intake of food has no significant effect on the bioavailability of olmesartan, so olmesartan medoxomil can be taken regardless of meals.

The plasma cmax of olmesartan is reached on average 2 h after oral administration of olmesartan medoxomil and increases approximately linearly with increasing single dose to 80 mg.

Olmesartan is characterized by high plasma protein binding (99.7%), but the potential for clinically significant shifts in protein binding magnitude when interacting olmesartan with other highly bindable and concomitantly used drugs is low (the absence of clinically significant interaction between olmesartan and warfarin is evidence of this). Binding of olmesartan to blood cells is insignificant. Mean volume of distribution after intravenous administration is low (16-29 liters).

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

Olmesartan is excreted in two ways. After a single oral dose of 14C-labeled olmesartan medoxomil, 10-16% of the radioactive substance was excreted by the kidneys (most within 24 h of olmesartan medoxomil administration), and the remaining radioactive substance was excreted 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 radioactive substance excreted was represented by olmesartan. No other metabolites were detected. Intestinal and hepatic recycling of olmesartan is minimal. Since most of the olmesartan is excreted through the hepatobiliary system, its use in patients with biliary tract obstruction is contraindicated (see section “Contraindications”). The half-life of olmesartan (T1/2) is 10-15 h after repeated oral administration. The equilibrium state is reached after the first few doses of the drug, no further cumulation is observed after 14 days of repeated use. Renal clearance is approximately 0.5-0.7 l/h and is independent of the drug dose.

There are no clinically significant differences in the pharmacokinetic parameters of olmesartan according to gender.

Amlodipine

Absorption and distribution: After oral administration at therapeutic doses amlodipine is well absorbed; time to reach maximum concentration (TSmax) 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%. Simultaneous intake of food has no significant effect on absorption of amlodipine.

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

Pharmacokinetics in patients aged 65 years and older

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

The time to reach the Cmax of amlodipine in plasma does not differ between elderly and younger patients. In elderly patients there is a tendency for decreased clearance of amlodipine, which leads to increased AUC and prolonged T1/2.

Pharmacokinetics in patients with renal impairment

In comparison with healthy volunteers, patients with mild, moderate and severe renal impairment have increased AUC of olmesartan by approximately 62%, 82% and 179%, respectively.

Renal insufficiency has no significant effect on the pharmacokinetics of amlodipine. Changes in amlodipine plasma concentrations do not correlate with the degree of renal impairment. Amlodipine is not excreted with dialysis.

Pharmacokinetics in patients with hepatic impairment

After a single oral administration, AUC values of olmesartan were 6% and 65% higher in patients with mild and moderate hepatic impairment, respectively, compared to healthy volunteers. The unbound fraction of olmesartan 2 hours after oral administration of a single dose of the drug in healthy volunteers, in patients with mild to moderate hepatic impairment was 0.26%, 0.34% and 0.41%, respectively. When administered repeatedly orally, the AUC of olmesartan in patients with moderate hepatic impairment was 65% higher than in healthy control volunteers. Mean Cmax values of olmesartan in patients with hepatic impairment and healthy volunteers were similar. The pharmacokinetics of olmesartan medoxomil in patients with severe hepatic impairment have not been studied.

The clinical experience with amlodipine in patients with hepatic impairment is limited. Amlodipine clearance is decreased and T1/2 is prolonged in patients in this group, resulting in an increase in AUC of approximately 40-60%.

Indications

Essential hypertension (if monotherapy with olmesartan medoxomil or amlodipine is ineffective).

Pharmacological effect

Pharmacotherapeutic group:

combined antihypertensive drug (BMCC + angiotensin II receptor antagonist)

ATX:

Olmesartan medoxomil and amlodipine

Pharmacodynamics:

The drug Attento® is a combined antihypertensive drug, which includes the angiotensin II receptor antagonist (ARA II) – olmesartan medoxomil and the blocker of “slow” calcium channels (SCBC) – amlodipine. The combination of two active ingredients has a synergistic antihypertensive effect, as a result of which blood pressure (BP) decreases to a greater extent than when taking each of them separately.

In an 8-week, double-blind, randomized, placebo-controlled study involving 1940 patients, it was shown that the antihypertensive effect of Attento® usually develops during the first 2 weeks of therapy. As shown in three studies, when administered once daily, the antihypertensive effect of Attento® was maintained for 24 hours, with residual/peak ratios for systolic blood pressure (SBP) and diastolic blood pressure (DBP) ranging from 71% to 82%. The antihypertensive effect was confirmed by ambulatory blood pressure monitoring and did not depend on age and gender, as well as on the presence of diabetes mellitus in patients. In two open-label, non-randomized extension studies, sustained efficacy of Attento 5 mg + 40 mg was demonstrated in 49-67% of patients over one year of use.

In a double-blind, randomized, placebo-controlled study, the addition of amlodipine at a dose of 5 mg when previous (for 8 weeks) monotherapy with olmesartan medoxomil at a dose of 20 mg was insufficiently effective led after 8 weeks to a decrease in SBP and DBP by 16.2 and 10.6 mmHg. Art. (p = 0.0006), respectively. The proportion of patients who achieved target blood pressure values ​​(<140/90 mmHg for patients without diabetes mellitus and <130/80 mmHg for patients with diabetes mellitus) was 44.5% with combination therapy of olmesartan medoxomil at a dose of 20 mg and amlodipine at a dose of 5 mg compared with 28.5% with monotherapy 20 mg olmesartan medoxomil.

In another study, the addition of 20 mg (40 mg) of olmesartan medoxomil when previous monotherapy with amlodipine at a dose of 5 mg (for 8 weeks) was insufficiently effective resulted in a decrease in SBP and DBP by 15.3 and 9.3 mm Hg after 8 weeks. Art., respectively (adding 40 mg of olmesartan medoxomil – by 16.7 and 9.5 mm Hg). In patients who continued to receive monotherapy with amlodipine at a dose of 5 mg, SBP and DBP after 8 weeks decreased by 9.9 and 5.7 mmHg. Art. respectively.

The proportion of patients who achieved target blood pressure values ​​(<140/90 mm Hg for patients without diabetes mellitus and <130/80 mm Hg for patients with diabetes mellitus) was 29.9% in the amlodipine monotherapy group at a dose of 5 mg, 53.5% in the Attento® drug group at a dosage of 5 mg + 20 mg and 50.5% - in the Attento® drug group at a dosage of 5 mg + 40 mg.

In an 8-week, double-blind, randomized, placebo-controlled study involving 1940 patients (71% Caucasian and 29% other races), Attento® (at any dose combination) resulted in significantly greater reductions in SBP and DBP compared with monotherapy. The degree of reduction in SBP/DBP depended on the doses of amlodipine/olmesartan medoxomil used: -24/-14 mm Hg. Art. (5 mg + 20 mg), -25/-16 mmHg. Art. (5 mg + 40 mg) and -30/-19 mm. rt. Art. (10 mg + 40 mg).

When using the drug Attento® at a dosage of 5 mg + 40 mg, an additional decrease in SBP/DBP in the sitting position by 2.5/1.7 mmHg was noted. Art. compared with the use of Attento® at a dosage of 5 mg + 20 mg. Similarly, the use of Attento® at a dosage of 10 mg + 40 mg led to an additional decrease in SBP/DBP in the sitting position by 4.7/3.5 mmHg. Art. compared with the use of Attento® at a dosage of 5 mg + 40 mg. The proportion of patients who managed to achieve target blood pressure values ​​(< 140/90 mm Hg for patients without diabetes mellitus and < 130/80 mm Hg for patients with diabetes mellitus) was 42.5%, 51.0% and 49.1% for Attento® drugs at a dosage of 5 mg + 20 mg, 5 mg + 40 mg and 10 mg + 40 mg respectively.

Olmesartan medoxomil, which is part of the drug Attento®, is a powerful specific ARA II (type AT1). Angiotensin II is the primary vasoactive component of the renin-angiotensin-aldosterone system and plays a significant role in the pathophysiology of arterial hypertension through its action on AT1 receptors. Olmesartan, by preventing the binding of angiotensin II to AT1 receptors in tissues (including vascular smooth muscle and adrenal glands), blocks its vasoconstrictor effect, as well as the effects associated with the influence of angiotensin II on aldosterone secretion. The specific antagonism of olmesartan towards AT1 receptors leads to an increase in the activity of renin, angiotensin I and II in the blood plasma, and also helps to reduce the plasma concentration of aldosterone.

In arterial hypertension, 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 reduction in blood pressure for 24 hours. Dividing the daily dose into two doses has an antihypertensive effect similar to that occurring when taking the same daily dose at the same time. The antihypertensive effect of olmesartan medoxomil usually occurs within 2 weeks, and the maximum effect develops approximately 8 weeks after the start of therapy.

At present, there are no data on the effect of olmesartan medoxomil on mortality and morbidity.

The randomized ROADMAP trial, involving 4447 patients with type 2 diabetes mellitus, normoalbuminuria, and at least one additional cardiovascular risk factor, assessed the ability of olmesartan to prolong the time to onset of microalbuminuria. During the study period (median follow-up was 3.2 g), patients took olmesartan or placebo in addition to other antihypertensive agents (excluding angiotensin-converting enzyme (ACE) inhibitors or other ACE inhibitors). The study showed a 23% risk reduction for the primary endpoint (time to onset of microalbuminuria) in favor of olmesartan (ORR 0.770; 95.1% CI: 0.630-0.941; p=0.0104). Cardiovascular events (secondary endpoints) were reported in 96 patients (4.3%) in the olmesartan group and in 94 patients (4.2%) in the placebo group.

The randomized ORIENT trial, conducted in Japan and China, examined the effects of olmesartan on renal and cardiovascular outcomes in 577 patients with type 2 diabetes mellitus and advanced nephropathy. During the study (median follow-up of 3.1 years), patients received olmesartan or placebo in addition to other antihypertensive drugs, including ACE inhibitors.

The primary composite endpoint (time to the first event to occur: 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%) (RR 0.97; 95% CI: 0.75-1.24; p = 0.791).

Amlodipine, which is part of the Attento® drug, is a BMCC that blocks the incoming transmembrane current of calcium ions into cardiomyocytes and vascular smooth muscle cells through voltage-gated L-type channels. Experimental data indicate that amlodipine interacts with both dihydropyridine and non-dihydropyridine binding sites. Amlodipine has relative vasoselectivity and has a greater effect on vascular smooth muscle cells than on cardiomyocytes. The mechanism of the antihypertensive effect 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, long-term 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 withdrawal syndrome.

When used in therapeutic doses in patients with arterial hypertension, amlodipine causes vasodilation, leading to a decrease in blood pressure (in the patient’s position “lying”, “sitting” and “standing”). With long-term use, the decrease in blood pressure is not accompanied by a significant change in heart rate (HR) and the concentration of catecholamines in the blood plasma. For arterial 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 functional class II-IV), amlodipine did not worsen the patient’s condition during a stress test, as assessed by exercise tolerance, left ventricular ejection fraction, and clinical signs and symptoms.

In a placebo-controlled study (PRAISE) in patients with heart failure (NYHA functional class III-IV) treated with digoxin, diuretics and ACE inhibitors, it was shown that amlodipine does not increase the risk of complications and/or mortality (overall and from cardiovascular causes) in patients with heart failure.

In a long-term placebo-controlled study (PRAISE-II) involving patients with heart failure (NYHA functional class III-IV) without clinical symptoms or objective data indicating coronary heart disease, taking ACE inhibitors, digoxin and diuretics, it was shown that the use of amlodipine had no effect on overall mortality and mortality from cardiovascular causes.

A double-blind, randomized trial (ALLHAT) compared the effectiveness of amlodipine 2.5-10 mg/day or lisinopril 10-40 mg/day as first-line therapy with the thiazide diuretic chlorthalidone 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 for an average of 4.9 years. The composite primary endpoint included death in patients with coronary artery disease or nonfatal myocardial infarction. There were no statistically significant differences in the effect on the primary endpoint of the study between the amlodipine and chlorthalidone groups. There was also no significant difference in all-cause mortality between these groups.

Pharmacokinetics:

After oral administration of Attento®, the maximum concentration (Cmax) of olmesartan and amlodipine in the blood plasma is achieved after 1.5-2 hours and 6-8 hours, respectively. The rate and extent of absorption of olmesartan medoxomil and amlodipine in Attento® correspond to the speed and extent of absorption of these components in the form of single drugs. Concomitant food intake does not affect the bioavailability of olmesartan medoxomil and amlodipine.

Olmesartan medoxomil

Absorption and distribution: Olmesartan medoxomil is a prodrug. It is rapidly converted to the pharmacologically active metabolite olmesartan by enzymes (esterases) in the intestinal mucosa and in portal blood during absorption from the gastrointestinal tract. Olmesartan medoxomil in unchanged form or with an intact medoxomil fragment is not detected in blood plasma and/or feces. The bioavailability of olmesartan averages 25.6%. Concomitant food intake does not have a significant effect on the bioavailability of olmesartan, therefore olmesartan medoxomil can be taken regardless of meals.

Cmax of olmesartan in blood plasma is achieved on average 2 hours after oral administration of olmesartan medoxomil and increases approximately linearly with increasing 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 the amount of protein binding when olmesartan interacts with other highly binding and concomitantly used drugs is low (this is confirmed by the lack of clinically significant interaction between olmesartan and warfarin). The association of olmesartan with blood cells is insignificant. The mean volume of distribution after intravenous administration is low (16-29 L).

Metabolism and elimination: Total plasma clearance is usually 1.3 L/h (coefficient of variation – 19%) and is relatively low compared to hepatic blood flow (approximately 90 L/h).

Olmesartan is eliminated in two ways. After a single oral dose of 14C-labeled olmesartan medoxomil, 10-16% of the radioactive substance was excreted by the kidneys (most of it within 24 hours after taking olmesartan medoxomil), and the remaining radioactive substance was excreted through the intestines. Taking into account the systemic bioavailability of 25.6%, it can be calculated that approximately 40% of absorbed olmesartan is excreted through the kidneys, and about 60% through the hepatobiliary system. The released radioactive substance was olmesartan. No other metabolites were detected. Enterohepatic recirculation of olmesartan is minimal. Since most of olmesartan is excreted through the hepatobiliary system, its use in patients with biliary obstruction is contraindicated (see section “Contraindications”). The half-life of olmesartan (T1/2) is 10-15 hours after repeated oral administration. An equilibrium state is achieved after taking the first few doses of the drug; after 14 days of repeated use, no further accumulation is observed. Renal clearance is approximately 0.5-0.7 l/h and is independent of the dose of the drug.

There were no clinically significant differences in the 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 maximum concentration (TCmax) is 6-12 hours after administration. Absolute bioavailability is about 64-80%. The volume of distribution is approximately 21 l/kg. Plasma protein binding in vitro for amlodipine circulating in the blood is approximately 97.5%. Concomitant food intake does not have a significant effect on the absorption of amlodipine.

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

Pharmacokinetics in patients aged 65 years and older

In elderly (65-75 years) and geriatric patients (75 years and older) with hypertension, the area under the concentration-time curve (AUC) (at steady state) for olmesartan is 35% and approximately 44% greater, respectively, compared with the olmesartan AUC in younger patients, which may be due in part to age-related declines in renal function.

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

Pharmacokinetics in patients with renal failure

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

Renal failure does not significantly affect the pharmacokinetics of amlodipine. Changes in plasma concentrations of amlodipine do not correlate with the degree of renal dysfunction. Amlodipine is not excreted from the body during dialysis.

Pharmacokinetics in patients with liver failure

After a single oral dose, the AUC values ​​of olmesartan were 6% and 65% higher in patients with mild and moderate hepatic impairment, respectively, compared to healthy volunteers. The unbound fraction of olmesartan 2 hours after oral administration of a single dose of the drug in healthy volunteers and in patients with mild and moderate hepatic impairment was 0.26%, 0.34% and 0.41%, respectively. After repeated oral administration, the AUC of olmesartan in patients with moderate hepatic impairment was 65% higher than in healthy control volunteers. The mean Cmax values ​​of olmesartan in patients with liver failure and healthy volunteers were similar. The pharmacokinetics of olmesartan medoxomil in patients with severe hepatic impairment have not been studied.

Clinical experience with amlodipine in patients with liver failure is limited. In patients in this group, there is a decrease in amlodipine clearance and prolongation of T1/2, which leads to an increase in AUC by approximately 40-60%.

Special instructions

In patients with chronic heart failure in whom renal function may be significantly dependent on the activity of the RAAS (for example, in patients with bilateral renal artery stenosis or arterial stenosis of a single functioning kidney), the use of drugs that affect the RAAS, such as ARB II, can lead to the development of acute arterial hypotension, oliguria, azotemia or, in rare cases, acute renal failure. Therefore, Attento® should be used with caution in patients with heart failure.

Because Attento® contains amlodipine, which, like other vasodilators, should be used with caution in patients with aortic and/or myrtial stenosis, as well as in patients with hypertrophic obstructive cardiomyopathy.

BMCC should be used with caution in patients with chronic heart failure, as there is evidence that they may increase the risk of cardiovascular complications and mortality. However, studies in patients with heart failure have shown that amlodipine does not increase the risk of complications and/or mortality.

In a long-term placebo-controlled study of amlodipine in patients with severe heart failure (NYHA class III and IV), there was an increase in reports of pulmonary edema in the amlodipine group compared with the placebo group.

As with any antihypertensive drugs, an excessive decrease in blood pressure in patients with coronary artery disease and cerebrovascular diseases can lead to the development of a heart attack or ischemic stroke.

In patients with hypovolemia and/or hyponatremia resulting from intensive diuretic therapy, dietary salt restriction, diarrhea or vomiting, symptomatic hypotension may occur, especially after taking the first dose of the drug. These conditions should be corrected before Attento® is prescribed, or the patient should be closely monitored during the initial phase of therapy.

As with the use of other ARB II and ACE inhibitors, hyperkalemia may develop when using Attento®, especially in patients with impaired renal function and/or heart failure. When prescribing Attento® to patients in this group, careful monitoring of potassium and creatinine levels in the blood plasma is recommended. The use of Attento® is contraindicated in severe renal failure (creatinine clearance less than 20 ml/min).

There is no experience with the use of Attento® in patients who have recently undergone kidney transplantation or in patients with end-stage renal failure (creatinine clearance less than 12 ml/min).

In patients with liver failure, the effect of amlodipine and olmesartan medoxomil may be enhanced. Attento® should be used with caution in patients with mild or moderate hepatic impairment (Child-Pugh score less than 9). In patients with moderate hepatic impairment, the dose of olmesartan medoxomil should not exceed 20 mg. In patients with hepatic impairment, amlodipine should be started at the lowest dose and caution should be exercised both when initiating treatment and when increasing the dose. The use of Attento® is contraindicated in patients with severe liver failure (more than 9 points on the Child-Pugh scale).

Attento® should be used with caution concomitantly with potassium supplements, potassium-sparing diuretics, table salt substitutes containing potassium or other drugs that may increase potassium levels (heparin, etc.); In this case, regular monitoring of potassium levels in the blood is recommended.

Patients with primary aldosteronism usually do not respond to antihypertensive drugs that suppress the RAAS. Therefore, the use of Attento® is not advisable for patients in this category.

As with the use of other ARA II, the antihypertensive effect of Attento® in representatives of the black race may be slightly less than in other patients, possibly due to the higher prevalence of low renin levels in this population.

Cases have been reported in which reversible biochemical changes in the head of the sperm have occurred in patients taking BMCC. There is insufficient clinical data regarding the potential effects of amlodipine on fertility.

Given the presence of amlodipine in the Attento® drug, during the use of the Attento® drug it is necessary to control the following parameters: body weight, amount of table salt consumed, oral hygiene and dental observation (to prevent pain, bleeding and gum hyperplasia).

Sprue-like enteropathy

In very rare cases, the development of severe chronic diarrhea accompanied by significant weight loss has been reported in patients taking olmesartan medoxomil for several months to several years. It is possible that these effects are based on a local delayed hypersensitivity reaction. According to the biopsy results, intestinal villous atrophy was often observed in these cases. If the above symptoms appear during the use of olmesartan medoxomil, other possible causes of diarrhea should be excluded. If possible causes cannot be established, the use of drugs containing olmesartan medoxomil should be discontinued. If a biopsy confirms the presence of sprue-like enteropathy, the use of drugs containing olmesartan medoxomil should not be resumed, even after the symptoms have disappeared.

Impact on the ability to drive vehicles. Wed and fur.:

During treatment with Attento®, care must be taken when driving vehicles and other mechanisms, when engaging in potentially hazardous activities that require increased concentration and speed of psychomotor reactions (since side effects such as headache, dizziness, nausea and increased fatigue may develop, especially at the beginning of treatment).

Active ingredient

Amlodipine, Olmesartan medoxomil

Composition

Core:

Active ingredients:

olmesartan medoxomil – 40.00 mg,

amlodipine besylate – 13.888 mg (in terms of amlodipine base – 10.00 mg).

Excipients:

pregelatinized starch – 70,000 mg,

microcrystalline siliconized cellulose* – 65.312 mg,

croscarmellose sodium – 10.0 mg,

magnesium stearate – 0.800 mg.

Film casing:

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,

red iron oxide dye (E 172) – 0.4000 mg.

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

Contraindications

Hypersensitivity to olmesartan medoxomil, amlodipine and other dihydropyridine derivatives or to other components of the drug;

– severe liver failure (more than 9 points on the Child-Pugh scale);

– obstruction of the biliary tract and cholestasis;

– severe arterial hypotension (SBP less than 90 mm Hg);

– shock (including cardiogenic);

– hemodynamically unstable heart failure after myocardial infarction;

– severe renal failure (creatinine clearance (CC) less than 20 ml/min, no experience of clinical use);

– condition after kidney transplantation (no experience of clinical use);

– conditions accompanied by severe impairment of blood outflow from the left ventricle (for example, severe aortic stenosis);

– pregnancy;

– breastfeeding period;

– age under 18 years (efficacy and safety have not been established);

– simultaneous use with aliskiren and aliskiren-containing drugs in patients with diabetes mellitus and/or impaired renal function (glomerular filtration rate less than 60 ml/min/1.73 m2 body surface area).

With caution:

– Stenosis of the aortic and mitral valve;

– hypertrophic obstructive cardiomyopathy;

– simultaneous use with lithium preparations (see also section “Interaction with other drugs”);

– hyperkalemia, hyponatremia;

– hypovolemia (including due to diarrhea, vomiting or simultaneous use of diuretics), as well as in patients on a diet with limited salt intake;

– renal failure of mild to moderate severity (creatinine clearance 20-60 ml/min);

– primary aldosteronism;

– renovascular hypertension (bilateral renal artery stenosis or stenosis of the artery of a single kidney);

– other conditions accompanied by activation of the renin-anginotensin-aldosterone system;

– chronic heart failure (CHF) (III-IV functional class according to the NYHA classification);

– chronic forms of coronary heart disease;

– acute forms of coronary heart disease (acute myocardial infarction, including within one month after it; unstable angina);

– sick sinus syndrome;

– arterial hypotension;

– cerebrovascular diseases;

– liver failure of mild to moderate severity (less than 9 points on the Child-Pugh scale);

– age over 65 years;

– use in patients of the Negroid race.

Side Effects

Possible side effects are listed below according to the World Health Organization (WHO) classification in descending frequency of occurrence: very common (≥ 1/10), common (≥ 1/100,

Combination of amlodipine and olmesartan medoxomil

From the immune system

Rarely: allergic reactions, hypersensitivity reactions.

From the nervous system

Common: dizziness, headache;

Uncommon: hypoesthesia, paresthesia, postural dizziness, drowsiness;

Rarely: syncope.

Mental disorders

Uncommon: decreased libido.

From the cardiovascular system

Uncommon: palpitations, tachycardia, marked decrease in blood pressure, orthostatic hypotension;

Rarely: flushes of blood to the face.

From the respiratory system, chest organs and mediastinum

Uncommon: cough, dyspnea.

Hearing and labyrinth disorders

Uncommon: vertigo.

From the gastrointestinal tract

Uncommon: dry mouth, abdominal pain, constipation, diarrhea, dyspepsia, nausea, vomiting.

From the skin and subcutaneous tissues

Uncommon: skin rash.

Rarely: urticaria.

From the musculoskeletal system

Uncommon: back pain, muscle cramps, pain in limbs.

From the kidneys and urinary tract

Uncommon: pollakiuria.

From the genital organs and mammary glands

Uncommon: erectile dysfunction/impotence.

General violations

Common: increased fatigue, peripheral edema, soft tissue swelling;

Uncommon: asthenia;

Rarely: facial swelling.

From the laboratory parameters

Uncommon: increase/decrease in plasma potassium levels, increased plasma uric acid concentrations, increased plasma creatinine concentrations, increased gammaglutamyltransferase activity.

Olmesartan medoxomil (monotherapy)

From the blood and lymphatic system

Uncommon: thrombocytopenia.

From the immune system

Uncommon: anaphylactic reactions.

Metabolism and nutrition

Often: increased concentration of triglycerides in the blood plasma, increased concentration of uric acid in the blood plasma.

Rarely: increased potassium levels in the blood plasma.

From the nervous system

Common: dizziness, headache.

From the respiratory system, chest organs and mediastinum

Often: pharyngitis, rhinitis, bronchitis, cough.

Hearing and labyrinth disorders

Uncommon: vertigo.

From the digestive system

Common: diarrhea, dyspepsia, gastroenteritis, abdominal pain, nausea;

Uncommon: vomiting.

Very rare: sprue-like enteropathy.

From the liver and biliary tract

Often: increased activity of liver enzymes.

From the skin and subcutaneous tissues

Uncommon: exanthema, allergic dermatitis, urticaria, skin rash, itching;

Rarely: angioedema.

From the musculoskeletal system

Common: back pain, bone pain, arthritis;

Uncommon: myalgia.

Rarely: muscle cramps.

From the kidneys and urinary tract

Common: hematuria, urinary tract infections;

Rarely: acute renal failure, renal failure.

From the cardiovascular system

Uncommon: angina pectoris;

Rarely: marked decrease in blood pressure.

General violations

Common: chest pain, peripheral edema, flu-like symptoms, fatigue, pain of unspecified localization;

Uncommon: facial swelling, asthenia, general malaise.

Rarely: drowsiness.

From the laboratory parameters

Often: increased concentration of urea in the blood plasma, increased activity of creatine phosphokinase;

Rarely: increased plasma creatinine concentration.

Isolated cases of rhabdomyolysis have also been reported, which in terms of development time was associated with taking AT-II receptor antagonists.

Amlodipine (monotherapy)

From the blood and lymphatic system

Very rare: leukopenia, thrombocytopenia, thrombocytopenic purpura.

From the immune system

Very rare: hypersensitivity reactions.

Metabolism and nutrition

Very rare: increased plasma glucose concentration.

From the mental side

Uncommon: depression, insomnia, irritability, mood lability (including anxiety);

Rarely: confusion.

From the nervous system

Common: dizziness, headache, drowsiness;

Uncommon: taste disturbance, sleep disturbance, hypoesthesia, paresthesia, syncope, tremor, ataxia, amnesia, peripheral neuropathy;

Very rare: hypertonicity, parosmia, apathy, agitation.

From the side of the organ of vision

Uncommon: visual disturbances (including diplopia), xerophthalmia, conjunctivitis, eye pain.

Hearing and labyrinth disorders

Uncommon: tinnitus.

From the cardiovascular system

Often: “flushes” of blood to the face, palpitations;

Uncommon: angina pectoris (including exacerbation of coronary heart disease), marked decrease in blood pressure.

Very rare: cardiac arrhythmia (including bradycardia, ventricular tachycardia and atrial fibrillation), development or worsening of CHF, orthostatic hypotension, myocardial infarction, vasculitis.

From the respiratory system, chest organs and mediastinum

Uncommon: dyspnea, rhinitis, nosebleeds;

Very rare: cough.

From the digestive system

Common: abdominal pain, nausea.

Uncommon: functional bowel disorders (including diarrhea and constipation), dry mouth, dyspepsia, vomiting.

Very rare: gastritis, gingival hyperplasia, pancreatitis.

From the liver and biliary tract

Very rare: increased activity of liver enzymes (in most cases due to cholestasis), hepatitis, jaundice, hyperbilirubinemia.

From the skin and subcutaneous tissues

Uncommon: alopecia, exanthema, increased sweating, skin itching, skin rash (including hemorrhagic), skin pigmentation disorders;

Very rare: angioedema, erythema multiforme, exfoliative dermatitis, photosensitivity, Quincke’s edema, Stevens-Johnson syndrome, urticaria.

From the musculoskeletal system

Common: swelling in the ankle area;

Uncommon: arthralgia (joint pain), back pain, myalgia, muscle cramps.

Rarely: myasthenia gravis.

From the kidneys and urinary tract

Uncommon: frequent urination, painful urge to urinate, nocturia.

Very rare: dysuria, polyuria.

From the reproductive system and mammary glands

Uncommon: erectile dysfunction/impotence, gynecomastia.

General violations

Often: increased fatigue, swelling;

Uncommon: asthenia, chest pain, general malaise, pain of unspecified localization.

Other violations

Uncommon: weight loss/gain.

Isolated cases of extrapyramidal syndrome have also been reported in patients taking amlodipine.

Interaction

Combination of amlodipine and olmesartan medoxomil

The antihypertensive effect of Attento® may be enhanced when used simultaneously with other antihypertensive drugs (for example, alpha-blockers, diuretics).

Olmesartan medoxomil

Concomitant use with potassium-sparing diuretics, potassium supplements, table salt substitutes containing potassium, or other drugs that increase plasma potassium levels (for example, non-steroidal anti-inflammatory drugs (NSAIDs) (including selective cyclooxygenase-2 (COX-2) inhibitors), immunosuppressants (for example, cyclosporine or tacrolimus), trimethoprim, inhibitors is not recommended angiotensin-converting enzyme (ACE), heparin). If it is necessary to use these drugs simultaneously with olmesartan medoxomil, careful monitoring of the potassium content in the blood plasma is necessary.

Data from clinical studies show that dual blockade of the renin-angiotensin-aldosterone system (RAAS) with concomitant use of ACE inhibitors, ARB II or aliskiren is associated with a higher incidence of side effects such as hypotension, hyperkalemia and decreased renal function (including the development of acute renal failure) than with the use of only one drug acting on the RAAS. Therefore, the simultaneous use of ACE inhibitors, ARB II or aliskiren is not recommended.

The simultaneous use of olmesartan medoxomil and drugs containing aliskiren is contraindicated in patients with diabetes mellitus and renal failure (with a glomerular filtration rate less than 60 ml/min/1.73 m2 body surface area) (see section “Contraindications”).

In patients with diabetic nephropathy, ACE inhibitors and ARB II should not be used simultaneously.

In cases where the simultaneous use of two drugs acting on the RAAS is necessary, their use should be carried out under the supervision of a physician and accompanied by regular monitoring of renal function, blood pressure and electrolyte levels in the blood plasma.

When used simultaneously with antacids (magnesium and aluminum hydroxide), a moderate decrease in the bioavailability of olmesartan medoxomil is observed.

With simultaneous use of olmesartan, medoxomil does not have a clinically significant effect on the pharmacokinetics and pharmacodynamics of warfarin or the pharmacokinetics of digoxin.

Concomitant use of olmesartan medoxomil with pravastatin in healthy volunteers did not have clinically significant effects on the pharmacokinetics of either drug.

There are reports of a reversible increase in plasma lithium concentrations and toxicity with simultaneous use of lithium preparations with ACE inhibitors and ARA II, therefore the use of olmesartan medoxomil in combination with lithium preparations is not recommended. If it is necessary to use appropriate combination therapy, regular monitoring of lithium concentrations in the blood plasma is recommended.

No clinically significant inhibitory effect of olmesartan on the isoenzymes CYP1A1/2, CYP2A6, CYP2C8/9, CYP2C19, CYP2D6, CYP2E1 and CYP3A4 of the human cytochrome P450 system in vitro was detected; a minimal or zero inducing effect was noted for rat cytochrome P450, which suggests the absence of clinically significant interactions with simultaneous use of olmesartan medoxomil and drugs metabolized with the participation of the above isoenzymes of the cytochrome P450 system.

With simultaneous use of NSAIDs, including non-selective NSAIDs, selective COX-2 inhibitors, acetylsalicylic acid (at a dose of more than 3 g / day), and ARA II, the risk of developing acute renal failure may increase, therefore it is recommended to monitor renal function, especially at the beginning of use, as well as regular intake of sufficient fluid by the patient.

However, the simultaneous use of NSAIDs and ARA II may lead to a weakening of the antihypertensive effect of ARA II, leading to a partial loss of their therapeutic effectiveness.

Colesevelam (bile acid sequestrant)

With the simultaneous use of colesevelam hydrochloride (a bile acid sequestrant) and olmesartan medoxomil, a weakening of the systemic effect of olmesartan medoxomil and a decrease in its Cmax and T1/2 are observed. Taking olmesartan medoxomil at least 4 hours before taking colesevelam hydrochloride reduces this interaction. Olmesartan medoxomil should be taken at least 4 hours before colesevelam hydrochloride.

Amlodipine

With the simultaneous use of amlodipine and other antihypertensive drugs, their antihypertensive effects are additive.

When amlodipine is used simultaneously with strong or moderate inhibitors of the CYP3A4 isoenzyme (protease inhibitors, azole antifungals, macrolides such as erythromycin or clarithromycin, verapamil or diltiazem), a significant increase in the concentration of amlodipine in the blood plasma is possible. Clinical manifestations of this interaction may be more pronounced in elderly patients, which may require additional monitoring of the patient’s condition and dose adjustment.

There are no data on the effect of inducers of the CYP3A4 isoenzyme on the pharmacokinetics of amlodipine. However, it should be taken into account that when used simultaneously with inducers of the CYP3A4 isoenzyme (such as rifampicin, St. John’s wort), a decrease in the concentration of amlodipine in the blood plasma is possible. Amlodipine should be used concomitantly with inducers of the CYP3A4 isoenzyme with caution.

In animal studies, after taking BMCC (verapamil) and intravenous administration of dantrolene (a drug for the treatment of malignant hyperthermia), cases of ventricular fibrillation and the development of cardiovascular failure with a fatal outcome were observed against the background of the development of hyperkalemia.

Due to the risk of developing hyperkalemia in patients prone to malignant hyperthermia, as well as against the background of the use of dantrolene for malignant hyperthermia, it is recommended to avoid the use of BMCCs such as amlodipine. Despite the fact that when using amlodipine, a negative inotropic effect is usually not observed, some BMCCs may enhance the severity of the negative inotropic effect of antiarrhythmic drugs that cause prolongation of the QT interval (for example, amiodarone, quinidine).

A single dose of sildenafil in a dose of 100 mg in patients with essential hypertension does not affect the pharmacokinetic parameters of amlodipine. Single and repeated doses of amlodipine at a dose of 10 mg do not affect the pharmacokinetics of ethanol.

Antiviral agents (for example, ritonavir) increase plasma concentrations of BMCC, including amlodipine.

Neuroleptics and isoflurane enhance the antihypertensive effect of BMCC dihydropyridine derivatives.

Calcium supplements may reduce the effect of BMCC.

Cimetidine does not affect the pharmacokinetics of amlodipine.

The simultaneous use of aluminum or magnesium-containing antacids does not have a significant effect on the pharmacokinetics of amlodipine.

In clinical studies for drug interactions, no effect of amlodipine on the pharmacokinetics of atorvastatin, digoxin, warfarin or cyclosporine was noted.

The simultaneous use of amlodipine (10 mg) and simvastatin (80 mg) for a long time led to an increase in the concentration of simvastatin in the blood plasma by 77% compared to taking simvastatin alone. The dose of simvastatin in patients taking amlodipine should not exceed 20 mg per day.

The simultaneous use of amlodipine and grapefruit juice is not recommended, because in some patients, it is possible to increase the bioavailability and enhance the antihypertensive effect of amlodipine.

With simultaneous use, amlodipine may enhance the toxic effect of tacrolimus or cyclosporine, therefore it is necessary to monitor the concentration of cyclosporine and tacrolimus in the blood plasma and adjust the dose if necessary.

Overdose

Cases of overdose of Attento® have not been reported.

Symptoms:

in case of an overdose of olmesartan medoxomil, symptoms such as a pronounced decrease in blood pressure and tachycardia are most likely to appear; Bradycardia can develop in case of parasympathetic stimulation (vagus nerve).

In case of an overdose of amlodipine, the most characteristic symptoms are: a pronounced decrease in blood pressure with the possible development of reflex tachycardia and excessive peripheral vasodilation. The risk of developing a pronounced and prolonged decrease in blood pressure, including the development of shock and death, should be taken into account.

Treatment

The use of activated carbon is recommended, especially during the first 2 hours after an overdose, and gastric lavage (in some cases). Taking activated charcoal within 2 hours after taking amlodipine orally significantly reduces its absorption.

If there is a pronounced decrease in blood pressure, it is recommended to place the patient in a horizontal position with his legs elevated and carry out therapy aimed at replenishing the volume of circulating blood, maintaining the function of the cardiovascular system and correcting disturbances in water and electrolyte balance. It is necessary to monitor the performance of the heart and lungs, control the volume of circulating blood and diuresis. To restore vascular tone and blood pressure, in the absence of contraindications, it is possible to prescribe vasoconstrictor drugs.

To eliminate calcium channel blockade, intravenous administration of calcium gluconate is recommended.

Since amlodipine is highly bound to plasma proteins, hemodialysis is ineffective. There are no data on the elimination of olmesartan during hemodialysis.

Storage conditions

Store at a temperature not exceeding 25 °C.

Keep out of the reach of children.

Shelf life

5 years.

Do not use after the expiration date stated on the package.

Manufacturer

Berlin-Chemie AG/Daichi Sankyo Europe GmbH, Germany