Attento, 5 mg+20 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 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 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 administration of 14C-labeled olmesartan medoxomil, 10-16% of the radioactive substance was excreted by the kidneys (most within 24 h of administration of olmesartan medoxomil), 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. The intestinal and hepatic recirculation 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 to the AUC of olmesartan in younger patients, which may be due in part to age-related decline in 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 in patients with mild, moderate and severe renal impairment the AUC of olmesartan is increased 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

Active ingredient

Composition

Core:

Active ingredients:

olmesartan medoxomil – 20.00 mg,

amlodipine besylate – 6.944 mg (in terms of amlodipine base – 5.00 mg).

Auxiliary substances:

Pregelatinized starch – 35.000 mg,

Microcrystalline silica cellulose* – 32.656 mg,

croscarmellose sodium – 5.0 mg,

magnesium stearate – 0.400 mg.

Film Coating:

Opadray II white 85F18422, consisting of: polyvinyl alcohol – 2.0000 mg,

titanium dioxide (E 171) – 1.2500 mg,

macrogol – 1.0100 mg,

talc – 0.7400 mg.

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

How to take, the dosage

Ingestion. Attento® is taken orally once a day, at the same time, regardless of the time of meals, without chewing, with enough fluids (e.g., a glass of water).

To find the optimal dosing regimen, it is advisable to use the most appropriate dosage of the drug.

Before prescribing Attento® combination therapy, it is recommended that doses of each active ingredient separately (i.e., olmesartan medoxomil and amlodipine) be pre-selected. In case of clinical indications it is allowed to transfer patient from monotherapy directly to combined therapy.

Patients receiving combined therapy with olmesartan medoxomil and amlodipine monotherapy may be switched to Attento® containing olmesartan medoxomil and amlodipine in similar doses.

The recommended dose:

Daily, 1 tablet of Attento® dosage 5 mg + 20 mg containing 20 mg olmesartan medoxomil and 5 mg amlodipine, in the absence of adequate BP reduction on monotherapy with olmesartan medoxomil at a dose of 20 mg or amlodipine at a dose of 5 mg.

If there is inadequate BP reduction with Attento 5 mg + 20 mg, then Attento® 5 mg + 40 mg (1 tablet) daily containing 40 mg olmesartan medoxomil and 5 mg amlodipine may be used.

If there is inadequate BP reduction with Attento® 5 mg + 40 mg (1 tablet), then Attento® 10 mg + 40 mg (1 tablet) daily containing 40 mg olmesartan medoxomil and 10 mg amlodipine may be used.

The maximum daily dose of olmesartan medoxomil is 40 mg. The maximum daily dose of amlodipine is 10 mg.

The use in patients aged 65 years and older

In patients aged 65 years and older with normal renal function, no adjustment of the drug dose is required.

When increasing the dose of olmesartan medoxomil to the maximum dose (40 mg daily) in elderly patients, close monitoring of BP is necessary.

The use in patients with renal impairment

In patients with mild to moderate renal impairment (CKR 20-60 ml/min), periodic monitoring of plasma potassium and creatinine is recommended during use of Attento®. The maximum dose of olmesartan medoxomil for patients with mild to moderate renal insufficiency is 20 mg once daily, since experience with higher doses in this category of patients is limited.

In patients with severe renal impairment (CKD less than 20 ml/min) the use of Attento® is contraindicated.

Patient use in patients with hepatic impairment

In patients with mild to moderate hepatic impairment (less than 9 points on the Child-Pugh score), Atento® should be used with caution.

In mild to moderate hepatic impairment, the maximum dose of olmesartan medoxomil is 20 mg once daily. The use of amlodipine in patients with hepatic impairment should be started with the lowest dose (5 mg).

In concomitant use with diuretics and/or other hypotensive drugs in patients with hepatic impairment, close monitoring of BP and renal function is recommended.

The use of Attento® is contraindicated in patients with severe hepatic impairment (greater than 9 points on the Child-Pugh score) (no experience) (see section “Contraindications”).

Interaction

The combination of amlodipine and olmesartan medoxomil

The antihypertensive effect of Attento® may be enhanced with other hypotensive drugs (e.g., alpha-adrenoblockers, diuretics).

Olmesartan medoxomil

. Concomitant use with potassium-saving diuretics, potassium preparations, food salt substitutes containing potassium, or other medications that increase plasma potassium (e.g, non-steroidal anti-inflammatory drugs (NSAIDs) (including selective cyclooxygenase-2 (COX-2) inhibitors), immunosuppressants (such as cyclosporine or tacrolimus), trimethoprim, angiotensin-converting enzyme (ACE) inhibitors, heparin.) If concomitant use of the above drugs and olmesartan medoxomil is necessary, careful monitoring of plasma potassium is required.

The data from clinical studies demonstrate that dual blockade of the renin-angiotensin-aldosterone system (RAAS) with concomitant use of ACE inhibitors, ARA II or aliskiren, is associated with a higher incidence of side effects such as arterial hypotension, hyperkalemia and decreased renal function (including development of acute renal function).development of acute renal failure) than when using only one RAAS-acting drug. Thus, concomitant use of ACE inhibitors, ARA II or aliskiren is not recommended.

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

In patients with diabetic nephropathy, ACE inhibitors and ARA II should not be used concomitantly.

If simultaneous use of two drugs acting on RAAS is necessary, they should be used under medical supervision and accompanied by regular monitoring of renal function, BP and plasma electrolyte content.

In concomitant use with antacids (magnesium and aluminum hydroxide) a moderate decrease in bioavailability of olmesartan medoxomil is observed.

Concomitant use of olmesartan medoxomil has no clinically significant effect on the pharmacokinetics and pharmacodynamics of warfarin or the pharmacokinetics of digoxin.

The concomitant use of olmesartan medoxomil with pravastatin in healthy volunteers had no clinically significant effects on the pharmacokinetics of either drug.

There have been reports of reversible increases in plasma lithium concentration and toxicity with concomitant use of lithium with ACE inhibitors and with ARA II, so the use of olmesartan medoxomil in combination with lithium preparations is not recommended. If appropriate combination therapy is required, regular monitoring of plasma lithium concentrations is recommended.

. Clinically significant inhibitory effect of olmesartan on CYP1A1/2, CYP2A6, CYP2C8/9, CYP2C19, CYP2D6, CYP2E1 and CYP3A4 isoenzymes of human cytochrome P450 system was not revealed in vitro, minimal or no inducing effect was noted regarding rat cytochrome P450, which suggests the absence of clinically significant interactions when concomitant use of olmesartan medoxomil and drugs metabolized with the participation of the above cytochrome P450 isoenzymes.

When concomitant use of NSAIDs, including non-selective NSAIDs, selective COX-2 inhibitors, acetylsalicylic acid (in dose greater than 3 g/day), and ARA II may increase risk of acute renal failure; therefore it is recommended to monitor renal function, especially at first use, and to take plenty of fluids regularly.

However, concomitant use of NSAIDs and ARA II can decrease the antihypertensive effect of ARA II, resulting in partial loss of their therapeutic efficacy.

Colesevelam (bile acid sequestrant)

The concomitant use of colesevelam hydrochloride (bile acid sequestrant) and olmesartan medoxomil shows a decrease in the systemic effects of olmesartan medoxomil, decreasing its Cmax and T1/2 . Taking olmesartan medoxomil at least 4 h before taking colesevelam hydrochloride results in attenuation of this interaction. Olmesartan medoxomil should be taken at least 4 h before taking colesevelam hydrochloride.

Amlodipine

When amlodipine and other hypotensive drugs are used concomitantly, their antihypertensive effects are summarized.

In concomitant use of amlodipine with potent or moderate CYP3A4 isoenzyme inhibitors (protease inhibitors, azole antifungal drugs, macrolides such as erythromycin or clarithromycin, verapamil or diltiazem) a significant increase in plasma concentration of amlodipine is possible. Clinical manifestations of this interaction may be more pronounced in elderly patients, which may require additional patient monitoring and dose adjustment.

There are no data on the effect of CYP3A4 isoenzyme inducers on amlodipine pharmacokinetics. However, it should be taken into account that concomitant use with CYP3A4 isoenzyme inducers (such as rifampicin, St. John’s Wort) may decrease the blood plasma concentration of amlodipine. Caution should be exercised when using amlodipine concomitantly with inducers of CYP3A4 isoenzyme.

In animal studies, after administration of DMARDs (verapamil) and intravenous dantrolene (a drug for treatment of malignant hyperthermia), there have been cases of ventricular fibrillation and lethal cardiovascular failure against the background of hyperkalemia.

Because of the risk of hyperkalemia in patients prone to malignant hyperthermia, as well as against the background of dantrolene use in malignant hyperthermia, it is recommended to avoid use of PBMCs such as amlodipine. Although no adverse inotropic effects are generally seen with amlodipine, some PBMCs can increase the negative inotropic effect of antiarrhythmic drugs that cause QT interval prolongation (e.g., amiodarone, quinidine).

A single sildenafil administration at a dose of 100 mg in patients with essential hypertension has no effect on amlodipine pharmacokinetic parameters. A single and repeated administration of amlodipine at a dose of 10 mg has no effect on the pharmacokinetics of ethanol.

Antiviral agents (e.g., ritonavir) increase plasma concentrations of PBMCs, including amlodipine.

Neuroleptics and isoflurane increase the antihypertensive effects of dihydropyridine derivatives BMCCs.

Calcium preparations may decrease the effect of BMCCs.

Cimetidine does not affect the pharmacokinetics of amlodipine.

The concomitant use of aluminum- or magnesium-containing antacids has no significant effect on the pharmacokinetics of amlodipine.

In clinical studies for drug interactions no effect of amlodipine on pharmacokinetics of atorvastatin, digoxin, warfarin or cyclosporine has been observed.

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

The concomitant use of amlodipine and grapefruit juice is not recommended because in some patients the bioavailability and antihypertensive effect of amlodipine may increase.

In concomitant use amlodipine may increase toxic effects of tacrolimus or cyclosporine, therefore it is necessary to monitor plasma concentrations of cyclosporine and tacrolimus and adjust the dose if necessary.

Special Instructions

In patients with chronic heart failure in whom renal function may significantly depend on the activity of the RAAS (e.g., patients with bilateral renal artery stenosis or artery stenosis of the only functioning kidney), the use of drugs affecting the RAAS, such as ARA II, may lead to acute hypotension, oliguria, azotemia or, in rare cases, acute renal failure. Thus, 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 myrtle stenosis and in patients with hypertrophic obstructive cardiomyopathy.

BMCs should be used with caution in patients with chronic heart failure because there is evidence that they may increase the risk of cardiovascular complications and mortality. However, in studies involving patients with heart failure, it has been 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 were increased reports of pulmonary edema in the amlodipine group compared to the placebo group.

As with any hypotensive medication, excessive lowering of blood pressure in patients with CHD and with cerebrovascular disease may lead to the development of a heart attack or ischemic stroke.

In patients with hypovolemia and/or hyponatremia resulting from intensive therapy with diuretics, restriction of dietary salt intake, diarrhea or vomiting, symptomatic arterial hypotension may occur, especially after the first dose of the drug. These conditions should be corrected prior to administration of Attento® or the patient should be closely monitored during initial therapy.

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

The use of Attento® in patients with recent kidney transplantation or in patients with terminal renal failure (creatinine clearance less than 12 mL/min) is not known.

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

Atento® should be used with caution when taking potassium supplements, potassium-saving diuretics, potassium salt substitutes, or other drugs that may increase potassium (heparin, etc.), and regular monitoring of blood potassium is recommended.

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

As with other ARAs II, the antihypertensive effect of Attento® may be somewhat less in non-Hispanic patients than in other patients, possibly due to the higher prevalence of low renin levels in this population.

There have been reported cases where reversible biochemical changes in the sperm head have occurred in patients taking BMCC. Clinical data regarding the potential effects of amlodipine on fertility are scarce.

As amlodipine is present in Attento®, the following parameters should be monitored during use of Attento®: body weight, dietary salt intake, oral hygiene and dental care (to prevent soreness, bleeding and gum hyperplasia).

Spru-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 underlying these effects is a local delayed hypersensitivity reaction. Biopsy results in these cases often showed atrophy of the intestinal villi. If the above symptoms occur during the use of olmesartan medoxomil, other possible causes of diarrhea should be excluded. If no possible causes can be identified, the use of drugs containing olmesartan medoxomil should be discontinued. If sprue-like enteropathy is confirmed by biopsy, use of drugs containing olmesartan medoxomil should not be restarted even after symptoms have disappeared.

Impact on the ability to drive:

During treatment with Attento®, caution should be exercised when driving vehicles and other machinery, and when engaging in potentially hazardous activities that require increased concentration and rapid psychomotor reactions (because side effects such as headache, dizziness, nausea and increased fatigue may occur, especially at the beginning of treatment).

Contraindications

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

– severe hepatic impairment (greater than 9 points on the Child-Pugh scale);

– biliary obstruction and cholestasis;

– severe arterial hypotension (BP less than 90 mm Hg systolic blood pressure less than 90 mm Hg.);

– shock (including cardiogenic shock);

– hemodynamically unstable heart failure after myocardial infarction;

– severe renal insufficiency (creatinine clearance (CK) less than 20 ml/min, no experience with clinical use);

– conditions after renal transplantation (no experience with clinical use);

– conditions involving significant left ventricular outflow tract abnormality (e.g., severe aortic orifice stenosis);

– pregnancy;

– breastfeeding;

– age less than 18 years (efficacy and safety not established);

– concomitant 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 drugs (see.

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

– hyperkalemia, hyponatremia;

– hypovolemia (including due to diarrhea, vomiting or simultaneous use of diuretics), and also in patients adhering to a diet with restricted consumption of table salt;

– mild to moderate renal insufficiency (CKR 20-60 ml/min);

– primary aldosteronism;

– Vasorenal hypertension (bilateral stenosis of the renal arteries or stenosis of the artery of the sole kidney);

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

– Chronic heart failure (CHF) (NYHA functional class III-IV);

– Chronic forms of coronary heart disease;

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

– sinus node weakness syndrome;

– arterial hypotension;

– cerebrovascular disease;

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– mild to moderate hepatic impairment (less than 9 points on the Child-Pugh scale);

– age older than 65 years;

– use in patients of non-human race.

Side effects

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

Combination of amlodipine and olmesartan medoxomil

Immune system disorders

Rare: allergic reactions, hypersensitivity reactions.

Nervous system disorders

Often: dizziness, headache;

Infrequent: hypoesthesia, paresthesia, postural dizziness, drowsiness;

Rarely: syncope.

Psychiatric disorders

Infrequent: decreased libido.

Cardiovascular system disorders

Infrequent: palpitations, tachycardia, marked BP decrease, orthostatic hypotension;

Rarely: “rushes” of blood to the face.

Respiratory system, thorax and mediastinum disorders

Infrequent: cough, dyspnea.

Hearing organ and labyrinth disorders

Infrequent: vertigo.

Gastrointestinal tract disorders

Infrequent: dry oral mucosa, abdominal pain, constipation, diarrhea, dyspepsia, nausea, vomiting.

Skin and subcutaneous tissue disorders

Infrequent: skin rash.

Rarely: urticaria.

Musculoskeletal disorders

Infrequent: back pain, muscle cramps, pain in the extremities.

Renal and urinary tract disorders

Infrequent: pollakiuria.

Gender and mammary gland disorders

Infrequent: erectile dysfunction/impotence.

General disorders

Often: increased fatigue, peripheral edema, soft tissue edema;

Infrequent: asthenia;

Rarely: facial edema.

Laboratory findings

Infrequent: increased/decreased plasma potassium, increased plasma uric acid concentration, increased plasma creatinine concentration, increased gammaglutamyltransferase activity.

Olmesartan medoxomil (monotherapy)

Blood and lymphatic system disorders

Infrequent: thrombocytopenia.

Immune system disorders

Infrequent: anaphylactic reactions.

Metabolism and nutrition disorders

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

Rarely: increase in plasma potassium.

Nervous system disorders

Often: dizziness, headache.

Respiratory system, chest and mediastinal organs

Often: pharyngitis, rhinitis, bronchitis, cough.

Hearing organ and labyrinth disorders

Infrequently: vertigo.

Digestive system disorders

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

Infrequent: vomiting.

Very rare: sprue-like enteropathy.

Liver and biliary tract disorders

Often: increased activity of “liver” enzymes.

Skin and subcutaneous tissue disorders

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

Rarely: angioedema.

Musculoskeletal system disorders

Often: back pain, bone pain, arthritis;

Infrequently: myalgia.

Rarely: muscle cramps.

Renal and urinary tract disorders

Often: hematuria, urinary tract infections;

Rarely: acute renal failure, renal failure.

Cardiovascular system disorders

Infrequent: angina pectoris;

Rarely: marked BP decrease.

General disorders

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

Infrequent: facial edema, asthenia, general malaise.

Rarely: somnolence.

Laboratory findings

Often: increased plasma urea concentration, increased creatine phosphokinase activity;

Rarely: increased plasma creatinine concentration.

There have also been single reported cases of rhabdomyolysis, which in terms of time of development has been associated with the intake of AT-II receptor antagonists.

Amlodipine (monotherapy)

Blood and lymphatic system disorders

Very rare: leukopenia, thrombocytopenia, thrombocytopenic purpura.

Immune system disorders

Very rare: hypersensitivity reactions.

Metabolism and nutrition disorders

Very rare: increase in plasma glucose concentration.

Psychiatric disorders

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

Rarely: confusion.

Nervous system disorders

Often: dizziness, headache, drowsiness;

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

Very rare: hypertonicity, parosmia, apathy, agitation.

Visual organ disorders

Infrequent: visual impairment (including diplopia), xerophthalmia, conjunctivitis, pain in the eye.

Hearing organ and labyrinth disorders

Infrequent: tinnitus.

Cardiovascular system disorders

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

Infrequent: angina pectoris (including exacerbation of coronary heart disease), pronounced BP decrease.

very rarely: cardiac arrhythmias (including bradycardia, ventricular tachycardia, and atrial fibrillation), development or worsening of CHF, orthostatic hypotension, myocardial infarction, vasculitis.

Respiratory system, thorax and mediastinum disorders

Infrequent: dyspnea, rhinitis, nasal bleeding;

Very rare: cough.

Digestive system disorders

Often: abdominal pain, nausea.

Infrequent: functional bowel disorders (including diarrhea and constipation), dry oral mucosa, dyspepsia, vomiting.

very rarely: gastritis, gum hyperplasia, pancreatitis.

Hepatic and biliary tract disorders

very rarely: increased activity of liver enzymes (in most cases with cholestasis), hepatitis, jaundice, hyperbilirubinemia.

Skin and subcutaneous tissue disorders

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

Very rare: Angioneurotic edema, polymorphic erythema, exfoliative dermatitis, photosensitization, Quincke’s edema, Stevens-Johnson syndrome, urticaria.

Musculoskeletal system disorders

Often: edema of the ankles;

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

Rarely: myasthenia gravis.

Kidney and urinary tract disorders

Infrequent: rapid urination, painful urge to urinate, nycturia.

very rarely: dysuria, polyuria.

Reproductive system and breast disorders

Infrequent: erectile dysfunction/impotence, gynecomastia.

General disorders

Often: increased fatigue, edema;

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

Other disorders

Infrequent: weight loss/increase.

In patients who have taken amlodipine, single cases of extrapyramidal syndrome have also been reported.

Overdose

No cases of overdose of Attento® have been reported.

Symptoms:

In overdose of olmesartan medoxomil the most likely symptoms are marked BP decrease and tachycardia; bradycardia may develop in case of parasympathetic stimulation (vagus nerve).

In amlodipine overdose the most characteristic symptoms are: marked BP decrease with possible development of reflex tachycardia and excessive peripheral vasodilation. Consider the risk of significant and prolonged BP decrease up to the development of shock and lethal outcome.

Treatment

The use of activated charcoal, especially during the first 2 hours after overdose, gastric lavage (in some cases) is recommended. Administration of activated charcoal for 2 hours after oral amlodipine significantly reduces its absorption.

In case of significant BP decrease, the patient should be placed horizontally with elevated legs and therapy should be performed to replenish circulating blood volume, to support cardiovascular function and to correct electrolyte and water balance abnormalities. Monitoring of heart and lung function parameters, control of circulating blood volume and diuresis is necessary. Prescription of vasoconstrictor drugs is possible for restoration of vascular tone and BP if there are no contraindications.

Injection of calcium gluconate is recommended for elimination of calcium channel blockade.

As amlodipine is largely bound to blood plasma proteins, hemodialysis is ineffective. There are no data on excretion of olmesartan by hemodialysis.