Attento - instructions for use, dose, side effects, contraindications

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Dosage form: & nbsptfilm-covered laths

Composition:

For one tablet:

Tablets, 5 mg + 20 mg

Core:

Active substances: Olmesartan medoxomil - 20.00 mg, amlodipine besylate - 6,944 mg (in terms of amlodipine base - 5,00 mg).

Excipients: pregelatinized starch - 35,000 mg, microcrystalline silicified cellulose * - 32.656 mg, croscarmellose sodium - 5.0 mg, magnesium stearate - 0.400 mg.

Film sheath:

Foam II white 85F18422, consisting of: polyvinyl alcohol - 2.0000 mg, titanium dioxide (E 171) - 1.2500 mg, macrogol - 1.0100 mg, talcum 0.7400 mg.

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

Tablets, 5 mg + 40 mg

Core:

Active substances: olmesartan medoxomil - 40.00 mg, amlodipine besylate - 6,944 mg (in terms of amlodipine base - 5,00 mg).

Excipients: pregelatinized starch - 70,000 mg, microcrystalline silicified cellulose * - 72,256 mg, croscarmellose sodium - 10.0 mg, magnesium stearate - 0.800 mg.

Film sheath:

Fallen II yellow 85F22093, consisting of: polyvinyl alcohol - 3.2000 mg, titanium dioxide (E 171) - 1.9600 mg, macrogol - 1.6160 mg, talcum - 1.1840 mg, dye oxide iron yellow (E 172) - 0.0400 mg.

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

Tablets, 10 mg + 40 mg

Core:

Active substances: 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 silicified cellulose * - 65,312 mg, croscarmellose sodium - 10,0 mg, magnesium stearate - 0,800 mg.

Film sheath:

Fallen 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, iron oxide yellow oxide (E 172) 0, 1080 mg, the iron oxide red dye (E 172) is 0.4000 mg.

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

Description:

Tablets, 5 mg + 20 mg: round, biconvex tablets, coated with a film shell, white, embossed "C73" on one side; on the cross-section the nucleus is white.

Tablets, 5 mg + 40 mg: round, biconvex tablets, film-coated, pale yellow, embossed "C75" on one side; on the cross-section the nucleus is white.

Tablets, 10 mg + 40 mg: round, biconcave tablets, film-coated, reddish brown, with "C77" embossed on one side; on the cross-section the nucleus is white.

Pharmacotherapeutic group:A combined hypotensive drug (BCCA + angiotensin II receptor antagonist)

ATX: & nbsp

Olmesartan medoxomil and amlodipine

Pharmacodynamics:

Atteno ® - combined antihypertensive drug, which includes angiotensin II receptor antagonist (APA II) - olmesartan medoxomil and blocker of "slow" calcium channels (BCC) - amlodipine. The combination of the two active substances has a synergistic antihypertensive effect, so that the blood pressure (BP) decreases more than with the reception of each of them separately.

In an 8-week, double-blind, randomized, placebo-controlled study of 1940 patients, it was shown that the antihypertensive effect of Attento® is usually developed during the first 2 weeks of therapy. As was shown in three studies, once the drug was applied once a day, the antihypertensive effect of the Attento® drug persisted for 24 hours, with the residual / peak ratio for systolic blood pressure and diastolic blood pressure ranging from 71% to 82% . The antihypertensive effect was confirmed with outpatient monitoring of blood pressure and was independent of age and sex, as well as the presence of diabetes in patients.In two open, non-randomized, extended trials, the potent efficacy of Attento® at a dosage of 5 mg + 40 mg was shown for 49-67% of patients for one year of use.

In a double-blind, randomized, placebo-controlled study, the addition of 5-mg amlodipine with an insufficient 8-week effectiveness of olmesartan monotherapy with medoxomil at a dose of 20 mg resulted in 8 weeks reduction in SBP and DBP by 16.2 and 10.6 mm Hg . Art. (p = 0.0006), respectively. The proportion of patients who achieved the target blood pressure (<140/90 mm Hg for patients without diabetes mellitus and <130/80 mm Hg for patients with diabetes mellitus) was 44.5% with combined therapy olmesartan medoxomil at a dose of 20 mg and amlodipine at a dose of 5 mg compared with 28.5% with monotherapy with 20 mg of olmesartan medoxomil.

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

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

In an 8-week, double-blind, randomized, placebo-controlled study of 1940 patients (71% European and 29% other races), the use of Attento® (with any combination of doses of its components) resulted in a significantly more significant decrease in SBP and DBP compared with monotherapy. The rate of decrease in SBP / DBP depended on the applied doses of amlodipine / olmesartan medoxomil: -24 / -14 mm Hg. Art. (5 mg + 20 mg), -25 / -16 mm Hg. Art. (5 mg + 40 mg) and -30 / -19 mm. gt; Art. (10 mg + 40 mg).

When using the drug Attento in a dosage of 5 mg + 40 mg, there was an additional decrease in SBP / DBP in the "sitting" position by 2.5 / 1.7 mm Hg. Art. compared with the use of the drug Attento® in 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 mm Hg. Art. in comparison with the use of the drug Attento® in a dosage of 5 mg + 40 mg. The proportion of patients who failed to achieve target BP values (<140/90 mm Hg. Art. For patients without diabetes and <130/80 mm Hg. Art. For diabetic patients) was 42.5%, 51, 0% and 49.1% for Atteno® preparations at a dosage of 5 mg + 20 mg, 5 mg + 40 mg and 10 mg + 40 mg, respectively.

Olmesartan medoxomil, part of the preparation of Attento®, is a potent specific ARA II (type AT₁). Angiotensin II is the primary vasoactive component of the renin-angiotensin-aldosterone system plays a significant role in the pathophysiology of hypertension by exposing the AT₁-receptors. Olmesartan, preventing the binding of angiotensin II with AT₁receptors in tissues (Including vascular smooth muscle and the adrenal glands), it blocks the vasoconstrictor effects and effects associated with the angiotensin II effect on the secretion of aldosterone. The specific antagonism of olmesartan against AT₁-receptors leads to an increase in the activity of renin, angiotensin I and II in blood plasma,and also helps to reduce the plasma concentration of aldosterone.

With 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, about tachyphylaxis during long-term treatment or about the "withdrawal" syndrome (a sharp increase in blood pressure after the removal of olmesartan medoxomil).

The use of olmesartan medoxomil once a day provides an effective and gentle decrease in blood pressure within 24 hours. The division of the daily dose into two doses has an antihypertensive effect similar to that occurring when taking the same daily dose at a time. The antihypertensive effect of olmesartan medoxomil occurs, as a rule, after 2 weeks, and the maximum effect develops approximately 8 weeks after the initiation of therapy.

To date, there is no evidence of the effect of olmesartan medoxomil on mortality and morbidity.

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

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

The primary combined endpoint (the time before the event that will occur first: doubling the plasma creatinine concentration, the development of the terminal stage of 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%) (OBS 0.97, 95% CI: 0.75-1.24, p = 0.791).

Amlodipine, which is part of the Atteno® preparation, is a BCCI blocking the incoming transmembrane current of calcium ions into cardiomyocytes and smooth muscle cells of the vessels through the potential-dependent channels L-type. Experimental data indicate that amlodipine interacts with both dihydropyridine and non-dihydropyridine binding sites. Amlodipine has a relative vasoselectivity and has a greater effect on the smooth muscle cells of the vessels than on cardiomyocytes. The mechanism of antihypertensive action of amlodipine is associated with a direct relaxing effect on the smooth muscle of the vessels, which causes a decrease in peripheral resistance of blood vessels and a decrease in blood pressure.

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

When used in therapeutic doses in patients with hypertension amlodipine causes vasodilation, leading to a decrease in blood pressure (in the patient's position "lying", "sitting" and "standing").With prolonged use, a decrease in blood pressure is not accompanied by a significant change in the heart rate (heart rate) and the concentration of catecholamines in the blood plasma. With 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 alteration of the filtration fraction and proteinuria level.

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

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

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

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

Pharmacokinetics:

After ingestion of the drug Attento® maximum concentration (С_mOh) of olmesartan and amlodipine in blood plasma is achieved after 1.5-2 hours and 6-8 hours, respectively. The speed and degree of absorption of olmesartan medoxomil and amlodipine in the formulation of Attento® correspond to the rate and degree of absorption of these components in the form of monopreparations. Simultaneous food intake does not affect the bioavailability of olmesartan medoxomil and amlodipine.

Olmesartan medoxomil

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

FROM_mOh Olmesartan in blood plasma is on average 2 hours after taking olmesartan medoxomil inside and increases approximately linearly with a single dose increase to 80 mg.

Olmesartan is characterized by a high degree of binding to blood plasma proteins (99.7%), but the potential for a clinically significant shift in the amount of binding to proteins in the interaction of olmesartan with other highly-linked and concomitantly used drugs is low (the absence of a clinically significant interaction between olmesartan and warfarin). The association of olmesartan with blood cells is negligible. The average volume of distribution after intravenous administration is low (16-29 l).

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

Elimination of olmesartan is carried out in two ways. After a single oral administration of olmesartan medoxomil labeled with an isotope ¹⁴C, 10-16% of the radioactive substance was excreted by the kidneys (most within 24 hours after taking olmesartan medoxomil), and the remaining radioactive substance was released through the intestine. Given the systemic bioavailability of 25.6%, it can be calculated that approximately 40% of the absorbed olmesartan is excreted through the kidneys, and about 60% through the hepatobiliary system. The released radioactive substance was represented by olmesartan. No other metabolites were detected. The intestinal and hepatic recirculation of olmesartan is minimal. Since most of the olmesartan is excreted through the hepatobiliary system, its use in patients with obstruction of the biliary tract is contraindicated (see section "Contraindications"). The half-life of olmesartan (T_1/2) is 10-15 hours after repeated ingestion. The equilibrium state is achieved after taking several first doses of the drug, after 14 days of repeated use, further cumulation is not observed.Kidney clearance is approximately 0.5-0.7 l / h and does not depend on the dose of the drug.

Clinically significant differences in pharmacokinetic parameters of olmesartan, depending on sex, were not revealed.

Amlodipine

Absorption and distribution: after oral administration at therapeutic doses amlodipine well absorbed, time to reach maximum concentration (TC_mOh) is 6-12 hours after administration. Absolute bioavailability is about 64-80%. The volume of distribution is about 21 l / kg. Binding to plasma proteins in vitro for circulating amlodipine in the blood is approximately 97.5%. Simultaneous food intake does not significantly affect the absorption of amlodipine.

Metabolism and excretion: after a single dose of T_1/2 from the blood plasma in the terminal phase is about 35-50 hours. Amlodipine is metabolized to a great extent in the liver with the formation of inactive metabolites, 10% of the starting material and 60% of the metabolites are secreted by the kidneys.

Pharmacokinetics in patients aged 65 years and older

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

Time to reach C_mOh Amlodipine in blood plasma does not differ in elderly patients and in young patients. In elderly patients there is a tendency to decrease the clearance of amlodipine, which leads to an increase AUC and elongation T_1/2.

Pharmacokinetics in patients with renal insufficiency

In comparison with healthy volunteers in patients with mild, moderate and severe renal failure AUC Olmesartan increases by approximately 62%, 82% and 179%, respectively.

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

Pharmacokinetics in patients with hepatic impairment

After a single oral intake AUC olmesartan were 6% and 65% higher in patients with mild to moderate hepatic insufficiency, respectively, compared with healthy volunteers.The unbound fraction of olmesartan 2 hours after ingestion of a single dose of the drug in healthy volunteers, in patients with mild to moderate hepatic insufficiency was 0.26%, 0.34%, and 0.41%, respectively. With repeated ingestion AUC Olmesartan in patients with moderate degree of hepatic insufficiency was 65% higher than in healthy volunteers from the control group. Mean values of C_mOh Olmesartan in patients with hepatic insufficiency and healthy volunteers were similar. The pharmacokinetics of olmesartan medoxomil in patients with hepatic insufficiency of severe severity has not been studied.

The experience of clinical use of amlodipine in patients with hepatic insufficiency is limited. In patients in this group, amlodipine clearance decreases and lengthening T_1/2, which leads to an increase in AUC of approximately 40-60%.

Indications:

Essential hypertension (with ineffectiveness of olmesartan monotherapy with medoxomil or amlodipine).

Contraindications:

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

- hepatic failure of severe severity (more than 9 points on the scale Child-Pugh);

- bile duct obstruction and cholestasis;

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

- shock (including cardiogenic);

- hemodynamically unstable heart failure after myocardial infarction;

- renal failure of severe severity (creatinine clearance (CC) less than 20 ml / min, clinical experience is not available);

- condition after kidney transplantation (clinical experience absent);

- conditions accompanied by a marked violation of outflow of blood from the left The ventricle (for example, stenosis of the aorta of the severe degree);

- Pregnancy;

- the period of breastfeeding;

- age under 18 years (effectiveness and safety not established);

- simultaneous use with aliskiren and aliskirenoderzhaschimi drugs in patients with diabetes mellitus and / or renal dysfunction (glomerular filtration rate less than 60 ml / min / 1.73 m² surface area of the body).

Carefully:

- Stenosis of the aortic and mitral valve;

- hypertrophic obstructive cardiomyopathy;

- 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), as well as in patients who follow a diet with restriction of consumption of table salt;

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

- primary aldosteronism;

- vasorenal hypertension (bilateral stenosis of the renal arteries or stenosis of the artery of a single kidney);

- Other conditions accompanied by activation of renin-anginotenzin-aldosterone system;

- chronic heart failure (CHF) (III-IV functional class by classification NYHA);

- chronic forms of ischemic heart disease;

acute forms of ischemic heart disease (acute myocardial infarction, including in one month after it; unstable angina);

- syndrome of weakness of the sinus node;

- arterial hypotension;

- cerebrovascular diseases;

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

- age over 65;

- use of Negroid race in patients.

Pregnancy and lactation:

There are no data on the use of Attento® during pregnancy.However, in view of the available reports of severe teratogenic effects of drugs acting directly on the renin-angiotensin-aldosterone system, the use of Attento® during pregnancy is contraindicated.

In the case of APA II in the second and third trimesters of pregnancy, ultrasound should be performed to assess the kidney function and ossification of the fetal bones. Newborns whose mothers took ARA II should be monitored for possible development of arterial hypotension and impaired renal function.

Data from observations of a limited number of pregnant women did not show that amlodipine or other BCCI have a negative effect on the fetus. However, there is a risk of increasing the duration of labor.

Patients planning a pregnancy are recommended to be transferred to antihypertensive drugs of other groups, the safety of their use in pregnancy is proved, except for cases when the drug Atento® is prescribed for life indications. In case of pregnancy during therapy with the drug Attento® the drug should be immediately discontinued and, if necessary, an alternative treatment with a proven safety profile of the application during pregnancy.

Shown, that olmesartan medoxomil penetrates into breast milk in rats, but similar data for humans are absent. In connection with the lack of reliable data, the use of the drug Attento ® during breastfeeding it is contraindicated.

Dosing and Administration:

Inside. The drug Atento ® is taken orally once a day, at the same time, regardless of the time of ingestion, without chewing, squeezed with enough liquid (for example, a glass of water).

To select the optimal dosage regimen, it is advisable to use the most suitable dosage of the drug.

Prior to the appointment of the combination drug Atento ®, a preliminary selection of the doses of each of the active substances alone (ie, olmesartan medoxomil and amlodipine) is recommended. In the presence of clinical indications, a patient can be transferred from monotherapy immediately to the use of a combined preparation.

Patients receiving combination therapy with olmesartan monosomal preparations andamlodipine can be transferred to the Atteno® preparation containing olmesartan medoxomil and amlodipine in similar doses.

Recommended dose:

Every day, 1 tablet of the Atteno® preparation at a dosage of 5 mg + 20 mg containing 20 mg of olmesartan medoxomil and 5 mg of amlodipine, in the absence of an adequate reduction in BP against a background of olmesartan monotherapy with a dose of 20 mg or amlodipine at a dose of 5 mg.

In the absence of an adequate reduction in blood pressure, at the dose of 5 mg + 20 mg, Atento® can be used at a dosage of 5 mg + 40 mg (1 tablet) per day containing 40 mg of olmesartan medoxomil and 5 mg of amlodipine.

In the absence of an adequate reduction in blood pressure in the dose of 5 mg + 40 mg, Attento® can be used at a dosage of 10 mg + 40 mg (1 tablet) per day containing 40 mg of olmesarton medoxomil and 10 mg of amlodipine.

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

Use in patients aged 65 years and over

In patients aged 65 years and older with normal renal function, dose adjustment is not required.

With an increase in the dose of olmesartan medoxomil to a maximum (40 mg per day) in elderly patients, a thorough control of blood pressure is necessary.

Use in patients with renal insufficiency

In the case of using Attento ® in patients with mild and moderate renal insufficiency (CC 20-60 ml / min) it is recommended to conduct periodic monitoring of the content of potassium and creatinine in the blood plasma. The maximum dose of olmesartan medoxomil for patients with mild to moderate renal insufficiency is 20 mg 1 time per day, since experience with higher doses is limited in this category of patients.

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

Use in patients with hepatic impairment

In patients with mild to moderate hepatic insufficiency (less than 9 on the Child-Pugh scale), Attento® should be used with caution.

In liver failure of mild to moderate severity, the maximum dose of olmesartan medoxomil is 20 mg once daily.The use of amlodipine in patients with impaired liver function should begin with a minimal dose (5 mg).

When used simultaneously with diuretics and / or other antihypertensive drugs in patients with impaired liver function, careful monitoring of blood pressure and kidney function is recommended.

The use of Attento® is contraindicated in patients with severe hepatic insufficiency (more than 9 on the Child-Pugh scale) (no experience is available) (see section "Contraindications").

Side effects:

Possible side effects are listed below in accordance with the World Health Organization (WHO) qualifications for the descending frequency of occurrence: very often (≥ 1/10), often (≥1 / 100, <1/10), infrequently (≥1 / 1000, < 1/100), rarely (≥1 / 10000, <1/1000), very rarely, including individual messages (<1/10000), the frequency is unknown (it is impossible to set the frequency according to available data).

The combination of amlodipine and olmesartan medoxomil

From the immune system

Rarely: allergic reactions, hypersensitivity reactions.

From the nervous system

Often: dizziness, headache;

Infrequently: hypesthesia, paresthesia, postural dizziness, drowsiness;

Rarely: syncope.

Disorders of the psyche

Infrequently: decreased libido.

From the side of the cardiovascular system

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

Rarely: "tides" of blood to the face.

From the respiratory system, organs of the chest and mediastinum

Infrequently: cough, dyspnea.

From the side of the hearing organ and labyrinthine disorders

Infrequently: Vertigo.

From the gastrointestinal tract

Infrequently: dryness of the oral mucosa, abdominal pain, constipation, diarrhea, indigestion, nausea, vomiting.

From the skin and subcutaneous tissues

Infrequently: skin rash.

Rarely: hives.

From the side of the musculoskeletal system

Infrequently: back pain, muscle cramps, pain in the limbs.

From the side of the kidneys and urinary tract

Infrequently: pollakiuria.

From the genitals and mammary glands

Infrequently: erectile dysfunction / impotence.

Common violations

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

Infrequently: asthenia;

Rarely: swelling of the face.

From the laboratory indicators

Infrequently: increase / decrease of potassium content in blood plasma, increase of uric acid concentration in blood plasma, increase of creatinine concentration in blood plasma, increase in activity of gamma glutamyl transferase.

Olmesartan medoxomil (monotherapy)

On the part of the blood and lymphatic system

Infrequently: thrombocytopenia.

From the immune system

Infrequently: anaphylactic reactions.

From the side of metabolism and nutrition

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

Rarely: an increase in the content of potassium in the blood plasma.

From the nervous system

Often: dizziness, headache.

From the respiratory system, organs of the chest and mediastinum

Often: pharyngitis, rhinitis, bronchitis, cough.

From the side of the hearing organ and labyrinthine disorders

Infrequently: Vertigo.

From the side of the digestive system

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

Infrequently: vomiting.

Rarely: sprue-like enteropathy.

From the liver and biliary tract

Often: increased activity of "liver" enzymes.

From the skin and subcutaneous tissues

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

Rarely: angioedema.

From the side of the musculoskeletal system

Often: back pain, bone pain, arthritis;

Infrequently: myalgia.

Rarely: muscle cramps.

From the side of the kidneys and urinary tract

Often: hematuria, urinary tract infections;

Rarely: acute renal failure, renal failure.

From the side of the cardiovascular system

Infrequently: angina pectoris;

Rarely: marked decrease in blood pressure.

Common violations

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

Infrequently: edema of the face, asthenia, general malaise.

Rarely: drowsiness.

From the laboratory indicators

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

Rarely: increase in the concentration of creatinine in the blood plasma.

Also reported on single cases rhabdomyolysis, which was associated with the administration of antagonists of AT-II receptors by developmental time.

Amlodipine (monotherapy)

On the part of the blood and lymphatic system

Rarely: leukopenia, thrombocytopenia, thrombocytopenic purpura.

From the immune system

Rarely: hypersensitivity reactions.

From the side of metabolism and nutrition

Rarely: increase in the concentration of glucose in the blood plasma.

From the side of the psyche

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

Rarely: confusion.

From the nervous system

Often: dizziness, headache, drowsiness;

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

Rarely: hypertonia, parosmia, apathy, agitation.

From the side of the organ of vision

Infrequently: impaired vision (including diplopia), xerophthalmia, conjunctivitis, pain in the eyes.

From the side of the hearing organ and labyrinthine disorders

Infrequently: noise in ears.

From the side of the cardiovascular system

Often: "tides" of blood to the face, a feeling of palpitations;

Infrequently: angina (including exacerbation of ischemic heart disease), marked decrease in blood pressure.

Rarely: violation of the rhythm of the heart (including bradycardia, ventricular tachycardia and atrial fibrillation), development or exacerbation of CHF, orthostatic hypotension, myocardial infarction, vasculitis.

On the part of the respiratory system, the organs of the thorax and the mediastinum

Infrequently: dyspnea, rhinitis, epistaxis;

Rarely: cough.

From the side of the digestive system

Often: pain in the abdomen, nausea.

Infrequently: functional disorders of the intestine (including diarrhea and constipation), dryness of the oral mucosa, indigestion, vomiting.

Rarely: gastritis, gingival hyperplasia, pancreatitis.

From the liver and biliary tract

Rarely: increased activity of liver enzymes (in most cases, against the background of cholestasis), hepatitis, jaundice, and hyperbilirubinemia.

From the skin and subcutaneous tissues

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

Rarely: angioedema, polymorphic erythema, exfoliative dermatitis, photosensitivity, Quincke's edema, Stevens-Johnson syndrome, urticaria.

From the side of the musculoskeletal system

Often: swelling in the ankles;

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

Rarely: myasthenia gravis.

From the side of the kidneys and urinary tract

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

Rarely: dysuria, polyuria.

From the side of the reproductive system and mammary glands

Infrequently: erectile dysfunction / impotence, gynecomastia.

Common violations

Often: increased fatigue, swelling;

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

Other violations

Infrequently: decrease / increase in body weight.

In patients who took amlodipine, it was also reported single cases development of extrapyramidal syndrome.

Overdose:

Cases of overdose of Attento® are not registered.

Symptoms: with an overdose of olmesartan medoxomil, the most likely appearance of such symptoms as pronounced decrease in blood pressure and tachycardia; bradycardia can develop in the case of parasympathetic stimulation (vagus nerve).

In case of an overdose amlodipine the most typical symptoms are: a marked decrease in blood pressure with the possible development of reflex tachycardia and excessive peripheral vasodilation. It is necessary to take into account the risk of developing a pronounced and prolonged BP reduction, up to the development of shock and death.

Treatment

It is recommended to use activated carbon, especially during the first 2 hours after an overdose, gastric lavage (in some cases). Reception activated coal within 2 hours after taking amlodipine inside significantly reduces its absorption.

At a marked decrease in blood pressure, it is recommended to put the patient in a horizontal position, lifting his legs and performing therapy aimed at replenishing the volume of circulating blood, maintaining the function of the cardiovascular system and correcting the violations of the water-electrolyte balance. It is necessary to monitor the performance of the heart and lungs, control the volume of circulating blood and diuresis. To restore the tone of blood vessels and blood pressure in the absence of contraindications, it is possible to prescribe vasoconstrictive drugs.

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

Because the amlodipine largely associated with blood plasma proteins, hemodialysis is ineffective. Data on excretion of olmesartan in hemodialysis are absent.

Interaction:

The combination of amlodipine and olmesartan medoxomil

The antihypertensive effect of Attento® can be enhanced by simultaneous use with other antihypertensive drugs (eg, alpha-blockers, diuretics).

Olmesartan medoxomil

It is not recommended to use the potassium-sparing diuretics, potassium preparations, substitutes for edible salt containing potassium, or other drugs that increase the level of potassium in the blood plasma (for example, non-steroidal anti-inflammatory drugs (NSAIDs) (including selective inhibitors of cyclooxygenase-2 (COX-2)), immunosuppressants (eg, ciclosporin or tacrolimus), trimethoprim, angiotensin-converting enzyme (ACE) inhibitors, heparin). In case of necessity of simultaneous application of these drugs and olmesartan medoxomil, a careful control of the potassium content in the blood plasma is necessary.

Clinical studies show that the double blockade of the renin-angiotensin-aldosterone system (RAAS) with simultaneous use of ACE inhibitors, APA II or aliskiren, associated with a higher frequency the occurrence of such side effects as hypotension, hyperkalemia and decreased renal function (including the development of acute renal failure) than with the use of only one drug that affects RAAS.Thus, simultaneous use of ACE inhibitors, APA II or aliskiren is not recommended.

Simultaneous use of olmesartan medoxomil and preparations containing aliskiren, is contraindicated in patients with diabetes mellitus and renal insufficiency (at a glomerular filtration rate of less than 60 ml / min / 1.73 m²body surface area) (see section "Contraindications").

Patients with diabetic nephropathy should not simultaneously apply ACE inhibitors and ARA II.

In the case when the simultaneous use of two agents that affect the RAAS is necessary, their application should be carried out under the supervision of a physician and be accompanied by regular monitoring of renal function, blood pressure and electrolyte levels in blood plasma.

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

With simultaneous application olmesartan medoxomil does not have a clinically significant effect on pharmacokinetics and pharmacodynamics warfarin or pharmacokinetics digoxin.

The simultaneous use of olmesartan medoxomil with pravastatinhealthy volunteers did not have clinically significant effects on the pharmacokinetics of each of the drugs.

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

Clinically significant inhibitory action of olmesartan on isoenzymes CYP1A1/2, CYP2A6, CYP2C8/9, CYP2C19, CYP2D6, CYP2E1 and CYP3A4 systems of human cytochrome P450 in vitro it was not revealed that minimal or zero inducing effect was noted with respect to rat cytochrome P450, suggesting the absence of clinically significant interactions with the simultaneous use of olmesartan medoxomil and drugs metabolized with the participation of the above isoenzymes of the cytochrome P450 system.

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

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

Wheezevels (sequestrant of bile acids)

With the simultaneous use of colisevelam hydrochloride (bile acid sequestrant) and olmesartan medoxomil, weakened systemic action of olmesartan medoxomil, a decrease in its C_mOh and T_1/2 . The administration of olmesartan medoxomil at least 4 hours before the administration of colisevelam hydrochloride results in the weakening of this interaction. Olmesartan medoxomil should be taken at least 4 hours prior to taking kolesevelam hydrochloride.

Amlodipine

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

With the simultaneous use of amlodipine with powerful or moderate isoenzyme inhibitors CYP3A4 (protease inhibitors, azole antifungal agents,macrolides such as erythromycin or clarithromycin, verapamil or diltiazem) a significant increase in the concentration of amlodipine in the blood plasma. 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.

Data on the impact inducers of isoenzyme CYP3A4 on the pharmacokinetics of amlodipine is not available. However, it should be borne in mind that when applied simultaneously with isoenzyme inducers CYP3A4 (such as rifampicin, St. John's wort perforated) it is possible to reduce the concentration of amlodipine in the blood plasma. Use amlodipine simultaneously with inducers of isoenzyme CYP3A4 follows from caution.

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

In connection with the risk of developing hyperkalemia in patients prone to malignant hyperthermia, as well as against the use of dantrolene in malignant hyperthermia, it is recommended to avoid the use of BCCC, such as amlodipine. Despite the fact that with the use of amlodipine negative inotropic action is usually not observed, some BCCI can increase the severity negative inotropic action antiarrhythmic drugs, causing an elongation interval QT (eg, amiodarone, quinidine).

Single Reception sildenafil in a dose of 100 mg in patients with essential hypertension does not affect the pharmacokinetics parameters of amlodipine. Single and repeated administration of amlodipine at a dose of 10 mg does not affect the pharmacokinetics ethanol.

Antiviral drugs (eg, ritonavir) increase plasma concentrations of BCCC, including amlodipine.

Neuroleptics and isoflurane increase the antihypertensive effect of BCCC derivatives of dihydropyridine.

Calcium preparations can reduce the effect of BCCI.

Cimetidine does not affect the pharmacokinetics of amlodipine.

Simultaneous application aluminum- or magnesium-containing antacids has no significant effect on the pharmacokinetics of amlodipine.

In clinical studies for drug interactions, the effects of amlodipine on the pharmacokinetics of atorvastatin, digoxin, warfarin, or cyclosporine were not observed.

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

It is not recommended simultaneous use of amlodipine and grapefruit juice, tk. in some patients, increased bioavailability and increased antihypertensive effects of amlodipine.

With simultaneous application amlodipine can enhance toxic effects tacrolimus or cyclosporine, so it is necessary to monitor the concentration of cyclosporine and tacrolimus in the blood plasma and adjust the dose if necessary.

Special instructions:

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

Because Atteno® contains amlodipine, which, like other vasodilator drugs, should be used with caution in patients with aortic and / or myrtle stenosis, as well as in patients with hypertrophic obstructive cardiomyopathy.

BCCI 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, in studies involving patients with heart failure, it was shown that amlodipine does not increase the risk of complications and / or mortality.

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

As with any antihypertensive drugs,the excessive reduction in blood pressure in patients with ischemic heart disease and with cerebrovascular disease can 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 consumption of table salt with food, diarrhea or vomiting, symptomatic arterial hypotension may occur, especially after taking the first dose of the drug. These conditions should be corrected prior to the appointment of the drug Attento® or the patient should be carefully monitored at the initial stage of therapy.

As with the use of other APA II and ACE inhibitors, the use of Attento ® may develop hyperkalemia, especially in patients with impaired renal function and / or heart failure. At the appointment of the drug Attento® patients of this group are recommended careful monitoring of the content of potassium and creatinine in the blood plasma. The use of Attento® is contraindicated in renal failure of severe severity (creatinine clearance less than 20 ml / min).

The experience of using Attento® in patients who have recently undergone kidney transplantation, or in patients with terminal renal failure (creatinine clearance less than 12 ml / min) is absent.

In patients with hepatic insufficiency, amplification of the effect of amlodipine and olmesartan medoxomil is possible. Atento ® should be administered with caution to patients with mild or moderate hepatic impairment (less than 9 on the Child-Pugh scale). In patients with moderate liver failure, the dose of olmesartan medoxomil should not exceed 20 mg. In patients with hepatic insufficiency, amlodipine should be started at the lowest dose and caution should be taken both at the beginning of treatment and with increasing doses. The use of the drug Attento® is contraindicated in patients with severe hepatic insufficiency (more than 9 on the Child-Pugh scale).

Attento® The drug should be used with caution in conjunction with potassium supplements, potassium-sparing diuretics, dietary salt substitutes that contain potassium or other drugs that may enhance the potassium content (heparin, etc.); while regular monitoring of potassium in the blood is recommended.

Patients with primary aldosteronism usually do not respond to antihypertensive drugs suppressing RAAS. Therefore, the appointment of the drug Attento® is inappropriate for patients of this category.

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

It has been reported that patients receiving BCCI experience reversible biochemical changes in the sperm head. The clinical data on the potential impact of amlodipine on fertility is not enough.

Given the presence of Attento® amlodipine in the Atteno® preparation, the following parameters should be monitored during the use of the Attento®: body weight, amount of salt consumed, oral hygiene and monitoring by the dentist (to prevent soreness, bleeding and gingival hyperplasia).

Sprue-like enteropathy

In very rare cases, the development of severe chronic diarrhea, accompanied by a significant loss of body weight in patients taking olmesartan medoxomil from several months to several years. It is possible that these effects are based on a local delayed hypersensitivity reaction. By results of a biopsy in these cases atrophy of villi of an intestine was often observed. In the case of the appearance of the above symptoms, against the background of the use of olmesartan medoxomil, other possible causes the occurrence of diarrhea. If the possible causes can not be established, the use of drugs containing olmesartan medoxomil, should be discontinued. If biopsies confirm the presence of spruce-like enteropathy, the use of medications containing olmesartan medoxomil should not be resumed, even after the symptoms have disappeared.

Effect on the ability to drive transp. cf. and fur:

During the period of treatment with the drug Atento®, care should be taken when driving vehicles and other mechanisms when engaging in potentially dangerous activities requiring increased concentration of attention and speed of psychomotor reactions (since the development of side effects such as headache, dizziness, nausea and increased fatigue, especially at the beginning of treatment).

Form release / dosage:

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

Packaging:

For 14 tablets in a contour mesh package (blister) of aluminum foil / aluminum foil.

For 1, 2 or 4 blisters with instructions for use in a cardboard bundle.

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 expiry date printed on the package.

Terms of leave from pharmacies:On prescription

Registration number:LP-003818

Date of registration:01.09.2016

Expiration Date:01.09.2021

The owner of the registration certificate:Berlin-Chemie, AGBerlin-Chemie, AG Germany

Manufacturer: & nbsp

BERLIN-CHEMIE, AG Germany

Representation: & nbspBERLIN-CHEMI / MENARINI PHARMA GmbH BERLIN-CHEMI / MENARINI PHARMA GmbH Germany

Information update date: & nbsp04.10.2017

Illustrated instructions

Instructions

Attento® (Attento®)