Aprovask 10mg+300mg 28 pcs film-coated tablets

Compound

Description of the dosage form

Tablets, 5 + 150 mg: oval, biconvex, white film-coated, with “150/5” engraved on one side.

Tablets, 10 + 150 mg: oval, biconvex, pink film-coated, with “150/10” engraved on one side.

Tablets, 5 + 300 mg: oval, biconvex, yellow film-coated, with “300/5” engraved on one side.

Tablets, 10 + 300 mg: oval, biconvex, white film-coated, with a score and a bevel to the score on one side.

Pharmacodynamics

The pharmacodynamic properties of each of the active substances included in the drug Aprovask®, irbesartan and amlodipine, contribute to their additive antihypertensive effect when used in combination compared to that when using each of these drugs separately. Both angiotensin II receptor antagonists (ARAII) and CCBs reduce blood pressure by reducing peripheral vascular resistance, but blocking the entry of calcium into the cell and reducing the vasoconstrictor effect caused by angiotensin II are complementary mechanisms.

Irbesartan

Irbesartan is a selective, potent APAII (AT1 subtype). Angiotensin II is an important component of the RAAS, involved in the pathophysiology of arterial hypertension and sodium ion homeostasis. Irbesartan does not require metabolic activation to exert its effect.

Irbesartan blocks the strong vasoconstrictor and aldosterone-secreting effects of angiotensin II due to selective antagonism of angiotensin II receptors (AT1 subtype) located in the cells of vascular smooth muscle and the adrenal cortex. Irbesartan does not have agonistic activity towards AT1 receptors. Its affinity for AT1 receptors is 8500 times greater than for AT2 receptors (receptors that have not been shown to be associated with maintaining balance (homeostasis) of the cardiovascular system).

Irbesartan does not inhibit RAAS enzymes (such as renin, ACE), and also does not affect other hormonal receptors or ion channels in the cardiovascular system involved in the regulation of blood pressure and sodium ion homeostasis. Blockade of AT1 receptors by irbesartan breaks the feedback loop in the renin-angiotensin system, increasing plasma concentrations of renin and angiotensin II. When using irbesartan, the plasma concentration of aldosterone decreases, however, when using the drug in recommended doses, there are no significant changes in the potassium content in the blood serum (the average increase in the potassium content in the blood serum is less than 0.1 mEq/L). Irbesartan does not have a significant effect on the concentrations of triglycerides, cholesterol or glucose in the blood serum. Irbesartan does not affect serum uric acid concentrations or renal excretion of uric acid.

The antihypertensive effect of irbesartan develops after taking the first dose and becomes significant within 1–2 weeks of treatment, with the maximum effect occurring after 4–6 weeks. In long-term observational studies, the effect of irbesartan persisted for more than 1 year.

A single dose of irbesartan in doses up to 900 mg/day caused a dose-dependent decrease in blood pressure. A single dose of irbesartan in doses of 150–300 mg/day resulted in a greater reduction in SBP/DBP (24 hours after dosing) in the supine or sitting position (on average by 8–13/5–8 mm Hg) than when taking placebo. The effect of the drug 24 hours after dosing was 60–70% of the corresponding maximum reduction in DBP and SBP. Optimal effectiveness in reducing blood pressure within 24 hours is achieved with a single dose of the drug per day.

Blood pressure decreases to approximately the same extent in standing and lying positions. Orthostatic effects are rare and, as with ACE inhibitors, may be expected to occur in patients with hyponatremia or hypovolemia. The antihypertensive effect of irbesartan and thiazide diuretics is additive. In patients who fail to achieve target blood pressure values ​​with irbesartan monotherapy, adding small doses of hydrochlorothiazide (12.5 mg) to irbesartan once daily leads to an additional (compared to the effect of adding placebo) reduction in sBP/dBP, determined by 24 hours after taking them, by 7–10/3–6 mm Hg. Art. respectively.

Age and gender do not affect the effectiveness of irbesartan. As in the case of treatment with other drugs that affect the RAAS, patients of the Negroid race have a weaker antihypertensive effect with irbesartan monotherapy. When irbesartan is taken with low doses of hydrochlorothiazide (eg 12.5 mg/day), the antihypertensive effect in black patients approaches that in Caucasian patients.

After discontinuation of irbesartan, blood pressure gradually returns to its original level. No withdrawal syndrome was observed upon discontinuation of irbesartan.

Amlodipine

Amlodipine is a CCB from the group of dihydropyridine derivatives, which inhibits the transmembrane entry of calcium ions into myocardial cells and vascular smooth muscle. The mechanism of the antihypertensive effect of amlodipine is associated with a direct relaxing effect on vascular smooth muscle.

The exact mechanism by which amlodipine reduces the frequency and severity of angina attacks is not fully established, but amlodipine reduces myocardial ischemia through the following two effects.

Amlodipine dilates peripheral arterioles and thereby reduces peripheral vascular resistance, the so-called. afterload. Since heart rate practically does not increase when taking amlodipine, this decrease in the load on the heart muscle reduces the energy consumption of the myocardium and its need for oxygen.

The mechanism of the antianginal action of amlodipine also appears to be associated with the dilation of the main coronary arteries and coronary arterioles, both in areas of the myocardium with normal blood flow and in ischemic areas of the myocardium. This dilation of the coronary vessels increases oxygen delivery to the myocardium in patients with coronary artery spasm (Prinzmetal's angina or variant angina).

In patients with arterial hypertension, taking amlodipine once a day provides a clinically significant decrease in blood pressure in the supine and standing position for 24 hours. Due to the slow onset of its action, amlodipine is not intended for the relief of hypertensive crises.

In patients with angina pectoris, a single daily dose of amlodipine during an exercise test increases the total time of physical activity, the time before the onset of an angina attack and the time before the appearance of ST segment depression on an ECG with a depth of 1 mm. In addition, taking the drug reduces the daily number of angina attacks and the daily need for taking nitroglycerin tablets.

No adverse metabolic effects or changes in blood lipid concentrations were observed when taking amlodipine. Amlodipine can be taken by patients with bronchial asthma, diabetes mellitus and gout.

Clinical evidence of the efficacy of the fixed-dose combination of irbesartan and amlodipine was obtained from two multicenter, prospective, open-label, parallel-group, blinded efficacy studies: the I-ADD and I-COMBINE studies. The results of both studies demonstrated significantly greater efficacy of fixed-dose combinations of irbesartan and amlodipine compared with amlodipine monotherapy or irbesartan monotherapy.

Aprovask, 28 pcs., 5 mg+150 mg, film-coated tablets

Frequency of adverse events/reactions (AEs/ARs) reported in clinical studies of the fixed-dose combination of irbesartan and amlodipine (clinical studies I-ADD, I-COMBINE and I-COMBO), in clinical studies of irbesartan and its post-marketing use, as well as in clinical studies on the use of amlodipine, was determined according to the WHO classification as follows: very often (≥10%); often (≥1 and <10%); uncommon (≥0.1 and <1%); rare (≥0.01 and <0.1%); very rare (<0.01%), frequency unknown - the frequency of occurrence of AEs/ARs cannot be estimated from the available data.

The frequency of HP reported during post-marketing use of the drug was defined as frequency unknown because information about these HPs came from spontaneous reports, without indicating the number of patients taking the drug.

In clinical studies comparing fixed-dose combinations of amlodipine + irbesartan with irbesartan or amlodipine monotherapy, the types and incidence of treatment-emergent AEs possibly related to the study treatment were similar to those observed in prior clinical studies or in post-marketing reports with irbesartan monotherapy and amlodipine.

The most commonly reported adverse event was peripheral edema, primarily related to amlodipine.

AEs observed during treatment and possibly related to the study drug in clinical studies of amlodipine/irbesartan (I-ADD, I-COMBINE and I-COMBO)

General disorders and disorders at the injection site: often - peripheral edema, edema; infrequently - asthenia.

From the organ of hearing and labyrinthine disorders: infrequently - vertigo.

From the side of the heart: often - palpitations; infrequently - sinus bradycardia.

From the nervous system: often - dizziness, headache, drowsiness; infrequently - paresthesia.

From the genital organs and breast: rarely - erectile dysfunction.

From the respiratory system, chest and mediastinal organs: infrequently - cough.

Vascular disorders: often - orthostatic hypotension; infrequently - excessive decrease in blood pressure.

From the gastrointestinal tract: often - swelling of the gums; infrequently - nausea, pain in the upper abdomen, constipation.

From the kidneys and urinary tract: often - proteinuria; infrequently - azotemia, hypercreatinemia.

From the side of metabolism and nutrition: infrequently - hyperkalemia.

From the musculoskeletal and connective tissue side: infrequently - joint stiffness, arthralgia, myalgia.

AEs observed with irbesartan in clinical studies (including the I-ADD, I-COMBINE and I-COMBO clinical studies) and during its post-marketing use

From the immune system: frequency unknown - hypersensitivity reactions (allergic reactions).

From the side of metabolism and nutrition: frequency unknown - hyperkalemia.

From the organ of hearing and labyrinthine disorders: often - vertigo; frequency unknown - tinnitus.

From the nervous system: often - dizziness, headache*; infrequently - orthostatic dizziness.

*The incidence of headache in the I-ADD, I-COMBINE and I-COMBO studies was rated as “uncommon”.

From the heart: infrequently - tachycardia.

From the skin and subcutaneous tissues: frequency unknown - leukocytoclastic vasculitis.

From the respiratory system, chest and mediastinal organs: infrequently - cough.

From the gastrointestinal tract: often - nausea/vomiting, pain in the upper abdomen, disorders of the tongue, including dysgeusia (perversion of taste), glossodynia (burning sensation and pain in the tongue), glossitis (inflammation of the tongue); infrequently - diarrhea, dyspepsia, heartburn.

From the liver and biliary tract: frequency unknown - jaundice, increased liver function tests, hepatitis.

From the skin and subcutaneous tissues: infrequently - alopecia; frequency unknown - angioedema, urticaria.

From the musculoskeletal system and connective tissue: frequency unknown - myalgia.

From the kidneys and urinary tract: frequency unknown - impaired renal function, including isolated cases of renal failure in patients with risk factors for its development.

From the genital organs and breast: rarely - erectile dysfunction.

General disorders and disorders at the injection site: often - increased fatigue*, swelling; uncommon - chest pain; frequency unknown - asthenia.

*The incidence of fatigue in the I-ADD, I-COMBINE and I-COMBO studies was assessed as infrequent.

Injuries, intoxications and complications of manipulations: frequency unknown - falls.

Adverse events observed with amlodipine in clinical studies (including the I-ADD, I-COMBINE and I-COMBO clinical studies)

From the blood and lymphatic system: very rarely - thrombocytopenia.

From the immune system: very rarely - allergic reactions.

Metabolism and nutrition: very rarely - hyperglycemia.

Mental disorders: infrequently - insomnia, mood lability.

From the nervous system: often - dizziness, headache*, drowsiness; infrequently - hypoesthesia, paresthesia, tremor, taste disturbances, syncope; very rarely - peripheral neuropathy.

*The incidence of headache in the I-ADD, I-COMBINE and I-COMBO studies was rated as “uncommon”.

From the organ of vision: infrequently - visual disturbances.

From the organ of hearing and labyrinthine disorders: infrequently - ringing in the ears, vertigo.

From the side of the heart: often - palpitations; very rarely - myocardial infarction, cardiac arrhythmias, ventricular tachycardia and atrial fibrillation (atrial fibrillation).

From the side of blood vessels: often - a rush of blood to the skin with a feeling of heat, redness of the skin*; infrequently - excessive decrease in blood pressure; very rarely - vasculitis.

* The incidence of skin redness in the I-ADD, I-COMBINE and I-COMBO studies was assessed as infrequent.

From the respiratory system, chest and mediastinal organs: often - cough; infrequently - shortness of breath, rhinitis; very rarely - coughing.

From the digestive system: often - nausea, abdominal pain, glossodynia, glossitis; infrequently - dyspepsia, vomiting, change in the rhythm of bowel movements, dryness of the mucous membranes of the oral cavity; very rarely - pancreatitis, gastritis, gum hyperplasia.

From the liver and biliary tract: very rarely - hepatitis, jaundice and increased activity of liver enzymes (mainly associated with cholestasis).

From the skin and subcutaneous tissues: often - contact dermatitis; uncommon - skin rash, itching, purpura, increased sweating, changes in skin pigmentation (appearance of discolored areas of the skin), alopecia; very rarely - angioedema, erythema multiforme, urticaria.

From the musculoskeletal and connective tissue side: infrequently - arthralgia, muscle cramps, myalgia, back pain.

From the kidneys and urinary tract: infrequently - increased frequency of urination, painful urge to urinate, nocturia.

From the genital organs and mammary gland: infrequently - impotence, gynecomastia.

General disorders and disorders at the injection site: often - increased fatigue, edema*, peripheral edema; infrequently - chest pain, asthenia, feeling of malaise, pain; rarely - swelling of the face.

*According to the I-ADD, I-COMBINE and I-COMBO studies, incidence of edema: uncommon.

Laboratory and instrumental data: infrequently - increase in body weight, loss of body weight.

Pharmacokinetics

Irbesartan

Irbesartan is an orally active drug that does not require biotransformation to exhibit its activity. After oral administration, irbesartan is quickly and completely absorbed. Tmax of irbesartan in blood plasma is 1.5–2 hours after oral administration. The absolute bioavailability of irbesartan when taken orally is 60–80%. Food intake does not affect the bioavailability of irbesartan.

Irbesartan is approximately 96% bound to blood plasma proteins and practically does not bind to blood cells. Vd of irbesartan is 53–93 l/kg.

After oral or intravenous administration of 14C irbesartan, unchanged irbesartan in the blood plasma accounts for 80–85% of the radioactivity circulating in the systemic circulation. Irbesartan is metabolized in the liver by conjugation with glucuronic acid and oxidation. The main metabolite found in the systemic circulation is irbesartan glucuronide (approximately 6%). Irbesartan is subject to oxidation, mainly with the help of the cytochrome P450 isoenzyme - CYP2C9; the CYP3A4 isoenzyme plays a minor role in the metabolism of irbesartan. Irbesartan is not metabolized by most isoenzymes commonly involved in drug metabolism, such as CYP1A1, CYP1A2, CYP2A6, CYP2B6, CYP2D6 or CYP2E1, and does not significantly induce or inhibit these isoenzymes. Irbesartan does not inhibit the CYP3A4 isoenzyme.

Irbesartan and its metabolites are excreted both by the liver (with bile) and the kidneys. After oral or intravenous administration of 14C irbesartan, about 20% of the radioactivity is found in the urine with a small residual amount in the feces. Less than 2% of the dose is excreted by the kidneys as unchanged irbesartan. T1/2 of irbesartan is 11–15 hours. The total clearance with intravenous administration of irbesartan is 157–176 ml/min, of which 3–3.5 ml/min accounts for renal clearance.

Irbesartan, when used in a therapeutic dose range, has linear pharmacokinetics. Css is achieved on the third day after starting to take the drug once a day. There is limited accumulation of irbesartan in the blood plasma (<20%) during a course of taking the drug once a day. In women with arterial hypertension, compared with men with arterial hypertension, higher (11–44%) plasma concentrations of irbesartan were observed after a single dose, however, against the background of a course of irbesartan in women and men, there were no differences in the accumulation of irbesartan or its T1/2. No gender-related differences in the clinical efficacy of irbesartan were observed.

In nonhypertensive elderly patients (men and women 65–80 years of age) with clinically normal renal and hepatic function, plasma AUC and Cmax were approximately 20–50% higher than in younger patients (18–40 years of age) , however, T1/2 in young and elderly patients were comparable. There were no significant age-related differences in the clinical efficacy of irbesartan.

In black patients with normal blood pressure, the AUC and T1/2 of irbesartan were approximately 20–25% higher than in Caucasian patients with normal blood pressure, but the Cmax of irbesartan was almost the same.

In patients with renal failure (regardless of its severity) and in patients on hemodialysis, the pharmacokinetics of irbesartan does not change significantly. Irbesartan is not removed from the blood by hemodialysis.

In patients with liver failure due to mild or moderate liver cirrhosis, the pharmacokinetics of irbesartan does not change significantly.

The effectiveness and safety of irbesartan in children has not been established.

Amlodipine

After oral administration in therapeutic doses, amlodipine is well absorbed with Tmax in the blood - between 6 and 12 hours after its administration. Absolute bioavailability is 64–90%. Eating does not interfere with the absorption of amlodipine.

The Vd of amlodipine is approximately 21 l/kg. In vitro studies have shown that approximately 97.5% of amlodipine in the systemic circulation is bound to plasma proteins.

Amlodipine is extensively metabolized in the liver to form inactive metabolites.

10% of unchanged amlodipine and 60% of its metabolites are excreted through the kidneys; T1/2 from blood plasma is approximately 35–50 hours when dosing once a day.

In elderly and younger people, the Tmax of amlodipine in the blood is the same. In elderly patients, the clearance of amlodipine tends to decrease, resulting in an increase in AUC and T1/2.

In children 6–12 years old and adolescents 13–17 years old, the clearance of amlodipine when taking the drug orally was 22.5 and 27.4 l/h, respectively, in boys and 16.4 and 21.3 l/h, respectively, in girls. There was wide variability in systemic exposure to amlodipine between children and adolescents. Data obtained on the use of the drug in children under 6 years of age are limited.

As with other CCBs, in case of liver failure, an increase in T1/2 of amlodipine is possible (see “Contraindications”, “Precautions” and “Special Instructions”).

In patients with CHF (in all age groups), an increase in AUC and T1/2 was observed.

Pharmacokinetics when using the combination of amlodipine/irbesartan in adults

Simultaneous administration of irbesartan and amlodipine in the form of fixed combinations in tablets or in the form of free combinations did not affect the pharmacokinetics of each of the active substances of this combination.

The three fixed dose combinations of amlodipine and irbesartan (10/150 mg, 5/300 mg and 10/300 mg) are bioequivalent to the free dose combinations (10/150 mg, 5/300 mg and 10/300 mg), both in terms of rate, and in relation to the degree of absorption. When taken separately or simultaneously in doses of 10 and 300 mg, the time until the median Cmax of amlodipine and irbesartan in the blood plasma remains unchanged, i.e. 5 and 0.75–1 hours after administration, respectively. Similarly, the Cmax and AUC of amlodipine and irbesartan when taken separately or simultaneously at doses of 10 and 300 mg are in the same ranges, resulting in a relative bioavailability of amlodipine of 98% and 95% of irbesartan when taken together. The average T1/2 value for amlodipine and irbesartan, taken individually or in combination, is almost the same: 58.5 versus 52.1 hours for amlodipine and 17.6 versus 17.7 hours for irbesartan. The elimination of amlodipine and irbesartan does not change when taken separately or together. The pharmacokinetics of amlodipine and irbesartan were linear when using amlodipine in doses from 5 to 10 mg and irbesartan in doses from 150 to 300 mg.

Pharmacokinetics when using the combination of amlodipine/irbesartan in children

There is no information on the use of a fixed combination of amlodipine and irbesartan in children.

Aprovask film-coated tablets 5mg + 150mg No. 28

Pharmacokinetics

Combined antihypertensive drug.
The pharmacodynamic properties of each of the active substances included in the drug Aprovac®, irbesartan and amlodipine, contribute to their additive antihypertensive effect when used in combination compared to that when each of these drugs is used separately. Both angiotensin II receptor antagonists (ARA II) and slow calcium channel blockers reduce blood pressure by reducing peripheral vascular resistance, blocking the entry of calcium into the cell and reducing the vasoconstrictor effect caused by angiotensin II are complementary mechanisms. Irbesartan

Irbesartan is a selective, potent ARA II (subtype-AT1). Angiotensin II is an important component of the RAAS, involved in the pathophysiology of the development of arterial hypertension and in the homeostasis of sodium ions. Irbesartan does not require metabolic activation to exert its effect.

Irbesartan blocks the strong vasoconstrictor and aldosterone-secreting effects of angiotensin II due to selective antagonism of angiotensin II receptors (AT1 subtype) located in vascular smooth muscle cells and the adrenal cortex. Irbesartan does not have agonistic activity towards AT1 receptors. Its affinity for AT1 receptors is 8500 times greater than for AT2 receptors (receptors that have not been shown to be associated with maintaining cardiovascular equilibrium [homeostasis]).

Irbesartan does not inhibit RAAS enzymes (such as renin, ACE), and also does not affect other hormonal receptors or ion channels in the cardiovascular system involved in the regulation of blood pressure and sodium ion homeostasis. Blockade of AT1 receptors by irbesartan breaks the feedback loop in the renin-angiotensin system, increasing plasma concentrations of renin and angiotensin II. When using irbesartan, the plasma concentration of aldosterone decreases, however, when using the drug in recommended doses, there are no significant changes in the potassium content in the blood serum (the average increase in the potassium content in the blood serum is less than 0.1 mEq/L). Irbesartan does not have a significant effect on the concentrations of triglycerides, cholesterol or glucose in the blood serum. Irbesartan does not affect serum uric acid concentrations or renal excretion of uric acid.

The antihypertensive effect of irbesartan develops after the first dose and becomes significant within 1-2 weeks of treatment, with the maximum effect occurring after 4-6 weeks. In long-term observational studies, the effect of irbesartan was maintained for more than 1 year.

A single dose of irbesartan in doses up to 900 mg/day caused a dose-dependent decrease in blood pressure. A single dose of irbesartan in doses of 150-300 mg/day led to a greater decrease in systolic (SBP)/diastolic (DBP) blood pressure (24 hours after dosing) in the supine or sitting position (on average by 8-13/5-8 mm Hg) than when taking placebo. The effect of the drug 24 hours after dosing was 60-70% of the corresponding maximum reduction in DBP and SBP. Optimal effectiveness in reducing blood pressure within 24 hours is achieved with a single dose of the drug per day.

Blood pressure decreases to approximately the same extent in standing and lying positions. Orthostatic effects are rare and, as with ACE inhibitors, may be expected to occur in patients with hyponatremia or hypovolemia.

The antihypertensive effect of irbesartan and thiazide diuretics is additive. In patients who fail to achieve target blood pressure values ​​with irbesartan monotherapy, adding small doses of hydrochlorothiazide (12.5 mg) to irbesartan once a day leads to an additional (compared to the effect of adding placebo) reduction in SBP/DBP determined after 24 hours after taking them, by 7-10/3-6 mm Hg. Art., respectively.

Age and gender do not affect the effectiveness of irbesartan. As in the case of treatment with other drugs that affect the RAAS, patients of the Negroid race have a weaker antihypertensive effect with irbesartan monotherapy. When irbesartan is taken with low doses of hydrochlorothiazide (eg, 12.5 mg/day), the antihypertensive effect in black patients approaches that in Caucasian patients.

After discontinuation of irbesartan, blood pressure gradually returns to its original level. No withdrawal syndrome was observed upon discontinuation of irbesartan.

Amlodipine

Amlodipine is a slow calcium channel blocker from the group of dihydropyridine derivatives, which inhibits the transmembrane entry of calcium ions into myocardial cells and vascular smooth muscle. The mechanism of the antihypertensive effect of amlodipine is associated with a direct relaxing effect on vascular smooth muscle.

The exact mechanism by which amlodipine reduces the frequency and severity of angina attacks is not fully established, but amlodipine reduces myocardial ischemia through the following two effects.

1) Amlodipine dilates peripheral arterioles and thereby reduces peripheral vascular resistance, the so-called afterload. Because Heart rate practically does not increase when taking amlodipine; this decrease in the load on the heart muscle reduces the energy consumption of the myocardium and its need for oxygen.

2) The mechanism of the antianginal action of amlodipine also appears to be associated with the expansion of the main coronary arteries and coronary arterioles, both in areas of the myocardium with normal blood flow and in ischemic areas of the myocardium. This dilation of the coronary vessels increases oxygen delivery to the myocardium in patients with coronary artery spasm (Prinzmetal's angina or variant angina).

In patients with arterial hypertension, taking amlodipine 1 time per day provides a clinically significant decrease in blood pressure in the supine and standing position for 24 hours. Due to the slow onset of its action, amlodipine is not intended for the relief of hypertensive crises.

In patients with angina pectoris, a single daily dose of amlodipine during an exercise test increases the total time of physical activity, the time before the onset of an angina attack and the time before the appearance of ST segment depression on an ECG with a depth of 1 mm. In addition, taking the drug reduces the daily number of angina attacks and the daily need for taking nitroglycerin tablets.

No adverse metabolic effects or changes in blood lipid concentrations were observed when taking amlodipine. Amlodipine can be prescribed to patients with bronchial asthma, diabetes mellitus and gout.

Clinical evidence of the efficacy of the fixed-dose combination of irbesartan and amlodipine was obtained from two multicenter, prospective, open-label, parallel-group, blinded efficacy studies: the I-ADD and I-COMBINE studies. The results of both studies demonstrated significantly greater efficacy of fixed-dose combinations of irbesartan and amlodipine compared with amlodipine monotherapy or irbesartan monotherapy.

Contraindications

hypersensitivity to irbesartan, amlodipine and other dihydropyridine derivatives, as well as excipients of the drug;

cardiogenic shock;

clinically significant aortic stenosis;

unstable angina (with the exception of Prinzmetal angina);

simultaneous use with drugs containing aliskiren in patients with diabetes mellitus or with moderate to severe renal failure (glomerular filtration rate (GFR) <60 ml/min/1.73 m2 body surface area) (see "Interaction" and " Special instructions");

simultaneous use with ACE inhibitors in patients with diabetic nephropathy (see “Interaction” and “Special instructions”);

pregnancy;

breastfeeding period;

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

With caution: hypovolemia and hyponatremia, which occur, for example, during intensive treatment with diuretics, hemodialysis, following a diet with limited salt intake, diarrhea, vomiting (danger of excessive reduction in blood pressure, see “Special Instructions”); patients whose renal function depends on the activity of the RAAS (including arterial hypertension with renal artery stenosis of one or both kidneys, chronic heart failure of functional class III–IV according to the NYHA classification), treatment with drugs affecting the RAAS was associated with the development of oliguria and/or progressive azotemia and rarely - acute renal failure and/or death, the risk of which cannot be excluded when taking ARAII, including irbesartan) (see "Special Instructions"); chronic heart failure of functional class II–IV according to the NYHA classification of non-ischemic etiology (due to the content of the drug amlodipine, the use of which in such patients was associated with an increase in reports of the development of pulmonary edema compared with placebo, despite the absence of differences in the incidence of cardiac progression insufficiency) (see “Special instructions”); liver failure (risk of increasing T1/2 of amlodipine - see “Special Instructions”); renal failure and after kidney transplantation (due to the content of irbesartan in the drug, monitoring of potassium content and creatinine concentration in the blood is recommended); after a recent kidney transplant (lack of experience in the clinical use of irbesartan); aortic or mitral valve stenosis or hypertrophic obstructive cardiomyopathy; coronary heart disease and/or clinically significant cerebral atherosclerosis (with an excessive decrease in blood pressure, there is a risk of increased ischemic disorders, including the development of acute myocardial infarction and stroke); sick sinus syndrome (due to the content of amlodipine in the drug).

Aprovask, 10 mg+300 mg, film-coated tablets, 28 pcs.

Frequency of adverse events/reactions (AEs/ARs) reported in clinical trials of the fixed-dose combination of irbesartan and amlodipine ( I-ADD

,
I-COMBINE
and
I-COMBO
), in clinical studies on the use of irbesartan and during its post-marketing use, as well as in clinical studies on the use of amlodipine, was determined according to the WHO classification as follows: very often (≥10%); often (≥1 and <10%); uncommon (≥0.1 and <1%); rare (≥0.01 and <0.1%); very rare (<0.01%), frequency unknown - the frequency of occurrence of AEs/ARs cannot be estimated from the available data.

The frequency of HP reported during post-marketing use of the drug was defined as frequency unknown because information about these HPs came from spontaneous reports, without indicating the number of patients taking the drug.

In clinical studies comparing fixed-dose combinations of amlodipine + irbesartan with irbesartan or amlodipine monotherapy, the types and incidence of treatment-emergent AEs possibly related to the study treatment were similar to those observed in prior clinical studies or in post-marketing reports with irbesartan monotherapy and amlodipine.

The most commonly reported adverse event was peripheral edema, primarily related to amlodipine.

AEs observed during treatment and possibly related to the study drug in clinical studies of amlodipine/irbesartan (I-ADD, I-COMBINE and I-COMBO)

General disorders and disorders at the injection site:

often - peripheral edema, edema; infrequently - asthenia.

Hearing and labyrinth disorders:

infrequently - vertigo.

From the heart:

often - a feeling of palpitations; infrequently - sinus bradycardia.

From the nervous system:

often - dizziness, headache, drowsiness; infrequently - paresthesia.

From the genital organs and breast:

infrequently - erectile dysfunction.

From the respiratory system, chest and mediastinal organs:

infrequently - cough.

From the side of blood vessels:

often - orthostatic hypotension; infrequently - excessive decrease in blood pressure.

From the gastrointestinal tract:

often - swelling of the gums; infrequently - nausea, pain in the upper abdomen, constipation.

From the kidneys and urinary tract:

often - proteinuria; infrequently - azotemia, hypercreatinemia.

Metabolism and nutrition:

infrequently - hyperkalemia.

From the musculoskeletal and connective tissue side:

infrequently - joint stiffness, arthralgia, myalgia.

AEs observed with irbesartan in clinical studies (including the I-ADD, I-COMBINE and I-COMBO clinical studies) and during its post-marketing use

From the immune system:

frequency unknown - hypersensitivity reactions (allergic reactions).

Metabolism and nutrition:

frequency unknown - hyperkalemia.

Hearing and labyrinth disorders:

often - vertigo; frequency unknown - tinnitus.

From the nervous system:

often - dizziness, headache*; infrequently - orthostatic dizziness.

*Headache incidence in I-ADD

,
I-COMBINE
and
I-COMBO
was rated as “uncommon”.

From the heart:

infrequently - tachycardia.

For the skin and subcutaneous tissues:

frequency unknown - leukocytoclastic vasculitis.

From the respiratory system, chest and mediastinal organs:

infrequently - cough.

From the gastrointestinal tract:

often - nausea/vomiting, pain in the upper abdomen, tongue disorders, including dysgeusia (taste distortion), glossodynia (burning sensation and soreness in the tongue), glossitis (inflammation of the tongue); infrequently - diarrhea, dyspepsia, heartburn.

From the liver and biliary tract:

frequency unknown - jaundice, increased liver function tests, hepatitis.

For the skin and subcutaneous tissues:

infrequently - alopecia; frequency unknown - angioedema, urticaria.

From the musculoskeletal system and connective tissue:

frequency unknown - myalgia.

From the kidneys and urinary tract:

frequency unknown - impaired renal function, including isolated cases of renal failure in patients with risk factors for its development.

From the genital organs and breast:

infrequently - erectile dysfunction.

General disorders and disorders at the injection site:

often - increased fatigue*, swelling; uncommon - chest pain; frequency unknown - asthenia.

* Incidence of fatigue in I-ADD

,
I-COMBINE
and
I-COMBO
were rated as uncommon.

Injuries, intoxications and complications of manipulations:

frequency unknown - falls.

Adverse events observed with amlodipine in clinical studies (including the I-ADD, I-COMBINE and I-COMBO clinical studies)

From the blood and lymphatic system:

very rarely - thrombocytopenia.

From the immune system:

very rarely - allergic reactions.

Metabolism and nutrition:

very rarely - hyperglycemia.

Mental disorders:

infrequently - insomnia, mood lability.

From the nervous system:

often - dizziness, headache*, drowsiness; infrequently - hypoesthesia, paresthesia, tremor, taste disturbances, syncope; very rarely - peripheral neuropathy.

*Headache incidence in I-ADD

,
I-COMBINE
and
I-SOMBO
were rated as “uncommon.”

From the side of the organ of vision:

infrequently - visual disturbances.

Hearing and labyrinth disorders:

infrequently - ringing in the ears, vertigo.

From the heart:

often - a feeling of palpitations; very rarely - myocardial infarction, cardiac arrhythmias, ventricular tachycardia and atrial fibrillation (atrial fibrillation).

From the side of blood vessels:

often - a rush of blood to the skin with a feeling of heat, redness of the skin*; infrequently - excessive decrease in blood pressure; very rarely - vasculitis.

* Incidence of skin redness in I-ADD

,
I-COMBINE
and
I-COMBO
were rated as uncommon.

From the respiratory system, chest and mediastinal organs:

often - cough; infrequently - shortness of breath, rhinitis; very rarely - coughing.

From the digestive system:

often - nausea, abdominal pain, glossodynia, glossitis; infrequently - dyspepsia, vomiting, change in the rhythm of bowel movements, dryness of the mucous membranes of the oral cavity; very rarely - pancreatitis, gastritis, gum hyperplasia.

From the liver and biliary tract:

very rarely - hepatitis, jaundice and increased activity of liver enzymes (mainly associated with cholestasis).

For the skin and subcutaneous tissues:

often - contact dermatitis; uncommon - skin rash, itching, purpura, increased sweating, changes in skin pigmentation (appearance of discolored areas of the skin), alopecia; very rarely - angioedema, erythema multiforme, urticaria.

From the musculoskeletal and connective tissue side:

uncommon - arthralgia, muscle cramps, myalgia, back pain.

From the kidneys and urinary tract:

infrequently - increased frequency of urination, painful urge to urinate, nocturia.

From the genital organs and breast:

infrequently - impotence, gynecomastia.

General disorders and disorders at the injection site:

often - increased fatigue, edema*, peripheral edema; infrequently - chest pain, asthenia, feeling of malaise, pain; rarely - swelling of the face.

*Based on I-ADD

,
I-COMBINE
and
I-COMBO
incidence of edema: uncommon.

Laboratory and instrumental data:

infrequently - weight gain, weight loss.

Use during pregnancy and breastfeeding

When irbesartan was administered at doses ≥50 mg/kg/day (which, when calculated per 1 kg of body weight, is approximately equivalent to the maximum recommended dose of irbesartan in humans (MRDIH) of 300 mg/day) in pregnant rats from days 0 to 20 Transient effects (slight to moderate dilatation of the renal pelvis, hydroureter and/or absence of renal papillae) were observed in rat fetuses during gestation. When irbesartan was administered in doses ≥180 mg/kg/day (approximately equivalent to 4×MRDICH per 1 kg of body weight) by pregnant rats from days 0 to 20 of gestation, the development of subcutaneous edema was observed in fetal rats. Since these developmental abnormalities were not observed when oral irbesartan was restricted to 50, 150, and 450 mg/kg/day in pregnant rats from days 6 to 15 of gestation, they appear to be late gestational effects of irbesartan. In rabbits, irbesartan 30 mg/kg/day was associated with maternal mortality and abortion. Surviving females receiving this dose, equivalent to 1.5xMRDICH per kg body weight, had a slight increase in fetal resorption and, accordingly, a decrease in the number of live fetuses in the litter. It was found that irbesartan penetrates the placental barrier in rats and rabbits.

The teratogenic effect of amlodipine was not detected in rats and rabbits.

There are no sufficient and well-controlled studies of the use of the drug Aprovask® in pregnant women. Fetal exposure to ACE inhibitors taken by pregnant women during the second and third trimesters of pregnancy has resulted in damage and death of the developing fetus. Like any other drugs that directly affect the RAAS, Aprovask® is contraindicated during pregnancy. Aprovask® should not be used in women of childbearing potential unless they use effective methods of contraception. If pregnancy is detected during treatment with Aprovask®, you should stop taking it as soon as possible (see “Contraindications”).

The drug Aprovask® is contraindicated during breastfeeding (see “Contraindications”).

Aprovask tab p/pl/o 5mg+150mg N28 (Sanofi)

Combined antihypertensive drug. The pharmacodynamic properties of each of the active substances included in the drug Aprovac®, irbesartan and amlodipine, contribute to their additive antihypertensive effect when used in combination compared to that when each of these drugs is used separately. Both angiotensin II receptor antagonists (ARA II) and slow calcium channel blockers reduce blood pressure by reducing peripheral vascular resistance, blocking the entry of calcium into the cell and reducing the vasoconstrictor effect caused by angiotensin II are complementary mechanisms. Irbesartan Irbesartan is a selective, highly active APA II (subtype-AT1). Angiotensin II is an important component of the RAAS, involved in the pathophysiology of the development of arterial hypertension and in the homeostasis of sodium ions. To exert its effect, irbesartan does not require metabolic activation. Irbesartan blocks the strong vasoconstrictor and aldosterone-secreting effects of angiotensin II due to selective antagonism of angiotensin II receptors (subtype AT1), located in the cells of vascular smooth muscle and the adrenal cortex. Irbesartan does not have agonistic activity towards AT1 receptors. Its affinity for AT1 receptors is 8500 times greater than for AT2 receptors (receptors that have not been shown to be associated with maintaining equilibrium [homeostasis] of the cardiovascular system). Irbesartan does not inhibit RAAS enzymes (such as renin, ACE), and also does not affect other hormonal receptors or ion channels in the cardiovascular system involved in the regulation of blood pressure and sodium ion homeostasis. Blockade of AT1 receptors by irbesartan breaks the feedback loop in the renin-angiotensin system, increasing plasma concentrations of renin and angiotensin II. When using irbesartan, the plasma concentration of aldosterone decreases, however, when using the drug in recommended doses, there are no significant changes in the potassium content in the blood serum (the average increase in the potassium content in the blood serum is less than 0.1 mEq/L). Irbesartan does not have a significant effect on the concentrations of triglycerides, cholesterol or glucose in the blood serum. Irbesartan does not affect serum uric acid concentrations or renal excretion of uric acid. The antihypertensive effect of irbesartan develops after the first dose and becomes significant within 1-2 weeks of treatment with the maximum effect occurring after 4-6 weeks. In long-term observational studies, the effect of irbesartan persisted for more than 1 year. A single dose of irbesartan in doses up to 900 mg/day caused a dose-dependent decrease in blood pressure. A single dose of irbesartan in doses of 150-300 mg/day led to a greater decrease in systolic (SBP)/diastolic (DBP) blood pressure (24 hours after dosing) in the supine or sitting position (on average by 8-13/5-8 mm Hg) than when taking placebo. The effect of the drug 24 hours after dosing was 60-70% of the corresponding maximum reduction in DBP and SBP. Optimal effectiveness in reducing blood pressure within 24 hours is achieved with a single dose of the drug per day. Blood pressure decreases to approximately the same extent in the standing and lying position. The orthostatic effect is rare and, as with the use of ACE inhibitors, its occurrence can be expected in patients with hyponatremia or hypovolemia. The antihypertensive effect of irbesartan and thiazide diuretics is additive. In patients who fail to achieve target blood pressure values ​​with irbesartan monotherapy, adding small doses of hydrochlorothiazide (12.5 mg) to irbesartan once a day leads to an additional (compared to the effect of adding placebo) reduction in SBP/DBP determined after 24 hours after taking them, by 7-10/3-6 mm Hg. Art., respectively. Age and gender do not affect the effectiveness of irbesartan. As in the case of treatment with other drugs that affect the RAAS, patients of the Negroid race have a weaker antihypertensive effect with irbesartan monotherapy. When irbesartan is taken with small doses of hydrochlorothiazide (for example, 12.5 mg/day), the antihypertensive effect in black patients approaches that in Caucasian patients. After discontinuation of irbesartan, blood pressure gradually returns to its original level. No withdrawal syndrome was observed upon discontinuation of irbesartan. Amlodipine Amlodipine is a slow calcium channel blocker from the group of dihydropyridine derivatives, which inhibits the transmembrane entry of calcium ions into myocardial cells and vascular smooth muscle. The mechanism of the antihypertensive effect of amlodipine is associated with a direct relaxing effect on vascular smooth muscle. The exact mechanism by which amlodipine reduces the frequency and severity of angina attacks is not fully established, but amlodipine reduces myocardial ischemia due to the following two effects. 1) Amlodipine expands peripheral arterioles and due to this reduces the peripheral vascular resistance, the so-called afterload. Because Heart rate practically does not increase when taking amlodipine; this decrease in the load on the heart muscle reduces the energy consumption of the myocardium and its oxygen demand. 2) The mechanism of the antianginal action of amlodipine also appears to be associated with the expansion of the main coronary arteries and coronary arterioles, as in areas of the myocardium with normal blood flow and in ischemic areas of the myocardium. This expansion of the coronary vessels increases the delivery of oxygen to the myocardium in patients with spasm of the coronary arteries (with Prinzmetal's angina or variant angina). In patients with arterial hypertension, taking amlodipine 1 time per day provides a clinically significant reduction in blood pressure in the supine and standing position for 24 hours. Due to the slow onset of its action, amlodipine is not intended for the relief of hypertensive crises. In patients with angina pectoris, a single daily dose of amlodipine during an exercise test increases the total time of physical activity, the time before the onset of an angina attack and the time before the appearance of ST segment depression on the ECG 1 mm deep. In addition, taking the drug reduces the daily number of angina attacks and the daily need for taking nitroglycerin tablets. When taking amlodipine, no undesirable metabolic effects or changes in blood lipid concentrations were observed. Amlodipine can be prescribed to patients with bronchial asthma, diabetes mellitus and gout. Clinical evidence of the effectiveness of the fixed-dose combination of irbesartan and amlodipine was obtained from two multicenter, prospective, open-label, parallel-group studies with blinded assessment of efficacy indicators: the I-ADD and I-COMBINE studies. The results of both studies demonstrated significantly greater efficacy of fixed-dose combinations of irbesartan and amlodipine compared with amlodipine monotherapy or irbesartan monotherapy.