Aprovel, 28 pcs., 150 mg, film-coated tablets

Instructions for use APROVEL

Mechanism of action

When taken orally, irbesartan is an active selective antagonist of angiotensin II receptors (type AT1). It blocks all physiologically significant effects of angiotensin II through the AT1 receptor, regardless of the source or pathway of angiotensin II synthesis. The specific antagonistic effect on angiotensin II receptors (AT1) leads to an increase in the concentration of renin and angiotensin II and a decrease in the concentration of aldosterone in the blood plasma. When using the recommended doses of the drug, the concentration of potassium ion in the blood serum does not change significantly. Irbesartan does not inhibit kininase II. Irbesartan does not require metabolic activation to exert its effect.

Hypertension

Irbesartan dose-dependently (when used up to 900 mg/day) reduces blood pressure with minimal changes in heart rate.

The maximum reduction in blood pressure is achieved 3-6 hours after taking the drug orally, and the hypotensive effect persists for at least 24 hours. 24 hours after taking the recommended doses, the reduction in blood pressure is 50-70% compared to the maximum diastolic and systolic response HELL. When using the drug in a daily dose of 150-300 mg 24 hours after a single dose, the average decrease in blood pressure (in a lying or sitting position) is 8-13/5-8 mm Hg. (systolic/diastolic blood pressure) compared with placebo.

The hypotensive effect of the drug Aprovel develops within 1-2 weeks, and the maximum therapeutic effect is achieved 4-6 weeks after the start of treatment. The antihypertensive effect persists during long-term treatment. After cessation of treatment, blood pressure gradually returned to its original value; no withdrawal syndrome was observed.

The hypotensive effects of irbesartan and thiazide-type diuretics are additive. In patients who cannot control blood pressure with irbesartan monotherapy, the administration of small doses of hydrochlorothiazide (12.5 mg) leads to an additional reduction in blood pressure.

Irbesartan does not affect the level of uric acid in the blood serum or the excretion of uric acid in the urine.

Children and teenagers

Blood pressure lowering using planned titrated doses of irbesartan of 0.5 mg/kg (low), 1.5 mg/kg (moderate), and 4.5 mg/kg (high) was studied over 3 weeks in 318 pediatric and adolescent patients (6 to 16 years old) with hypertension or risk of developing it (diabetes, family history of hypertension). At the end of the 3-week period, the mean decrease from baseline in the primary effect variable, nadir steady-state systolic blood pressure (SBP), was 11.7 mmHg. (low dose), 9.3 mmHg (medium dose) and 13.2 mmHg. (high dose). No significant difference was observed between doses. The adjusted mean change in lowest steady-state diastolic blood pressure (LSBP) was as follows:

• 3.8 mmHg (low dose), 3.2 mmHg. (average dose) and 5.6 mm Hg. (high dose). During the subsequent 2-week period, in which patients were randomized to the active substance and placebo groups, in patients with placebo, the SDC and UDDC increased by 2.4 mmHg and 2.0 mmHg compared with +0.1 and -0.3 mm Hg, respectively, observed in patients receiving all indicated doses of irbesartan.

Hypertension and type 2 diabetes mellitus with kidney disease

The IDNT (Irbesartan for Diabetic Nephropathy) clinical trial showed that irbesartan slows the progression of kidney damage in patients with chronic renal failure and severe proteinuria. IDNT is a double-blind, controlled clinical morbidity and mortality study comparing Aprovel with amlodipine and placebo. In 1715 patients with type 2 diabetes mellitus with hypertension, proteinuria ≥900 mg/day and serum creatinine levels between 1.0 and 3.0 mg/dL, the long-term (mean 2.6 years) effect of Aprovel on the progression of kidney disease and mortality was studied. Doses were titrated from 75 mg to a maintenance dose of 300 mg, amlodipine doses from 2.5 mg to 10 mg, and placebo depending on individual tolerability. In all groups, patients received 2-4 antihypertensive drugs (eg, diuretics, beta-blockers, alpha-blockers) to achieve a pre-specified, desired blood pressure ≥135/85 mmHg. or a decrease in systolic pressure by 10 mm Hg, if the initial pressure was above 160 mm Hg. In the placebo group, sixty percent (60%) of patients achieved the required blood pressure level, and in the irbesartan and amlodipine groups - 76% and 78% of patients, respectively. Aprovel significantly reduced the relative risk of a two-fold increase in serum creatinine, end-stage renal disease, or mortality from any cause. Only about 33% of patients in the Aprovel group achieved the composite renal primary endpoint, compared with 39% and 41% in the placebo and amlodipine groups [20% relative risk reduction versus placebo (p=0.024) and 23% versus amlodipine (p= 0.006)].

When analyzing individual components of the primary endpoint, there was no effect on all-cause mortality, whereas there was a positive trend towards a reduction in end-stage renal disease and a significant reduction in the doubling of serum creatinine.

Therapeutic effect was assessed by subgroups based on sex, race, age, duration of diabetes, baseline blood pressure, serum creatinine level, and albumin excretion rate. In the subgroups of female and black patients, representing 32% and 26% of the total study population, a renoprotective effect was not obvious, although, judging by the confidence intervals, it is not excluded. Regarding the secondary endpoint (fatal and non-fatal cardiovascular changes), there were no differences between the three groups in the general population, although in the irbesartan group there was an increase in non-fatal myocardial infarction in women and a decrease in non-fatal myocardial infarction in men, compared with the therapeutic regimen , based on placebo. An increased incidence of non-fatal myocardial infarction and stroke was observed in women taking irbesartan when compared with a regimen that included amlodipine, while the incidence of hospitalization for heart failure decreased in the general population. However, no proper explanation was found for these phenomena observed in women.

The IRMA 2 trial (“Effect of irbesartan on microalbuminuria in hypertensive patients with type 2 diabetes mellitus”) showed that in patients with microalbuminuria, taking Aprovel at a daily dose of 300 mg slows down the transition of microalbuminuria to severe proteinuria. IRMA 2 was a double-blind, placebo-controlled clinical trial conducted in 590 patients with type 2 diabetes mellitus with microalbuminuria (30-300 mg/day) and normal renal function (serum creatinine ≤1.5 mg/dL in men and <1.1 mg /dl in women). The study examined the long-term (2 years) effects of Aprovel on progression to clinical (severe) proteinuria (urinary albumin excretion rate (UAMR) >300 mg/day and an increase in VAAM by at least 30% compared to baseline). Desired blood pressure was ≥135/85 mmHg. To achieve the desired blood pressure, additional antihypertensive drugs were used, if necessary (with the exception of ACE inhibitors, angiotensin II receptor antagonists and dihydropyridine calcium channel blockers). Although similar blood pressure levels were achieved in all treatment groups, fewer patients developed severe proteinuria in the Aprovel 300 mg group (5.2%) than in the placebo group (14.9%) and in the Aprovel 150 mg group (9.7%). demonstrating a 70% reduction in relative risk (at the higher (300 mg) daily dose) compared with placebo (p=0.0004). During the first three months of treatment, no simultaneous improvement in glomerular filtration rate (GFR) was observed. Slowing of the progression of clinical proteinuria was evident after three months and was maintained for 2 years. Recovery of renal function to the level of normoalbuminuria (<30 mg/day) was observed more often in the 300 mg Aprovel group (34%) than in the placebo group (21%).

Preclinical safety data

There were no signs of systemic or organ toxicity at clinically relevant doses. In preclinical safety studies, high doses of irbesartan (≥250 mg/kg/day for rats and ≥100 mg/kg/day for macaques) resulted in deterioration of red blood cell parameters (number, hemoglobin, hematocrit).

At very high doses (≥500 mg/kg/day), irbesartan caused degenerative changes in the kidneys of rats and macaques (such as interstitial nephritis, tubular distension, basophilic renal tubules, increased concentrations of urea and creatinine in plasma), these are considered secondary (after hypotensive) effect of the drug leading to a decrease in renal perfusion. Moreover, irbesartan induced hyperplasia or hypertrophy of juxtaglomerular cells (in rats at a dose of ≥90 mg/kg/day, in macaques ≥10 mg/kg/day). All these changes were considered to be a consequence of the pharmacological action of irbesartan. At therapeutic doses of irbesartan, hyperplasia and hypertrophy of human renal juxtaglomerular cells does not have any significance.

No evidence of mutagenicity, clastogenicity or carcinogenicity was observed.

Animal studies of irbesartan revealed transient toxic effects on the rat fetus (enlargement of the renal pelvic cavity, hydroureter and subcutaneous edema), which resolved after birth. Abortions or early resorption have been reported in rabbits at doses causing significant maternal toxicity, including mortality. No teratogenic effect was observed in rats and rabbits.

Aprovel®

Excessive decrease in blood pressure in patients with hypovolemia

The drug Aprovel® rarely caused an excessive decrease in blood pressure in patients with arterial hypertension without other concomitant pathology. As with ACE inhibitors, an excessive decrease in blood pressure with corresponding symptoms can develop in patients with hypovolemia/hyponatremia (for example, as a result of intensive diuretic therapy, diarrhea, vomiting, following a diet with limited salt intake), as well as in patients on hemodialysis. Hyponatremia and/or hypovolemia should be corrected before starting treatment with Aprovel, or a lower starting dose should be considered.

Hypoglycemia

Aprovel® may cause hypoglycemia, especially in patients receiving medications for the treatment of diabetes mellitus. Therefore, dosage adjustments of diabetes medications such as repaglinide or insulin may be necessary.

Prenatal/newborn morbidity and mortality

Although there is no experience with the use of Aprovel® in pregnant women, it has been reported that in utero exposure to ACE inhibitors, when taken by pregnant women in the second and third trimesters, can lead to impaired development and fetal death. Aprovel® is contraindicated for use during pregnancy, like any other drug that has a direct effect on the RAAS. If pregnancy is detected during treatment, use of Aprovel® should be discontinued as soon as possible (see sections “Contraindications”, “Use during pregnancy and breastfeeding”).

Patients with renal function dependent on RAAS activity

As a consequence of RAAS inhibition, deterioration of renal function can be expected in predisposed patients. In patients with renal function dependent on the activity of the RAAS (patients with arterial hypertension and renal artery stenosis of one or both kidneys, patients with chronic heart failure of functional class III and IV [NYHA classification]), treatment with drugs that affect the RAAS, has been associated with oliguria and/or progressive azotemia and rarely with acute renal failure and/or death. The possibility of a similar effect when using angiotensin II receptor antagonists, including irbesartan, cannot be excluded.

Kidney failure and kidney transplantation

When using the drug Aprovel® in patients with renal failure, periodic monitoring of potassium levels and creatinine concentrations in the blood serum is recommended. There are no clinical data regarding the use of Aprovel® in patients who have recently undergone kidney transplantation.

Patients with arterial hypertension and diabetes mellitus and type 2 diabetes with impaired renal function

The beneficial effect of Aprovel® in slowing the progression of renal and cardiovascular disorders had varying degrees of severity in different groups of patients; it was less pronounced in women and in patients not belonging to the Caucasian race. In the IDNT clinical trial in patients with hypertension and type 2 diabetes mellitus with proteinuria (≥ 900 mg/day), in a subgroup of patients at high risk of renal artery stenosis, no patients receiving Aprovel® experienced an acute early increase in creatinine concentration in serum associated with renal artery stenosis.

Double blockade of the RAAS with simultaneous use of irbesartan with ACE inhibitors or aliskiren

Double blockade of the RAAS when using a combination of irbesartan with ACE inhibitors or aliskiren is not recommended, since compared with monotherapy there is an increased risk of a sharp decrease in blood pressure, the development of hyperkalemia and renal dysfunction. Concomitant use of irbesartan with aliskiren or drugs containing aliskiren is contraindicated in patients with diabetes mellitus and/or moderate or severe renal impairment with a GFR <60 ml/min/1.73 m2 body surface area (see sections "Contraindications", " Interaction with other drugs") and is not recommended in other patients. The simultaneous use of irbesartan with ACE inhibitors is contraindicated in patients with diabetic nephropathy (see sections “Contraindications”, “Interaction with other drugs”) and is not recommended in other patients.

Psoriasis

In patients with psoriasis (including a history), the decision to use the drug should be made only after a thorough assessment of the risk/benefit ratio due to the possible exacerbation of psoriasis.

Hyperkalemia

As with the use of other drugs that affect the RAAS, hyperkalemia may develop during treatment with Aprovel®, especially in the presence of. kidney failure and/or heart disease. In such patients, it is recommended to monitor serum potassium levels.

Aortic or mitral valve stenosis, hypertrophic obstructive cardiomyopathy

As with other vasodilators, caution should be exercised when taking Aprovel@ in patients with aortic or mitral stenosis or hypertrophic obstructive cardiomyopathy.

Primary hyperaldosteronism

Patients with primary hyperaldosteronism usually do not respond to antihypertensive drugs that act through inhibition of the RAAS. Therefore, the use of Aprovel® in such cases is not advisable.

Patients with coronary heart disease and/or clinically significant cerebral atherosclerosis

As with the use of other antihypertensive drugs, a significant decrease in blood pressure in patients with coronary heart disease and/or severe cerebral atherosclerosis can lead to the development of myocardial infarction or stroke. Treatment of such patients should be carried out under strict blood pressure control.

Aprovel tablets ppo 150mg No. 28

Compound

Active substance: irbesartan 150 mg.
Excipients: lactose monohydrate, microcrystalline cellulose, croscarmellose sodium, hypromellose, magnesium stearate, silicon dioxide. Film shell composition: white dye*, carnauba wax.

Pharmacokinetics

Suction

After oral administration, irbesartan is quickly and completely absorbed. Cmax of irbesartan in blood plasma is achieved 1.5-2 hours after oral administration. Absolute bioavailability is 60-80%. Concomitant food intake does not significantly affect the bioavailability of the drug.

Distribution

Plasma protein binding is approximately 96%. Binding to cellular components of blood is negligible. Vd is 53-93 l.

With daily intake of irbesartan 1 time/day, Css is achieved after 3 days, while its limited accumulation in plasma is observed (less than +20%).

Metabolism

After oral or intravenous administration of 14C-irbesartan, 80-85% of the radioactivity in circulating plasma is unchanged irbesartan.

Irbesartan is metabolized in the liver by oxidation and conjugation with glucuronic acid. The oxidation of irbesartan occurs mainly with the participation of the CYP2C9 isoenzyme; the participation of the CYP3A4 isoenzyme in the metabolism of irbesartan is insignificant. The main metabolite found in the systemic circulation is irbesartan glucuronide (about 6%).

Irbesartan is not metabolized by most isoenzymes that are usually involved in the metabolism of drugs (isoenzymes CYP1A1, CYP1A2, CYP2A6, CYP2B6, CYP2D6 or CYP2E1), and does not cause their inhibition or induction. Irbesartan does not induce or inhibit the CYP3A4 isoenzyme.

Removal

Irbesartan and its metabolites are excreted from the body, both through the intestines and the kidneys. Less than 2% of the administered dose is excreted by the kidneys as unchanged irbesartan. The final T1/2 is 11-15 hours. The total clearance of intravenously administered irbesartan is 157-176 ml/min, and its renal clearance is 3-3.5 ml/min.

Pharmacokinetics in special clinical situations

Floor. Women (compared to men) had slightly higher plasma concentrations of irbesartan. However, no gender-related differences in T1/2 and accumulation of irbesartan were detected. No dose adjustment of irbesartan is required in women. There were no gender-related differences in the effects of irbesartan.

Elderly patients. The AUC and Cmax values ​​of irbesartan in elderly patients (65-80 years) with clinically normal renal and hepatic function were approximately 20-50% higher than in younger patients (18-40 years). Final T1/2 values ​​were comparable. There were no age-related differences in the effects of irbesartan.

Liver dysfunction. In patients with mild (functional class A or 5-6 points on the Child-Pugh scale) and moderately severe (functional class B or 7-9 points on the Child-Pugh scale) liver failure due to cirrhosis, the pharmacokinetic parameters of irbesartan do not change significantly.

Renal dysfunction. In patients with impaired renal function or patients undergoing hemodialysis, the pharmacokinetics of irbesartan do not change significantly. Irbesartan is not excreted from the body by hemodialysis.

Race. In representatives of the Negroid race without arterial hypertension, the AUC and T1/2 of irbesartan are approximately 20-25% higher than in representatives of the Caucasian race; Their Cmax of irbesartan was almost similar to that of representatives of the Caucasian race.

Indications for use

• Arterial hypertension (as monotherapy and in combination with other antihypertensive drugs, for example, thiazide diuretics, beta-blockers, long-acting slow calcium channel blockers);
• nephropathy in arterial hypertension and type 2 diabetes mellitus (as part of combination antihypertensive therapy).

Contraindications

• Hypersensitivity to irbesartan or any of the excipients of the drug;
• severe liver failure (functional class C or more than 9 points on the Child-Pugh scale) (lack of experience in clinical use);
• simultaneous use with drugs containing aliskiren in patients with diabetes mellitus and/or with moderate to severe renal failure (GFR <60 ml/min/1.73 m2 body surface area);
• simultaneous use with ACE inhibitors in patients with diabetic nephropathy;
• pregnancy;
• lactation period (breastfeeding);
• age under 18 years (efficacy and safety have not been established);
• hereditary galactose intolerance, lactase deficiency or glucose/galactose malabsorption syndrome;

Carefully

• with stenosis of the aortic or mitral valve, hypertrophic obstructive cardiomyopathy;
• with hypovolemia, hyponatremia, which occurs, for example, during intensive treatment with diuretics, hemodialysis, diarrhea, vomiting, following a diet with limited salt intake (risk of excessive reduction in blood pressure);
• in patients with renal function dependent on the activity of the RAAS, such as patients with arterial hypertension with bilateral or unilateral renal artery stenosis or patients with chronic heart failure of functional class III-IV (according to the NYHA classification);
• with ischemic 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);
• in case of renal failure (monitoring of potassium levels and creatinine concentrations in the blood is required), recent kidney transplantation (lack of experience in clinical use);
• with simultaneous use of NSAIDs, including selective COX-2 inhibitors (increased risk of renal dysfunction, including the possibility of acute renal failure and increased serum potassium, especially in elderly patients, patients with hypovolemia [including patients taking diuretics] or patients with impaired renal function);
• when used in combination with ACE inhibitors or aliskiren, since, compared with monotherapy, with double blockade of the RAAS there is an increased risk of developing an excessive decrease in blood pressure, hyperkalemia and renal dysfunction;
• in patients with psoriasis (including a history) due to a possible exacerbation of psoriasis.

Directions for use and doses

The drug is taken orally, regardless of food intake. Swallow the tablet whole with water.

The initial dose is 150 mg 1 time/day.

For patients in whom additional reduction in blood pressure is required to achieve target blood pressure values, the dose can be increased to 300 mg 1 time / day.

In case of insufficient reduction in blood pressure during monotherapy with irbesartan, diuretics (for example, hydrochlorothiazide 12.5 mg / day) or other antihypertensive drugs (for example, beta-blockers, long-acting calcium channel blockers) can be added to treatment.

In patients with nephropathy due to arterial hypertension and type 2 diabetes mellitus, the preferred maintenance dose is 300 mg 1 time / day.

The maximum daily dose is 300 mg/day.

The use of the drug in children and adolescents under the age of 18 is contraindicated (there is insufficient clinical data on the safety and effectiveness of the drug).

Elderly patients (over 65 years): no dose adjustment is required.

Patients with impaired renal function: no dose adjustment is required.

Patients with impaired liver function: in patients with mild to moderate hepatic impairment (5-9 points on the Child-Pugh scale), no dose adjustment is required. There is no experience with the use of the drug in patients with severe liver failure.

Patients with hypovolemia: in patients with severe hypovolemia and/or hyponatremia, such as patients receiving intensive diuretic therapy or on hemodialysis, hypovolemia and hyponatremia should be corrected before using Aprovel®.

Storage conditions

The drug should be stored out of the reach of children at a temperature not exceeding 30°C.

Best before date

3 years. Do not use the drug after the expiration date indicated on the package.

special instructions

Excessive decrease in blood pressure in patients with hypovolemia

The use of the drug Aprovel® has so far rarely been accompanied by an excessive decrease in blood pressure in patients with arterial hypertension without concomitant diseases. As with the use of ACE inhibitors, an excessive decrease in blood pressure, accompanied by clinical symptoms, can develop in patients with hyponatremia/hypovolemia (for example, as a result of intensive diuretic therapy, diarrhea or vomiting, following a diet with limited sodium intake), as well as in patients on hemodialysis. Before starting the use of Aprovel®, it is necessary to correct hypovolemia and/or hyponatremia.

Patients with renal function dependent on RAAS activity

Due to inhibition of the RAAS, deterioration of renal function can be expected in predisposed patients. In patients with renal function dependent on the activity of the RAAS (patients with arterial hypertension and renal artery stenosis of one or both kidneys or patients with chronic heart failure of NYHA functional classes III and IV), treatment with drugs that affect the RAAS was associated with oliguria and/or progressive azotemia and rarely with acute renal failure and/or death. The possibility of a similar effect when using angiotensin II receptor antagonists, including irbesartan, cannot be excluded.

Kidney failure and kidney transplant

When using Aprovel® in patients with renal failure, periodic monitoring of serum potassium and creatinine concentrations is recommended. There are no clinical data regarding the use of Aprovel® in patients who have undergone kidney transplantation.

Patients with arterial hypertension and type 2 diabetes mellitus with impaired renal function

The beneficial effect of Aprovel® in slowing the progression of renal and cardiovascular disorders had varying degrees of severity in different groups of patients: it was less pronounced in women and non-Caucasian patients.

In the IDNT clinical trial in patients with arterial hypertension and type 2 diabetes mellitus with proteinuria (≥900 mg/day), in the subgroup of patients at high risk of renal artery stenosis, no acute early increase in concentration was observed in any patient taking Aprovel® serum creatinine associated with renal artery stenosis.

Double blockade of the RAAS with simultaneous use of irbesartan with ACE inhibitors or aliskiren

Double blockade of the RAAS when using a combination of irbesartan with ACE inhibitors or aliskiren is not recommended, because Compared with monotherapy, there is an increased risk of a sharp decrease in blood pressure, the development of hyperkalemia and renal dysfunction.

Concomitant use of irbesartan with aliskiren or drugs containing aliskiren is contraindicated in patients with diabetes mellitus and/or moderate or severe renal impairment with GFR <60 ml/min/1.73 m2 body surface area and is not recommended in other patients.

Concomitant use of irbesartan with ACE inhibitors is contraindicated in patients with diabetic nephropathy and is not recommended in other patients.

Psoriasis

In patients with psoriasis (including a history of psoriasis), the decision to use the drug should be made only after a thorough assessment of the risk/benefit ratio due to the possible exacerbation of psoriasis.

Hyperkalemia

As with the use of other drugs that affect the RAAS, hyperkalemia may develop during treatment with Aprovel®, especially in the presence of renal failure and/or heart disease. In such patients, it is recommended to monitor serum potassium levels.

Aortic or mitral valve stenosis, obstructive hypertrophic cardiomyopathy

As with the use of other vasodilators, caution is required when prescribing Aprovel® to patients with aortic or mitral stenosis or hypertrophic obstructive cardiomyopathy.

Primary hyperaldosteronism

Patients with primary hyperaldosteronism usually do not respond to antihypertensive drugs that inhibit the RAAS. Therefore, the use of Aprovel® in such cases is not advisable.

IHD and/or clinically significant cerebral atherosclerosis

As with the use of other antihypertensive drugs, a significant decrease in blood pressure in patients with coronary artery disease and/or severe cerebral atherosclerosis can lead to the development of myocardial infarction or stroke. Treatment should be carried out under blood pressure monitoring.

Description

Angiotensin II receptor antagonist.

Use in children

The use of the drug is contraindicated in children and adolescents under 18 years of age (efficacy and safety have not been established).

Pharmacodynamics

Selective antagonist of angiotensin II receptors (AT1 type). Irbesartan does not require metabolic activation to acquire pharmacological activity.

Angiotensin II is an important component of the RAAS and is involved in the pathogenesis of arterial hypertension, as well as sodium homeostasis. Irbesartan blocks all physiologically significant effects of angiotensin II, regardless of the source or route of its synthesis, incl. a pronounced vasoconstrictor effect and increased secretion of aldosterone, realized through AT1 type receptors located on the surface of vascular smooth muscle cells and in the adrenal cortex. Irbesartan does not have agonistic activity against AT1 receptors and has a much greater (more than 8500 times) affinity for AT1 receptors than for AT2 receptors (receptors not associated with the regulation of the cardiovascular system).

Irbesartan does not inhibit RAAS enzymes (such as renin, ACE) and does not affect other hormone receptors or ion channels involved in the regulation of blood pressure and sodium homeostasis. Blocking AT1 receptors with irbesartan interrupts the feedback chain in the renin-angiotensin system, which leads to an increase in plasma concentrations of renin and angiotensin II. After taking irbesartan in recommended doses, the plasma concentration of aldosterone decreases, without having a significant effect on the content of potassium in the blood serum (the average increase is <0.1 mEq/L).

Irbesartan has no significant effect on serum concentrations of triglycerides, cholesterol and glucose. Irbesartan does not affect the concentration of uric acid in the blood serum or the rate of excretion of uric acid by the kidneys.

The antihypertensive effect of irbesartan appears after taking its first dose and becomes significant within 1-2 weeks of administration, its maximum antihypertensive effect is achieved by 4-6 weeks of treatment. In long-term clinical studies, the antihypertensive effect of irbesartan was observed to persist for more than one year.

The antihypertensive effect with a single daily dose of irbesartan in doses up to 900 mg is dose-dependent. Irbesartan, when taken once a day in doses of 150-300 mg, reduces blood pressure, measured in a lying or sitting position at the end of the interdose interval (24 hours after taking a dose of irbesartan, i.e. before taking the next dose of irbesartan), by an average of 8 -13/5-8 mm Hg. Art. (systolic/diastolic blood pressure) compared with placebo. The antihypertensive effect of irbesartan before taking the next dose is 60-70% of the maximum values ​​for reducing diastolic and systolic blood pressure. The optimal reduction in blood pressure within 24 hours is achieved by taking irbesartan once a day.

Irbesartan reduces blood pressure to approximately the same extent in a standing and lying position. Orthostatic effects are rare, however, as with ACE inhibitors, in patients with hyponatremia and/or hypovolemia, an excessive decrease in blood pressure with clinical manifestations is possible.

The antihypertensive effect of irbesartan and thiazide diuretics is additive. In patients with insufficient reduction in blood pressure during monotherapy with irbesartan, the addition of hydrochlorothiazide in low doses (12.5 mg) once a day to its intake leads to an additional decrease in blood pressure by 7-10/3-6 mm Hg. (systolic/diastolic) versus adding placebo.

The effectiveness of irbesartan does not depend on age or gender. As with the use of other drugs that affect the RASS, the antihypertensive effect of irbesartan in black patients is noticeably less pronounced, however, when irbesartan is used simultaneously with hydrochlorothiazide in low doses (for example, 12.5 mg / day), the antihypertensive response in black patients approaches effectiveness to that in Caucasian patients.

After discontinuation of irbesartan, blood pressure returns to its original level gradually. There is no withdrawal syndrome observed.

In patients with hypertension and type 2 diabetes mellitus receiving irbesartan 300 mg, there was a 20% reduction (compared with placebo) and 23% reduction (compared with amlodipine 10 mg) in the relative risk of the first occurrence of any of the following conditions : doubling of serum creatinine concentration, development of end-stage renal failure or death from any cause (with a comparable reduction in blood pressure achieved when using irbesartan and amlodipine).

Side effects

The safety of Aprovel® was studied in clinical studies in approximately 5000 patients, including 1300 patients with hypertension who took the drug for more than 6 months, and 400 patients who took the drug for 1 year or more. Adverse events in patients taking Aprovel® were usually moderate and transient, and their frequency did not depend on the dose taken, as well as gender, age and race.

In placebo-controlled studies in which 1965 patients took irbesartan (for an average of 1-3 months), discontinuation of treatment due to the development of any clinical or laboratory adverse reactions was required in 3.3% of patients taking Aprovel®, and in 4.5% of patients taking placebo (differences were statistically significant).

In patients with nephropathy in arterial hypertension and type 2 diabetes mellitus (clinical studies IDNT and IRMA 2), adverse events are similar to those in patients with arterial hypertension, with the exception of orthostatic symptoms (dizziness (10.2%) (with placebo 6%), orthostatic dizziness (5.4%) (2.7% with placebo) and orthostatic hypotension (5.4%) (3.2% with placebo).

Treatment discontinuation rates due to orthostatic symptoms with Aprovel compared with placebo were 0.3% versus 0.5% for dizziness, 0.2% versus 0.0% for orthostatic dizziness, and 0.0% versus 0.0% for orthostatic hypotension, respectively.

The incidence of adverse reactions was determined according to the WHO classification: very often (≥1/10), often (≥1/100, <1/10), infrequently (≥1/1000, <1/100), rarely (≥1 /10,000, <1/1000), very rare (<1/10,000), frequency unknown (cannot be calculated based on available data).

The following are adverse reactions observed in clinical studies in patients with arterial hypertension1, in patients with nephropathy in arterial hypertension and type 2 diabetes mellitus (clinical studies IDNT and IRMA 2)2 or during post-marketing use of the drug3.

From the hematopoietic system: frequency unknown - thrombocytopenia, incl. thrombocytopenic purpura1.

From the immune system: frequency unknown - hypersensitivity reactions3 (such as angioedema, skin rash, urticaria, anaphylactic reactions, anaphylactic shock).

From the side of metabolism and nutrition: frequency unknown - hyperkalemia3.

From the nervous system: often - dizziness1,2, orthostatic dizziness2, headache1; infrequently - orthostatic dizziness1; frequency unknown - vertigo1.

On the part of the hearing organ: frequency unknown - ringing in the ears3.

From the cardiovascular system: often - orthostatic hypotension2; infrequently - edema1, tachycardia1, flushing1.

From the respiratory system: infrequently - cough1.

From the digestive system: often - nausea1, vomiting1; infrequently - diarrhea1, dyspepsia1, heartburn1; frequency unknown - dysgeusia1.

From the liver and biliary tract: infrequently - jaundice3; frequency unknown - increased activity of liver enzymes1 and bilirubin concentration in the blood3, hepatitis3.

From the skin and subcutaneous tissues: frequency unknown - leukocytoclastic vasculitis3, psoriasis1, incl. increased manifestation of psoriasis symptoms, photosensitivity reactions3.

From the musculoskeletal system: often - musculoskeletal pain2; frequency unknown - myalgia1 (in some cases may be associated with an increase in the concentration of creatine kinase in the blood plasma), arthralgia3, muscle spasms3.

From the urinary system: frequency unknown - renal dysfunction3, incl. cases of renal failure in patients at risk.

From the genital organs and breast: uncommon - sexual dysfunction1.

Other: often - increased fatigue1; uncommon - chest pain1; frequency unknown - asthenia1.

From the data of laboratory and instrumental studies: during controlled clinical studies in patients with arterial hypertension, no clinically significant changes in laboratory parameters were observed. No special monitoring of laboratory parameters is required for patients with arterial hypertension taking Aprovel®.

Hyperkalemia2: In the IDNT clinical trial, the percentage of patients with hyperkalemia (>6 mEq/L) was 18.6% in the Aprovel group compared to 6.0% in the placebo group. In the IRMA 2 clinical trial, the percentage of patients with hyperkalemia (>6 mEq/L) was 1.0% in the Aprovel® drug group, and no hyperkalemia was observed in the placebo group. In the IDNT clinical trial, treatment discontinuation rates due to hyperkalemia with Aprovel and placebo were 2.1% and 0.36%, respectively. In the IRMA clinical trial, the rate of treatment discontinuation due to hyperkalemia when taking Aprovel® and placebo was 0.5% and 0%, respectively.

Use during pregnancy and breastfeeding

Pregnancy

There is no experience with the use of irbesartan during pregnancy. Considering that when pregnant women took ACE inhibitors in the second and third trimesters of pregnancy, damage and death of the developing fetus were observed, irbesartan, like any other drug that acts directly on the RAAS, should not be used during pregnancy (I, II, III trimesters ).

If pregnancy is diagnosed during treatment, the drug should be discontinued immediately.

Breastfeeding period

Irbesartan is excreted in milk in lactating rats. It is not known whether irbesartan/its metabolites can be excreted in breast milk in women. Irbesartan is contraindicated during breastfeeding. Therefore, after assessing the ratio of the expected benefit of taking the drug for the mother and the potential risk for the child, either breastfeeding or taking irbesartan should be stopped.

Fertility

In studies in male and female rats, irbesartan did not affect fertility or reproductive function, even at doses that had some parental toxicity (up to 650 mg/kg/day). There was no significant effect on the number of corpora lutea, implanted embryos or live fetuses. Irbesartan did not affect survival, development or reproduction of offspring.

Interaction

Based on data from in vitro studies, irbesartan is not expected to interact with drugs metabolized by the isoenzymes CYP1A1, CYP1A2, CYP2A6, CYP2B6, CYP2E1 or CYP3A4. Irbesartan is mainly metabolized by the CYP2C9 isoenzyme and, to a lesser extent, undergoes glucuronidation. No significant pharmacokinetic and pharmacodynamic interactions were observed when irbesartan was co-administered with warfarin, a drug metabolized by the CYP2C9 isoenzyme. Irbesartan does not change the pharmacokinetics of digoxin and simvastatin. When irbesartan is co-administered with hydrochlorothiazide or nifedipine, the pharmacokinetics of irbesartan does not change.

Medicines containing aliskiren

Concomitant use of irbesartan with medicinal products containing aliskiren is contraindicated in patients with diabetes mellitus or with moderate to severe renal impairment (GFR <60 ml/min/1.73 m2 body surface area) and is not recommended in other patients.

ACE inhibitors

The use of irbesartan in combination with ACE inhibitors is contraindicated in patients with diabetic nephropathy and is not recommended in other patients.

Potassium supplements and potassium-sparing diuretics, heparin

Based on the experience gained with the use of other drugs that affect the RAAS, with the simultaneous use of potassium preparations; salt substitutes containing potassium; Potassium-sparing diuretics or other drugs that can increase blood potassium levels (heparin) can sometimes significantly increase serum potassium concentrations, which requires careful monitoring of plasma potassium levels in patients during treatment.

NSAIDs, including selective COX-2 inhibitors

With simultaneous use of angiotensin II receptor antagonists and NSAIDs (including selective COX-2 inhibitors), the hypotensive effect of irbesartan may be weakened. In elderly patients, patients with hypovolemia, or patients with impaired renal function, the use of NSAIDs, including COX-2 inhibitors, concomitantly with angiotensin II receptor antagonists, including irbesartan, may lead to a deterioration of renal function, including the possible development of acute renal failure. These effects are usually reversible. Renal function should be periodically monitored in patients taking irbesartan and NSAIDs, including COX-2 inhibitors, concomitantly.

Lithium preparations

An increase in the concentration of lithium in the blood serum and an increase in its toxicity have been reported with the simultaneous use of lithium salts with irbesartan.

Diuretics and other antihypertensive drugs

With simultaneous use of irbesartan and other antihypertensive drugs, the antihypertensive effect may be enhanced. Irbesartan has been used concomitantly with other antihypertensive agents, such as beta-blockers, long-acting calcium channel blockers and thiazide diuretics, without any undesirable effects.

Previous treatment with diuretics in high doses may lead to hypovolemia and an increased risk of excessive reduction in blood pressure at the beginning of treatment with Aprovel®.

Overdose

Experience with the use of the drug in adult patients in doses up to 900 mg/day for 8 weeks did not reveal any toxicity.

Treatment: There is no specific information regarding the treatment of overdose of Aprovel®. In case of overdose, it is recommended to induce vomiting and/or perform gastric lavage. Constant monitoring of the patient's condition should be established and, if necessary, symptomatic and supportive therapy should be provided. Irbesartan is not excreted from the body by hemodialysis.

Impact on the ability to drive vehicles and operate machinery

The effect of the drug on the ability to drive vehicles or engage in other potentially hazardous activities that require increased attention and high speed of psychomotor reactions has not been studied. However, based on its pharmacodynamic properties, the drug should not affect the ability to drive vehicles and engage in other potentially hazardous activities (including working at heights, working as an air traffic controller, working with machinery). If dizziness and weakness occur, attention may decrease and psychomotor reactions may slow, so care must be taken when operating vehicles and machinery.