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Pharmacological properties

mechanism of action. Irbesartan is a potent, oral active, selective angiotensin ii receptor antagonist (type at1). it can block all the effects of angiotensin ii mediated by the at1 receptor, regardless of the source or method of synthesis of angiotensin ii.

Selective angiotensin II receptor antagonism (AT1) causes an increase in the level of renin and angiotensin II in blood plasma, as well as a decrease in the concentration of aldosterone in blood plasma. Irbesartan alone does not have a significant effect on potassium levels in blood plasma when used in recommended doses. Irbesartan does not inhibit ACE (kininase II), an enzyme that catalyzes the formation of angiotensin II and the degradation of bradykinin to inactive metabolites. Irbesartan is active without metabolic activation.

Clinical efficacy. AH. Irbesartan lowers blood pressure by minimizing heart rate. A decrease in blood pressure is dose-dependent, with a tendency to hold a plateau against the background of 300 mg doses. When using the drug in doses of 150-300 mg once a day, blood pressure in a lying or sitting position at the time of the minimum effectiveness of the drug (that is, 24 hours after taking the dose) an average of 8-13 / 5-8 mm RT. Art. (systolic / diastolic) is lower than with placebo.

The maximum decrease in blood pressure occurs within 3–6 hours after taking the drug, and the effect of lowering blood pressure persists for 24 hours. When using the recommended doses, the decrease in blood pressure 24 hours after taking the drug is 60–70% of the corresponding maximum response of diastolic and systolic blood pressure. Taking a drug in a dose of 150 mg once a day provides a minimal effect and an average daily result similar to that observed when taking a medicine 2 times a day in the same total daily dose.

The effect of lowering blood pressure from the use of the drug Irbetan develops within 1–2 weeks, with the maximum effect occurring in 4–6 weeks from the start of therapy. This antihypertensive effect is maintained during long-term therapy. After drug withdrawal, blood pressure gradually returns to its original level. Ricochet AH is not observed.

The effect of lowering blood pressure from the use of irbesartan and thiazide diuretics is additive. In patients for whom irbesartan monotherapy does not provide adequate blood pressure control, the addition of low-dose hydrochlorothiazide to irbesartan (12.5 mg) once a day led to an additional decrease (adjusted for placebo) in blood pressure by 7-10 / 3-6 mm Hg. Art. (systolic / diastolic) at the time of minimal drug effectiveness.

The effectiveness of the drug Irbetan does not depend on age or gender. As with the use of other drugs that affect the renin-angiotensin-aldosterone system (RAAS), in patients of the Negroid race with hypertension, a significantly lower response to irbesartan monotherapy is revealed. If irbesartan is used simultaneously with a low dose of hydrochlorothiazide (for example, 12.5 mg / day), the antihypertensive response in patients of the Negroid race approaches that of patients of the Caucasian race.

There is no clinically significant effect of the drug on plasma uric acid levels or urinary acid secretion in the urine.

Pharmacokinetics After oral administration, irbesartan is well absorbed: bioavailability is 60–80%. The bioavailability of irbesartan at the same time does not have any significant effect. The binding of irbesartan to plasma proteins is approximately 96%, and the binding to cellular components of the blood is negligible. The volume of distribution of irbesartan is 53–93 liters. After oral or intravenous administration 14C-irbesartan 80–85% of the radioactivity circulating in the blood plasma refers to unchanged irbesartan.

Irbesartan is metabolized in the liver due to conjugation with glucuronides and oxidation.

The main circulating metabolite of irbesartan is glucuronide (approximately 6%). There is information that irbesartan is oxidized mainly by the CYP 2C9 cytochrome P450 enzyme; isoenzyme CYP 3A4 takes an insignificant part in its metabolism.

Irbesartan has linear and dose-proportional pharmacokinetic characteristics within the range of doses from 10 to 600 mg. A less than proportional increase in absorption of the drug was observed after oral administration with doses of more than 600 mg (which is twice the maximum recommended dose); the mechanism for this is not clear.

WITHmax in blood plasma are achieved after 1.5–2 hours after oral administration of the drug.

The total and renal clearance of the drug are 157–176 and 3–3.5 ml / min, respectively.

Terminal T½ irbesartan is 11-15 hours. Equilibrium plasma concentrations are reached within 3 days after the start of the drug in the regimen 1 time per day. With repeated use of irbesartan 1 time per day, limited accumulation of the drug in blood plasma is noted (20%). It is known that female patients with hypertension had slightly higher plasma levels of irbesartan in comparison with men. However, the differences in T½ and cumulation of irbesartan in men and women has not been identified. In female patients, dose adjustment of the drug is not required. AUC and C valuemax irbesartan was also slightly higher in elderly patients (≥65 years old) than in young patients (18–40 years old).

However terminal T½ not significantly different. In elderly patients, dose adjustment of the drug is not required.

Irbesartan and its metabolites are excreted in both bile and urine. Both after oral and intravenous administration 14About 20% of radioactivity of S-irbesartan was excreted in urine, and the rest with feces. Less than 2% of the dose was excreted in the urine as unchanged irbesartan.

Impaired renal function. In patients with renal failure or on hemodialysis, the pharmacokinetics of irbesartan are not significantly changed. Irbesartan is not excreted by hemodialysis.

Impaired liver function. In patients with mild or moderate liver cirrhosis, the pharmacokinetics of irbesartan are not significantly changed.

Studies involving patients with severe hepatic dysfunction have not been conducted.

Indications

Treatment of essential ag in adults. treatment of chronic kidney disease in adult patients with ag and type 2 diabetes mellitus as part of an antihypertensive therapy regimen.

Application

The drug is intended for oral use.

The usual recommended starting and maintenance dose is 150 mg (½ tablets) once daily, regardless of food intake. Irbesartan at a dose of 150 mg once a day, as a rule, provides a better daily control of blood pressure than at a dose of 75 mg. However, the appropriateness of starting treatment with a dose of 75 mg should be assessed, in particular in patients on hemodialysis, as well as in the elderly over 75 years of age.

In patients in whom a dose of irbesartan 150 mg once daily does not provide sufficient control, the dose may be increased to 300 mg (1 tablet) or other antihypertensive agents may be additionally prescribed. In particular, it has been shown that the additional use of such a diuretic as hydrochlorothiazide has an additive effect on the action of the drug Irbetan (see INTERACTIONS).

In patients with hypertension and type 2 diabetes mellitus, irbesartan therapy should begin with a dose of 150 mg 1 time per day and titrated to a dose of 300 mg 1 time per day, which is the desired maintenance dose in the treatment of chronic kidney disease.The benefits of the drug Irbetan regarding renal function in patients with hypertension and type 2 diabetes mellitus are demonstrated by studies in which irbesartan was used in addition to other antihypertensive drugs, if necessary, to achieve the target level of blood pressure.

Impaired renal function. In patients with impaired renal function, dose adjustment of the drug is not required. In patients using hemodialysis, the appropriateness of prescribing a low initial dose of the drug (75 mg) should be carefully considered (see SPECIAL INSTRUCTIONS).

Impaired liver function. Patients with mild or moderate hepatic dysfunction do not require dose adjustment of the drug. There is no clinical experience with the use of the drug in patients with severe hepatic dysfunction.

Elderly patients. For patients over the age of 75 years, the feasibility of starting treatment with a drug in a dose of 75 mg should be considered, dose adjustment is usually not required.

Contraindications

Hypersensitivity to the active substance or any of the auxiliary components (see composition). pregnant women or women planning a pregnancy (see use during pregnancy and lactation). concomitant use of the drug irbetan with preparations containing aliskiren is contraindicated in patients with diabetes mellitus or renal dysfunction (glomerular filtration rate of 60 ml / min / 1.73 m2) (see interactions).

Side effects

In a placebo-controlled study involving patients with ag, the overall incidence of side effects in the groups of patients taking irbesartan (56.2%) and placebo (56.5%) did not differ. drug withdrawal due to any clinical or laboratory side effect in the irbesartan group (3.3%) was less likely than in the placebo group (4.5%). the frequency of side effects did not depend on the dose of the drug (within the recommended dose range), gender, age, race of patients or duration of treatment.

Among patients with hypertension and diabetes mellitus with microalbuminuria and normal renal function, orthostatic dizziness and orthostatic arterial hypotension while taking the drug occurred in 0.5% of patients (i.e. infrequently), but more often than in the placebo group.

Adverse reactions reported in a placebo-controlled study, in which 1,965 hypertensive patients received irbesartan, are presented below. The periods marked with an asterisk (*) indicate additional adverse reactions, which were additionally reported, which were observed in 2% of patients with hypertension, diabetes mellitus, chronic renal failure and obvious proteinuria and whose frequency was higher than in the placebo group.

Adverse reactions are also listed that are additionally registered as part of the experience of post-registration use of the drug. Spontaneous reports have been received about these adverse reactions.

From the immune system: hypersensitivity reactions, such as angioedema, rash, urticaria.

Metabolic and nutritional disorders: hyperkalemia.

From the nervous system: dizziness, orthostatic dizziness, vertigo, headache.

From the side of the organ of hearing and balance: tinnitus.

From the side of the heart: tachycardia.

From the vessels: orthostatic hypotension, hyperemia.

From the respiratory system, chest and mediastinum: cough.

From the digestive tract: nausea / vomiting, diarrhea, dyspepsia / heartburn, dysgeusia.

From the hepatobiliary system: jaundice, hepatitis, impaired liver function.

On the part of the skin and subcutaneous tissue: leukocytoclastic vasculitis.

From the musculoskeletal system and connective tissue: muscle and bone pain, arthralgia, myalgia (in some cases associated with elevated levels of creatine kinase in the blood plasma), muscle cramps.

On the part of the kidneys and urinary tract: impaired renal function, including cases of renal failure in patients with an increased risk of this complication (see SPECIAL INSTRUCTIONS).

From the reproductive system and mammary glands: impaired function.

General disorders and reactions at the injection site: increased fatigue, chest pain.

Research results: hyperkalemia * in patients with diabetes mellitus receiving irbesartan occurred more often than in patients taking placebo. In patients with hypertension, diabetes mellitus, microalbuminuria and normal renal function, hyperkalemia (≥5.5 mEq / L) developed in 29.4% of cases in the irbesartan group at a dose of 300 mg and in 22% of patients in the placebo group. In patients with hypertension, diabetes mellitus, chronic renal failure and obvious proteinuria, hyperkalemia (≥5.5 mEq / L) was observed in 46.3% of cases in the irbesartan group and in 26.3% in the placebo group.

Persons treated with irbesartan often had a significant increase in plasma creatinine kinase levels (1.7%). Not a single case of such an increase was associated with clinical manifestations of the musculoskeletal system that could be identified.

1.7% of patients with hypertension and advanced stage diabetic nephropathy who were treated with irbesartan had a decrease in hemoglobin *, which was not clinically significant.

Pediatric population. In a randomized study involving 318 children and adolescents with hypertension from 6 to 16 years of age, the following adverse reactions occurred during the 3-week double-blind phase: headache (7.0%), arterial hypotension (2.2%), dizziness (1.9%), cough (0.9%). In the 26-week open period of this study, the most frequent abnormalities on the part of laboratory test results were an increase in creatinine levels (6.5%) and an increase in creatine kinase levels in 2% of children receiving the drug.

special instructions

Intravascular hypovolemia. in patients who, as a result of intensive diuretic therapy, limited salt intake with food, diarrhea or vomiting, develop hypovolemia and / or natriemia, symptomatic hypotension may occur, especially after taking the first dose of the drug. such conditions should be corrected before the use of the drug irbetan.

Renovascular hypertension. There is an increased risk of severe arterial hypotension and renal failure when patients with bilateral renal artery stenosis or artery stenosis of a single functioning kidney receive drugs that affect RAAS. Thus, when using any angiotensin II receptor antagonists, similar effects should be expected.

Renal failure and kidney transplantation. When using the drug in patients with impaired renal function, it is recommended to periodically monitor the level of potassium and creatinine in blood plasma. There is no experience with the use of the drug Irbetan in patients who have recently undergone kidney transplantation.

Patients with hypertension, type 2 diabetes and chronic kidney disease. The effect of irbesartan on both the kidneys and the cardiovascular system was not the same in all subgroups analyzed in a study involving patients with chronic kidney disease in the later stages. In particular, its advantages were less pronounced in women and persons not belonging to the Caucasian race.

Double blockade of RAAS.There is evidence that the simultaneous use of ACE inhibitors, angiotensin II receptor antagonists or aliskiren increases the risk of arterial hypotension, hyperkalemia and impaired renal function (including the development of acute renal failure). In this regard, the double blockade of RAAS by the combined use of ACE inhibitors, angiotensin II receptor antagonists or aliskiren is not recommended (see INTERACTIONS). If therapy in the form of such a double blockade is regarded as absolutely necessary, it should be used only under the supervision of a specialist and subject to frequent monitoring of renal function, electrolyte content and blood pressure. ACE inhibitors and angiotensin II receptor antagonists cannot be used simultaneously in patients with diabetic nephropathy.

Hyperkalemia Like other drugs that affect RAAS, hyperkalemia can occur during treatment with irbesartan, especially against the background of renal dysfunction, obvious proteinuria due to diabetic nephropathy and / or heart failure. It is recommended that close monitoring of the level of potassium in the blood plasma be performed in patients at risk of developing this complication (see INTERACTIONS).

Lithium. The use of lithium and irbesartan at the same time is not recommended (see INTERACTIONS).

Stenosis of aortic and mitral valves, obstructive hypertrophic cardiomyopathy. As with other vasodilators, special precautions should be taken for patients with aortic or mitral valve stenosis or obstructive hypertrophic cardiomyopathy.

Primary aldosteronism. Patients with primary aldosteronism, as a rule, do not respond to treatment with antihypertensive drugs, which act by inhibiting RAAS. In this regard, the use of the drug Irbetan is not recommended for such patients.

General warnings. In patients whose vascular tone and renal function mainly depend on RAAS activity (for example, in patients with severe congestive heart failure or with primary kidney disease, including renal artery stenosis), the use of ACE inhibitors or angiotensin II receptor antagonists that affect this system associated with cases of acute arterial hypotension, azotemia, oliguria or (rarely) with the onset of acute renal failure. As with any antihypertensive drug, an excessive decrease in blood pressure in patients with ischemic cardiopathy or ischemic cardiovascular disease can lead to myocardial infarction or stroke. Like ACE inhibitors, irbesartan and other angiotensin antagonists were less effective in lowering blood pressure in people of the Negroid race than in people of other races, which can be explained by the high prevalence of reduced levels of renin among the population of patients of the Negroid race with hypertension (see PHARMACOLOGICAL PROPERTIES).

Lactose. This medicine contains lactose. Patients with rare inherited disorders such as galactose intolerance, Lapp lactase deficiency, or glucose-galactose malabsorption syndrome should not take this medicine.

Use during pregnancy and lactation. Pregnancy. The drug should not be used by pregnant women or women planning a pregnancy. If pregnancy is confirmed during treatment with this agent, the drug should be stopped immediately and replaced with another drug approved for use during pregnancy.

The period of breastfeeding. Since there is no information on the use of the drug Irbetan during breastfeeding, taking the drug is not recommended for such patients,Preference should be given to alternative medicines with better-studied safety profiles during breastfeeding, especially when feeding newborns or premature babies. It is not known whether irbesartan or its metabolites passes into breast milk.

Fertility. Irbesartan did not affect the fertility of rats and their offspring in doses that caused the first signs of toxicity to the mothers body.

Children. The safety and effectiveness of the drug Irbetan for children (under the age of 18 years) have not been established.

The effect of irbesartan was studied in pediatric populations of patients aged 6 to 16 years, but the data available today are not enough to expand indications for the use of the drug in children (see ADVERSE EFFECTS) until additional information on this appears.

The ability to influence the reaction rate when driving vehicles or working with other mechanisms. Studies to study the effect of the drug on the ability to drive vehicles and work with mechanisms have not been conducted. Based on the pharmacodynamic properties of irbesartan, its effect on this ability is unlikely. But when driving vehicles or working with mechanisms, it should be borne in mind that during treatment, dizziness or increased fatigue may occur.

Interactions

Diuretics and other antihypertensive drugs. The risk of developing arterial hypotension while taking irbesartan can be increased when it is used simultaneously with other antihypertensive drugs, however, irbesartan has been used safely with some other antihypertensive drugs, such as β-adrenergic receptor blockers, long-acting calcium channel blockers and thiazide diuretics. preliminary treatment with high doses of diuretics can lead to hypovolemia and increase the risk of developing arterial hypotension after taking irbetan (see special instructions).

Aliskiren-containing drugs or ACE inhibitors. It is known that the double blockade of RAAS through the combined use of ACE inhibitors, angiotensin II receptor antagonists, or aliskiren is associated with an increased incidence of adverse events such as arterial hypotension, hyperkalemia, and impaired renal function (including the development of acute renal failure) compared to some one remedy affecting RAAS (see CONTRAINDICATIONS, SPECIAL INDICATIONS).

Potassium supplements and potassium-sparing diuretics. Based on the experience of using other drugs that affect RAAS, the simultaneous use of potassium-sparing diuretics, potassium dietary supplements, potassium salt substitutes or other drugs that can increase the level of potassium in the blood plasma (for example, heparin) can lead to an increase in the level of potassium in the plasma blood and therefore not recommended (see SPECIAL INSTRUCTIONS).

Lithium. A reversible increase in plasma lithium concentration and toxic effects of lithium was noted with the simultaneous use of lithium preparations with ACE inhibitors. At this time, very rare cases of the development of such effects with the use of irbesartan have been reported. Therefore, such a combination is not recommended (see SPECIAL INSTRUCTIONS). If this combination is necessary, then careful monitoring of the level of lithium in blood plasma should be carried out.

NSAIDs. If angiotensin II antagonists are used simultaneously with NSAIDs (namely: with selective COX-2 inhibitors, acetylsalicylic acid 3 g / day and NSAIDs), a weakening of the antihypertensive effect may be noted.

As with the use of ACE inhibitors, the simultaneous administration of angiotensin II antagonists and NSAIDs can lead to a decrease in renal function, including the occurrence of acute renal failure, and to an increase in the level of potassium in the blood plasma, especially in patients with pre-existing renal impairment. This combination should be used carefully, especially in elderly patients.

Patients should be adequately hydrated, and it may be appropriate for them to monitor renal function at the beginning of such combination therapy, as well as periodically in the future.

Additional information on the interaction of irbesartan. In clinical studies, hydrochlorothiazide does not affect the pharmacokinetics of irbesartan. Irbesartan is metabolized primarily by the enzyme CYP 2C9 and to a lesser extent due to glucuronidation. Significant pharmacokinetic or pharmacodynamic interactions with the simultaneous use of irbesartan with warfarin (a drug that is metabolized by the CYP 2C9 enzyme) were not observed. The effect of CYP 2C9 inducers such as rifampicin on the pharmacokinetics of irbesartan has not been evaluated.

With the simultaneous use of irbesartan with digoxin, the pharmacokinetics of digoxin did not change.

Overdose

When using the drug in adults at a dose of up to 900 mg / day for 8 weeks, no toxic reactions were observed. the most likely manifestations of an overdose of irbesartan are considered arterial hypotension and tachycardia; also with an overdose, bradycardia may occur. no specific information on the treatment of drug overdose is currently available. the patients condition must be constantly monitored, and therapy should be symptomatic and supportive.

Recommended measures include stimulating vomiting and / or gastric lavage.

When treating an overdose, activated charcoal may be helpful.

Irbesartan is not excreted by hemodialysis.

Storage conditions

In the original packaging at temperatures up to 25 ° C.

Tags: Irbesartan