Irbesartan Canon, 150 mg tablets 28 pcs

– Arterial hypertension (in monotherapy and in combination with other hypotensive agents, e.g. thiazide diuretics, beta-adrenoblockers, long-acting slow calcium channel blockers (LCCBs)).

Indications

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

Pharmacological effect

Pharmacotherapeutic group: angiotensin II receptor antagonist.

ATX code: C09CA04

Pharmacological action
Pharmacodynamics

Irbesartan is a 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 reninangiotensin-aldosterone system (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, including its strongly expressed vasoconstrictor and aldosterone-secreting effects, realized through AT1 type receptors located on the surface of vascular smooth muscle cells and in the adrenal cortex. It does not have agonistic activity towards 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, angiotensin-converting enzyme (ACE)) and does not affect other hormone receptors or ion channels involved in the regulation of blood pressure (BP) 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 potassium content 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.

With a single oral dose of irbesartan per day in doses of up to 900 mg, the antihypertensive effect is dose-dependent. Irbesartan, when taken once a day in doses of 150-300 mg, reduces blood pressure, measured in the “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 the position

“standing” and in the “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 with irbesartan monotherapy, adding low doses of hydrochlorothiazide (12.5 mg) once a day to its administration leads to an additional reduction in blood pressure by 7-10/3-6 mmHg. Art. (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 low doses of hydrochlorothiazide (for example, 12.5 mg per day), the antihypertensive response in black patients approaches the effectiveness of that in Caucasian patients.

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

In the multicenter, randomized, active (amlodipine) and placebo-controlled, double-blind clinical trial IDNT, involving 1715 patients with hypertension and type 2 diabetes mellitus (proteinuria >900 mg/day and serum creatinine concentration in the range of 1.0-3.0 mg/dl), a 20% (p = 0.024) reduction (compared with placebo) was shown and 23% (p = 0.006) reduction (compared with amlodipine) 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 (when achieving a comparable reduction in blood pressure with the use of irbesartan and amlodipine).

In a multicenter, randomized, placebo-controlled, double-blind clinical trial examining the effects of irbesartan on microalbuminuria in patients with hypertension and type 2 diabetes mellitus (IRMA 2), involving 590 patients with hypertension and type 2 diabetes mellitus with microalbuminuria (20-200 mcg/min, 30-300 mg/day) and normal renal function (serum creatinine concentration < 1.5 mg/dL in men and < 1.1 mg/dL in women), the effect of long-term treatment (for 2 years) with irbesartan on the progression of clinically significant proteinuria was assessed. When taking the drug at a dose of 300 mg per day, a 70% reduction in the relative risk of developing clinically significant proteinuria was demonstrated (compared with placebo, p = 0.0004), and at a dose of 150 mg, a 39% reduction in the relative risk of developing clinically significant proteinuria (compared with placebo, p = 0.085). Slowing of the progression of clinically significant proteinuria was noted after three months and continued throughout the entire 2-year clinical study period. The decrease in 24-hour creatinine clearance was not significantly different between treatment groups. Regression of microalbuminuria to normal albuminuria levels (<20 mcg/min; <30 mg/day) was more often observed in the irbesartan 300 mg group (34%) compared to the placebo group (21%).

Pharmacokinetics

Absorption

After oral administration, irbesartan is rapidly and completely absorbed, its absolute bioavailability is approximately 60-80%. Concomitant food intake does not significantly affect the bioavailability of irbesartan. After oral administration, the maximum plasma concentration (Cmax) of irbesartan is achieved after 1.5-2 hours. Distribution

The binding to plasma proteins is approximately 96%. Binding to cellular components of blood is negligible. The distribution volume is 53-93 l.

Metabolism

After oral or intravenous administration of 14C-irbesartan, 80-85% of the radioactivity circulating in the blood plasma is unchanged irbesartan. Irbesartan is metabolized by the liver by oxidation and conjugation with glucuronic acid. The main metabolite found in the systemic circulation is irbesartan glucuronide (approximately 6%). The oxidation of irbesartan is carried out mainly by the cytochrome P450 isoenzyme CYP2C9; the participation of the CYP3A4 isoenzyme in the metabolism of irbesartan is insignificant. 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.

Irbesartan and its metabolites are excreted from the body, both through the intestines (with bile) and the kidneys. After oral or intravenous administration of 14C-irbesartan, about 20% of the radioactivity is found in the urine, and the rest in the feces. Less than 2% of the administered dose is excreted by the kidneys as unchanged irbesartan.

The terminal half-life of irbesartan (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. With a single daily dose for

After taking irbesartan for a day, the equilibrium plasma concentration (Css) is achieved after 3 days, while its limited accumulation in the blood plasma is observed (less than +20%).

Special patient groups

Effect of gender on the pharmacokinetics of irbesartan

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.

Pharmacokinetics of irbesartan in elderly patients

The AUC (area under the concentration-time pharmacokinetic curve) 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). The final T1/2 are comparable. There were no age-related differences in the effects of irbesartan.

Pharmacokinetics of irbesartan in 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 liver cirrhosis, the pharmacokinetic parameters of irbesartan do not change significantly.

Pharmacokinetics of irbesartan in renal impairment

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. The influence of race on the pharmacokinetics of irbesartan

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

Special instructions

Excessive decrease in blood pressure – patients with hypovolemia

The use of irbesartan to date has 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 to use the drug Irbesartan Canon, it is necessary to correct hypovolemia and/or hyponatremia.

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 (according to the 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 transplant

When using irbesartan 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 Irbesartan Canon in patients who have recently undergone a kidney transplant. Patients with arterial hypertension and type 2 diabetes mellitus with impaired renal function

The beneficial effect of irbesartan 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 non-Caucasian patients.

In the IDNT clinical trial in hypertensive patients with type 2 diabetes mellitus with proteinuria (>900 mg/day), a subgroup of patients at high risk for renal artery stenosis, no patients receiving irbesartan experienced an acute early increase in serum creatinine concentrations associated with renal artery stenosis.

Double blockade of the RAAS when combining Irbesartan Canon with ACE inhibitors or aliskiren

Double blockade of the RAAS when using a combination of Irbesartan Canon 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.

The simultaneous use of irbesartan with aliskiren is contraindicated in patients with diabetes mellitus and/or with moderate or severe renal failure (GFR less than 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.

Hyperkalemia

As with the use of other drugs that affect the RAAS, hyperkalemia may develop during treatment with Irbesartan Canon, 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, hypertrophic obstructive cardiomyopathy

As with the use of other vasodilators, caution should be exercised when taking Irbesartan Canon in patients with aortic or mitral stenosis, or with 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 the drug Irbesartan Canon in such cases is inappropriate.

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.

Impact on the ability to drive vehicles and machinery

The effect of Irbesartan Canon 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 (work at height, work as an air traffic controller, work with machinery, etc.). But if dizziness and weakness occur, attention may decrease and psychomotor reactions may slow down. In patients who have such adverse reactions, the decision about the possibility of engaging in any potentially hazardous activities should be made by the doctor individually.

Active ingredient

Irbesartan

Composition

1 tablet 150 mg contains:
active ingredient: irbesartan 150.0 mg;
excipients: pregelatinized corn starch 51.0 mg, croscarmellose sodium 12.0 mg, lactose monohydrate 44.0 mg, magnesium stearate 2.0 mg, povidone K-30 10.0 mg, talc 3.0 mg, microcrystalline cellulose 28.0 mg.

1 tablet 300 mg contains:
active ingredient: irbesartan 300.0 mg;
excipients: pregelatinized corn starch 102.0 mg, croscarmellose sodium 24.0 mg, lactose monohydrate 88.0 mg, magnesium stearate 4.0 mg, povidone K-30 20.0 mg, talc 6.0 mg, microcrystalline cellulose 56.0 mg.

Pregnancy

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 with irbesartan, it should be discontinued as soon as possible.
Breastfeeding period
It is not known whether irbesartan or its metabolites are excreted into breast milk. 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.

Contraindications

– Hypersensitivity to irbesartan or to any component of the drug.
– Concomitant use with aliskiren and drugs containing aliskiren in patients with diabetes mellitus and/or moderate or severe renal impairment (glomerular filtration rate (GFR) less than 60 ml/min/1.73 m2 body surface area).
– Concomitant use with ACE inhibitors in patients with diabetic nephropathy.
– Pregnancy.
– Breastfeeding period.
– Age up to 18 years (efficacy and safety have not been established).
– Hereditary lactose intolerance, lactase deficiency, glucose-galactose malabsorption.
– In case of severe liver failure (functional class C or more than 9 points on the Child-Pugh scale) (lack of experience in clinical use).
With caution
– For aortic or mitral valve stenosis or hypertrophic obstructive cardiomyopathy (HOCM).
– In case of hypovolemia, hyponatremia, which occurs, for example, during intensive treatment with diuretics, hemodialysis, following a diet with limited salt intake, diarrhea, vomiting (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 (NYHA classification) (see section “Special instructions”).
– In case of 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).
– 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 non-steroidal anti-inflammatory drugs (NSAIDs), including selective cyclooxygenase-2 (COX-2) inhibitors (increased risk of developing renal dysfunction, including the possibility of acute renal failure and an increase in serum potassium, especially in elderly patients, patients with hypovolemia [including patients taking diuretics] or in patients with impaired renal function (see section “Interaction with other drugs”).
– When used in combination with ACE inhibitors or aliskiren, because 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 (see section “Special instructions”).

Side Effects

The following adverse events are presented in accordance with the following gradations of the frequency of their occurrence (according to the World Health Organization (WHO) classification): very often (≥ 1/10); often (≥ 1/100, < 1/10); infrequently useful messages); unknown frequency (it is not possible to determine the frequency of occurrence of an adverse event based on available data).

The safety of irbesartan 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 one year or more. Adverse events in patients taking irbesartan were usually moderate and transient, and their frequency was not related to the dose taken. The incidence of adverse events did not depend on gender, age or 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 events was required in 3.3% of patients taking irbesartan and in 4.5% of patients taking placebo (the differences were statistically significant).

Adverse events observed in placebo-controlled clinical trials with the use of irbesartan in arterial hypertension, probably or possibly related to its use, or without an established relationship with the drug.

Interaction

Based on in vitro data, irbesartan is not expected to interact with drugs metabolized by CYP1A1, CYP1A2, CYP2A6, CYP2B6, CYP2E1 or CYP3A4. Irbesartan is mainly metabolized by the CYP2C9 isoenzyme and is subject to glucuronidation to a lesser extent. 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.

With medicinal products containing aliskiren

The simultaneous use of irbesartan with medicinal products containing aliskiren is contraindicated in patients with diabetes mellitus and/or with moderate or severe renal failure (GFR less than 60 ml/min/1.73 m2 body surface area) and is not recommended in other patients (see sections “Contraindications”, “With caution”, “Special instructions”).

With 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 (see sections “Contraindications”, “With caution”, “Special instructions”).

With 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 potassium levels in the blood (heparin) can sometimes significantly increase serum potassium concentrations, which requires careful monitoring of plasma potassium levels in patients during treatment.

With NSAIDs, including selective cyclooxygenase-2 (COX-2) inhibitors

With simultaneous use of angiotensin II receptor antagonists and NSAIDs (including selective COX-2 inhibitors), the antihypertensive 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 common in patients taking irbesartan and NSAIDs, including COX-2 inhibitors, concomitantly.

With lithium preparations

Increased serum concentrations of lithium and increased toxicity have been reported with the simultaneous use of lithium salts and irbesartan.

With 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 CBCIs, and thiazide diuretics, without any problems. 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 Irbesartan Canon.

Storage conditions

At a temperature not exceeding 25 °C in secondary packaging (cardboard pack). Keep out of the reach of children.

Shelf life

3 years. Do not use after expiration date.

Manufacturer

Kanonpharma production CJSC, Russia