Irsar^® (Tablets) Instructions for Use

Marketing Authorization Holder

Canonpharma Production, CJS (Russia)

ATC Code

C09CA04 (Irbesartan)

Active Substance

Irbesartan (Rec.INN registered by WHO)

Dosage Forms

	Irsar®	Tablets 150 mg: 7, 10, 14, 15, 20, 28, 30, 40, 56 or 60 pcs.
		Tablets 300 mg: 7, 10, 14, 15, 20, 28, 30, 40, 56 or 60 pcs.

Dosage Form, Packaging, and Composition

Tablets white or almost white, round, biconvex, with a score; slight marbling is allowed.

Excipients: pregelatinized starch – 51 mg, croscarmellose sodium (primellose) – 12 mg, lactose monohydrate (milk sugar) – 44 mg, magnesium stearate – 2 mg, povidone K30 – 10 mg, talc – 3 mg, microcrystalline cellulose – 28 mg.

7 pcs. – blister packs (1) – cardboard packs.
7 pcs. – blister packs (2) – cardboard packs.
7 pcs. – blister packs (4) – cardboard packs.
7 pcs. – blister packs (8) – cardboard packs.
10 pcs. – blister packs (1) – cardboard packs.
10 pcs. – blister packs (2) – cardboard packs.
10 pcs. – blister packs (3) – cardboard packs.
10 pcs. – blister packs (6) – cardboard packs.
14 pcs. – blister packs (1) – cardboard packs.
14 pcs. – blister packs (2) – cardboard packs.
14 pcs. – blister packs (4) – cardboard packs.
15 pcs. – blister packs (1) – cardboard packs.
15 pcs. – blister packs (2) – cardboard packs.
15 pcs. – blister packs (4) – cardboard packs.

Tablets white or almost white, round, biconvex, with a score; slight marbling is allowed.

Excipients: pregelatinized starch – 102 mg, croscarmellose sodium (primellose) – 24 mg, lactose monohydrate (milk sugar) – 88 mg, magnesium stearate – 4 mg, povidone K30 – 20 mg, talc – 6 mg, microcrystalline cellulose – 56 mg.

7 pcs. – blister packs (1) – cardboard packs.
7 pcs. – blister packs (2) – cardboard packs.
7 pcs. – blister packs (4) – cardboard packs.
7 pcs. – blister packs (8) – cardboard packs.
10 pcs. – blister packs (1) – cardboard packs.
10 pcs. – blister packs (2) – cardboard packs.
10 pcs. – blister packs (3) – cardboard packs.
10 pcs. – blister packs (6) – cardboard packs.
14 pcs. – blister packs (1) – cardboard packs.
14 pcs. – blister packs (2) – cardboard packs.
14 pcs. – blister packs (4) – cardboard packs.
15 pcs. – blister packs (1) – cardboard packs.
15 pcs. – blister packs (2) – cardboard packs.
15 pcs. – blister packs (4) – cardboard packs.

Clinical-Pharmacological Group

Angiotensin II receptor antagonist

Pharmacotherapeutic Group

Angiotensin II receptor antagonist

Pharmacological Action

Selective angiotensin II receptor antagonist (type AT₁). It blocks all physiologically significant effects of angiotensin II mediated by AT₁ receptors, regardless of the source or pathway of angiotensin II synthesis. Selective antagonism to angiotensin II receptors (AT₁) leads to an increase in plasma concentrations of renin and angiotensin II and a decrease in plasma concentration of aldosterone. Serum potassium concentrations usually do not change significantly when taking irbesartan at recommended doses. Irbesartan does not inhibit ACE (kininase-II), an enzyme involved in the synthesis of angiotensin II and cleaving bradykinin into inactive metabolites. Metabolic activation of irbesartan is not required for its action to manifest.

Irbesartan reduces blood pressure with minimal change in heart rate. When used in doses up to 300 mg once daily, the reduction in blood pressure is dose-dependent, but with a further increase in the dose of irbesartan, the increase in the antihypertensive effect is insignificant.

The maximum reduction in blood pressure is achieved 3-6 hours after a single oral dose and persists for at least 24 hours. After 24 hours, blood pressure remains at 60-70% of the maximum reduction in diastolic and systolic blood pressure when taking recommended doses. After taking 150-300 mg once daily for 24 hours (i.e., at the end of the interdose interval), blood pressure (systolic/diastolic) in the supine or sitting position decreases by 8-13/5-8 mmHg, respectively, which is significantly greater than when taking placebo.

Using the drug at a dose of 150 mg once daily leads to a hypotensive effect comparable to twice the same dose divided into 2 doses.

A stable antihypertensive effect develops within 1-2 weeks of therapy, and the maximum therapeutic effect is achieved 4-6 weeks after the start of treatment. There is no withdrawal syndrome upon discontinuation of the drug.

The effectiveness of the drug Irsar^® does not depend on age and gender. Patients of the Black race respond less well to monotherapy with the drug Irsar^® (as with all other drugs affecting the RAAS).

Irbesartan has virtually no effect on the concentration of uric acid in the blood serum or on the excretion of uric acid by the kidneys.

Pharmacokinetics

Absorption

After oral administration, Irbesartan is well absorbed. C_max in blood plasma is reached 1.5-2 hours after oral administration. The absolute bioavailability is approximately 60-80%. Simultaneous food intake does not significantly affect the bioavailability of irbesartan.

Distribution

The pharmacokinetic parameters of irbesartan are linear and proportional in the dose range from 10 to 600 mg; when used in doses above 600 mg (a dose twice the recommended maximum dose of the drug), the kinetics of irbesartan becomes nonlinear (decreased absorption).

Binding to plasma proteins is approximately 96%. V_d is 53-93 L. With daily single oral administration of irbesartan, C_ss is reached in 3 days.

Metabolism

Irbesartan is metabolized in the liver by oxidation and conjugation with glucuronic acid to form the main metabolite – irbesartan glucuronide (approximately 6%). The oxidation of irbesartan is carried out mainly with the help of cytochrome P450, the participation of the isoenzyme CYP3A4 in the metabolism of irbesartan is insignificant.

Excretion

Total clearance and renal clearance are 157-176 and 3-3.5 ml/min, respectively. The terminal T_1/2 is 11-15 hours. Irbesartan and its metabolites are excreted from the body both with bile (80%) and by the kidneys (20%), with less than 2% of the taken dose of irbesartan excreted by the kidneys unchanged.

Pharmacokinetics in special patient groups

Female patients (compared to male patients) with arterial hypertension had higher plasma concentrations of irbesartan. However, no differences in T_1/2 and accumulation of irbesartan were found. Dose adjustment of the drug in female patients is not required.

The AUC and C_max values of irbesartan in elderly patients (over 65 years) are somewhat higher than in younger patients (18-40 years). The terminal T_1/2 in elderly patients is not significantly changed. Dose adjustment in elderly patients is not required.

In case of impaired renal function, the pharmacokinetic parameters of irbesartan do not change significantly. Hemodialysis is ineffective.

In patients with mild or moderate liver cirrhosis, the pharmacokinetic parameters of irbesartan do not change significantly. Pharmacokinetic studies in patients with severe hepatic impairment have not been conducted.

Indications

• Essential hypertension;
• Nephropathy in arterial hypertension and type 2 diabetes mellitus (as part of combined antihypertensive therapy).

ICD codes

Dosage Regimen

The drug is taken orally, once daily, regardless of meals. The tablet should be swallowed whole with water.

The recommended initial and maintenance dose is 150 mg once daily.

In patients with reduced blood volume (including with diarrhea, vomiting), with hyponatremia during treatment with diuretics or adherence to a diet with limited salt intake, patients on hemodialysis, as well as patients over 75 years of age, the recommended initial dose of the drug Irsar^® is 75 mg/day (1/2 tab. of 150 mg).

If the therapeutic effect is insufficient, the dose of the drug is increased to 300 mg/day. A further increase in the dose at intervals of 1-2 weeks (more than 300 mg/day) does not lead to an increase in the severity of the antihypertensive effect.

In the absence of effect with monotherapy, a combination with another antihypertensive drug is possible, for example, with diuretics in low doses (hydrochlorothiazide).

For the treatment of nephropathy in patients with arterial hypertension and type 2 diabetes mellitus, the recommended initial dose is 150 mg once daily; if the therapeutic effect is insufficient, the dose can be increased (at 2-week intervals) to 300 mg once daily – a dose that is the preferred maintenance dose for the treatment of nephropathy.

In patients with impaired renal function, no dose adjustment is required.

The initial dose of the drug in patients on hemodialysis is 75 mg/day (1/2 tablet of 150 mg).

Patients with mild to moderate hepatic impairment do not require dose adjustment of the drug. Clinical experience of use in patients with severe hepatic impairment is lacking.

Treatment of patients over 75 years of age is recommended to start with a dose of 75 mg (1/2 tab. of 150 mg).

Adverse Reactions

The frequency of development of the side effects listed below was determined in accordance with the following World Health Organization classification: very common (>1/10), common (from >1/100 to <1/10), uncommon (from >1/1000 to <1/100), rare (from >1/10,000 to <1/1000), very rare (from <1/10,000, including isolated reports).

Arterial hypertension

From the CNS common – dizziness.

From the cardiovascular system uncommon – tachycardia, flushing.

From the respiratory system uncommon – cough.

From the digestive system common – nausea and/or vomiting; uncommon – diarrhea, dyspepsia and/or heartburn.

From the reproductive system uncommon – sexual dysfunction.

From laboratory parameters common – increased CPK activity (without clinical manifestations from the musculoskeletal system and absence of hyperkalemia).

Other common – increased fatigue, asthenia; uncommon – chest pain.

Nephropathy in arterial hypertension and type 2 diabetes mellitus

From the CNS common – dizziness when changing body position (transition from lying to standing).

From the cardiovascular system common – excessive decrease in blood pressure, including orthostatic hypotension.

From the musculoskeletal system common – arthralgia, myalgia.

From laboratory parameters very common – hyperkalemia, decrease in hemoglobin (clinically insignificant).

During post-marketing use of irbesartan, the following side effects were noted, the frequency of which cannot be established (based on spontaneous reports).

From the CNS headache.

Allergic reactions hypersensitivity reactions (skin rash, urticaria, angioedema), leukocytoclastic vasculitis.

From the hearing organ tinnitus.

From the digestive system dysgeusia, impaired liver function, hepatitis.

From the musculoskeletal system arthralgia, myalgia (in some cases associated with increased CPK activity), muscle cramps.

From the urinary system very rare – impaired renal function (including isolated cases of renal failure in at-risk patients).

If severe side effects develop, treatment should be discontinued.

Contraindications

• Lactase deficiency, lactose intolerance, glucose/galactose malabsorption syndrome;
• Pregnancy;
• Lactation period;
• Age under 18 years;
• Hypersensitivity to irbesartan or any component of the drug.

With caution the drug should be prescribed for hyponatremia; adherence to a diet with limited salt intake; bilateral renal artery stenosis or stenosis of the artery of a single functioning kidney; reduced blood volume (including with diarrhea, vomiting); prior diuretic therapy; renal failure; hemodialysis; condition after kidney transplantation (lack of clinical experience); severe hepatic failure (lack of clinical experience); hyperkalemia; simultaneous use with lithium preparations; stenosis of the aortic and mitral valves; hypertrophic obstructive cardiomyopathy (HOCM); primary hyperaldosteronism; chronic heart failure (III-IV functional class according to NYHA classification); coronary artery disease and/or atherosclerotic cerebrovascular disease; patients over 75 years of age.

Use in Pregnancy and Lactation

The use of the drug Irsar^®, like any drug that directly affects the RAAS, is not recommended during pregnancy.

The use of angiotensin II receptor antagonists is not recommended in the first trimester of pregnancy. The drug is contraindicated in the second and third trimesters of pregnancy, as it can cause fetotoxic effects (decreased renal function, oligohydramnios, delayed ossification of the fetal skull bones) and neonatal toxic effects (renal failure, arterial hypotension, hyperkalemia). If the drug is taken in the second and third trimesters of pregnancy, an ultrasound of the fetal kidneys and skull bones should be performed.

Transition to an appropriate alternative antihypertensive therapy should be carried out before planning pregnancy. If pregnancy occurs, the drug Irsar^® should be discontinued as soon as possible.

It is not known whether Irbesartan is excreted in breast milk. If it is necessary to use the drug during lactation, the issue of stopping breastfeeding should be decided.

Use in Hepatic Impairment

The drug should be used with caution in patients with severe hepatic impairment (lack of clinical experience).

Patients with mild to moderate hepatic impairment do not require dose adjustment of the drug. Clinical experience of use in patients with severe hepatic impairment is lacking.

Use in Renal Impairment

The drug should be used with caution in patients with renal failure.

In patients with impaired renal function, no dose adjustment is required.

The initial dose of the drug in patients on hemodialysis is 75 mg/day (1/2 tablet of 150 mg).

Pediatric Use

The use of the drug in children and adolescents under 18 years of age is contraindicated.

Geriatric Use

The drug should be used with caution in patients over 75 years of age.

Special Precautions

Water and electrolyte imbalance

Before using the drug Irsar^® in patients with reduced blood volume (including due to diarrhea or vomiting, intensive diuretic therapy, adherence to a diet with limited salt intake), it is necessary to restore blood volume, eliminate hyponatremia, because there is a risk of developing symptomatic arterial hypotension, especially after taking the first dose.

Renovascular hypertension

The risk of developing severe arterial hypotension and renal failure potentially increases in patients with bilateral renal artery stenosis or stenosis of the artery of a single functioning kidney.

Renal failure and kidney transplantation

It is recommended to monitor the content of potassium and creatinine in the blood serum in patients with renal failure. There are no clinical data regarding the use of the drug Irsar^® in patients after kidney transplantation.

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

The favorable effect of irbesartan noted in slowing the progression of renal and cardiovascular disorders has varying degrees of severity in different patient groups: less pronounced in women and in patients not of Caucasian race.

Hyperkalemia

It is recommended to monitor potassium levels in patients taking potassium preparations, potassium-sparing diuretics, and heparin simultaneously with the drug Irsar^®, especially in the presence of renal failure and/or cardiovascular diseases.

Stenosis of the aortic and mitral valves, HOCM

As with the use of any vasodilators, the drug Irsar^® must be used with caution.

Primary hyperaldosteronism

The use of the drug Irsar^® in primary hyperaldosteronism is not advisable.

Other

In patients whose vascular tone and renal function predominantly depend on the activity of the RAAS (for example, patients with chronic heart failure of NYHA functional class III-IV, concomitant renal diseases, including renal artery stenosis), therapy with ACE inhibitors or angiotensin II receptor antagonists is accompanied by the development of arterial hypotension, azotemia, oliguria and, in rare cases, acute renal failure.

As with the use of other antihypertensive agents, a significant decrease in blood pressure in patients with coronary artery disease and/or atherosclerotic cerebrovascular disease may lead to the development of myocardial infarction or stroke.

When treating such patients, blood pressure should be strictly monitored.

Effect on the ability to drive vehicles and machinery

During treatment, caution should be exercised when driving vehicles and engaging in other potentially hazardous activities that require increased concentration and speed of psychomotor reactions.

Overdose

Symptoms excessive decrease in blood pressure, tachycardia, rarely – bradycardia.

Treatment gastric lavage, administration of activated charcoal; symptomatic and supportive therapy under constant patient monitoring. Hemodialysis is not effective.

Drug Interactions

Other antihypertensive agents and diuretics may enhance the hypotensive effect of irbesartan. Irbesartan can be used in combination with drugs such as beta-blockers, long-acting calcium channel blockers, and thiazide diuretics.

Prior therapy with high doses of diuretics may lead to dehydration and increase the risk of arterial hypotension at the beginning of therapy with Irsar^®.

Concomitant use of irbesartan with potassium supplements and potassium-sparing diuretics, as well as heparin, may increase serum potassium levels.

Concomitant use of irbesartan with lithium preparations may potentially lead to a reversible increase in serum lithium levels and an increase in its toxicity. Therefore, it is recommended to regularly monitor serum lithium concentration.

Concomitant use with NSAIDs (including selective COX-2 inhibitors, acetylsalicylic acid (>3 g/day) and non-selective NSAIDs) may reduce the antihypertensive effect.

In case of concomitant use with NSAIDs, there is a potential increased risk of impaired renal function, up to the development of acute renal failure and hyperkalemia (especially in patients with pre-existing renal impairment). This combination should be used with caution, especially in elderly patients.

Patients should restore circulating blood volume before starting combination therapy, and renal function should be monitored before starting therapy and periodically during combination therapy.

Hydrochlorothiazide and nifedipine do not affect the pharmacokinetic parameters of irbesartan.

Irbesartan is metabolized primarily by the CYP2C9 isoenzyme and, to a lesser extent, by glucuronidation. No significant pharmacokinetic or pharmacodynamic interaction was noted with warfarin (which is metabolized by the CYP2C9 isoenzyme). The effects of inducers of the CYP2C9 isoenzyme, such as rifampicin, on the pharmacokinetics of irbesartan have not been studied.

Irbesartan does not affect the pharmacokinetic parameters of digoxin.

Storage Conditions

The drug should be stored out of the reach of children, in a dry, light-protected place at a temperature not exceeding 25°C (77°F).

Shelf Life

The shelf life is 2 years.

Dispensing Status

The drug is dispensed by prescription.

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.