Irbesartan, 300 mg 28 pcs

Pharmacotherapeutic group

An angiotensin II receptor antagonist

ATX code

C09CA04

Pharmacodynamics:

Irbesartan is a selective angiotensin II receptor antagonist (type AT1). Reduces plasma aldosterone concentration (does not inhibit bradykinin-depleting kinase II); eliminates the vasoconstrictor effect of angiotensin II; reduces total peripheral vascular resistance reduces postload systemic arterial pressure (BP) and pressure in the “small” circulatory circle. It does not affect the concentration of triglycerides cholesterol glucose uric acid in plasma and uric acid excretion.

The maximum BP reduction is achieved 3-6 h after oral administration and the antihypertensive effect is maintained for at least 24 h. Twenty-four hours after ingestion at recommended doses, the BP reduction is 60-70% compared to the maximum diastolic and systolic BP reduction in response to drug administration. When administered once daily in a dose of 150-300 mg, the degree of BP reduction (systolic/diastolic) at the end of the interdose interval (i.e. 24 hours after drug administration) in patient lying or sitting position is on average 8-13/5-8 mmHg (respectively) greater compared to placebo. The administration of 150 mg once daily causes the same antihypertensive response (decrease of BP before the next dose and the average BP decrease within 24 hours) as the administration of the same dose divided into 2 doses. The antihypertensive effect of irbesartan develops within 1-2 weeks, and the maximum therapeutic effect is achieved 4-6 weeks after the start of treatment. The antihypertensive effect is maintained during long-term treatment. After discontinuation of treatment, BP gradually returns to the initial value of “withdrawal” syndrome was not observed.

The efficacy of the drug is independent of age and sex.

Patients of non-hyrogenic race respond less well to irbesartan monotherapy (as to all other drugs affecting the renin-angiotensin-aldosterone system (RAAS)). Pharmacokinetics:

Intake

After oral administration, irbesartan is well absorbed from the gastrointestinal tract (GIT). Maximal concentration (Cmax) of irbesartan in blood plasma is reached 15-2 hours after oral administration. Absolute bioavailability is 60-80%. Concomitant intake of food does not significantly affect the bioavailability of the drug. Irbesartan has linear and dose-proportional pharmacokinetics in the dosage range from 10 to 600 mg; at doses greater than 600 mg (2-fold higher than the recommended maximum dose) kinetics of irbesartan becomes non-linear (decrease of absorption).

Distribution

The binding to plasma proteins is approximately 96%. Binding to cellular components of the blood is insignificant. The volume of distribution is 53-93 liters. With daily administration once a day the equilibrium concentration is reached after 3 days. Limited accumulation of irbesartan in blood plasma (less than 20%) is observed after repeated dosing once daily. After oral administration or intravenous administration of 14C-irbesartan 80-85% of radioactivity in circulating blood is due to unchanged irbesartan.

Metabolism

Irbesartan is biotransformed in the liver by oxidation and conjugation to glucuronic acid.

Irbesartan is oxidized primarily by the CYP2C9 isoenzyme. The CYP3A4 isoenzyme is not significantly involved in the metabolism of irbesartan. The main metabolite in the systemic blood stream is irbesartan glucuronide (about 6%). Irbesartan is not metabolized by most isoenzymes that are usually involved in metabolism of drugs (CYP1A1 CYP1A2 CYP2A6 CYP2B6 CYP2D6 or CYP2E1 isoenzymes) and does not cause their inhibition or induction. Irbesartan does not induce or inhibit the CYP3A4 isoenzyme.

Elimination

Total clearance and renal clearance are 157-176 ml/min and 3-3.5 ml/min, respectively. The final elimination half-life (T1/2) is 11-15 h. Irbesartan and its metabolites are excreted by the kidneys through the intestine with the bile. After oral administration of 14C-irbesartan about 20% of radioactivity is found in urine and the rest – in feces.

Less than 2% of the administered dose is excreted by the kidneys as unchanged irbesartan.

Special patient groups

The effect of sex on the pharmacokinetics of irbesartan

Slightly higher plasma concentrations of irbesartan have been observed in women (compared to men). However, no differences in the T1/2 value and accumulation of irbesartan were found. No dose adjustment of irbesartan in women is required.

There were no gender-related differences in the effects of irbesartan.

Pharmacokinetics of irbesartan in elderly patients

The AUC (area under the concentration-time curve) and Stath values of irbesartan were slightly higher in elderly patients (over 65 years) than in younger patients but the final T1/2 were not significantly different. No dose adjustment of irbesartan is required in elderly patients.

Pharmacokinetics in renal impairment

In patients with impaired renal function or patients undergoing hemodialysis, the pharmacokinetics of irbesartan are not significantly altered. Irbesartan is not eliminated from the body by hemodialysis.

Pharmacokinetics in hepatic impairment

In patients with mild (Child-Pugh score 5-6) or moderate (Child-Pugh score 7-9) cirrhosis, the pharmacokinetic parameters of irbesartan are not significantly altered. No pharmacokinetic studies have been performed in patients with severe (greater than 9 points on the Child-Pugh scale) hepatic impairment.

The effect of race on the pharmacokinetics of irbesartan

The AUC and T1/2 of irbesartan were approximately 20-25% higher in black volunteers without arterial hypertension than in those of the Caucasian race; their Cmax of irbesartan was virtually the same as that of the Caucasian race.

Indications

– Arterial hypertension (in monotherapy and in combination with other hypotensive agents such as thiazide diuretics beta-adrenoblockers slow calcium channel blockers (DCBs);

Nephropathy in arterial hypertension and type 2 diabetes (as part of combined hypotensive therapy).

Active ingredient

Composition

Active ingredient:

Irbesartan – 300.00 mg.

Auxiliary substances (core):

Lactose monohydrate (milk sugar) – 186.40 mg,

Microcrystalline cellulose – 96.00 mg,

croscarmellose sodium – 28.80 mg,

povidone-K25 – 19.20 mg,

magnesium stearate – 6.40 mg,

colloidal silicon dioxide – 3.20 mg.

Excipients (coating):Hypromellose – 8.80 mg, macrogol-4000 – 2.40 mg, titanium dioxide – 4.80 mg.

How to take, the dosage

The drug should be taken orally regardless of the time of eating. The tablet should be swallowed whole with water.

The starting and maintenance dose is 150 mg once daily regardless of the time of meals. This dose provides better 24-hour BP control than the 75 mg/day dose. However, in some cases, especially in hemodialysis patients or in patients older than 75 years old, the starting dose should be 75 mg.

If the therapeutic effect of Irbesartan 150 mg once daily is insufficient, the dose can be increased to 300 mg once daily.

If Irbesartan monotherapy is insufficient to reduce BP, diuretics (e.g., hydrochlorothiazide 125 mg daily) or other hypotensive agents (e.g., beta-adrenoblockers or long-acting DMARDs) may be added.

In patients with arterial hypertension and type 2 diabetes mellitus, treatment should begin with a dose of 150 mg once daily and gradually increase to 300 mg, the preferred maintenance dose for nephropathy.

The use in special patient groups

In clinical studies, in general, no differences in efficacy and safety were observed between patients aged 65 years and older and patients of younger age.

While it is recommended that patients over the age of 75 years begin treatment with a dose of 75 mg usually older patients do not require dosing adjustments.

Patients with impaired renal function

In patients with impaired renal function, dosing adjustments are not required.

Patients with hypovolemia

In patients with impaired water-electrolyte balance the circulating blood volume (CBC) should be restored and/or hyponatremia corrected before starting the drug.

In patients on hemodialysis the starting dose should be 75 mg/day.

Patients with hepatic impairment

In patients with mild (5-6 points on the Child-Pugh scale) or moderate (7-9 points on the Child-Pugh scale) hepatic impairment no dosing adjustments are required. There is no clinical experience of using the drug in patients with severe (more than 9 points on the Child-Pugh scale) liver dysfunction (see section “Contraindications”).

The safety and effectiveness of the drug in patients under 18 years of age has not been established.

Interaction

The concomitant use of irbesartan with drugs containing aliskiren is contraindicated in patients with diabetes mellitus or with moderate to severe renal impairment (FFR less than 60 ml/min/173 m2 body surface area) and is not recommended in other patients (see Sections “Contraindications” “Caution” “Precautions”).

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” “Caution” “Special Precautions”).

Diuretics and other hypotensive agents

The simultaneous use of irbesartan with other hypotensive agents may increase the antihypertensive effect. Irbesartan has been used in combination with other hypotensive drugs such as long-acting β-adrenoblockers DMARDs and thiazide diuretics.

Pre-treatment with high-dose diuretics may lead to dehydration and increased risk of arterial hypotension at initiation of therapy with Irbesartan.

Potassium and potassium-saving diuretics, heparin

Based on experience with other potassium-acting drugs, concomitant use of potassium-containing water electrolyte solutions with potassium-saving diuretics or other drugs that can increase potassium in the blood, including heparin, can increase potassium levels.including heparin, serum potassium may increase.

Lithium

A reversible increase in serum lithium concentration or toxicity has been noted with concomitant use of lithium with ACE inhibitors. To date, such effects have rarely been observed with irbesartan.

If this combination is necessary, serum lithium concentrations should be monitored closely during treatment.

Non-steroidal anti-inflammatory drugs (NSAIDs including cyclooxygenase-2 inhibitors (COX-2))

When angiotensin II receptor antagonists (ARA II) and NSAIDs (including selective inhibitors of nSAIDs) are used concomitantly.including selective COX-2 inhibitors of acetylsalicylic acid (more than 3 g/day) and nonselective NSAIDs), the antihypertensive effect of irbesartan may be weakened.

As with concomitant use of ACE inhibitors and NSAIDs, co-administration of APA II and NSAIDs may increase risk of renal dysfunction including possibility of acute renal failure and increased serum potassium especially in patients with already impaired renal function. Caution should be exercised when using this combination especially in elderly patients and in patients with hypovolemia. Circulating blood volume should be restored and renal function should be monitored during the entire period of combined therapy and periodically after its termination.

Other Interactions

Irbesartan is not expected to interact with drugs metabolized by CYP1A1 CYP1A2 CYP1A6 CYP2B6 CYP2E1 or CYP3A4 isoenzymes based on in vitro studies.

Irbesartan is primarily metabolized with the CYP2C9 isoenzyme and is less subject to glucuronidation. No significant pharmacokinetic or pharmacodynamic interactions have been observed with concomitant use of irbesartan with warfarin drugs metabolized by the CYP2C9 isoenzyme. There have been no studies of the effect of inducers of CYP2C9 isoenzyme activity (including rifampicin) on pharmacokinetics of irbesartan.

Irbesartan does not alter the pharmacokinetics of digoxin and simvastatin. Simultaneous use of irbesartan with hydrochlorothiazide or nifedipine does not alter the pharmacokinetics of irbesartan.

In elderly patients and patients with impaired renal function, concomitant use of ACE inhibitors and ARA II with sulfamethoxazole/trimethoprim has been associated with severe hyperkalemia thought to be caused by trimethoprim. The drug should be used with caution with drugs containing trimethoprim, regularly monitoring blood potassium levels.

Special Instructions

Excessive BP lowering – patients with hypovolemia

The use of irbesartan has so far rarely been accompanied by excessive BP lowering in patients with arterial hypertension without comorbidities. As with ACE inhibitors, excessive BP lowering accompanied by clinical symptoms may develop in patients with hyponatremia/hypovolemia (e.g., as a result of intensive diuretic therapy with diarrhea or vomiting on a salt restricted diet) and in patients on hemodialysis. Hypovolemia and/or hyponatremia should be corrected before initiating the use of Irbesartan.

The use in patients with renal function dependent on RAAS activity

As a consequence of RAAS inhibition, worsening of renal function can be expected in predisposed patients. In patients with renal function depending on the activity of RAAS (patients with arterial hypertension and stenosis of the renal artery of one or both kidneys, patients with chronic heart failure III and IV functional class according to NYHA classification) treatment with the medications acting on 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 cannot be excluded with the use of ARA II including irbesartan.

Kidney dysfunction and renal transplantation

In patients with impaired renal function, periodic monitoring of serum potassium and creatinine concentrations is recommended when using irbesartan. There are no clinical data regarding the use of irbesartan in patients with recent kidney transplantation.

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

The benefit of irbesartan in delaying the progression of renal and cardiovascular events varied among patient groups and was less pronounced in women and in non Caucasian patients.

Double RAAS blockade with ACE inhibitors or with aliskiren

Double RAAS blockade is not recommended with irbesartan combined with ACE inhibitors or with aliskiren because of the increased risk of hyperkalemia and renal dysfunction when compared to monotherapy.

The use of Irbesartan in combination with aliskiren is contraindicated in patients with diabetes mellitus or renal impairment (FFR less than 60 ml/min/173m2 of body surface area) (see “Contraindications” “Interaction with other medicinal products”) and is not recommended in other patients.

The use of Irbesartan in combination with ACE inhibitors is contraindicated in patients with diabetic nephropathy (see “Contraindications” “Interaction with other drugs”) and is not recommended in other patients.

Hyperkalemia

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

Aortic or mitral valve stenosis hypertrophic obstructive cardiomyopathy

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

Primary hyperaldosteronism

Patients with primary hyperaldosteronism usually do not respond to hypotensive drugs acting via RAAS inhibition. Therefore it is not appropriate to use the drug in these cases.

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

As with the use of other hypotensive drugs, significant BP decrease in patients with coronary heart disease and/or significant atherosclerosis of cerebral vessels may lead to myocardial infarction or stroke. Treatment of such patients should be carried out under strict control of BP.

Contraindications

– Hypersensitivity to irbesartan and any of the excipients of the drug;

– pregnancy;

– period of breastfeeding;

– childhood and adolescence under 18 years of age (efficacy and safety not established);

– galactose intolerance lactase deficiency and glucose-galactose malabsorption syndrome;

– concomitant use with aliskiren and aliskiren-containing drugs in patients with diabetes or with moderate to severe renal impairment (glomerular filtration rate (GFR) less than 60 ml/min/173 m2 body surface area).

– concomitant use with angiotensin-converting enzyme (ACE) inhibitors in patients with diabetic nephropathy.

– severe hepatic insufficiency (more than 9 points by the Child-Pugh scale) (no clinical experience of use).

With caution, use the drug in aortic or mitral valve stenosis hypertrophic obstructive cardiomyopathy hypovolemia hyponatremia diarrhea vomiting adherence to a diet with limited table salt therapy diuretics; bilateral renal artery stenosis unilateral artery stenosis of the uniciliary artery chronic heart failure III-IV functional class according to the NYHA classification coronary heart disease (CHD) and/or atherosclerotic cerebral vascular disease hyperkalemia renal insufficiency hemodialysis after kidney transplantation (no clinical experience of use) age older than 75 years; concomitant use with nonsteroidal anti-inflammatory drugs including cyclooxygenase II inhibitors; when used in combination with ACE inhibitors or aliskiren, since compared to monotherapy with dual RAAS blockade there is an increased risk of excessive BP reduction hyperkalemia and renal function impairment; primary hyperaldosteronism.

Side effects

The adverse events listed below are presented according to the following frequency gradations (according to the World Health Organization classification): Very common (≥1/10) common (≥1/100 to < 1/10) infrequent (≥1/1,000 to < 1/100) rare (≥1/10,000 to < 1/1,000) very rare (< 1/10,000) frequency unknown (no estimate can be made based on available data).

Indications observed in placebo-controlled studies in arterial hypertension

Central nervous system: common – dizziness headache; infrequent – orthostatic dizziness.

Cardiovascular system: infrequent – edema tachycardia.

Respiratory system: infrequent – cough.

Gastrointestinal system: frequently – nausea, vomiting; infrequent – diarrhea dyspepsia heartburn.

As to the sexual system: infrequent – sexual dysfunction.

As to the body in general: often – fatigue; infrequent – pain in the chest.

Laboratory parameters: during the study in patients with arterial hypertension no clinically significant changes in laboratory parameters were observed.

Arterial hypertension and type 2 diabetes mellitus with impaired renal function

. The adverse events were similar to those in patients with arterial hypertension except for orthostatic symptoms (dizziness (102%) (with placebo 6%) orthostatic vertigo (54%) (with placebo 27%) and orthostatic hypotension (54%) (with placebo 32%).

Hyperkalemia

In the IDNT clinical trial, the percentage of patients with hyperkalemia (greater than 6 mEq/L) was 186% in the irbesartan group versus 60% in the placebo group. In the IRMA2 study, the percentage of patients with hyperkalemia (greater than 6 mEq/L) was 1% in the irbesartan group and no hyperkalemia was observed in the placebo group.

In the IDNT clinical trial, the discontinuation rate due to hyperkalemia with irbesartan and placebo was 21% and 036%, respectively. In the IRMA2 clinical trial, the discontinuation rate due to hyperkalemia with irbesartan and placebo was 05% and 00%, respectively.

Indications observed with post-marketing use of irbesartan

Intestinal system disorders: very rare allergic reactions (urticaria angioedema).

Metabolism and nutrition: frequency unknown – hyperkalemia.

Nervous system disorders: frequency unknown – vertigo.

Hepatic disorders: frequency unknown – increased activity of “liver” enzymes and bilirubin concentration in the blood hepatitis jaundice.

Hearing organ: frequency is unknown – tinnitus.

Skeletal and muscular system: frequency unknown – myalgia.

Recreational and urinary system: frequency unknown – renal dysfunction including development of renal failure in patients at risk (see section “Special Precautions”).

General disorders: frequency unknown – asthenia.

Overdose

Symptoms: pronounced BP decrease is most likely. tachycardia bradycardia.

Treatment: in case of accidental ingestion of the drug in high doses artificial vomiting and/or gastric lavage activated charcoal carrying out symptomatic and supportive therapy is indicated. Hemodialysis is ineffective.

Pregnancy use

There is no experience with the use of Irbesartan in pregnancy. Given that the use of ACE inhibitors by pregnant women in the second and third trimesters of pregnancy has resulted in damage and death of the developing fetus, irbesartan, like any other drug that directly affects the RAAS, should not be used during pregnancy. If pregnancy is established during treatment with irbesartan, the drug should be discontinued as soon as possible.

It is not known whether irbesartan and its metabolites are excreted into breast milk. Irbesartan is contraindicated during breastfeeding. Therefore, after assessing the balance of the expected benefit to the mother and the potential risk to the baby, breastfeeding or Irbesartan should be stopped.

Similarities