Irbebartan - instructions for use, dose, side effects, contraindications

Excipients (core): lactose monohydrate (sugar milk) - 46,60 mg, microcrystalline cellulose - 24,00 mg, croscarmellose sodium - 7.20 mg, povidone-K25 - 4.80 mg, magnesium stearate - 1.60 mg, silicon dioxide colloid - 0 , 80 mg.

Auxiliary substances (shell): hypromellose - 2.20 mg, macrogol-4000 - 0.60 mg, titanium dioxide - 1.20 mg.

Composition per tablet 150 mg:

Active substance: irbesartan - 150.00 mg.

Excipients (core): lactose monohydrate (sugar milk) - 93.20 mg, microcrystalline cellulose - 48.00 mg, croscarmellose sodium - 14.40 mg, povidone-K25 - 9.60 mg, magnesium stearate - 3.20 mg, silicon dioxide colloid - 1 , 60 mg.

Auxiliary substances (shell): hypromellose - 4.40 mg, macrogol-4000 - 1.20 mg, titanium dioxide - 2.40 mg.

Composition per tablet 300 mg:

Active substance: irbesartan - 300.00 mg.

Excipients (core): lactose monohydrate (sugar milk) - 186.40 mg, microcrystalline cellulose - 96.00 mg, croscarmellose sodium - 28.80 mg, povidone-K25 - 19.20 mg, magnesium stearate - 6.40 mg, silicon dioxide colloid - 3 , 20 mg.

Auxiliary substances (shell): hypromellose - 8.80 mg, macrogol-4000 - 2.40 mg, titanium dioxide - 4.80 mg.

Description:Round, biconvex tablets, film coating "white or almost white." Two layers are visible on the cross section: a white or almost white core and a film membrane.

Pharmacotherapeutic group:Angiotensin II receptor antagonist

ATX: & nbsp

C.09.C.A.04 Irbesartan

Pharmacodynamics:

Irbesartan is a selective angiotensin receptor antagonist II (of the type AT₁). Reduces the concentration of aldosterone in the blood plasma (does not inhibit kinase II, destroying bradykinin); eliminates the vasoconstrictive effect of angiotensin II; reduces overall peripheral vascular resistance, reduces afterload, systemic arterial pressure (BP), and pressure in the "small" circulation. Does not affect the concentration of triglycerides, cholesterol, glucose, uric acid in the plasma and the excretion of uric acid.

The maximum decrease in blood pressure is achieved 3 to 6 hours after ingestion, and the antihypertensive effect persists for at least 24 hours. At 24 hours after administration, at recommended doses, blood pressure reduction is 60-70% compared with the maximum decrease in diastolic and systolic BP in response to the use of the drug. When taking 1 time / day at a dose of 150-300 mg, the degree of blood pressure reduction (systolic / diastolic) at the end of the inter-dose interval (ie, 24 hours after taking the drug) in the patient's position lying or sitting on average 8-13 / 5 -8 mmHg (respectively) greater compared with placebo. Taking the drug at a dose of 150 mg 1 time / day causes the same antihypertensive response (a decrease in blood pressure before taking the next dose of the drug and an average BP decrease for 24 hours), as well as taking 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. Antihypertensive effect persists in long-term treatment. After discontinuation of treatment, blood pressure gradually returns to the initial value, the syndrome of "withdrawal" was not observed.

The effectiveness of the drug does not depend on age and sex.

Patients of the Negroid race react weakly to monotherapy with irbesartan (as well as all other medicines affecting the renin-angiotensin-aldosterone system (RAAS)).

Pharmacokinetics:

Suction

After oral administration irbesartan well absorbed from the gastrointestinal tract (GIT). Maximum concentration (FROM_mOh) Irbesartan in blood plasma is achieved after 1.5-2 hours after ingestion. Absolute bioavailability is 60-80%. Simultaneous food intake does not significantly affect the bioavailability of the drug. Irbesartan has a linear and proportional dose of pharmacokinetics in the dose range of 10 to 600 mg; at doses in excess of 600 mg (2 times the recommended maximum dose) kinetics of irbesartan becomes nonlinear (decrease in absorption).

Distribution

Binding to plasma proteins is approximately 96%. Binding to the cellular components of blood is negligible. The volume of distribution is 53-93 liters. With daily intake of 1 time / day, the equilibrium concentration is achieved after 3 days. With repeated administration of 1 time / day there is a limited accumulation of irbesartan in the blood plasma (less than 20%).After ingestion or intravenous administration ¹⁴C-irbesargan 80-85% of radioactivity in the circulating blood accounts for the unchanged irbesartan.

Metabolism

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

Irbesartan is oxidized, mainly by isoenzyme CYP2C9, isoenzymatic participation CYP3A4 in the metabolism of irbesartan is insignificant. The main metabolite in the systemic circulation is irbesartan glucuronide (about 6%). Irbesartan It is not metabolized by most isoenzymes, which 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 isoenzyme CYP3A4.

Excretion

The total clearance and renal clearance are 157-176 ml / min and 3-3.5 ml / min, respectively. The final half-life (T₁_/₂) is 11-15 hours. Irbesartan and its metabolites are excreted by the kidneys, through the intestine with bile. After oral administration ¹⁴FROM-irbesartan about 20% of radioactivity is found in the urine, the rest - in the feces.

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

Special patient groups

Influence of sex on the pharmacokinetics of irbesartan

Several higher concentrations of irbesartan in blood plasma are noted in women (compared to men). However, the differences in the value of T_1/2and the accumulation of irbesartan is not revealed. Correction of irbesartan dose in women is not required.

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

The pharmacokinetics of irbesartan in elderly patients

Values AUC (the area under the concentration-time curve) and Stach irbesartan were slightly higher in elderly patients (over 65 years) than in younger patients, but the values of the final T_1/2did not differ significantly. Correction of irbesartan dose in elderly patients is not required.

Pharmacokinetics in renal dysfunction

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

Pharmacokinetics for violations of liver function

In patients with cirrhosis of the liver of the lung (5-6 points on the Child-Pugh scale) or in the medium-severe course (7-9 on the Child-Pugh scale), the pharmacokinetic parameters of irbesartan do not change significantly.Pharmacokinetic studies in patients with severe (more than 9 points on the Child-Pugh scale) were not performed with hepatic insufficiency.

Influence of race on the pharmacokinetics of irbesartan

The volunteers of the Negroid race, without hypertension, AUC and T_1/2irbesartan were approximately 20-25% higher than in the representatives of the Caucasoid race; FROM_maxirbesartan in them was almost identical with that of representatives of the Caucasoid race.

Indications:

- Arterial hypertension (in monotherapy and in combination with other antihypertensive drugs, for example, thiazide diuretics, beta-blockers, blockers of "slow" calcium channels (BCCC) of long-acting);

- Nephropathy in arterial hypertension and type 2 diabetes mellitus (consisting of combined antihypertensive therapy).

Contraindications:

- Pincreased sensitivity to irbesartan and to any of the auxiliary components of the drug;

- pregnancy;

- the period of breastfeeding;

- children and adolescents under 18 years of age (efficacy and safety not established);

- intolerance to galactose, deficiency of lactase and glucose-galactose malabsorption syndrome;

- simultaneous use with aliskiren and aliskirenoderzhaschimi drugs in patients with diabetes mellitus or with moderate and severe renal failure (glomerular filtration rate (GFR) less than 60 ml / min / 1.73 m² surface area of the body).

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

- severe hepatic insufficiency (more than 9 on the Child-Pugh scale) (lack of clinical experience).

Carefully:

Carefully should be used for stenosis of the aortic or mitral valve, hypertrophic obstructive cardiomyopathy, hypovolemia, hyponatremia, diarrhea, vomiting, diet with limited intake of salt, diuretic therapy; bilateral stenosis of the renal arteries, unilateral stenosis of the artery of a single kidney, chronic cardiac insufficiency of the III-IV functional class according to the NYHA classification, coronary heart disease (CHD) and / or atherosclerotic lesions of the cerebral vessels, hyperkalemia, renal failure, hemodialysis,after kidney transplantation (lack of clinical experience), age over 75; when used simultaneously with non-steroidal anti-inflammatory drugs, including cyclooxygenase II inhibitors; when used in combination with ACE inhibitors or aliskiren, since, in comparison with monotherapy with double blockade of RAAS, there is an increased risk of developing excessive blood pressure lowering, hyperkalemia and renal dysfunction; primary hyperaldosteronism.

Pregnancy and lactation:

Experience with the drug Irbesartan when pregnancy is absent. In view of the fact that during the reception of ACE inhibitors by pregnant women in the second and third trimester of pregnancy the damage and death of the developing fetus was observed, irbesartan, like any other drug that acts directly on RAAS, can not be used during pregnancy. When establishing pregnancy during drug treatment Irbesartan should be stopped as soon as possible.

It is not known whether irbesartan and its metabolites into breast milk. During breastfeeding, taking the drug Irbesartan is contraindicated.Therefore, after assessing the ratio of the perceived benefit of taking the drug to the mother and the potential risk to the baby, stop breastfeeding or taking the drug Irbesartan.

Dosing and Administration:

The drug should be taken orally regardless of the time of ingestion. The tablet is swallowed whole, washed down with water.

The initial and maintenance dose is 150 mg 1 time / day, regardless of the time of ingestion. The use of the drug at this dose provides a more optimal 24-hour BP control than at a dose of 75 mg / day. However, in some cases, especially in patients on hemodialysis, or in patients older than 75 years, the initial dose should be 75 mg.

If there is insufficient therapeutic effect with the drug Irbesartan in a dose of 150 mg 1 time / day, the dose can be increased to 300 mg once a day.

In case of insufficient reduction of blood pressure in monotherapy with the drug Irbesartan to treatment can be added diuretics (for example, hydrochlorothiazide 12.5 mg per day) or other antihypertensive agents (eg, beta-blockers or long-acting BCCC).

In patients with hypertension and type 2 diabetes, treatment should be started at a dose of 150 mg once a day and gradually increased to 300 mg, the dose that is the preferred maintenance dose for the treatment of nephropathy.

Use in special patient groups

In clinical trials, overall, there was no difference in efficacy and safety between patients aged 65 years and older and patients of a younger age.

Although it is recommended that patients over the age of 75 start with a dose of 75 mg, usually patients of advanced age correction of the dosing regimen is not required.

Patients with impaired renal function

Patients with impaired renal function are not required to adjust the dosage regimen.

Patients with hypovolaemia

In patients with a disturbance of the water-electrolyte balance, the volume of circulating blood (BCC) and / or the elimination of hyponatremia should be restored before taking the drug.

For patients on hemodialysis, the initial dose should be 75 mg / day.

Patients with impaired hepatic function

In patients with impaired hepatic function (5-6 points on the Child-Pugh scale) or an average (7-9 points on the Child-Pugh scale), the dosage regimen does not need to be corrected.Clinical experience in the use of the drug in patients with severe (more than 9 points on the scale Child-Pugh) violations of liver function is absent (see the section "Contraindications").

Safety and effectiveness of the drug in patients under the age of 18 years are not established.

Side effects:

The following undesirable phenomena are presented in accordance with the following grades of their incidence (according to the classification of the World Health Organization): Often (≥1/10), often (≥1/100 - <1/10), infrequently (≥1/1 000 - <1/100), rarely (≥1/10 000 - <1/1 000), rarely (<1/10 000), frequency unknown (the evaluation can not be carried out on the basis of available data).

Undesirable effects observed in placebo-controlled studies in hypertension

From the central nervous system: often - dizziness, headache; infrequently Orthostatic dizziness.

From the cardiovascular system: infrequently - edema, tachycardia.

From the respiratory system: infrequently - cough.

From the digestive system: often - nausea, vomiting; infrequently - diarrhea, dyspepsia, heartburn.

On the part of the reproductive system: infrequently - sexual dysfunction.

From the body as a whole: often - increased fatigue; infrequently chest pain.

From the laboratory indicators: During the studies in patients with arterial hypertension, there were no clinically significant changes in laboratory parameters.

Arterial hypertension and type 2 diabetes mellitus with impaired renal function

Adverse events were similar to those in patients with hypertension, with the exception of orthostatic symptoms (dizziness (10.2%) (with placebo 6%), orthostatic dizziness (5.4%) (with placebo 2.7%) and orthostatic hypotension (5.4%) (when taking placebo 3.2%).

Hyperkalemia

In a clinical study IDNT the percentage of patients with hyperkalemia (more than 6 mEq / L) was 18.6% in the irbesartan group versus 6.0% in the placebo group. In the study IRMA2 the percentage of patients with hyperkalemia (more than 6 mEq / L) was 1% in the irbesartan group, and in the placebo group, no hyperkalemia was observed.

In a clinical study IDNT the frequency of cessation of treatment due to the development of hyperkalemia with the use of irbesartan and placebo was 2.1% and 0.36%, respectively. In a clinical study IRMA2 the frequency of cessation of treatment due to the development of hyperkalemia with irbesartan and placebo was 0.5% and 0.0%, respectively.

Undesirable effects observed during post-marketing application of irbesartan

From the immune system: rarely - allergic reactions (hives, angioedema).

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

From the nervous system: frequency unknown - Vertigo.

From the side of the liver: frequency unknown - increased activity of "hepatic" enzymes and bilirubin concentration in the blood, hepatitis, jaundice.

From the organ of hearing: frequency unknown - ringing in the ears.

From the musculoskeletal system: frequency unknown - myalgia.

From the side of the kidneys and the urinary system: frequency unknown - impaired renal function, including the development of renal failure in patients of the group risk (see section "Special instructions").

Common violations: frequency unknown - asthenia.

Overdose:

Symptoms: the most likely decrease in blood pressure. tachycardia, bradycardia.

Treatment: when the drug is randomly taken in high doses, artificial vomiting and / or gastric lavage are indicated, Activated carbon, symptomatic and maintenance therapy. Hemodialysis is ineffective.

Interaction:

With medications containing aliskiren

Simultaneous use of irbesartan with drugs containing aliskiren, is contraindicated in patients with diabetes mellitus or with moderate and severe renal failure (GFR less than 60 mL / min / 1.73 m² body surface area) and is not recommended in other patients (see the sections "Contraindications", "With caution", "Special instructions").

FROM 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 the sections "Contraindications", "With caution", "Special instructions").

Diuretics and other antihypertensives

With the simultaneous use of irbesartan with other antihypertensive agents, an increase in antihypertensive action is possible. Irbesartan was used in combination with other antihypertensive drugs, such as β- adrenoblockers, long-acting BCCC and thiazide diuretics.

Prior treatment with diuretics in high doses can lead todehydration of the body and increased risk of arterial hypotension at the beginning of treatment with the drug Irbesartan.

Potassium preparations and potassium-sparing diuretics, heparin

Based on the experience obtained with the use of other drugs that affect RAAS, with the simultaneous use of potassium, aqueous electrolyte solutions containing potassium, potassium-sparing diuretics, or other drugs that can increase the potassium content in the blood, incl. heparin, it is possible to increase the potassium content in the blood serum.

Lithium

Reversible increase in serum lithium concentration or its toxicity was It was noted with the simultaneous use of lithium with ACE inhibitors. To the present At the time when irbesartan was used, such effects were extremely rare.

If there is a need for this combination, then during treatment carefully monitor the concentration of lithium in the blood serum.

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

With the simultaneous use of receptor antagonists for angiotensin II (ARA II) and NSAIDs (incl.selective inhibitors of COX-2, acetylsalicylic acid (more than 3 g / day) and non-selective NSAIDs), the attenuation of the antihypertensive effect of irbesartan is possible.

As with the simultaneous use of ACE inhibitors and NSAIDs, the combined use of APA II and NSAIDs may increase the risk of renal dysfunction, including the possibility of developing acute renal failure, and an increase in serum potassium, especially in patients with renal impairment. It should be used with caution, this combination, especially in elderly patients and in patients with hypovolemia. It is necessary to restore the volume of circulating blood, and during the entire period of combined therapy, as well as periodically after its termination, monitor the kidney function.

Other types of interaction

Based on the research data in vitro, no interaction of irbesartan with drugs metabolized by isoenzymes is expected CYP1A1, CYP1A2, CYP1A6, CYP2B6, CYP2E1 or CYP3A4.

Irbesartan is mainly metabolized with the participation of isoenzyme CYP2C9 and is less exposed to glucuronidation.There was no significant pharmacokinetic or pharmacodynamic interaction with the simultaneous use of irbesartan with warfarin, drugs metabolized by isoenzyme CYP2C9. Studies of the effect of inducers of isoenzyme activity CYP2C9 (incl. rifampicin) on the pharmacokinetics of irbesartan was not performed.

Irbesartan does not change the pharmacokinetics of digoxin and simvastatin. With the simultaneous use of irbesartan with hydrochlorothiazide or nifedipine pharmacokinetics Irbesartan does not change.

In elderly patients and patients with impaired renal function, simultaneous administration of ACE inhibitors and APA II with sulfamethoxazole / trimethoprim was accompanied by severe hyperkalemia, which is believed to be caused by trimethoprim. The drug should be used with caution with drugs containing trimethoprim, regularly monitoring the potassium content in the blood.

Special instructions:

Excessive reduction in blood pressure - patients with hypovolaemia

Application of the drug irbesartan To date, rarely been accompanied by excessive reduction in blood pressure in patients with hypertension without concomitant diseases.As with the use of ACE inhibitors, excessive blood pressure lowering accompanied by clinical symptoms can develop in patients with hyponatremia / hypovolemia (for example, as a result of intensive diuretic therapy, diarrhea or vomiting, adherence to a diet limiting intake of table salt), as well as in patients, who are on hemodialysis. Before starting the preparation Irbesartan it is necessary to correct hypovolemia and / or hyponatraemia.

Application in patients with renal function, depending on the activity of RAAS

As a consequence of inhibition of RAAS, impairment of renal function in predisposed patients can be expected. In patients with renal function, depending on the activity of RAAS (patients with arterial hypertension and renal artery stenosis of one or both kidneys, patients with chronic cardiac insufficiency III and IV functional class by classification NYHA), treatment with drugs that affect RAAS was associated with oliguria and / or progressive azotemia and, rarely, with acute renal failure and / or death.It is impossible to exclude the possibility of such an effect when using APA II, including irbesartan.

Impaired renal function and kidney transplantation

When using the drug Irbesartan In patients with impaired renal function, periodic monitoring of potassium and serum creatinine concentrations is recommended. There are no clinical data on the use of irbesartan in patients who have recently undergone a kidney transplant.

Patients with hypertension and type 2 diabetes mellitus with impaired kidney function

The beneficial effect of irbesartan on slowing progression renal and cardiovascular disorders had different degrees of severity in different groups of patients, it was less expressed in women and in patients not belonging to the Europoid race.

Double blockade of RAAS when applied with ACE inhibitors or with aliskiren

Double blockade of RAAS with simultaneous application of irbesartan with ACE inhibitors or aliskiren is not recommended, as compared to monotherapy, there is an increased risk of a sharp decrease in blood pressure, the development of hyperkalemia and renal dysfunction.

Application of the drug Irbesartan in combination with aliskiren is contraindicated in patients with diabetes mellitus or renal insufficiency (GFR less than 60 ml / min / 1.73 m² body surface area) (see "Contraindications", "Interaction with other drugs") and is not recommended in other patients.

Application of the drug Irbesartan in combination with ACE inhibitors is contraindicated in patients with diabetic nephropathy (see the sections "Contraindications", "Interaction with other drugs") and is not recommended in other patients.

Hyperkalemia

As with the use of other drugs that affect RAAS, with drug therapy Irbesartan hyperkalemia may develop, especially if there is kidney failure and / or heart disease. In such patients it is recommended to monitor the potassium content in the blood serum.

Stenosis of the aortic or mitral valve, hypertrophic obstructive cardiomyopathy

As with the use of other vasodilators, when taking the drug Irbesartan Care should be taken 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 acting through inhibition of RAAS. Therefore, the use of the drug in such cases is impractical.

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

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

Effect on the ability to drive transp. cf. and fur:

Effect of the drug Irbesartan on the ability to drive vehicles or engage in other potentially hazardous activities requiring increased attention and high speed of psychomotor reactions, has not been studied. However, based on pharmacodynamic properties, the drug Irbesartan should not affect the ability to drive vehicles and engage in other potentially hazardous activities (work at height, the work of an air traffic controller,work with mechanisms, etc.), but in the case of dizziness and weakness, it is possible to reduce psychomotor reactions, therefore it is better to abstain from this kind of activity.

Form release / dosage:Tablets, film-coated, 75, 150 and 300 mg.

Packaging:

By 3, 4, 7, 10, 14, 15, 20, 25 or 30 tablets into a contoured cell packaging made of polyvinylchloride film and aluminum foil printed lacquered.

10, 14, 20, 28, 30, 40, 50, 60 or 100 tablets in cans of polyethylene terephthalate for medicinal products sealed with caps screwed on with first opening control or by a "push-turn" system of polypropylene or polyethylene or polypropylene cans for medicinal products means sealed with caps tightened with the control of the first opening from polyethylene or cans of polypropylene for medicinal products sealed with caps tightened with the control of the first opening of high pressure polyethylene.

One jar or 1, 2, 3, 4, 5, 6, 7, 8 or 10 cell packs, together with instructions for use, are placed in a cardboard package (bundle).

Storage conditions:

At a temperature not exceeding 25 FROM.

Keep out of the reach of children.

Shelf life:

3 years.

Do not use after the expiration date.

Terms of leave from pharmacies:On prescription

Registration number:LP-003987

Date of registration:01.12.2016

Expiration Date:01.12.2021

The owner of the registration certificate:ATOLL, LLC ATOLL, LLC Russia

Manufacturer: & nbsp

OZONE, LLC Russia

Representation: & nbspOZONE LLC OZONE LLC Russia

Information update date: & nbsp27.11.2017

Illustrated instructions

Instructions

Irbesartan (Irbesartan)