Expiration date: 03/2025

The composition and form of issue:

Tablets. 1 tablet contains irbesartan 150 or 300 mg

excipients: lactose monohydrate maize starch croscarmellose sodium pregelatinization poloxamer 188 silicon dioxide colloidal aqueous microcrystalline magnesium stearate 

blistere in 14 PCs., in box 1, 2 or 4 blisters.

Description pharmaceutical form:

Tablets 150 mg: biconvex, oval tablet white, or almost white engraved image of the heart on one side and "2772" on the other.

Tablets 300 mg: biconvex, oval tablet white, or almost white engraved image of the heart on one side and the numbers "2773" on the other.

Pharmacokinetics:

After intake of irbesartan is well absorbed, absolute bioavailability is approximately 60-80%. Simultaneous food intake does not significantly affect the bioavailability of irbesartan.

Linking blood plasma proteins is approximately 96%. Binding to cellular components of blood slightly. The volume of distribution is 53-93 L.

After oral or intravenous administration of 14C irbesartan, 80-85% of circulating radioactivity in plasma falls to unchanged irbesartan. Irbesartan is metabolized in the liver by oxidation and conjugation with glucuronic acid. The main metabolite in the bloodstream, is irbesartan glucuronide (approximately 6%). Irbesartan oxidized mainly via the cytochrome P450 CYP2C9, isoenzyme CYP3A4 has negligible effect.

In the therapeutic range of doses of irbesartan and doseproportional has linear pharmacokinetics in the range of doses from 10 to 600 mg (a dose 2 times the recommended dose) at doses above 600 mg irbesartan kinetics become nonlinear (decreases absorption). C max in plasma achieved through 1.5–2 h after ingestion. Total clearance from the body and renal clearance are 157-176 and 3-3. 5 ml/min, respectively. T1/2 of irbesartan for the final phase is 11-15 h Equilibrium concentration in plasma is achieved within 3 days after the beginning of the drug when taken 1 time a day. When re techniques according to the scheme 1 time per day there has been a limited accumulation of irbesartana in plasma (less than 20%). Slightly higher concentrations of irbesartan in plasma noted in female patients. However, the differences and the elimination half-life and accumulation of irbesartan were not. It was not necessary to adjust the dose in women. The values of AUC and Cmax irbesartan was slightly higher in elderly patients (over 65 years) than younger patients (18-40 years), the final half-lives did not differ significantly. It was not necessary to change the dose for elderly patients.

Irbesartan and its metabolites are excreted with bile and urine. After oral or intravenous administration of 14C irbesartan, 20% of the radioactivity found in the urine, the remainder in the feces. Less than 2% of the administered dose excreted in urine as unchanged irbesartan.

The impairment of renal function. In patients with impaired renal function or patients undergoing haemodialysis, the pharmacokinetic parameters of irbesartan did not substantially change. Irbesartan is not removed from the body during hemodialysis.

The liver dysfunction. Pharmacokinetic parameters of irbesartan did not significantly change in patients with cirrhosis of the liver, mild or moderate severity.

For patients with severe insufficiency of liver function studies have not been conducted.

Description pharmacological action:

Irbesartan is active when administered selective antagonist of the angiotensin II receptor (type AT1). It blocks all physiologically relevant effects of angiotensin II, realized through the receptor type AT1, regardless of the source or route of synthesis of angiotensin II. Specific antagonistic action against angiotensin II receptor (AT1) leads to an increase in the concentration of renin and angiotensin II in blood plasma and decrease the concentration of aldosterone in blood plasma. When applying the recommended doses of the drug, the concentration of potassium ions in the blood serum does not change significantly. Irbesartan does not inhibit kininase II. For the manifestation of its effect, irbesartan does not require metabolic activation.

Irbesartan dose-dependent (when using up to 300 mg/day) lowers blood pressure with minimal change in heart rate. However, with further increase of the dose of irbesartan increase the hypotensive effect is negligible. The maximum decrease in blood pressure achieved through 3-6 h after administration of the drug inside, and the hypotensive effect persisted at least for 24 h after 24 h after administration of the recommended doses decrease in blood pressure is 60-70% in comparison with the maximum response of DBP and garden. When taken once a day at a dose of 150-300 mg the degree of blood pressure reduction at the end midazolama interval (i.e. 24 h after ingestion) in the patient "lying" or "sitting" on average of 8-13/5-8 mm Hg. article (SBP/DBP) in comparison with placebo.

The degree of blood pressure reduction in the dose of 150 mg/day is the same as in single dose and split the dose on 2 reception.

Hypotensive effect of the drug Aprovel develops within 1-2 weeks, and maximum therapeutic effect is achieved by 4-6 weeks after start of treatment. The antihypertensive effect persists in long-term treatment. After cessation of treatment hell slowly returns to the initial value of the syndrome was not observed.

The effectiveness of Aprovel not depend on age and gender. Patients of black race is weaker than the respond to monotherapy Aproblem (and all other drugs influencing the renin-angiotensin-aldosterone system).

Irbesartan has no effect on uric acid content in blood serum, or the secretion of uric acid in the urine.

Indications:

• essential hypertension
  
• nephropathy with arterial hypertension and diabetes mellitus type 2 (in a combination antihypertensive therapy).
  

Contraindications:

• hypersensitivity to any component of the drug
  
• pregnancy
  
• lactation
  
• the age of 18 years (efficacy and safety not established)
  
• hereditary intolerance of galactose, lactase deficiency or malabsorption of glucose and galactose.
  

With caution in such States as:

• stenosis of the aortic or mitral valve
  
• obstructive hypertrophic cardiomyopathy
  
• dehydration
  
• hyponatremia
  
• diarrhea
  
• vomiting
  
• compliance with malosolenoj diet
  
• treatment diuretics
  
• bilateral renal artery stenosis
  
• unilateral stenosis of the artery only functioning kidney
  
• congestive heart failure stages III–IV (NYHA classification)
  
• IHD and/or atherosclerotic lesions of cerebral vessels
  
• hyperkalemia
  
• renal failure
  
• hemodialysis
  
• a recent kidney transplantation (no experience of clinical application)
  
• severe renal failure (no experience of clinical application).
  

Application of pregnancy and breast-feeding:

Pregnancy. The drug is contraindicated during all periods of pregnancy like any other drug that acts directly on the system of the renin-angiotensin-aldosterone.

The transition to an appropriate alternative therapy should be made prior to planning pregnancy.

If pregnancy occurs during treatment with Aproblem, it should be abolished as quickly as possible.

Lactation. Receiving Aprovel is contraindicated during breast-feeding. It is unknown whether irbesartan is excreted in breast milk.

Side effects:

Frequency of adverse reactions listed below is defined as follows: very common (&GE. 1/10), often (>1/100, <1/10), sometimes (>1/1000, <1/100) rare (>1/10000, <1/1000) very rare (<1/10000) (including private messages).

The frequency of side effects depended on the dose (in the recommended range of doses), sex, age, race of the patient or duration of treatment in placebo-controlled studies.

A. Arterial hypertension

In placebo-controlled trials in patients with hypertension, 1965 in which patients received irbesartan, the following were noted side effects. The frequency of side effects when taking irbesartan was the same as when taking placebo.

Disorders of the Central nervous system: often — dizziness.

Violations by the cardiovascular system: sometimes — tachycardia.

Vascular disorders: rarely — redness of the skin.

Respiratory: sometimes — cough.

From the digestive tract: often — nausea, vomiting and sometimes diarrhea, dyspepsia/heartburn.

From the reproductive system: sometimes — sexual dysfunction.

Common: often — fatigue and sometimes pain in the chest.

The laboratory parameters: often — significant increase in kreatininfosfokinaza blood plasma was observed (1,7%) in patients receiving irbesartan. None of these increases were not accompanied by clinical symptoms from the musculoskeletal system.

B. hypertension and diabetes mellitus type 2 with renal insufficiency

In addition to the adverse reactions referred to in connection with arterial hypertension, in patients with arterial hypertension, diabetes mellitus type 2, microalbuminuria without renal dysfunction orthostatic dizziness, and orthostatic hypotension was observed in 0.5% of patients (compared with the frequency of these adverse reactions when taken placebo).

Diabetic patients with hypertension and chronic renal insufficiency and severe proteinuria, the following adverse reactions have been observed more than 2% of patients in comparison with the frequency of their occurrence when taking a placebo.

From the nervous system: often — orthostatic dizziness.

Vascular disorders: often — orthostatic hypotension.

Disorders musculoskeletal, connective tissue and bones: often musculoskeletal pain.

Laboratory tests: hyperkalemia occurred more frequently in diabetic patients treated with irbesartan than placebo. Diabetic patients with high blood pressure with microalbuminuria with normal renal function hyperkalemia (>5.5% mmol/l) was found in 29,4% of patients receiving irbesartan 300 mg and in 22% of patients in the placebo group. Diabetic patients with high blood pressure, chronic renal insufficiency and severe proteinuria, hyperkalemia (>5.5% mmol/l) was found in 46,3% of patients in the irbesartan group and 26.3% of the patients in the placebo group.

The decrease in hemoglobin level, which was not clinically significant, was observed in 1.7% of patients with high blood pressure and diabetic nephropathy treated with irbesartan.

In addition, since the advent of irbesartan on the market, were also identified following adverse reactions:

Violations by the immune system: rarely — as all receptor antagonists of angiotensin II, was observed rare cases of allergic reactions such as rash, urticaria, angioedema.

Disorders of metabolism and nutrition: very rarely — hyperkalemia.

Violations of the nervous system: very rare — headache.

Hearing and vestibular system: very rarely — ringing in the ears.

Violations by the gastrointestinal tract: rarely — dysgeusia.

Of liver: very rarely — liver dysfunction, hepatitis.

Violations of the musculoskeletal system: rarely — myalgia, arthralgia (sometimes in combination with an increase in creatine kinase), seizures.

Disorders of the kidney and urinary system: very rarely — impaired renal function including isolated cases of renal failure in patients at higher risk.

Drug interactions:

Diuretics and other antihypertensive agents. When Irbesartan is prescribed together with thiazide-type diuretics, the hypotensive effect is enhanced. Irbesartan without any problems used in combination with other antihypertensive agents such as beta-blockers, long-acting CCB and thiazide diuretics. Previous treatment dioretikami in high doses can lead to dehydration and increases the risk of hypotension at the beginning of the drug treatment of Aprovel.

Hypotensive effects of irbesartan and thiazide diuretics are additive. In patients who cannot control blood pressure in the irbesartan monotherapy, the appointment of small doses of hydrochlorothiazide (12, 5 mg) leads to a further reduction (compared with placebo effect) HELL of 7-10/3-6 mm Hg.St. (SBP/DBP at the end midazolama period). When taking irbesartan with small doses of hydrochlorothiazide (12.5 mg/day) hypotensive effect of this combination in patients of Negroid race is approaching that of patients of European descent.

Potassium supplements and potassium-sparing diuretics, heparin: based on the experience obtained from the use of other drugs that affect the system of the renin-angiotensin-aldosterone, concomitant use of potassium-sparing diuretics, potassium supplements or salsamenteria containing potassium, or other drugs (heparin) may increase potassium levels in the blood serum.

Lithium: reversible increases in the concentrations of lithium in the blood serum toxicity was observed with simultaneous use of lithium and inhibitors of enzymes that convert angiotensin. In respect of irbesartana similar effects have been hitherto extremely rare, but for the simultaneous application of drugs is recommended careful monitoring of lithium levels in the serum.

NSAIDs: simultaneous administration of angiotensin II antagonists and NSAIDs (e.g., selective COX-2 inhibitors, acetylsalicylic acid >3 g/d and nonselective NSAIDs may be a weakening of the hypotonic effect.

As in the case of ACE inhibitors, joint application of angiotensin II antagonists and NSAIDs may increase the risk of renal function, including the probability of acute renal failure, and lead to increased levels of potassium in serum, especially in patients with already compromised renal function. With the introduction of this combination should take precautions, especially in older patients. Patients need to hold the appropriate hydration throughout a combination of therapy and periodically after graduation to monitor renal function.

Hydrochlorothiazide. Pharmacokinetics irbesartana is not changed when used together with hydrochlorothiazide.

Irbesartan is metabolized primarily by the CYP2C9 and to a lesser extent glukuronizatia. There were no significant pharmacokinetic or pharmacodynamic interactions when combined with the introduction of irbesartan warfarin, drug, subjected to metabolism via CYP2C9.

The effect of such stimulants CYP2C9 rifampicin on the pharmacokinetics of irbesartan have not been evaluated.

Irbesartan does not alter the pharmacokinetics of digoxin.

Method of application and dose:

Inside, regardless of meals, swallow the tablet whole with water. Usual initial and maintenance dose is 150 mg 1 time per day. Aprovel dose of 150 mg 1 time a day usually provides better 24-hour blood pressure control than a dose of 75 mg. However, it can be suggested initial therapy at a dose of 75 mg, especially in patients, on hemodialysis, or in elderly patients (over 75 years). Patients who have a therapeutic effect when taking Aprovel dose of 150 mg 1 time per day is inadequate, the dose of Aprovel may be increased to 300 mg, or perhaps the appointment of other antihypertensive agents. In particular, it was shown that the appointment of a diuretic, such as hydrochlorothiazide enhanced effect of Aprovel (see "Interactions").

In patients with hypertension and diabetes type 2 diabetes treatment should begin with a dose of 150 mg/day, which should gradually increase to 300 mg doses which is the preferred maintenance dose for treatment of nephropathy.

Evidence of the beneficial effects of Aprovel on the kidneys in patients with arterial hypertension and diabetes mellitus type 2 is obtained in studies in which it was used in combination with other antihypertensive drugs required to achieve target BP

The impairment of renal function. In patients with impaired renal function dose adjustment is not required. A lower starting dose (75 mg) may be offered for patients on hemodialysis.

Violation of water-electrolyte balance. BCC and/or sodium deficiency must be corrected before the application of Aprovel.

The liver dysfunction. Does not require dose adjustment in patients with impaired hepatic function mild or moderate severity. No clinical data for patients with severely impaired liver function.

Elderly patients. Although care must be taken at the beginning of therapy and start treatment at a dose of 75 mg for patients older than 75 years, usually for elderly patients dose adjustment is not required.

Use in Pediatrics. The safety and efficacy of the drug of Aprovel patients of children's age not established.

Overdose:

The experience of the drug in adults in doses up to 900 mg/day for 8 weeks did not reveal any toxicity.

Symptoms: the most likely manifestations — decrease in blood pressure and tachycardia bradycardia could also be a manifestation of overdose.

Treatment: no specific information in relation to the treatment of drug overdose Aprovel. For patients should be set carefully monitored, treatment should be symptomatic and supportive in nature, the induction of vomiting and/or gastric lavage appointment of activated carbon. Irbesartan is not removed from the body by hemodialysis..

Special instructions:

Violation of water-salt balance. In dehydrated patients and/or patients with deficiency of sodium ions (as a result of intensive treatment dioretikami, diarrhea or vomiting, limit the admission of salt with food), as well as in patients on hemodialysis may develop symptomatic hypotension, especially after the first dose of the drug. These pathological conditions should be adjusted before use of the drug Aprovel.

Renovascular hypertension. Patients with bilateral renal artery stenosis or stenosis of artery only kidneys taking other medicines that affect the system of the renin-angiotensin-aldosterone belong to the high-risk group in relation to the development of severe arterial hypotension or renal insufficiency. Although such cases are for drug Aprovel not described, a similar effect can be expected when using antagonists of angiotensin II receptors.

Renal failure and kidney transplant. When applying Aprovale in patients with renal insufficiency recommended periodic monitoring of potassium levels and serum creatinine blood. No clinical data on the use of Aprovel in patients undergoing kidney transplantation.

Patients with arterial hypertension with diabetes mellitus type 2 and kidney diseases. The effect of irbesartan on renal and cardiovascular manifestations in the different subgroups in the analysis conducted during the studies of the drug involving patients with severe nephropathy was different. In particular, it was less significant among women and in persons that are not related to the white race.

Hyperkalemia: as with other agents that affect the system of the renin-angiotensin-aldosterone, hyperkalemia may develop during treatment with Aproblem, especially in the presence of renal insufficiency and/or heart disease. For patients at risk recommended adequate control of potassium levels in the blood serum.

Stenosis of the aortic or mitral valve, obstructive hypertrophic cardiomyopathy: as with other vasodilators, it is necessary to take special precautions when treating patients with aortic or mitral stenosis or obstructive hypertrophic cardiomyopathy.

Primary aldosteronism: patients with primary aldosteronism do not usually react to antihypertensive drugs that inhibit the renin-angiotensin system. Therefore, the use of Aprovel in such cases is not recommended.

Other: In patients whose vascular tone and renal function is predominantly dependent on the activity of the renin-angiotensin-aldosterone (e.g. in patients with congestive heart failure stage III and IV — NYHA classification or with kidney disease, including renal artery stenosis). Treatment other medicines that affect this system has been associated with acute hypotension, azotemia, oliguria, and in rare cases with acute renal failure. As for other antihypertensive drugs, the reduction of high blood pressure in patients with atherosclerotic vascular lesions of the brain: to perform or coronary artery disease can eventually lead to myocardial infarction or stroke. Treatment must be under the control of AD.

Impact on the ability to drive

The influence of Aprovel on the ability to drive and perform work requiring increased attention has not been studied, but based on its pharmacodynamic properties, the drug should not affect this ability. When driving you must take into consideration that during treatment of arterial hypertension is sometimes possible dizziness and fatigue.