2010/09/21

Aprovel

Composition, structure and packing

The tablets are oval, biconvex, white or nearly white, engraved with a heart-shaped on one side and the number "2772" - on the other.

1 tab. irbesartan 150 mg.

Excipients: lactose monohydrate, pregelatinized corn starch, sodium croscarmellose, poloksamer 188, colloidal silicon dioxide, water, microcrystalline cellulose, magnesium stearate.

The tablets are oval, biconvex, white or nearly white, engraved with a heart-shaped on one side and the number "2773" - on the other.

1 tab. irbesartan 300 mg.

Excipients: lactose monohydrate, pregelatinized corn starch, sodium croscarmellose, poloksamer 188, colloidal silicon dioxide, water, microcrystalline cellulose, magnesium stearate.

LINIK-pharmacological group: The antagonist of angiotensin II.

Pharmacological action

Antihypertensive medication, specific antagonist of angiotensin II (type AT1). Eliminates the vasoconstrictor action of angiotensin II and lowers the concentration of aldosterone in blood plasma. Blocks all physiologically significant effects of angiotensin II, are realized through receptor type AT1, regardless of the source or route of synthesis of angiotensin II.

The specific antagonistic effect against angiotensin II (AT1) leads to increased concentrations of renin and angiotensin II in blood plasma and to reduce the concentration of aldosterone in blood plasma.

When using the recommended doses of the drug concentration of potassium ion in blood serum does not change. Irbesartan does not inhibit kininazu II, through which the formation of angiotensin II and destruction of bradykinin to inactive metabolites. To manifest its effect, irbesartan does not require metabolic activation. Irbesartan lowers blood pressure with minimal changes in heart rate.

When you receive a dose of 300 mg 1 time / day blood pressure reduction is dose-dependent nature, but with further increase in dose irbesartan increase the hypotensive effect is negligible.

The maximum blood pressure reduction is achieved within 3-6 hours after taking the drug orally, and the hypotensive effect persisted at least for 24 h. At 24 h after administration at the recommended doses of blood pressure reduction of 50-70% compared with the maximum reduction in diastolic and systolic blood pressure in response to the application of the drug.

When you receive a once a day at a dose of 150-300 mg of BP reduction (systolic / diastolic) at the end of mezhdozovogo interval (ie 24 h after drug administration) in the position of the patient lying down or sitting at an average of 8-13/5 -8 mm Hg (Respectively) compared with placebo.

Acceptance of the drug at a dose of 150 mg 1 time / day causes a hypotensive response (decrease in blood pressure before taking another dose and mean blood pressure reduction over 24 h) as the same dose divided into 2 admission. Hypotensive effect of the drug Aprovel develops within 1-2 weeks, and the maximum therapeutic effect is achieved by 4-6 weeks after starting treatment. Antihypertensive effect was maintained during prolonged treatment.

After the cessation of treatment BP gradually returned to its original value, withdrawal symptoms were observed. Irbesartan does not affect the content of uric acid in serum or on the excretion of uric acid in urine.

Pharmacokinetics in special clinical situations

Efficacy does not depend on age and sex. Patients blacks respond poorly to monotherapy Aprovelem (like all other drugs affecting the renin-angiotensin-aldosterone system).

Pharmacokinetics

Absorption

After oral administration is well absorbed from the gastrointestinal tract. Cmax of irbesartan in plasma achieved after 1.5-2 h after ingestion. The absolute bioavailability of 60-80%. Simultaneous food intake did not significantly affect the bioavailability of the drug.

Irbesartan has a linear and dose proportional pharmacokinetics in the dose range from 10 to 600 mg, with doses above 600 mg (2 times higher than the recommended maximum dose), the kinetics of irbesartan is nonlinear (reduced absorption).

Distribution

Binding to plasma proteins is approximately 96%.

Binding to cellular components of blood is negligible. Vd - 53-93 liters. Css achieved within 3 days after the start of drug administration 1 times / day. Repeated receptions 1 times / day at the limited accumulation of irbesartan in plasma (less than 20%).

Metabolism

Once inside, or in / in the introduction of 14C-irbesartan 80-85% of the radioactivity in the circulating blood accounts for the unchanged irbesartan. Irbesartan biotransformiruetsya in the liver by oxidation and conjugation with glucuronic acid. Irbesartan is oxidized primarily by CYP2S9 isoenzyme, isoenzyme CYP3A4 has negligible effect.

The main metabolite - irbesartan glucuronide (approximately 6%).

Withdrawal

The total clearance and renal clearance are 157-176 ml / min and 3-3.5 ml / min, respectively.

T1 / 2 for the terminal phase is 11-15 hours Irbesartan and its metabolites are excreted in bile and urine. Once inside, or in / in the introduction of 14C-irbesartan about 20% of the radioactivity found in urine and the rest - in the feces. Less than 2% of the administered dose excreted in the urine as unchanged irbesartan.

Pharmacokinetics in special clinical situations

Slightly higher concentration of irbesartan in plasma noted in women (than men). However, the differences in the value of T1 / 2 and accumulation of irbesartan are not revealed. Correction doses of irbesartan in women is not required. The values of AUC and Cmax of irbesartan were slightly higher in elderly patients (over 65 years) than in younger patients (18-40 years), T1 / 2 did not differ significantly.

Correction doses of irbesartan in elderly patients is not required. Patients with impaired renal function or patients who receive hemodialysis, pharmacokinetic parameters of irbesartan did not substantially change. Irbesatan not removed from the body during hemodialysis. In patients with cirrhosis of the liver or lung to moderate pharmacokinetic parameters of the drug did not significantly change.

Pharmacokinetic studies in patients with severe hepatic insufficiency were not conducted.

Statement
hypertension;
treatment of nephropathy in patients with hypertension and diabetes mellitus type 2 (in a combination of antihypertensive therapy).

Dosage regimen

The drug should be taken by mouth, swallow the pill whole, washed down with water. The starting and maintenance dose is 150 mg 1 time per day regardless of meals.

Use of the drug in a dose provides a more optimal 24-hour BP control than a dose of 75 mg / day. However, in some patients, especially in patients on hemodialysis, or patients over the age of 75 years, the initial dose should be 75 mg (may use Aprovelya in the table. 75 mg).

In case of insufficient therapeutic effect of applying Aprovelya a dose of 150 mg 1 time / day, dose can be increased to 300 mg, or should appoint another antihypertensive agent. In particular, it was shown that the use of diuretics such as hydrochlorothiazide, increases the effects Aprovelya.

In patients with hypertension and diabetes mellitus type 2 treatment should be started with a dose of 150 mg 1 time / day and gradually increase to 300 mg - a dose which is the preferred maintenance dose for the treatment of diabetic nephropathy. Evidence of the beneficial effects Aprovelya the kidneys in patients with hypertension and diabetes mellitus type 2 were obtained in studies where it was used in combination with other antihypertensive drugs required to achieve target BP levels. Prior to receiving Aprovelya should restore BCC and / or eliminate hyponatremia.

Patients with impaired renal function correct dosing regimen is not required. For patients on hemodialysis, the initial dose should be 75 mg / day (perhaps to use the drug Aprovel in Tab. 75 mg). Patients with hepatic impairment of mild or moderate severity does not require correction dosing regimen. Clinical experience with the drug in patients with severely impaired liver function is absent.

Although the recommended treatment for patients over the age of 75 years, starting with a dose of 75 mg (possibly using the product Aprovel in the table. 75 mg), usually elderly patients correct dosing regimen is not required.

Side effect

In describing the side effects we used the following criteria for frequency of occurrence: very common (> 10%), frequent (> 1%, <10%),> 0.1% <1%),> 0.01% <0.1%) ; very rare (<0.01%, including isolated reports). The frequency of side effects did not depend on the dose (in the recommended dose range), sex, age, race, patient or the duration of therapy.

Arterial hypertension

In placebo-controlled studies (1965 patients received irbesartan) were observed following adverse reactions.
From the side of the central nervous system: often - dizziness.
Since the cardiovascular system: sometimes - tachycardia, flushing of the skin.
On the part of the respiratory system: sometimes - cough.
On the part of the digestive system: frequent - nausea, vomiting and sometimes - diarrhea, indigestion, heartburn.
On the part of the reproductive system: sometimes - sexual dysfunction.
On the part of the body as a whole: often - fatigue, and sometimes - a pain in the chest.
From the laboratory tests: often - a significant increase in CK (1.7%), not accompanied by clinical manifestations of the musculoskeletal system.

Arterial hypertension and type 2 diabetes mellitus with microalbuminuria without renal dysfunction

In addition to the above adverse reactions when receiving irbesartan were observed:
Since the cardiovascular system: sometimes - orthostatic dizziness, orthostatic hypotension in 0.5% of patients (compared with the frequency of occurrence of these adverse reactions in patients receiving placebo).
From the laboratory data: very often - hyperkalemia (> 5.5% mmol / l) while taking 300 mg of irbesartan was observed in 29.4% of patients in the placebo group - 22% of patients. Arterial hypertension and type 2 diabetes mellitus with severe proteinuria and chronic renal failure The following adverse reactions were observed more than 2% of patients (compared with the frequency of their occurrence in patients receiving placebo).
From the side of the central nervous system: often - orthostatic dizziness, orthostatic hypotension.
On the part of the musculoskeletal system: often - pain in muscles and bones.
From the laboratory data: very often - hyperkalemia (> 5.5% mmol / l) when receiving irbesartan were observed in 46.3% of patients in the placebo group - with 26.3% of patients, often - clinically significant decrease in hemoglobin concentration from 1.7% of patients with high blood pressure and diabetic nephropathy. Since the advent of irbesartan on the market have also identified the following adverse reactions:
From the side of the central nervous system: very rarely - a headache.
On the part of the digestive system: very rarely - dysgeusia, disruption of liver function, hepatitis.
On the part of the musculoskeletal system: very rarely - myalgia, arthralgia (sometimes in combination with increased levels of creatine kinase), convulsions.
From the urinary system: very rarely - renal dysfunction (including isolated cases of renal failure in patients at risk).
From the senses: very rarely - ringing in the ears.
From the laboratory parameters: a very rare - hyperkalemia.

Allergic reactions: seldom - rash, urticaria, angioedema.

Contraindications
hereditary galactose intolerance, lactase deficiency or malabsorption of glucose and galactose;
Pregnancy
lactation;
childhood and adolescence to 18 years (effectiveness and safety have not been established);
Hypersensitivity to the drug's components.

With care use in patients with stenosis of the aortic or mitral valve, hypertrophic obstructive cardiomyopathy, dehydration, hyponatremia, diarrhea, vomiting, a diet with restricted salt intake, diuretic therapy, bilateral renal artery stenosis, unilateral stenosis of the artery of a sole kidney disease, chronic heart failure III -IV functional class according to the classification NYHA, CHD and / or atherosclerotic lesions of cerebral vessels, hyperkalemia, renal failure, hemodialysis, a recent kidney transplant (the lack of clinical experience in the application), severe hepatic insufficiency (lack of clinical experience in the application).

Use during pregnancy and breastfeeding Aprovel contraindicated in pregnancy.

If pregnancy occurs during treatment with the drug should be lifted immediately.

Go to the appropriate alternative therapy should be administered prior to planning pregnancy. If necessary, the appointment during lactation should decide on the termination of breastfeeding, as not known whether irbesartan is allocated through breast milk.

Application for violations of liver function

In patients with mild to moderate hepatic impairment dose adjustment is required. Data on the use of the drug in patients with hepatic insufficiency is not severe.

Application for violations of renal function

With caution is prescribed for hemodialysis, l unilateral or bilateral renal artery stenosis, renal insufficiency.

In patients with renal insufficiency (without electrolyte metabolism disorders) dose adjustment is required. Patients who are on hemodialysis, the recommended starting dose is 75 mg / day.

Cautions

Violations of water and electrolyte balance

During dehydration and / or deficiency of sodium ions (as a result of intensive treatment with diuretics, diarrhea or vomiting, restricting the salt in your food), as well as in patients on hemodialysis may develop clinically significant hypotension, especially after the first dose of the drug. Such pathological states needs to be adjusted before the drug Aprovel.

Renovascular hypertension

Patients with bilateral renal artery stenosis or stenosis of the artery of a sole kidney, taking other drugs affecting the renin-angiotensin-aldosterone system, are at increased risk for the development of severe arterial hypotension or renal insufficiency. Although the development of such complications for drug Aprovel not describe this effect can be expected when using antagonists of angiotensin II.

Renal failure and kidney transplant

In applying Aprovelya patients with renal insufficiency is recommended periodic monitoring of potassium level and serum creatinine. No clinical data regarding the application Aprovelya patients undergoing kidney transplants.

Arterial hypertension and diabetes mellitus type 2

A noted Aprovelya have a beneficial effect on slowing the progression of renal and cardiovascular lesions had varying degrees of severity in different groups of patients: it was less pronounced among women and persons who do not regard the European race.

Potassemia

Perhaps the development of hyperkalemia in the application Aprovelya (as the use of other drugs which affect the renin-angiotensin-aldosterone system), especially in patients with renal failure and / or heart disease. For patients at risk is recommended for adequate monitoring of potassium level in blood serum. Stenosis of the aortic or mitral valve, obstructive hypertrophic cardiomyopathy.

Must take special precautions when applying in patients with aortic or mitral stenosis or obstructive hypertrophic cardiomyopathy.

Primary aldosteronizm

Patients with primary aldosteronizmom usually do not respond to antihypertensive drugs that inhibit the renin-angiotensin.

Therefore, the application Aprovelya in such cases is not recommended. In the group of patients whose vascular tone and renal function is overwhelmingly dependent on the activity of the renin-angiotensin-aldosterone system (eg, patients with chronic heart failure, III and IV functional class by NYHA classification, or with the corresponding kidney disease, including renal artery stenosis ), drug treatment, affecting the system, was associated with acute arterial hypotension, azotemia, oliguria, and in rare cases - with acute renal failure.

As the use of other antihypertensive agents, reducing high blood pressure in patients with CHD may result in the occurrence of myocardial infarction or angina attack.

Treatment should be under the control of blood pressure.

Use in Pediatrics

Safety and efficacy of the drug Aprovel patients of childhood and adolescence is not installed.

Effects on ability to drive vehicles and management mechanisms

Influence Aprovelya the ability to engage in activities that require attention, has not been studied, but based on its pharmacodynamic properties, the drug should not affect this ability. When driving a car to be taken into consideration that during treatment of hypertension is sometimes possible dizziness and increased fatigue.

Overdose

In applying the drug in adult patients at a dose of 900 mg / day for 8 weeks is not revealed any toxicity. Symptoms: most likely marked reduction of blood pressure, tachycardia, bradycardia.

Treatment: Accidental taking the drug in high doses show artificial vomiting and / or gastric lavage, activated charcoal, holding symptomatic and supportive therapy. Hemodialysis is ineffective.

Drug Interactions

Diuretics and other antihypertensives

With simultaneous application of irbesartan with other antihypertensive drugs may be increased hypotensive action.

Irbesartan was used in combination with other antihypertensive drugs such as beta-blockers, blockers "slow" calcium channel long-acting thiazide diuretics. Antihypertensive effects of irbesartan and thiazide diuretics are additive.

Patients with uncontrolled BP with irbesartan monotherapy, the appointment of small doses of hydrochlorothiazide (12.5 mg / day) leads to an additional reduction (compared to the placebo effect) on BP 7-10/3-6 mm Hg. Art. (Systolic / diastolic BP at the end mezhdozovogo period).

In the application of irbesartan with small doses of hydrochlorothiazide (12.5 mg / day) hypertensive effects of this combination in patients Blacks coming in that of patients of European race.

Prior treatment with diuretics in high doses can lead to dehydration and an increased risk of arterial hypotension in the early treatment with Aprovel.

Preparations of potassium and Potassium-sparing diuretics, heparin.

Based on experience gained from the use of other drugs affecting the renin-angiotensin-aldosterone system, with the simultaneous use of potassium preparations, potassium-containing electrolyte solutions, potassium-sparing diuretics or other, can raise the level of potassium in the blood, drugs (heparin), may increase potassium level in blood serum.

Lithium

The reversible increase in the concentration of lithium in blood serum and its toxicity was noted with simultaneous application of lithium with ACE inhibitors. To date, the application of irbesartan Similar effects were observed extremely rarely.

If there is a need to use this combination, during treatment should carefully monitor the concentration of lithium in blood serum. NSAIDs when used with angiotensin II antagonists and NSAIDs (including selective COX-2 inhibitors, acetylsalicylic acid (> 3 g / day) and nonselective NSAIDs) may be weakening of the hypotensive effect.

As with the simultaneous use of ACE inhibitors and NSAIDs, with the joint application of angiotensin II antagonists and NSAIDs may increase the risk of renal dysfunction, including the possible development of acute renal failure, and increase serum potassium levels, especially in patients with already impaired renal function. Should be cautious to apply this combination, especially in elderly patients.

Patients need to restore the bcc and throughout the combination therapy, and periodically after its completion to monitor renal function.

Additional information on the interaction of irbesartan

With simultaneous application of irbesartan with hydrochlorothiazide pharmacokinetics of irbesartan are not altered. Irbesartan is mainly metabolised by CYP2C9 and to a lesser extent exposed glyukuronirovaniyu. There were no significant pharmacokinetic or pharmacodynamic interactions with the combination of irbesartan with warfarin, the drug, is metabolized by CYP2C9. Study the effect of inducers of the activity of CYP2C9 (including rifampicin), on the pharmacokinetics of irbesartan are not conducted. Irbesartan does not alter farmakrokinetiku digoxin.

Terms and Conditions of storage

List B. The drug should be stored out of reach of children, dry place at temperatures below 30 ° C. Shelf life - 3 years.