Апровель®

General characteristics. Structure:

Pharmacological properties:

Pharmacodynamics. Irbesartan is powerful, active at intake, the selection antagonist of receptors of angiotensin II (ATi type). It blocks all physiologically significant effects of angiotensin II which are implemented through receptors like AT | irrespective of a source or a way of synthesis of angiotensin II. Specific antagonistic action concerning angiotensin II receptors (ATO leads to increase in plasma concentration of a renin and angiotensin II and decrease in plasma concentration of Aldosteronum. At use of the recommended drug doses the maintenance of potassium ions in blood serum significantly does not change. Irbesartan does not inhibit kininazu-P (an angiotensin-converting enzyme - APF) by means of which there is a formation of angiotensin II and destruction of bradikinin to inactive metabolites. Manifestation of action of an irbesartan does not require its metabolic activation. Irbesartan reduces the arterial pressure (AP) at the minimum change of heart rate. At reception in doses to 300 mg once a day the lowering of arterial pressure has dozozavisimy character, however at further increase in a dose of an irbesartan the gain of anti-hypertensive effect is insignificant.
The maximum decrease in the ABP is reached in 3-6 hours after administration of drug inside, and the anti-hypertensive effect remains at least for 24 hours. In 24 hours after reception of the recommended doses of an irbesartan decrease in the ABP makes 60-70% in comparison with the maximum anti-hypertensive answer to drug from the diastolic and systolic ABP. At reception once a day in a dose of 150-300 mg the size of a lowering of arterial pressure by the end of an interdose interval (i.e. in 24 hours after administration of drug) in position of the patient "lying" or "sitting" on average on 8-13/5-8 mm hg (systolic/diastolic the ABP) more in comparison with that at placebo reception.
Administration of drug in a dose of 150 mg causes once a day the same anti-hypertensive answer (a lowering of arterial pressure before reception of the next dose of drug and an average lowering of arterial pressure in 24 hours) as well as reception of the same dose divided into two receptions.
Anti-hypertensive effect of the drug Aprovel® develops within 1-2 weeks, and the maximum therapeutic effect is reached in 4-6 weeks after an initiation of treatment. Anti-hypertensive action against the background of prolonged treatment remains. After the termination of treatment of the ABP gradually is returned to initial size. At drug withdrawal the withdrawal is absent.
In researches in which Aprovel® was applied in addition to other hypotensive drugs in need of achievement of the target objective of arterial pressure the evidence of favorable impact of the drug Aprovel® on kidneys at patients with arterial hypertension and a diabetes mellitus 2 types is obtained.
Efficiency of the drug Aprovel® does not depend on age and a floor. Patients of negroid race react to motor-therapy by the drug Aprovel® more weakly (as well as to all other medicines influencing system renin-angiotensin-aljdosteron). Irbesartan does not influence concentration of uric acid in blood serum or on release of uric acid kidneys.

Pharmacokinetics. After intake ирбесартан it is well soaked up, its absolute bioavailability makes about 60-80%. The concomitant use of food significantly does not influence bioavailability of an irbesartan.
Communication with proteins of a blood plasma makes about 96%. Linkng with cellular components of blood is insignificant. The volume of distribution makes 53-93 liters.
After intake or intravenous administration of a |4C-irbesartan of 80-85% of radioactivity of the circulating plasma it is necessary on not changed ирбесартан. Irbesartan is metabolized by a liver by oxidation and conjugation with glucuronic acid. Oxidation of an irbesartan is carried out, mainly, by means of an isoenzyme of P450 CYP2C9 cytochrome, participation of an isoenzyme of CYP3A4 in metabolism of an irbesartan is insignificant. Irbesartan is not metabolized by means of the majority of isoenzymes which usually participate in metabolism of medicines (isoenzymes of CYP1A1, CYP1A2, CYP2A6. CYP2B6 CYP2D6 or CYP2E1) also does not cause their inhibition or induction. Irbesartan does not induce and does not inhibit CYP3A4 isoenzyme. The main metabolite which is in a system blood-groove is the irbesartana a glucuronide (about 6%).
Irbesartan possesses to a linear and proportional dose pharmacokinetics in the range of doses from 10 to 600 mg; at doses over 600 mg (the dose twice exceeding the recommended maximum dose of drug) the kinetics of an irbesartan becomes nonlinear (reduction of a dozoproportsionalnost of absorption). After intake the maximum concentration in a blood plasma are reached in 1,5-2 hours. The general clearance and renal clearance make 157-176 and 3-3,5 ml/min., respectively. The final elimination half-life of an irbesartan makes 11-15 hours. At a daily single dose of drug equilibrium plasma concentration (Css) is reached in 3 days. At daily reception of an irbesartan of 1 times a day its limited accumulation in a blood plasma (less than 20%) is noted. At women (in comparison with men) a little higher plasma concentration of an irbesartan are noted. However the distinctions connected with a floor in an elimination half-life and accumulation of an irbesartan do not come to light. Dose adjustment of an irbesartan is not required from women. AUC values ("concentration time") and Stakh (the maximum plasma concentration) of an irbesartan at patients of advanced age (> 65 years) are slightly higher than the area under a pharmacokinetic curve, than at patients of younger age, however final elimination half-lives at them authentically do not differ. Dose adjustment is not required from elderly patients.
Irbesartan and his metabolites are brought out of an organism, as through intestines (with bile), and kidneys. After intake or intravenous administration of a 14C-irbesartan about 20% of radioactivity are found in urine, and other part - in Calais. Less than 2% of the entered dose are allocated with kidneys in the form of not changed irbesartan. Dysfunction of nights: At patients with a renal failure or patients to whom the hemodialysis is carried out indicators of pharmacokinetics of an irbesartan essentially do not change. Irbesartan does not leave from an organism when carrying out a hemodialysis.
Abnormal liver function: At patients with easy (a functional class A or 5-6 points on a scale of Chayld-Pyyu) and moderately expressed (a functional class B or 7-9 points on a scale of Chayld-Pyyu) a liver failure pharmacokinetic parameters of an irbesartan significantly do not change. Pharmacokinetic researches at patients with a heavy liver failure (a functional class C or more than 9 points on a scale of Chayld-Pyyu) were not conducted.

Indications to use:

Essential hypertensia.
Nephropathy at arterial hypertension and a diabetes mellitus 2 types (as a part of the combined hypotensive therapy).

Route of administration and doses:

Drug should be accepted inside. The tablet is swallowed entirely, washing down with water. Usually recommended for initial reception and maintenance dose makes 150 mg of 1 times a day regardless of meal. Апровель® in a dose of 150 mg of 1 times a day usually provides the best 24-hour control of the ABP, than in a dose of 75 mg. At patients at whom the therapeutic effect at administration of drug of Aprovel® in a dose of 150 mg of 1 times a day is insufficient the dose of the drug Aprovel® can be increased to 300 mg, or perhaps additional use of other hypotensive drug. In particular it was shown that additional reception of diuretic, such as a hydrochlorothiazide, strengthened effect of the drug Aprovel® (see the section "Interaction with Other Medicines").
At patients with arterial hypertension and a diabetes mellitus 2 types treatment has to begin with a dose of 150 mg of 1 times a day which has to increase gradually to 300 mg of 1 times a day - the dose which is a preferable maintenance dose for treatment of an iyefropatiya.
Renal failure. With an impaired renal function of correction of the mode of dosing it is not required from patients. For the patients who are on a hemodialysis, originally accepted dose has to make 75 mg (possibly use of the drug Aprovel® in tablets on 75 mg).
Disturbance of water and electrolytic balance. Prior to administration of drug of Aprovel® it is necessary to eliminate a gopovolemiya and/or a hyponatremia or to begin treatment with lower dose of an irbesartan (possibly use of the drug Aprovel® in a dose of 75 mg). If the lowering of arterial pressure to target values is not reached, then the dose can be increased.
Abnormal liver function. Usually correction of the mode of a drug dosing Aprovel® is not required from patients with abnormal liver functions easy or moderate severity (5-6 and 7-9 points on a scale of Chayld-Pyyu). There is no clinical experience of use of drug for patients with heavy abnormal liver functions. Patients of advanced age. Though treatment of patients aged is recommended 75 years are more senior to begin with a dose 75 mg (possibly use of the drug Aprovel® in tablets on 75 mg), usually it is not required to patients of advanced age of correction of the mode of dosing.
Use in pediatrics. Reception of an irbesartan was studied at children from 6 to 16 years, but the data which are available now are insufficient for development of recommendations about use of drug for children (obtaining additional data is required). Safety and an effekgivnost of use of the drug Aprovel® for patients of children's and youthful age are not established yet.

Features of use:

Disturbance of water and electrolytic balance. At patients with a hypovolemia and/or with a hyponatremia (as a result of intensive diuretic care, diarrhea or vomiting, observance of a diet with restriction of consumption of table salt), and also at the patients who are on a hemodialysis clinically significant arterial hypotension, especially after reception of the first dose of drug can develop. Before use of the drug Aprovel® it is necessary to correct all disturbances of water and electrolytic balance or it is necessary to begin treatment with lower doses.
Renovascular hypertensia. Patients with a bilateral stenosis of the renal arteries or a stenosis of an artery of the only functioning kidney at administration of drugs influencing system renin-angiotensin-Aldosteronum treat group of the increased risk concerning development of heavy arterial hypotension or a renal failure. Though documentary confirmation of emergence of such effects at administration of drug of Aprovel® is absent, it is necessary to take into account a possibility of their emergence at use of antagonists of receptors of angiotensin II (ATi type) for these patients.
Owing to system inhibition renin-angiotensin-Aldosteronum can be expected deterioration in function of kidneys at the patients predisposed to it. At patients whose function of kidneys depends on activity of system renin-angiotensin-Aldosteronum (patients with arterial hypertension and a renal artery stenosis of one or both kidneys or patients with chronic heart failure of III and IV functional classes
[on NYHA classification]), treatment by the drug Aprovel® was associated with an oliguria and/or the progressing azotemia and is rare with an acute renal failure and/or death.
Renal failure and renal transplantation. At use of the drug Aprovel® for patients with a renal failure periodic control of content of potassium and creatinine in blood serum is recommended. There are no clinical data on use of the drug Aprovel® for the patients who recently transferred renal transplantation.
Patients with arterial hypertension and a diabetes mellitus of type 2 with disturbances from kidneys. Otmechenoye at the drug Aprovel® favorable action concerning delay of progressing of renal and cardiovascular defeats had different degree of manifestation at different groups of patients, it was less expressed at women and at the persons which are not belonging to Caucasian race.
Hyperpotassemia. As well as at use of other medicines influencing system renin-angiotensin-Aldosteronum at treatment by the drug Aprovel® the hyperpotassemia, especially in the presence of a renal failure and/or heart diseases can develop. At such patients it is recommended to control the content of potassium in blood serum.
Stenosis of the aortal or mitral valve, hypertrophic subaortic stenosis. As well as at use of other vazodilatator, at administration of drug of Aprovel® by patients or with a hypertrophic subaortic stenosis it is necessary to be careful with an aortal or mitral stenosis. Primary aldosteronism. Patients with primary aldosteronism usually do not react to the hypotensive drugs operating through system inhibition renin-angiotensin-Aldosteronum. Therefore use of the drug Aprovel® in such cases is not reasonable.
Patients with coronary heart disease and/or clinically significant atherosclerosis of vessels of a brain
As well as at use of other hypotensive drugs, the considerable lowering of arterial pressure at patients with coronary heart disease and/or the expressed atherosclerosis of vessels of a brain can lead to development of a myocardial infarction or stroke. Treatment of such patients has to be performed under strict control of arterial pressure
Possible influence on ability to manage vehicles or to be engaged in other potentially dangerous types of activity
I povyshennoit influence of the drug Aprovel® on ability to manage vehicles or to be engaged in other potentially dangerous types of activity requiring attention, it was not studied. However, proceeding from its pharmakodinamichesky properties, Aprovel® should not influence this ability. But in case of developing of dizziness and weakness decrease in attention and delay of psychomotor reactions is possible. At the patients having such side effects the decision on a possibility of occupation any potentially dangerous types of activity has to be made by the doctor individually.

Side effects:

The side effects provided below are given in a soovetstviye with the following gradation of frequency of their emergence:: very often (> 1/10), it is frequent (> 1/100, <: 1/10); infrequently (> 1/1000, <1/100); seldom (> 1/10000. <1/1000); very seldom (<1/10000) (including separate messages), unknown frequency (to determine the frequency of occurrence of side effect by the available data it is not possible to define). Safety of the drug Aprovel® was studied in clinical trials approximately at 5000 patients, including 1300 patients with an arterial gipretenziya receiving drug within more than 6 months and more and 400 patients receiving drug within one year and more. The patients receiving Aprovel® had usually moderately expressed side effects and passing, and the frequency of their emergence did not depend on a dose (in the recommended interval of doses), a sex, age and race or on treatment duration.
In placebo - controlled researches in which 1965 patients received ирбесартан (on average within 1-3 months), the termination of treatment because of what development - or the clinical or laboratony adverse phenomena it was required from 3,3% of the patients receiving Aprovel® and at 4,5% of the patients receiving placebo (distinctions had statistical reliability).
The side effects observed at use of the drug Aprovel® at arterial a gipertensha (frequency of emergence of the listed below side effects at reception of an irbesartan statistically authentically did not differ from that at placebo reception).
Disturbances from a nervous system
Often: dizziness, headache.
Infrequently: orthostatic dizziness.
Disturbances from heart
Infrequently: tachycardia.
Disturbances from vessels
Infrequently: "inflows" of blood to face skin, hypostases.
Disturbances from respiratory system, bodies of a thorax and a mediastinum
Infrequently: cough.
Disturbances from digestive tract
Often: nausea/vomiting.
Infrequently: diarrhea, dyspepsia/heartburn.
Disturbances from generative organs and a mammary gland
Infrequently: sexual dysfunction.
General disturbances
Often: increased fatigue.
Infrequently: thorax pain.
From laboratory indicators
Often (1,7%):   reliable increase in activity of a kreatiifosfokinaza of a blood plasma at the patients receiving ирбесартан; any such case was not followed  by clinical  manifestations   from  a musculoskeletal system.
The collateral eefekta observed at use of the drug Aprovel® at a nephropathy at an arterial gshgertenziya and diabetes mellitus 2 types Side effects were similar to that, at patients with arterial hypertension, except for    orthostatic    symptoms    (dizziness,    orthostatic dizziness and orthostatic hypotension). At this group of patients except the side reactions specified at patients with arterial hypertension orthostatic symptoms were observed more often (see below). From a nervous system
Very often: dizziness (10,2%) (at reception of placebo of 6%).
Often: orthostatic dizziness (5,4%) (at reception of placebo of 2,7%).
From vessels
Often: orthostatic hypotension (5,4%) (at reception of placebo of 3,2%).
Percent of the termination of treatment because of orthostatic symptoms at administration of drug
Апровель® in comparison with placebo made for dizziness 0,3% against 0,5%,
for orthostatic dizziness of 0,2% against 0,0% and for orthostatic
hypotensions of 0,0% against 0,0%, respectively.
From a musculoskeletal system
Often: muscle and bones pains.
From laboratory indicators
The hyperpotassemia at reception of an irbesartan by patients met arterial hypertension and a diabetes mellitus more often than at placebo reception. At pratsiyent by a diabetes mellitus and the raised ABP, with a mikroapbuminuriya with normal function of kidneys a hyperpotassemia (> 5,5% of mmol/l) at reception of 300 mg of an irbesartan it was observed at 29,4% of patients (very often), and in group of placebo - at 22% of patients. At patients a diabetes mellitus and the raised ABP, with a chronic renal failure and the expressed proteinuria, a hyperpotassemia (> 5,5% of mmol/l) at reception of an irbesartan occurred at 46,3% of patients (very often), and in group of placebo - at 26,3% of patients. At 1,7% of the patients with the increased arterial pressure and a diabetic nephropathy receiving ирбесартан clinically insignificant decrease in concentration of hemoglobin was observed (often).
The side effects revealed after drug Aprovel® entry into the market
Disturbances from immune system
Very seldom: as well as at all antagonists of receptors angiotenzina-N, otmechalisredky cases of allergic reactions, such as skin rash, a small tortoiseshell, a Quincke's disease.
Narushensh from an acoustic organ and labyrinth disturbances
Unknown frequency: a ring in ears.
Disturbances from digestive tract
Unknown frequency: dysgeusia (food faddism).
The listed below side effects were observed at use of drug after its entry into the market, however the causal relationship was not always established with reception of an irbesartan.
Disturbances from a metabolism and food the Hyperpotassemia.
Disturbances from a nervous system Twirl го.
Disturbances from a liver and biliary tract
The increased values of activity of "hepatic" enzymes and concentration of bilirubin in blood, hepatitis, a zheltuz.
Disturbances from skeletal and muscular and connecting fabric
Mialgiya, an arthralgia (sometimes in combination with increase in activity of a creatine kinase),
muscular spasms.
Disturbances from kidneys and urinary tract
Renal failure, including cases of development of a renal failure at
patients of risk group (see the section "Special Instructions").
General disturbances
Adynamy.

Interaction with other medicines:

Diuretics and other hypotensive drugs. At simultaneous use of an irbesartan and other hypotensive drugs strengthening of hypotensive action is possible. Irbesartan with hardly any trouble at all applied along with other hypotensive drugs, such as beta adrenoblockers. blockers of "slow" calcium channels of the prolonged action and thiazide diuretics.
Anti-hypertensive effects of an irbesartan and thiazide diuretics have the additive character. At patients at whom it is not possible to control the ABP at monotherapy irbesartany additional reception of small doses of a hydrochlorothiazide (12,5 mg) leads to additional decrease (in comparison with effect of placebo) the arterial pressure upon 7-10/3-6 mm of mercury. (systolic/diastolic arterial pressure at the end of the interdose period). At reception of an irbesartan with small doses of a hydrochlorothiazide (12,5 mg a day) anti-hypertensive action of this combination at patients of negroid race comes nearer in that at patients of Caucasian race.
The previous treatment by diuretics in high doses can lead to a hypovolemia and increase in risk of developing of arterial hypotension in an initiation of treatment the drug Aprovel®.
Drugs of potassium and kaliysberegayushchy diuretics, heparin. On the basis of the experience got at use of other medicines influencing system renin-angiotensin-Aldosteronum at simultaneous use of drugs of potassium; the substitutes of salt containing potassium; kaliysberegayushchy diuretics or others capable to increase the content of potassium in blood of drugs (heparin), increase in content of potassium in blood serum is possible.
Lithium. Reversible increase in concentration of lithium in blood serum or its toxicity was noted at simultaneous use of drugs of lithium with inhibitors of an angiotensin-converting enzyme. By the present moment at reception of an irbesartan similar effects were observed extremely seldom. If there is a need for use of this combination, then during treatment it is necessary to monitorirovat carefully concentration of lithium in blood serum.
Non-steroidal anti-inflammatory drugs (NPVP). At simultaneous use of antagonists of receptors of angiotensin II and NPVP (for example, the selection TsOG-2 inhibitors (cyclooxygenase-2), acetylsalicylic acid (more than 3 g/days) and non-selective NPVP) easing of anti-hypertensive effect is possible. At patients of advanced age, patients with decrease in volume of the circulating blood or patients with an impaired renal function use of NPVP, including TsOG-2 inhibitors, along with antagonists of receptors of angiotensin II, including ирбесартан, as well as simultaneous use of APF and NPVP inhibitors, can lead to deterioration in function of kidneys, including possible development of an acute renal failure. These effects usually are reversible. Besides at them increase in content of potassium in blood serum, especially, at patients with already impaired renal function is possible. It is necessary to apply with care this combination at the listed above groups of patients. Patients, in case of need, should recover the volume of the circulating blood and during all combination therapy, and also periodically after its termination, to control function of kidneys.
Additional information on interaction of an irbesartan. At combined use of an irbesartan with a hydrochlorothiazide or nifedipine the pharmacokinetics of an irbesartan does not change.
Irbesartan is generally metabolized by means of an isoenzyme of CYP2C9 and to a lesser extent is exposed to a glyukuronirovaniye. Considerable pharmacokinetic or pharmakodinamichesky interactions at simultaneous use of an irbesartan and warfarin, the drug which is metabolized by means of CYP2C9 isoenzyme were not observed. Studying of influence of inductors of activity of an isoenzyme of CYP2C9, such as rifampicin, on a pharmakokipetika of an irbesartan it was not carried out. Irbesartan does not change a pharmakokipetika of digoxin and a simvastatitn.

Contraindications:

- Hypersensitivity to any of drug components.
- Pregnancy.
- Lactation period.
- Age up to 18 years (efficiency and safety are not established).
- Hereditary intolerance of a galactose, insufficiency of lactase or glyukozo-galaktozny malabsorption.

With care
At a stenosis of the aortal or mitral valve or a hypertrophic subaortic stenosis (GOKMP).
- At a hypovolemia, a hyponatremia, the diuretics arising, for example, at intensive treatment, a hemodialysis, observance of a diet with restriction of consumption of table salt, diarrhea, vomiting (danger of an excessive lowering of arterial pressure, especially at reception of the first dose).
- At a bilateral stenosis of renal arteries, a unilateral stenosis of an artery of the only functioning kidney, chronic heart failure of the III-IV functional class (on NYHA classification) (at treatment of such patients were observed by the drugs making impact on system renin-angiotensin-Aldosteronum: arterial hypotension, an oliguria and/or the progressing azotemia and seldom acute renal failure and/or death which risk of development cannot be excluded also at reception of an irbesartan) (see the section "Special Instructions").
- At coronary heart disease and/or clinically significant atherosclerosis of vessels of a brain (at an excessive lowering of arterial pressure there is a risk of strengthening of ischemic frustration up to development of an acute myocardial infarction and a stroke).
- At a renal failure (control of content of potassium and concentration of creatinine in blood is required), recent transplantation of a kidney (lack of experience of a clinical use).
- At a heavy liver failure (a functional class C or more than 9 points on a scale of Chayld-Pyyu) (lack of experience of a clinical use).
- At patients 75 years are more senior (though usually treatment is not required, recommended to begin dose adjustments with a dose of 75 mg to define the individual need for drug and to avoid a possible excessive lowering of arterial pressure).
- At simultaneous use of non-steroidal anti-inflammatory drugs (NPVP) (increase in risk of a renal failure, including a possibility of development of an acute renal failure and increase in content of potassium in blood serum, especially, at patients with already impaired renal function) (see the section "Interaction with Other Medicines").
Pregnancy and period of feeding by a breast Pregnancy
Experiment on use of the drug Aprovel® at pregnancy is absent. Taking into account that at reception of APF inhibitors by pregnant women in the second and third trimester of pregnancy damage and death of the developing fruit, ирбесартан were observed, as well as no other drug which influences directly system renin-angiotensin-Aldosteronum can be applied at pregnancy (I, II, 111th trimesters).
Transition to the corresponding alternative therapy by hypotensive drugs with the established safety profile at pregnancy has to be made prior to pregnancy planning.
When diagnosing pregnancy during treatment by the drug Aprovel®, it should be cancelled as soon as possible.
Feeding period breast. It is unknown whether it is excreted ирбесартан in maternal milk. During feeding by a breast administration of drug of Aprovel® is contraindicated. Therefore after assessment of a ratio of estimated advantage of administration of drug for mother and potential risk for the child it is necessary to stop either breastfeeding, or administration of drug of Aprovel®.

Overdose:

Experience of use of drug for adult patients in doses to 900 mg/days for 8 weeks did not reveal any toxicity. The most probable manifestations of overdose are the expressed lowering of arterial pressure and tachycardia; bradycardia can also be overdose manifestation.
There is no specific information concerning drug Aprovel® overdose treatment. It is necessary to establish constant observation of a condition of the patient and if necessary to carry out a symptomatic and maintenance therapy. At overdose it is recommended to cause vomiting and/or to carry out a gastric lavage. Absorbent carbon can be useful to reduction of overdose. The hemodialysis is inefficient.

Storage conditions:

To store at a temperature not above 30 °C. To store in the place, unavailable to children. Period of validity 3 years. Not to use drug after the period of validity specified on packaging.

Issue conditions:

According to the recipe

Packaging:

Tablets, film coated, 150 mg and 300 mg.
On 14 габ a yutok in the blister from PVH/PVDH/alizminiyeva a foil. On I, 2 and ш - Yoysh of a feather together with the application instruction in a cardboard pack.