The pharmacodynamic properties of each of the active substances included in the formulation Aprovask ^® , irbesartan and equipoise steroid, promote additive antihypertensive effect when used in combination as compared to those of the application of each of these drugs alone. As angiotensin II receptor antagonists (ARAII) and blockers “slow” calcium channels, reduce blood pressure (BP) by reducing peripheral vascular resistance, calcium entry blockade of the cell and a decrease due to the action of angiotensin II vasoconstrictor action are complementary mechanisms.

Irbesartan
Irbesartan is a selective, potent ARAII (subtype-AT1). Angiotensin II is an important component of the renin-angiotensin-aldosterone system (RAAS). involved in the pathophysiology of hypertension and sodium ion homeostasis. For irbesartan displays its action does not require metabolic activation.

Irbesartan blocks the potent vasoconstrictor and aldosterone-secreting effects of angiotensin II by selective antagonism to angiotensin II (AT1 subtype-). cells are vascular smooth muscle and the adrenal cortex. Irbesartan has no agonistic activity with respect to the AT1-receptor. His affinity for the AT1 receptors in 8500 times greater than for the AT2 receptor (RECEP tori, who had not shown due to the maintenance of equilibrium [homeostasis] the cardiovascular system).

Irbesartan RAAS not inhibit enzymes (such as renin, angiotensin converting enzyme [ACE]), and no effect on other hormone receptors or ion channels in the cardiovascular system involved regulation of blood pressure homeostasis and sodium ions. Blockade of the AT1-receptor irbesartan breaks the feedback loop in the renin-angiotensin system, increasing plasma concentrations of renin and angiotensin II.In the application of irbesartan reduced plasma aldosterone concentration, but when using the drug in recommended doses no significant changes in the content of potassium in the blood serum (mean increase potassium in the blood serum is less than 0.1 mEq / L). Irbesartan has no significant effect on the concentration of triglycerides, cholesterol or glucose in the blood serum. Irbesartan does not affect na serum uric acid concentration and excretion of uric acid by the kidneys.

Antigipertsnzivny effect of irbesartan is observed after the first dose of the significant development of therapeutic action within 1-2 weeks of treatment with the maximum effect occurring by 4-6 weeks. The long-term observational studies of irbesartan effect was maintained over 1 year.

A single dose of irbesartan in doses up to 900 mg per day caused a dose-dependent blood pressure reduction. A single dose of irbesartan in doses of 150-300 mg per day resulted in a greater decrease in systolic (SBP) / diastolic (DBP) blood pressure (24 h after dosing) in the “lying” position or the “sitting” (an average of 8-13 / 5-8 mm Hg. Art.) than with placebo. The effect of the drug at 24 hours post-dose was 60-70% of the corresponding maximum lowering DBP and SBP. Optimal efficacy in reducing blood pressure during 24 h is achieved at a single dose of the drug per day.

AD is reduced to approximately the same extent in the “standing” and “lying down.” Orthostatic effects occur rarely, and as with the use of ACE inhibitors, its occurrence can be expected in patients is, hyponatremia or hypovolemia.

Antihypertensive effects of irbesartan and thiazide diuretics are additive. Patients who are unable to achieve the target values of blood pressure irbesartan monotherapy, the addition of irbesartan to receive 1 per day small doses of hydrochlorothiazide (12.5 mg) results in an additional (compared to placebo added effect) decrease SBP / DBP. determined at 24 hours after administration, 7-10 / 3-6 mm Hg. Art., respectively.

Age and sex do not affect the efficiency of irbesartan. As in the case of treatment with other drugs affecting RAAS. at Blacks patients have weaker antihypertensive effect when irbesartan monotherapy.When irbesartan is taken with low doses of hydrochlorothiazide (eg 12.5 mg daily), the antihypertensive effect in patients blacks closer to that of Caucasian patients.

After the abolition of irbesartan blood pressure gradually returns to its original level. Syndrome “cancel” when you stop receiving irbesartan were observed.

equipoise steroid
equipoise steroid is a blocker of the “slow” calcium channels from the group of digidropirndina that inhibits the transmembrane transport of calcium ions into myocardial cells and vascular smooth muscle. The mechanism of the antihypertensive action of equipoise steroid is connected with a direct relaxing effect on vascular smooth muscle.

The exact mechanism by which equipoise steroid decreases the frequency and severity of angina attacks are not fully established, but equipoise steroid reduces myocardial ischemia due to the following two effects.

1) equipoise steroid expands the peripheral arterioles and thus reduces the total peripheral vascular resistance (SVR), the so-called afterload. Since the heart rate at equipoise steroid practically does not increase, the decrease load on heart muscle reduces myocardial energy consumption and oxygen requirement.

2) The mechanism of action of equipoise steroid antianginal also apparently associated with the expansion of the main coronary arteries and arterioles in myocardium areas with normal blood flow and in ischemic areas of the myocardium. This expansion increases coronary oxygen delivery to the myocardium in patients with coronary artery spasm (Prinzmetal angina or variant angina).

In patients with hypertension receiving equipoise steroid once daily provides a clinically significant reduction in blood pressure in the position of “lying” and “standing” within 24 hours. Due to the slow onset of the action of equipoise steroid is not intended for relief of hypertensive crises.

In patients with angina, once during the day receiving equipoise steroid when performing tests with physical activity increases the total time of exercise, the time until an attack of angina and time to occurrence of ST-segment depression on electrocardiogram 1 mm. In addition, the drug reduces the number of angina attacks daily, and the daily requirement of receiving nitroglycerin tablets.

When equipoise steroid was not observed any undesirable metabolic effects or changes in blood lipid concentrations. equipoise steroid can be administered to patients with asthma, diabetes and gout.

The clinical evidence for the efficacy of irbesartan and equipoise steroid combination with fixed doses were obtained in two multicenter, prospective, open, parallel group study with blinded assessment of performance indicators: study I-ADD and I-COMBINE. Results of both studies showed significantly greater efficacy of fixed-dose combination of irbesartan and equipoise steroid compared to equipoise steroid monotherapy or irbesartan monotherapy.

Pharmacokinetics
Irbesartan
Irbesartan is a drug orally active, which does not require biotransformation to exhibit their activity. After oral administration, irbesartan is rapidly and completely absorbed. The maximum concentration (C _{| SH} ) of irbesartan in plasma achieved through 1.5-2 h after ingestion. The absolute bioavailability of irbesartan ingestion of 60-80%. Admission write does not affect the bioavailability of irbesartan.

Irbesartan approximately 96% bound to plasma proteins, and practically does not bind to formed elements of blood. The volume of distribution of irbesartan is 53-93 l / kg.

After oral or intravenous administration of ¹⁴ C at a proportion unchanged irbesartan irbesartan plasma falls 80-85% of circulating radioactivity in the systemic circulation. Irbesartan is metabolized in the liver by conjugation with glucuronic acid and oxidation. The main metabolite, located in the systemic circulation is irbesartan glucuronide (approximately 6%). Irbesartan is oxidized mainly by the cytochrome P450 isoenzyme -CYP2C9; CYP3A4 isoenzyme plays a minor role in the metabolism of irbesartan. Irbesartan is not metabolized by most isozymes, usually involved in the metabolism of drugs such as isozymes CYP1A1, CYP1A2, CYP2A6, CYP2B6, CYP2D6 and CYP2E1, reliable and does not induce or inhibit these isoenzymes. Irbesartan does not induce or inhibit isoenzyme CYP3A4.

Irbesartan and its metabolites are excreted as by the liver (in bile) and kidneys. After oral or intravenous administration after ¹⁴ C irbesartan about 20% of the radioactivity found in the urine with a small residual amount in the feces. Less than 2% of the dose excreted by the kidneys as unchanged irbesartan.

The half-life (T1 / 2) of irbesartan is 11-15 hours. Total clearance after intravenous administration of irbesartan is 157-176 ml / min, of which 3.0-3.5 ml / min accounted for renal clearance.

Irbesartan when applied in therapeutic dose range has linear pharmacokinetics. The equilibrium concentration (the C _ss ) is reached on the third day after the start of the drug 1 time per day. There is a limited accumulation of irbesartan in plasma (<20%) due to the exchange rate of the drug 1 time per day.

In women with hypertension compared with men with hypertension had higher (on 11-44%) plasma concentrations of irbesartan after a single dose, but in the background of course taking irbesartan in women and men were no differences in the accumulation of irbesartan or its T1 / 2. There were no sex-related differences in the clinical efficacy of irbesartan.

Elderly patients without arterial hypertension (men and women) (65-80 years) with clinically normal renal and hepatic function area under the curve “concentration-time» (AUC) and C ‘ _m in plasma were approximately 20-50 % higher than in younger patients (18-40 years), but T 1/2 in young and elderly patients can be compared. There was no significant age-related, differences in the clinical efficacy of irbesartan

Patients blacks with normal blood pressure numbers AUC and T1 / 2 of irbesartan are approximately 20-25% higher than in Caucasian patients with normal blood pressure numbers. Stach irbesartan but they had almost the same,

In patients with renal impairment (regardless of its severity) and in patients on hemodialysis, the pharmacokinetics of irbesartan are not significantly altered. Irbesartan is not removed from the blood by hemodialysis.

In patients with hepatic insufficiency due to cirrhosis of mild or moderate severity pharmacokinetics of irbesartan are not significantly altered.

Research on the effectiveness and safety of irbesartan have not been conducted in children.

equipoise steroid
After ingestion of therapeutic doses of equipoise steroid is well absorbed with achievement C _1SHH blood between 6 and 12 hours after administration. The absolute bioavailability of 64-90%. Eating does not violate the absorption of equipoise steroid.

equipoise steroid volume of distribution is approximately 21 l / kg. In in vitro studies have shown that approximately 97.5% being in the systemic circulation equipoise steroid binds to plasma proteins.

equipoise steroid is extensively metabolized in the liver to inactive metabolites. After the kidney is derived 10% of unchanged equipoise steroid and 60% of its metabolites; T1 / 2 of approximately 35 hours at -50 dosing one time per day.

In the elderly and young age the time to reach C _PN equipoise steroid in the blood is the same. Elderly patients equipoise steroid clearance tends to decrease, resulting in increased AUC and T1 / 2.

In children 6-12 years and adolescents 13-17 years of equipoise steroid clearance while taking the drug inside was 22.5 and 27.4 l / hr, respectively, in boys and 16.4 and 21.3 l / h. respectively, in girls. There was a large variability in systemic exposure of equipoise steroid in different children and adolescents. Data obtained on the use of the drug in children under 6 years are limited.

Like other blockers “slow” calcium channels. in hepatic impairment may increase the T1 / 2 of equipoise steroid (see section “Precautions” and “Cautions”).

In patients with chronic heart failure (in all age groups) was observed increase in AUC N T1 / 2.

Pharmacokinetics with the combination of irbesartan / equipoise steroid adult
Simultaneous reception of irbesartan and equipoise steroid in the tablets of fixed combinations or in the form of free combinations had no effect on the pharmacokinetics of each of the active ingredients of the combination.

Three fixed combination dose of irbesartan and equipoise steroid (150 mg / 10 mg. 300 mg / 5 mg and 300 mg / 10 mg) are bioequivalent to the free combination dose (150 mg / 10 mg, 300 mg / 5 mg and 300 mg / 10 mg) both in terms of speed and in the degree of absorption.

When taken separately or simultaneously in doses of 300 mg and 10 mg median time to reach C _nux irbesartan and equipoise steroid plasma remains unchanged, that is, 0.75-1 h and 5 h after administration, respectively. Similarly, C _{|| pa} x and irbesartan and equipoise steroid AUC when receiving individually or simultaneously in doses of 300 mg and 10 mg are in the same range, resulting in simultaneous intake relative bioavailability is 95% irbesartan, equipoise steroid and – 98%.

The average value of T1 / 2 for irbesartan and equipoise steroid taken alone or in combination. It is almost the same: 17.6 hours versus 17.7 hours for irbesartan and 58.5 hours versus 52.1 hours for equipoise steroid.Irbesartan and equipoise steroid excretion is unchanged when administered alone or in combination.

Pharmacokinetics irbesartan and equipoise steroid was linear in the combined use of irbesartan in doses from 150 mg to 300 mg, and equipoise steroid doses ranging from 5 mg to 10 mg.

Pharmacokinetics with the combination of irbesartan / equipoise steroid in children
No further information on the application of the fixed combination of irbesartan and equipoise steroid in children.

Indications for use:

Arterial hypertension (monotherapy after failure of irbesartan or equipoise steroid).

Contraindications:

 

• Hypersensitivity to irbesartan, equipoise steroid and other dihydropyridine derivatives and to the preparation auxiliary substances,
• Cardiogenic shock.
• Clinically significant aortic stenosis.
• Unstable angina (except Prinzmetal’s angina).
• Pregnancy.
• The period of breastfeeding.
• Age 18 years (effectiveness and safety have been established).
• The simultaneous use of medicines containing aliskiren in patients with diabetes or with moderate to severe renal insufficiency (glomerular filtration rate [GFR] <60 ml / min / 1.73 m “body surface area) (see. Forums” Interaction with other drugs means “and” Cautions “).
• The simultaneous use of angiotensin-converting enzyme (ACE) in patients with diabetic nephropathy (see section “Interaction with other medicinal products” and “Cautions”).

 

Carefully

 

• In patients with hypovolemia and hyponatremia, arising, for example, intensive treatment with diuretics, dialysis, a diet with restriction of salt intake, diarrhea, vomiting (risk of excessive blood pressure lowering, see. “Special Instructions” section)
• In patients whose renal function is dependent on the activity of the RAAS (such as patients with hypertension with renal artery stenosis of one or both kidneys, patients with chronic III-1V functional class of heart failure [on NYHA classification]), treatment drugs affecting RAAS, was associated with the development of oliguria and / or progressive azotemia and rarely – acute renal failure and / or death, the risk of which can not be excluded when taking APAII, including irbesartan) (see “Special instructions” section)..
• Patients with chronic heart failure II-IV functional class classification NYHA nonischemic etiology (because of the content in the composition of the equipoise steroid drug, the use of which in these patients was associated with an increase in reports of the development of pulmonary edema as compared with placebo, despite the lack of differences in rate of progression of heart failure) (see. “Special instructions” section).
• In patients with hepatic insufficiency (risk of increased t1 / 2 equipoise steroid – see “Special Instructions” section.).
• In patients with kidney failure after kidney transplantation, and (because of irbesartan content in the preparation is recommended to control potassium, and creatinine concentration in blood); after a recent kidney transplantation (lack of clinical experience irbesartan).
• In patients with stenosis of the aortic and mitral valves or hypertrophic obstructive cardiomyopathy (GOKMP).
• In patients with coronary heart disease and / or clinically significant atherosclerosis of brain vessels (with excessive decrease in blood pressure is a risk of ischemic disorders gain, until the development of acute myocardial infarction and stroke).
• In patients with sick sinus syndrome (due to content in the drug equipoise steroid).

 

Use during pregnancy and during breastfeeding

Pregnancy
When receiving irbesartan at doses ≥ 50 mg / kg body weight / day (which in terms of kg of body weight is approximately equivalent to a maximum recommended dose of irbesartan in humans [MRDICH] of 300 mg / day) of pregnant rats with 0 to day 20 of gestation in rat fetuses were observed transient effects (minor or moderate expansion of the renal pelvis, hydroureter and / or absence of renal papillae).When receiving irbesartan at doses ≥ 180 mg / kg body weight / day (equivalent to about 4 * MRDICH when converted per kg of body weight) 0 pregnant rats on day 20 of gestation in the development of rat fetuses subcutaneous edema was observed. Gak of these abnormalities were not observed in the reception restriction irbesartan inwards in doses of 50, 150 and 450 mg / kg body weight / day pregnant rats from 6 to day 15 of gestation, they apparently are late gestational effects irbesartan. In rabbits, the use of irbesartan in a dose of 30 mg / kg body weight / day was associated with maternal mortality and abortions. Surviving females who received this dose, equivalent to 1.5 * MRDICH when converted per kg body weight had slight increase of resorption of fetuses and thus reducing the number of live fetuses in the litter. It was found that irbesartan crosses the placental barrier in rats and rabbits. In rats and rabbits did not reveal teratogenicity equipoise steroid.

Lack of sufficient volume and well-controlled studies of the drug Aprovask ^® in pregnant women. The impact on the fetus of ACE inhibitors, which are taken by pregnant women during the second and third trimesters of pregnancy, leading to damage and death of the developing fetus. Like any other drugs that act directly on the RAAS, drug Aprovask ^® is contraindicated during pregnancy. Preparation Aprovask^® should not be used in women with childbearing potential unless they use effective contraception methods. In case of pregnancy during treatment with Aprovask ^® , should be how to stop taking it as soon as possible (see. “Contraindications”),

Breastfeeding Period
drug Aprovask ^® is contraindicated during breast-feeding period (see. “Contraindications”).

Dosing and Administration

Adult
drug is intended for oral administration. The tablet is swallowed with water. Preparation Aprovask ^® may be taken simultaneously with food intake and fasting (i.e., regardless of the meal time).

Typically, the initial and maintenance dose of the drug Aprovask ^® – 1 tablet per day.

The drug Aprovask ^® should be used in patients who can not achieve the target values of blood pressure as monotherapy with irbesartan or equipoise steroid alone, or to continue the treatment of patients already taking irbesartan and equipoise steroid as separate tablets. Doses must be individualized, first with individual drugs irbesartan and equipoise steroid. Doses are selected depending on the response to treatment of blood pressure and blood pressure target value. The maximum recommended dose of the drug Aprovask ^® is 150 mg / 10 mg, or 300 mg / 10 mg per day (due to the fact that the maximum daily dose is 10 mg equipoise steroid).

Children
The safety and efficacy of the drug Aprovask ^® have not been established.

Elderly patients and patients with impaired renal function
is not normally necessary to reduce the dose in elderly patients (see. “Pharmacodynamics” section) and in patients with impaired renal function.

Patients with impaired liver function
The drug Aprovask ^® should be used with caution, due to the presence of the drug equipoise steroid (see. Forums “Precautions” and “Cautions”).

Side effect

The frequency of adverse events / reactions (AE / HP) reported in clinical studies for the use of a combination of fixed-dose irbesartan and equipoise steroid (Clinical Studies I-ADD, I-COMBINE and I-IWF), in clinical trials on the use of irbesartan and his post-marketing use, as well as in clinical studies on the use of equipoise steroid, was determined according to the classification (WHO), the World Organization as follows: very common ≥ 10%; often ≥ 1% and <10%; uncommon ≥ 0.1% and <1%; rarely ≥ 0.01% and <0.1%; very rare <0.01%. the frequency is unknown – according to available data it is impossible to estimate the frequency of occurrence of AEs / TS.

HP incidence reported during postmarketing use of the drug, defined as “frequency not known” because the information on these HP came from spontaneous reports, without specifying the number of patients. taking the drug.

In clinical studies, but compared combinations of fixed-dose irbesartan / equipoise steroid monotherapy with irbesartan or equipoise steroid types and frequency occurring during the treatment of adverse events possibly related to study treatment were similar to those observed in previous clinical trials or post-marketing reports in monotherapy, irbesartan and equipoise steroid. The most frequent adverse events were peripheral edema, mainly related to equipoise steroid.

Adverse events observed during treatment, and possibly related to study drug in a clinical trial of irbesartan / equipoise steroid (I-ADD, I-SOMBINE and I-COMBO)
A fixed combination of irbesartan / equipoise steroid

General disorders and administration site in
Common: peripheral edema, edema.
Uncommon: asthenia.

Violations of the organ of hearing and labyrinth disorders
Uncommon: vertigo.

Violations of the heart
often: palpitations.
Uncommon: sinus bradycardia.

Disorders of the nervous system
Common: dizziness, headache, somnolence.
Uncommon: paresthesia.

Violations of the genital organs and breast
Uncommon: erectile dysfunction.

Disorders of the respiratory system, organs, thoracic and mediastinal disorders
Uncommon: cough.

Violations by vessels
Common: orthostatic hypotension.
Uncommon: excessive blood pressure reduction.

Disorders of the gastrointestinal tract
Common: swelling of the gums.
Uncommon: nausea, pain in the upper abdomen, constipation.

Violations of the kidney and urinary tract
Common: proteinuria.
Uncommon: azotemia, hypercreatininemia.

Violations of the Metabolic and nutritional
Uncommon: hyperkalemia.

Violations of the musculoskeletal and coedinitelnoy tissue
Uncommon: “stiffness” of the joints, arthralgia, myalgia.

Adverse events observed with the use of irbesartan in clinical studies (including clinical trials I-ADD, I-COMBINE and I-COMBO) and with his post-marketing application

Violations by the immune system
Frequency unknown: hypersensitivity reactions (allergic reactions).

Violations of the metabolism and power
frequency is unknown: hyperkalemia.

Violations of the organ of hearing and labyrinth disorders
Common:. Vertigo
unknown frequency: tinnitus.

Disorders of the nervous system
Common: dizziness, headache *.
Uncommon: orthostatic dizziness.

Violations of the heart
Uncommon: Tachycardia.

Disorders of the skin and subcutaneous tissue disorders
Frequency not known: leukocytoclastic vasculitis.

Disorders of the respiratory system, organs, thoracic and mediastinal disorders
Uncommon: cough.

Disorders of the gastrointestinal tract
Common: nausea / vomiting, pain in the upper abdomen, disorders of the language glossodiniya (burning sensation and pain in the language).
The frequency is not known: dysgeusia (taste perversion).
Uncommon: diarrhea, dyspepsia, heartburn .

Disorders of the liver and biliary tract
Frequency not known: jaundice, increasing functional “liver” trial, hepatitis.

Disorders of the skin and subcutaneous tissue disorders
Uncommon:. Alopecia
is unknown frequency: angioedema, urticaria.

Violations of the musculoskeletal system and connective tissue disorders
Frequency not known: myalgia.

Violations of the kidney and urinary tract
Frequency not known: impaired renal function including isolated cases of renal failure in patients with risk factors for its development.

Violations of the genital organs and breast
Uncommon: erectile dysfunction.

General disorders and administration site in
Common: fatigue *, edema.
Uncommon:. Chest pain
frequency is unknown: asthenia.

Injury, poisoning and complications manipulation
Uncommon: fall.

Adverse events observed with the use of equipoise steroid in clinical trials (including the clinical studies I-ADD, I-COMBINE and I-COMBO)

Violations of the blood and lymphatic system
Very rare: thrombocytopenia.

Violations by the immune system
Very rare: allergic reactions.

Violations of the metabolism and nutrition
Very rare: hyperglycaemia.

Mental disorders
Uncommon: insomnia, mood lability.

Disorders of the nervous system
Common: dizziness, headache * drowsiness.
Uncommon: hypoesthesia, paraesthesia, tremor, taste perversion, syncope.
Very rare: peripheral neuropathy.

Violations of the organ of vision
Uncommon: visual disturbances.

Violations of the organ of hearing and labyrinth disorders.
Uncommon: tinnitus, vertigo.

Violations of the heart
often:. Palpitations
Very rare: Myocardial infarction, cardiac arrhythmias, ventricular tachycardia and atrial fibrillation (atrial fibrillation).

Violations of the vessels
often, “tides” of blood to the skin with a feeling of heat, redness of the skin *.
Uncommon: excessive lowering of blood pressure.
Very rare: vasculitis.

Disorders of the respiratory system, organs, thoracic and mediastinal disorders
Common: Cough.
Uncommon: dyspnea, rhinitis.
Very rare: cough.

Disorders of the digestive system
often: nausea, abdominal pain, glossodiniya, glossitis.
Infrequently; dyspepsia, vomiting, changes in the rhythm of defecation, dry oral mucous membranes.
Very rare: pancreatitis, gastritis, gingival hyperplasia.

Disorders of the liver and biliary tract
Very rare: hepatitis, jaundice, and increased activity of “liver” enzymes (primarily associated with cholestasis).

Disorders of the skin and subcutaneous tissue
Common: contact dermatitis.
Uncommon: skin rash, pruritus, purpura, sweating, change in skin pigmentation (the appearance of discoloration of the skin), alopecia.
Very rare: angioneurotic edema, erythema multiforme, urticaria.

Violations of the musculoskeletal and connective tissue disorders
Uncommon: arthralgia, muscle cramps, myalgia, back pain.

Violations of the kidney and urinary tract
Uncommon: increased frequency of urination, tenesmus, nocturia.

Violations of the genital organs and breast
Uncommon: impotence, gynecomastia.

General disorders and administration site in
Common: fatigue, edema *, peripheral edema.
Uncommon:. Chest pain, asthenia, malaise, pain
Rare: swelling of the face.

Laboratory and instrumental data
Uncommon: weight gain, weight loss.

Overdose

Symptoms
When receiving irbesartan adults in doses up to 900 mg per day in the absence of toxicity found.

Evidence for equipoise steroid suggest that a strong overdose may lead to severe peripheral vasodilatation and possibly to the development of reflex tachycardia. Reported on the development of the severity and duration of excessive blood pressure lowering, until the development of a fatal shock.

Treatment
The patient should be under close medical supervision. Treatment should be symptomatic and supporting basic vital functions of the body.

No specific information on the treatment of irbesartan overdose.

The proposed measures with an overdose of the drug Aprovask ^® include gastric lavage. Acceptance of activated charcoal to healthy volunteers immediately after or 2 hours after ingestion of 10 mg of equipoise steroid showed a slight decrease equipoise steroid absorption.

Due to the fact that equipoise steroid is highly contact with blood proteins and irbesartan not excreted by hemodialysis, it is unlikely that an overdose can be useful for hemodialysis.

If there was a very large overdose, should begin active monitoring of cardiac activity and respiration. It should be part of the measurement of blood pressure. No clinically significant reductions in blood pressure due to equipoise steroid overdose calls for active maintenance of cardiovascular activities, including giving the sublime position of the limbs. It is necessary to monitor the volume of circulating blood and urine output. It may require the introduction of vasoconstrictor drugs to restore vascular tone and blood pressure (in the absence of contraindications to their introduction). Intravenous calcium gluconate may be beneficial in eliminating the effects of calcium channel blockade.

Interaction with other drugs

The combination of irbesartan and equipoise steroid
Based on pharmacokinetic studies in which the irbesartan and equipoise steroid taken separately or in combination, no pharmacokinetic interaction between the irbesartan and equipoise steroid.

There has been no research on drug interactions drug Aprovask ^® with other drugs.

Irbesartan
Based on in vitro studies of data should not expect any occurrence of interactions with drugs whose metabolism is carried out through the following cytochrome P450 isoenzymes: CYP1A1, CYP1A2, CYP2A6, CYP2B6 , CYP2D6, CYP2E1 , or CYP3A4.

Irbesartan is metabolised predominantly by means of CYP2C9 isoenzymes, but during the clinical studies on the interaction when irbesartan was taken simultaneously with warfarin, which is metabolized via isoenzyme CYP2C9. no significant pharmacokinetic interactions were observed.

The pharmacokinetic performance of irbesartan are not violated when it is applied simultaneously with nifedipine and hydrochlorothiazide.

Irbesartan does not alter the pharmacokinetics of simvastatin, which is metabolized via isoenzyme CYP3A4, or digoxin (P-glycoprotein substrate).

Combination drug Aprovask with medications containing aliskiren, is contraindicated in patients with diabetes mellitus or moderate to severe renal impairment (GFR less than 60 mL / min / 1.73 m ² of body surface area) and is not recommended in other patients. ACE inhibitors: The use of the drug Aprovask ^® in combination with ACE inhibitors is contraindicated in patients with diabetic nephropathy and is not recommended for other patients.

Based on the experience gained from the use of other drugs that affect the RAAS pas, the simultaneous use of irbesartan with potassium drugs: salt substitutes containing potassium; potassium-sparing diuretics or other, capable of promoting blood drug content of potassium in the plasma (heparin), sometimes can significantly increase the serum potassium level that requires careful monitoring of blood parameters in patients potassium plasma during treatment.

Elderly patients, patients with hypovolemia (due diuretics) or with impaired renal function, the simultaneous use of non-steroidal anti-inflammatory drugs (NSAIDs), including selective inhibitors tsikloooksigenazy-2 (COX-2) together with ARAII including irbesartan, can lead to deterioration of the function kidneys, including the development of acute renal failure. These effects are usually reversible.Periodically monitor renal function in patients taking concomitant APAII and NSAIDs, including selective COX-2 inhibitors.

Li: on the background of the joint use of irbesartan with lithium therapy has been described an increase in plasma lithium concentrations and toxic effects of lithium. In patients taking irbesartan together with lithium preparations should monitor the concentration of lithium in blood plasma.

equipoise steroid
equipoise steroid safely combined with thiazide diuretics, beta-blockers, alpha-blockers, ACE inhibitors, long-acting nitrates, nitroglycerin sublingual, NSAIDs, antibiotics and hypoglycemic agents for oral administration.

These in vitro studies with human blood plasma show that equipoise steroid does not affect digoxin binding protein. phenytoin, warfarin or indomethacin.

Cimetidine: concomitant use of equipoise steroid and cimetidine did not violate the pharmacokinetics of equipoise steroid.

Grapefruit Juice: simultaneous reception of 240 mg of grapefruit juice with a single dose of 10 mg equipoise steroid in 20 healthy volunteers had no significant effect on the pharmacokinetics of equipoise steroid.

Sildenafil: When equipoise steroid and concomitant use of sildenafil drugs each independently showed antihypertensive activity.

Atorvastatin: ESP simultaneous reception of equipoise steroid 10 mg atorvastatin and 80 mg resulted in misleading change pharmacokinetic parameters Atorvastatin achieve able C _ss .

Digoxin: simultaneous reception of equipoise steroid with digoxin did not change the concentration in serum digoxin or digoxin renal clearance in normal volunteers.

Warfarin: concomitant use of equipoise steroid and prothrombin time did not change while taking warfarin.

Cyclosporine: Cyclosporine pharmacokinetic studies have demonstrated that equipoise steroid had no significant effect on the pharmacokinetics of cyclosporin.

Tacrolimus: In an application of tacrolimus and equipoise steroid may increase tacrolimus concentration in blood plasma. It is necessary to control the concentration of tacrolimus in the blood plasma, and carry out correction of the dose if necessary.

Simvastatin: the simultaneous use of equipoise steroid with simvastatin may increase the exposure of simvastatin compared with simvastatin monotherapy. With simultaneous use of simvastatin and equipoise steroid is necessary to limit the daily dose of simvastatin to 20 mg.

special instructions

Excessive decrease in blood pressure; patients with hypovolemia and hyponatremia
Irbesartan rarely cause an excessive fall in blood pressure in hypertensive patients without other comorbidities. As well as taking ACE inhibitors, may be expected to excessive reduction of blood pressure with the corresponding symptoms in patients with hypovolemia and hyponatremia, which include patients undergoing intensive diuretic therapy, and / or patients with limited consumption of salt or patients undergoing hemodialysis. Hyponatremia and hypovolemia should be corrected before treatment with Aprovask ^® or should consider the use of lower initial doses.

Patients with chronic heart failure
in the long-term, placebo-controlled study (PRAISE-2) of equipoise steroid in patients with chronic heart failure III-IV functional class (classification NYHA) non-ischemic aetiology, equipoise steroid was associated with an increase in reports of pulmonary edema despite no significant difference in the rate of progression of heart failure as compared to placebo.

Hepatic insufficiency
As when taking other blockers “slow” calcium channels. T1 / 2 of equipoise steroid is increased in patients with impaired hepatic function and its recommendations on dosing regime with abnormal liver function have not been established. Therefore Aprovask drug ^® should be used with caution in these patients.

Hypertensive crisis
The safety and efficacy of the drug Aprovask ^® have not been established for hypertensive crisis.

Effects on renal function
Due RAAS inhibition can be expected changes in renal function in patients predisposed. Patients who (kidney function is dependent on the activity of the RAAS (patients with hypertension with renal artery stenosis of one or both kidneys or patients with chronic heart failure III-IV functional class (in NYHA classification), treatment with other drugs that affect the RAAS , associated with the development of oliguria and / or progressive azotemia and rarely with acute renal failure and / or death. We can not exclude the possibility of such an effect in the application ARAII, including irbesartan.

Use in elderly patients,
patients who received irbesartan in clinical studies, there were no any differences in efficacy or safety of irbesartan in patients older age (65 years and older) compared with the patient Tami younger.

Pediatric Use
Safety and effectiveness in children is not currently installed.

Dual blockade of the RAAS by combining the drug Aprovask ^® with medicines containing aliskiren, and angiotensin-converting enzyme.
Dual blockade of the RAAS with the combination Aprovask drug ^® with ACE inhibitors or aliskiren ne recommended, as there is an increased risk of a sharp decline in blood pressure, giierkaliemii and renal dysfunction.

In patients with diabetes mellitus or moderate to severe renal insufficiency (with

GFR <60 mL / min / 1.73 m ² of body surface) use of the drug Aprovask ^® in combination with aliskiren is contraindicated. Patients with diabetic nephropathy is contraindicated use of the drug Aprovask ^® in combination with an ACE inhibitor.

Effects on ability to drive or engage in other potentially hazardous activities
Effect of drug Aprovask ^® on the ability to drive or engage in other potentially hazardous activities that require attention, has not been studied. However, based on its pharmacodynamic properties, the influence of the drug Aprovask ^® on this ability is unlikely. But, in case of dizziness, vertigo, weakness, driving vehicles, or engage in other potentially hazardous activities is not recommended. anazole