Aprovask - instructions for use, doses, side effects, contraindications

Active substanceAmlodipine + IrbesartanAmlodipine + Irbesartan

Similar drugsTo uncover

Aprovask®

pills inwards

Sanofi-Aventis de Mexico SA de S.V. Mexico

Dosage form: & nbspfilm coated tablets

Composition:

In one tablet, 5 mg + 150 mg contains: core:

active ingredients: Amlodipine besylate - 7.0 mg (in terms of amlodipine - 5.0 mg), irbesartan - 150.0 mg;

Excipients: microcrystalline cellulose 50 microns - 66.0 mg; croscarmellose sodium - 12.0 mg, hypromellose 6 mPa.s - 5.0 mg, cellulose microcrystalline 100 μm - 5,0 mg, silicon dioxide colloid - 2,5 mg, magnesium stearate - 2,5 mg;

shell: opada white¹ - 10.0 mg.

In one tablet, 10 mg + 150 mg contains: core:

active ingredients: Amlodipine besylate - 14.0 mg (in terms of amlodipine - 10,0 mg), irbesartan - 150.0 mg;

Excipients: microcrystalline cellulose 50 microns - 54.0 mg; croscarmellose sodium - 12.0 mg, hypromellose 6 mPa.s - 5.0 mg, cellulose microcrystalline 100 microns - 10.0 mg, silicon dioxide 2.5 mg, magnesium stearate 2.5 mg;

shell: opadrai pink² - 10.0 mg.

In one tablet 5 mg + 300 mg contains: the core:

active ingredients: Amlodipine besylate - 7.0 mg (in terms of amlodipine - 5.0 mg), irbesartan - 300.0 mg;

Excipients: cellulose microcrystalline 50 microns - 132.0 mg, croscarmellose sodium - 24.0 mg, hypromellose 6 mPa.s - 10.0 mg, cellulose microcrystalline 100 microns - 17.0 mg, silicon dioxide - 5.0 mg, magnesium stearate - 5,0 mg;

shell: opada yellow³ 20.0 mg.

In one tablet 10 mg + 300 mg contains: core:

active ingredients: Amlodipine besylate - 14.0 mg (in terms of amlodipine - 10,0 mg), irbesartan - 300.0 mg;

Excipients: microcrystalline cellulose 50 microns - 132.0 mg, croscarmellose sodium - 24.0 mg, hypromellose 6 mPa.s - 10.0 mg, cellulose microcrystalline 100 microns - 10.0 mg, silicon dioxide - 5.0 mg, magnesium stearate - 5,0 mg;

shell: opada white¹ 20.0 mg.

¹- Deficient white contains hypromellose - 62.50%, titanium dioxide (E 171) - 31.25%, macrogol-400 - 6.25%.

²- Opadrai pink contains hypromellose - 57.750%, titanium dioxide (E 171) - 29.366%, macrogol-400 - 9.080%, macrogol-8000 - 3.300%, iron oxide red oxide (E 172) - 0.504%.

³- Opaprai yellow contains hypromellose - 57.750%, titanium dioxide (E 171) - 29,080%, macrogol-400 - 9,080%, macrogol-8000 - 3,300%, ferric oxide yellow oxide (E 172) - 0.790%.

Description:

Tablets 5 mg +150 mg

Oval biconvex tablets, covered with a white film shell, with an engraving of 150/5 on one side.

Tablets 10 mg +150 mg

Oval biconvex tablets, covered with a pink film cover, with an engraving of 150/10 on one side.

Tablets 5 mg + 300 mg

Oval biconvex tablets, covered with a film coating of yellow color, with engraving 300/5 on one side.

Tablets 10 mg + 300 mg

Oval biconvex tablets, coated with a white film shell, with a risk and skew to risk on one side.

Pharmacotherapeutic group:Combined antihypertensive agent (blocker of "slow" calcium channels + angiotensin II receptor antagonist)

ATX: & nbsp

C.09.D.B.05 Irbesartan and amlodipine

Pharmacodynamics:

Pharmacodynamic properties of each of the active substances that make up the drug Aprovask®, irbesartan and amlodipine, contribute to their additive antihypertensive effect when used in combination, compared with those used with each of these drugs individually. Both angiotensin II receptor antagonists (APA11) and slow calcium channel blockers reduce arterial pressure (BP) by decreasing peripheral vascular resistance, calcium blockade in the cell, and reduction in angiotensin-mediated II vasoconstrictive actions are complementary mechanisms.

Irbesartan

Irbesartan is a selective strongly acting ARAP (subtype-AT₁). Angiotensin II is an important component of the renin-angiotensin-aldosterone system (RAAS) involved in the pathophysiology of arterial hypertension and in the homeostasis of sodium ions. To display its effect irbesartan does not need metabolic activation.

Irbesartan blocks strong vasoconstrictive and aldosterone-secreting action of angiotensin II due to selective antagonism to angiotensin receptors II (subtype-AT₁), located in the cells of the smooth muscles of the vessels and the cortex of the adrenal glands. Irbesartan has no agonistic activity in relation to AT₁receptors. Its affinity for AT₁-receptors are 8500 times greater than to AT₂-receptors (receptors, which have not been shown to be associated with maintaining the equilibrium [homeostasis] of the cardiovascular system).

Irbesartan does not inhibit RAAS enzymes (such as renin, angiotensin-converting enzyme [ACE]), nor does it affect other hormonal receptors or ion channels in the cardiovascular system, regulating blood pressure and homeostasis of sodium ions. Blockade of irbesartan AT₁receptors breaks the feedback loop in the renin-angiotensin system, increasing the plasma concentrations of renin and angiotensin II. When irbesartan is used, the plasma concentration of aldosterone decreases, however, when the drug is administered in recommended doses, there is no significant change in the potassium content in the blood serum (the average increase in serum potassium content 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 serum uric acid concentrations or the excretion of uric acid by the kidneys.

The antihypertensive effect of irbesartan is observed after the first dose with a significant development of the therapeutic effect within 1-2 weeks of treatment with the maximum effect occurring in 4-6 weeks. In long-term observational studies, the effect of irbesartan persisted for more than 1 year. A single dose of irbesartan in doses up to 900 mg per day caused a dose-dependent decrease in blood pressure. A single dose of irbesartan in doses of 150-300 mg per day resulted in a greater decrease in systolic (SBP) / diastolic (DBP) BP (24 hours after dosing) in the "lying" or "sitting" position (an average of 8-13 / 5-8 mm Hg.st.) than when taking placebo. The effect of the drug 24 hours after the dose was 60-70% of the corresponding maximum decrease in DBP and SBP. Optimum efficiency in terms of reducing blood pressure within 24 hours is achieved with a single dose of the drug per day.

BP decreases approximately in the same degree in the "standing" and "lying". Orthostatic effect occurs rarely, and, as with the use of ACE inhibitors, its occurrence can be expected in patients with hyponatremia or hypovolemia. The antihypertensive effect of irbesartan and thiazide diuretics is additive. In patients who fail to achieve target BP values with irbesartan monotherapy, the addition of small doses of hydrochlorothiazide (12.5 mg) once daily to irbesartan leads to an additional (compared with the placebo effect) decrease in SBP / DBP, determined by 24 h after their administration, by 7-10 / 3-6 mm Hg. art., respectively.

Age and gender do not affect the effectiveness of irbesartan. As in the case of treatment with other drugs that affect RAAS, the patients of the Negroid race have a weaker antihypertensive effect with monotherapy with irbesartan. When irbesartan is taken with small doses of hydrochlorothiazide (for example, 12.5 mg per day), the antihypertensive effect in patients of the Negroid race approximates that of patients of the Caucasian race.

After discontinuing irbesartan, blood pressure gradually returns to the initial level. The syndrome of "cancellation" with the discontinuation of irbesartan was not observed.

Amlodipine

Amlodipine is a blocker of "slow" calcium channels from the dihydropyridine derivative group, which inhibits the transmembrane transport of calcium ions into myocardial cells and smooth vascular muscle. Mechanism antihypertensive action of amlodipine is associated with a direct relaxing effect on the smooth muscles of the vessels.

The precise mechanism by which amlodipine reduces the frequency and severity of angina attacks, is not fully established, but amlodipine reduces myocardial ischemia due to the following two effects.

1. Amlodipine dilates the peripheral arterioles and thereby reduces the overall peripheral vascular resistance (OPSS), the so-called afterload. Since the heart rate when receiving amlodipine is practically not increased, this decrease in the load on the heart muscle reduces the energy consumption of the myocardium and its need for oxygen.

2. The mechanism of antianginal action of amlodipine also seems to be associated with the expansion of the main coronary arteries and arterioles, both in the zones of the myocardium with normal blood flow and in the ischemic zones of the myocardium. This dilatation of the coronary vessels increases the oxygen delivery to the myocardium in patients with spasm of the coronary arteries (with Prinzmetal angina or variant angina).

In patients with arterial hypertension, amlodipine once a day provides a clinically significant decrease in blood pressure in the "lying" and "standing" for 24 hours. Due to the slow onset of its action amlodipine It is not intended for relief of hypertensive crises.

In patients with angina, a single dose of amlodipine during a day during exercise with physical exertion increases the total time of exercise, the time before the onset of an attack of angina and the time until the appearance of a segment depression ST on the ECG by 1 mm. In addition, taking the drug reduces the daily number of angina attacks and the daily need for taking nitroglycerin tablets.

When receiving amlodipine, there were no undesirable metabolic effects or changes in lipid concentrations in the blood. Amlodipine can be taken in patients with bronchial asthma, diabetes and gout.

Clinical evidence of the efficacy of a combination of irbesartan and amlodipine with fixed doses was obtained in two multicenter, prospective, open-label studies of parallel groups with blind evaluation of efficacy: I-ADD and I-COMBINE. The results of both studies demonstrated a significantly greater efficacy of combinations with fixed doses of irbesartan and amlodipine compared to amlodipine monotherapy or irbesartan monotherapy.

Pharmacokinetics:

Irbesartan

Irbesartan is a drug that is active when ingested, which does not need biotransformation to display its activity. After oral administration irbesartan quickly and completely absorbed. The maximum concentration (C_m_Oh) irbesartan in the blood plasma is achieved after 1.5-2 h after ingestion. Absolute bioavailability of irbesartan upon ingestion is 60-80 %. Eating does not affect the bioavailability of irbesartan.

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

After ingestion or intravenous administration ¹⁴C irbesartan on the share of unchanged irbesartan in blood plasma accounts for 80-85% of circulating radioactivity in the systemic blood flow. Irbesartan metabolized in the liver by conjugation with glucuronic acid and oxidation. The main metabolite in the systemic circulation is irbesartan glucuronide (approximately 6%). Irbesartan is subjected to oxidation, mainly by means of the cytochrome isoenzyme P450 - CYP2C9; isoenzyme CYP3A4 plays an insignificant role in the metabolism of irbesartan. Irbesartan is not metabolized by most isoenzymes commonly involved in the metabolism of drugs, such as isozymes CYP1A1, CYP1A2, CYP2A6, CYP2B6, CYP2D6 or CYP2E1, and does not reliably induce or inhibit these isoenzymes. Irbesartan Does not induce or inhibit isoenzyme CYP3A4.

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

The half-life (T_1/2) of irbesartan is 11-15 hours. The total clearance for intravenous administration of irbesartan is 157-176 ml / min, of which 3.0-3.5 ml / min accounted for the proportion of renal clearance.

Irbesartan, when used in the therapeutic dose range, has linear pharmacokinetics. The equilibrium concentration (C_ss) is achieved on the third day after the start of the drug once a day. There is a limited accumulation of irbesartan in the blood plasma (<20%) against the background of the course of the drug once a day.

In women with arterial hypertension, compared with men with hypertension, higher plasma concentrations (11-44%) of irbesartan after a single dose were observed, but against the background of irbesartan intake in women and men, there was no difference in the accumulation of irbesartan or in its T_1/2. There were no gender-related differences in the clinical efficacy of irbesartan.

In elderly patients without hypertension (men and women) (65-80 years) with clinically normal renal and hepatic function, the area under the pharmacokinetic curve "concentration-time" (AUC) and C_max in blood plasma were approximately 20-50% higher than in patients younger (18-40 years), but T_1/2 in patients of young and elderly age were comparable. There were no significant age-related differences in the clinical efficacy of irbesartan.

In patients of the Negroid race with normal BP numbers AUC and T_1/2 irbesartan were approximately 20-25% higher than in patients of the Caucasoid race with normal BP numbers, however, C_max irbesartan they were almost the same.

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

In patients with hepatic insufficiency due to cirrhosis of mild or moderate severity, the pharmacokinetics of irbesartan do not change significantly. Studies of the efficacy and safety of irbesartan in children have not been conducted.

Amlodipine

After oral administration at therapeutic doses amlodipine well absorbed with the achievement of C_max in the blood between 6 and 12 hours after ingestion. Absolute bioavailability is 64-90%. Eating does not interfere with the absorption of amlodipine.

The volume of distribution of amlodipine is approximately 21 l / kg. In studies in vitro it was shown that approximately 97.5% of the amlodipine in the systemic circulation is associated with blood plasma proteins.

Amlodipine is extensively metabolized in the liver with the formation of inactive metabolites. Through the kidneys, 10% of unchanged amlodipine and 60% of its metabolites are excreted; T_1/2 is approximately 35-50 hours with dosing once a day.

In elderly and young people, the time to achieve ^_ax Amlodipine in the blood is the same. In elderly patients the clearance of amlodipine tends to decrease, resulting in an increase AUC and T_1/2.

In children aged 6-12 years and in adolescents aged 13-17 years, the clearance of amlodipine for oral administration was 22.5 and 27.4 l / h, respectively, in boys and 16.4 and 21.3 l / h, respectively, in girls . There was a great variability in the systemic exposure of amlodipine in different children and adolescents. Data obtained from the use of the drug in children younger than 6 years are limited.

As with other blockers of "slow" calcium channels, with liver failure, an increase in T_1/2 Amlodipine (see the sections "With caution" and "Special instructions").

Patients with chronic heart failure (in all age groups) experienced an increase AUC and T_1/2.

Pharmacokinetics in combination with irbesartan / amlodipine in adults Simultaneous reception of irbesartan and amlodipine in the form of fixed combinations in tablets or as free combinations did not affect the pharmacokinetics of each of the active substances of this combination.

Three fixed doses of irbesartan and amlodipine (150 mg / 10 mg, 300 mg / 5 mg and 300 mg / 10 mg) are bioequivalent free dose combinations (150 mg / 10 mg, 300 mg / 5 mg and 300 mg / 10 mg) , both in terms of speed and with respect to the degree of absorption.

When taken alone or simultaneously in doses of 300 mg and 10 mg, the time to achieve median C_m_Oh irbesartan and amlodipine in the blood plasma remains unchanged, that is, 0.75-1 h and 5 h after administration, respectively. Similarly C_max and AUC irbesartan and amlodipine, when taken alone or simultaneously in doses of 300 mg and 10 mg are in the same ranges, as a result of which when combined, the relative bioavailability of irbesartan is 95%, and amlodipine - 98%.

The mean value of T_1/2 for irbesartan and amlodipine, taken alone or in combination, is almost the same: 17.6 hours against 17.7 hours for irbesartan and 58.5 hours against 52.1 hours for amlodipine. The excretion of irbesartan and amlodipine does not change when they are taken alone or together.

The pharmacokinetics of irbesartan and amlodipine were linear with the simultaneous use of irbesartan at doses of 150 mg to 300 mg and amlodipine in doses ranging from 5 mg to 10 mg.

Pharmacokinetics in combination with irbesartan / amlodipine in children

There is no information on the use of a fixed combination of irbesartan and amlodipine in children.

Indications:Arterial hypertension (with ineffectiveness of monotherapy with irbesartan or amlodipine).

Contraindications:

- Hypersensitivity to irbesartan, amlodipine and other dihydropyridine derivatives, as well as to the excipients of the drug.

- Cardiogenic shock.

- Clinically significant aortic stenosis.

- Unstable angina (with the exception of Prinzmetal angina).

- Pregnancy.

- Breastfeeding period.

- Age to 18 years (effectiveness and safety not established).

- Simultaneous use with medicinal products containing aliskiren, in patients with diabetes mellitus or with moderately severe and severe renal failure (glomerular rate filtration [GFR] <60 ml / min / 1.73 m² surface of the body) (see the sections "Interaction with other drugs" and "Special instructions").

- Simultaneous use with angiotensin-converting enzyme (ACE inhibitors) in patients with diabetic nephropathy (see the sections "Interaction with other drugs" and "Special instructions").

Carefully:

- In patients with hypovolemia and hyponatraemia, for example, in intensive treatment with diuretics, hemodialysis, adherence to a diet restricting intake of table salt, diarrhea, vomiting (danger of excessive blood pressure lowering, see "Special instructions").

- In patients with renal function dependent on RAAS activity (such as patients with hypertension with renal artery stenosis of one or both kidneys, patients with chronic heart failure III-IV functional class [by classification NYHA]), treatment with drugs that affect 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 ruled out when taking ARAP, including irbesartan) (see section "Special instructions").

- In patients with chronic heart failure II-IV functional class by classification NYHA non-ischemic etiology (due to the content of amlodipine in the formulation, the use of which in such patients was associated with an increase in reports of pulmonary edema compared with placebo, despite the absence of differences in the incidence of progression of heart failure) (see "Special instructions") .

- In patients with hepatic insufficiency (the risk of an increase t_1/2 amlodipine - see the section "Special instructions").

- In patients with renal insufficiency and after kidney transplantation (due to the content of irbesartan, it is recommended to monitor the potassium content and creatinine concentration in the blood); after a recent kidney transplantation (lack of experience in the clinical use of irbesartan).

- In patients with stenosis of the aortic and mitral valve or hypertrophic obstructive cardiomyopathy (GOKMP).

- In patients with coronary heart disease and / or clinically significant atherosclerosis of cerebral vessels (with excessive lowering of blood pressure there is a risk of increasing ischemic disorders, up to the development of acute myocardial infarction and stroke).

- In patients with weakness syndrome sinus node (due to the content of the drug amlodipine).

Pregnancy and lactation:

Pregnancy

When taking irbesartan in doses ≥ 50 mg / kg body weight / day (which, when recalculated per kg body weight, is approximately equivalent to the maximum recommended dose of irbesartan in humans [MPHIH], 300 mg / day) in pregnant rats from 0 to 20 day gestation in fetuses rats, transient effects (minor or moderate enlargement of renal pelvis, hydroureter and / or absence of renal papillae) were observed. When irbesartan was taken at doses ≥ 180 mg / kg body weight / day (approximately equivalent to 4 × MRPD when recalculated per kg of body weight), development of subcutaneous edema was observed in pregnant rats from 0 to 20 days of gestation in rat fetuses.Since these developmental abnormalities were not observed with limited intake of irbesartan at doses of 50, 150 and 450 mg / kg of body weight / day in pregnant rats from 6 to 15 days of gestation, they appear to be late gestational effects of irbesartan. In rabbits, irbesartan at a dose of 30 mg / kg body weight / day was associated with maternal mortality and abortion. Surviving females who received this dose, equivalent to 1.5 × MDI in terms of body weight, had a slight increase in the resorption of fruits and, correspondingly, a decrease in the number of live fetuses in the litter. It was found that irbesartan penetrates the placental barrier in rats and rabbits. In rats and rabbits, teratogenic action of amlodipine was not detected. There are no sufficient and well-controlled studies of the use of Aprovask® in pregnant women. The effect on the fetus of ACE inhibitors, which were taken by pregnant women in the second and third trimesters of pregnancy, resulted in damage and death of the developing fetus. Like any other medicines that directly affect RAAS, the drug Aprovask® is contraindicated during pregnancy.The drug Aprovask® should not be used in women with childbearing potential unless they use effective methods of contraception. In case of detection of pregnancy during treatment with Aprovask®, stop taking it as soon as possible (see the section "Contraindications").

Breastfeeding period

The drug Aprovask® is contraindicated during the period of breastfeeding (see section "Contraindications").

Dosing and Administration:

Adults

Inside, washing with water, regardless of the time of eating.

The initial and maintenance dose of AproVasc ® - 1 tablet per day.

The drug Aprovask^® should be used in patients who can not achieve the target values of BP with monotherapy with irbesartan or monotherapy with amlodipine, or for continuing treatment of patients already taking irbesartan and amlodipine in the form of individual tablets. Doses should be selected individually, first with the use of individual preparations of irbesartan and amlodipine. Doses are selected depending on the response of BP to the therapy and the target blood pressure. The maximum recommended dose of the drug is 150 mg / 10 mg or 300 mg / 10 mg per day (due to the fact that the maximum daily dose of amlodipine is 10 mg).

Children

The safety and efficacy of AproVasc® have not been established.

Older patients and patients with impaired renal function

Correction of the dose is not required.

Patients with impaired hepatic function

The drug Aprovask® should be used with caution, due to the presence of amlodipine in the formulation (see the sections "With caution" and "Special instructions").

Side effects:

The incidence of adverse events / reactions (AE / NR) reported in clinical trials using fixed-dose combinations of irbesartan and amlodipine (clinical trials I-ADD, I-COMBINE and I-COMBO), in clinical studies on the use of irbesartan and in its post-marketing application, as well as in clinical studies on the use of amlodipine, was defined by the classification of the World Health Organization (WHO) as follows: very often ≥ 10%; often ≥ 1% and <10%; infrequently ≥ 0.1% and <1%; rarely ≥ 0.01% and <0.1%; very rarely <0.01%, the frequency is unknown - according to the available data, it is impossible to estimate the incidence of AE / HP.

The incidence of HP reported during post-marketing use of the drug was defined as "frequency unknown," since information about these HPs came from spontaneous reports, without indicating the number of patients taking the drug.

In clinical trials comparing fixed-dose combinations of irbesartan / amlodipine with irbesartan or amlodipine monotherapy, the types and frequency of adverse events likely to be associated with the treatment studied were similar to those observed in previous clinical studies or post-marketing reports in monotherapy with irbesartan and amlodipine. The most common undesirable phenomenon was peripheral edema, mainly associated with amlodipine.

Adverse events observed during treatment and possibly related to the study drug in clinical studies of irbesartan / amlodipine (I-ADD, I-COMBINE and I-COMBO)

The fixed combination of irbesartan / amlodipine

General disorders and disorders at the site of administration

Often: peripheral edema, swelling.

Infrequently: asthenia.

Hearing disorders and labyrinthine disorders

Infrequently: Vertigo.

Heart Disease

Often: a feeling of palpitations.

Infrequently: sinus bradycardia.

Disturbances from the nervous system

Often: dizziness, headache, drowsiness.

Infrequently: paresthesia.

Violations of the genitals and mammary gland

Infrequently: erectile disfunction.

Disturbances from the respiratory system, chest and mediastinal organs

Infrequently: cough.

Vascular disorders

Often: orthostatic hypotension.

Infrequently: excessive decrease in blood pressure.

Disorders from the gastrointestinal tract

Often: swelling of the gums.

Infrequently: nausea, pain in the upper abdomen, constipation.

Disorders from the kidneys and urinary tract

Often: proteinuria.

Infrequently: azotemia, hypercreatininaemia.

Disorders from the metabolism and nutrition

Infrequently: hyperkalemia.

Disturbances from musculoskeletal and connective tissue

Infrequently: "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 in its post-marketing application

Immune system disorders

Frequency unknown: reactions of hypersensitivity (allergic reactions).

Disorders from the metabolism and nutrition

Frequency unknown: hyperkalemia.

Hearing disorders and labyrinthine disorders

Often: Vertigo.

Frequency unknown: tinnitus.

Disturbances from the nervous system

Often: dizziness, headache *.

Infrequently: orthostatic dizziness.

* frequency of occurrence of a headache in studies I-ADD, I-COMBINE and I-COMBO was assessed as "infrequently".

Heart Disease

Infrequently: tachycardia.

Disturbances from the skin and subcutaneous tissues

Frequency unknown: leukocytoclastic vasculitis.

Disturbances from the respiratory system, chest and mediastinal organs

Infrequently: cough.

Disorders from the gastrointestinal tract

Often: nausea / vomiting, pain in the upper abdomen, language disorders, glossodynia (burning sensation and soreness in the tongue).

Frequency unknown: dysgeusia (perversion of taste).

Infrequently: diarrhea, dyspepsia, heartburn.

Disturbances from the liver and bile ducts

Frequency unknown: jaundice, increased indicators of functional "hepatic" samples, hepatitis.

Disturbances from the skin and subcutaneous tissues

Infrequently: alopecia.

Frequency unknown: angioedema, urticaria.

Disturbances from musculoskeletal system and connective tissue

Frequency unknown: myalgia.

Disorders from the kidneys and urinary tract

Frequency unknown: impaired kidney function, including individual cases of kidney failure in patients with risk factors for its development.

Violations of the genitals and mammary gland

Infrequently: erectile disfunction.

General disorders and disorders at the site of administration

Often: increased fatigue *, swelling.

Infrequently: pain in the chest.

Frequency unknown: asthenia.

*- frequency of occurrence of increased fatigue in studies I-ADD, I-COMBINE and I-COMBO was assessed as "infrequently".

Trauma, intoxication and complications of manipulation

Infrequently: falling.

Adverse events observed with amlodipine in clinical trials (including clinical trials I-ADD, I-COMBINE and I-COMBO) Disturbances from the blood and lymphatic system

Rarely: thrombocytopenia.

Immune system disorders

Rarely: allergic reactions.

Disorders from the metabolism and nutrition

Rarely: hyperglycemia.

Disorders of the psyche

Infrequently: insomnia, lability of mood.

Disturbances from the nervous system

Often: dizziness, headache *, drowsiness.

Infrequently: hypesthesia, paresthesia, tremor, perversion of taste, syncopal conditions.

Rarely: peripheral neuropathy.

* - incidence of headache in studies I-ADD, I-COMBINE and I- COMBO was assessed as "infrequently".

Disturbances on the part of the organ of sight

Infrequently: visual disorders.

Hearing disorders and labyrinthine disturbances.

Infrequently: ringing in the ears, vertigo.

Heart Disease

Often: a feeling of palpitations.

Rarely: myocardial infarction, heart rhythm disturbances, ventricular tachycardia and atrial fibrillation (atrial fibrillation).

Vascular disorders

Often: "tides" of blood to the skin with a feeling of heat, redness of the skin *.

Infrequently: excessive decrease in blood pressure.

Rarely: vasculitis.

* - incidence of redness of skin in studies I-ADD, I- COMBINE and I-COMBO was assessed as "infrequently".

Disturbances from the respiratory system, chest and mediastinal organs

Often: cough.

Infrequently: dyspnea, rhinitis.

Rarely: coughing.

Disorders from the digestive system

Often: nausea, abdominal pain, glossodynia, glossitis.

Infrequently: dyspepsia, vomiting, a change in the rhythm of defecation, dryness of the mucous membranes of the oral cavity.

Rarely: pancreatitis, gastritis, gingival hyperplasia.

Disturbances from the liver and bile ducts

Rarely: hepatitis, jaundice and increased activity of "hepatic" enzymes (mainly associated with cholestasis).

Disturbances from the skin and subcutaneous tissues

Often: contact dermatitis.

Infrequently: skin rash, itching, purpura, increased sweating, changes in skin pigmentation (appearance of discolored skin areas), alopecia.

Rarely: angioedema, erythema multiforme, urticaria.

Disturbances from musculoskeletal and connective tissue

Infrequently: arthralgia, muscle cramps, myalgia, back pain.

Disorders from the kidneys and urinary tract

Infrequently: increased frequency of urination, painful urge to urinate, nocturia.

Violations of the genitals and mammary gland

Infrequently: impotence, gynecomastia.

General disorders and disorders at the site of administration

Often: increased fatigue, edema *, peripheral edema.

Infrequently: pain in the chest, asthenia, a feeling of malaise, pain.

Rarely: swelling of the face.

* - according to research data I-ADD, I-COMBINE and I-COMBO incidence of edema: "infrequently".

Laboratory and instrumental data

Infrequently: weight gain, weight loss.

Overdose:

Symptoms

When adults take irbesartan in doses up to 900 mg per day, there is no toxicity.

Available data for amlodipine suggest that a severe overdose can lead to severe peripheral vasodilation and, possibly, the development of reflex tachycardia. It was reported about the development of pronounced and prolonged excessive decrease in blood pressure, up to the development of shock with a fatal outcome.

Treatment

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

There is no specific information on the treatment of an overdose of irbesartan. The proposed measures for the overdose of the drug AproVasc® include gastric lavage. The intake of activated charcoal by healthy volunteers immediately after or 2 hours after ingestion of 10 mg of amlodipine showed a slight decrease in the absorption of amlodipine.

Due to amlodipine has a high connection with blood proteins, and irbesartan is not excreted from the body by hemodialysis, it is unlikely that hemodialysis may be helpful in overdose.

If there is a very large overdose, you should begin an active monitoring of cardiac activity and breathing. A frequent measurement of blood pressure is necessary. A clinically significant reduction in blood pressure due to an overdose of amlodipine requires active maintenance of cardiovascular activity, including the elevation of the limbs. It is necessary to monitor the volume of circulating blood and the release of urine. It may be necessary to administer vasoconstrictive drugs to restore vascular tone and blood pressure (provided there are no contraindications to their administration). Intravenous administration of calcium gluconate can be useful in eliminating the effects of calcium channel blockade.

Interaction:

Combination of irbesartan and amlodipine

Based on pharmacokinetic studies in which irbesartan and amlodipine were taken separately and in combination, there were no pharmacokinetic interactions between irbesartan and amlodipine.

There have been no studies on drug interactions between Aprovask® and other drugs.

Irbesartan

Based on the research data in vitro no interactions with drugs whose metabolism is mediated by the following cytochrome isoenzymes should be expected P450: CYP1A1, CYP1A2, CYP2A6, CYP2B6, CYP2D6, CYP2E1 or CYP3A4.

Irbesartan is mainly metabolized by isoenzyme CYP2C9, However, during clinical studies on the interaction, when irbesartan was taken concomitantly with warfarin, which is metabolized by isoenzyme CYP2C9, no significant pharmacokinetic interactions were observed.

The pharmacokinetic parameters of irbesartan are not affected by its simultaneous use with nifedipine and hydrochlorothiazide.

Irbesartan does not change the pharmacokinetics of simvastatin, which is metabolized by isoenzyme CYP3A4, or digoxin (substrate Pglycoprotein).

Combination of AproVasc® with preparations containing aliskiren, is contraindicated in patients with diabetes mellitus or moderately severe and severe renal failure (GFR less than 60 mL / min / 1.73 m² body surface area) and is not recommended in other patients.

ACE inhibitors: The use of AproVasc® in combination with ACE inhibitors contraindicated in patients with diabetic nephropathy and not recommended to other patients.

Based on the experience gained with the use of other drugs that affect RAAS, the simultaneous use of irbesartan with potassium preparations; substitutes for salt containing potassium; potassium-sparing diuretics or others capable of increasing the potassium content of blood plasma with drugs (heparin), can sometimes significantly increase the serum potassium content, which requires careful monitoring of blood plasma potassium in patients during treatment.

In elderly patients, patients with hypovolemia (due to taking diuretics) or with impaired renal function, the simultaneous use of non-steroidal anti-inflammatory drugs (NSAIDs), including selective inhibitors of cyclooxygenase-2 (COX-2)II, including irbesartan, can lead to impaired renal function, including the development of acute renal failure. These effects are usually reversible.Periodically monitor renal function in patients who simultaneously take ARAII and NSAIDs, including selective inhibitors of COX-2.

Lithium: against the background of the joint use of irbesartan with lithium preparations, an increase in the concentration of lithium in the blood plasma and the toxic effect of lithium have been described. In patients receiving irbesartan together with lithium preparations, should monitor the concentration of lithium in blood plasma.

Amlodipine

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

Data in vitro studies with human plasma showed that amlodipine does not affect the binding to the protein of digoxin, phenytoin, warfarin or indomethacin.

Cimetidine: simultaneous administration of amlodipine and cimetidine did not interfere with the pharmacokinetics of amlodipine.

Grapefruit juice: simultaneous administration of 240 mg of grapefruit juice with a single dose of amlodipine 10 mg in 20 healthy volunteers did not have a significant effect on the pharmacokinetics of amlodipine.

Sildenafil: with the simultaneous use of amlodipine and sildenafil, each of the drugs independently showed an antihypertensive effect.

Atorvastatin: simultaneous course of amlodipine in a dose of 10 mg and Atorvastatin at a dose of 80 mg led to unreliable changes in the pharmacokinetic parameters of atorvastatin in the state of achievement C_ss.

Digoxin: simultaneous reception of amlodipine with digoxin did not change serum concentration of digoxin or renal clearance of digoxin in healthy volunteers.

Warfarin: simultaneous reception of amlodipine and did not change prothrombin time when taking warfarin.

Cyclosporine: pharmacokinetic studies with cyclosporine have demonstrated that amlodipine does not have a significant effect on the pharmacokinetics of cyclosporine.

Tacrolimus: With simultaneous application of tacrolimus and amlodipine, tacrolimus concentration in the blood plasma can be increased. It is necessary to monitor the concentration of tacrolimus in the blood plasma and, if necessary, to correct its dose.

Simvastatin: simultaneous use of amlodipine with simvastatin may increase the exposure of simvastatin, compared with simvastatin monotherapy. When simvastatin and amlodipine are used concomitantly, the daily dose of simvastatin should be limited to 20 mg.

Special instructions:

Excessive reduction in blood pressure: patients with hypovolemia and hyponatraemia

Irbesartan rarely caused an excessive decrease in blood pressure in patients with hypertension without other concomitant pathologies. As with the administration of ACE inhibitors, excessive BP reduction with the corresponding symptomatology in patients with hypovolemia and hyponatraemia, which include patients undergoing intensive diuretic therapy and / or patients with restricted intake of sodium chloride or patients on hemodialysis, may be expected. Hyponatremia and hypovolemia should be corrected before starting treatment with Aprovask® or should consider the use of lower initial doses.

Patients with chronic heart failure

In a long-term placebo-controlled study (PRAISE-2) Amlodipine in patients with chronic heart failure III-IV functional class (according to the classification NYHA) non-ischemic etiology amlodipine was associated with an increase in pulmonary edema reports, despite the absence of a significant difference in the incidence of progression of heart failure compared with placebo.

Liver failure

As with the reception of other blockers of "slow" calcium channels, Tu₂ Amlodipine is increased in patients with impaired hepatic function, and recommendations on the regimen of its dosing in cases of impaired liver function are not established. Therefore, the drug Aprovask^® should be used with caution in such patients.

Hypertensive crisis

The safety and efficacy of the drug AproVasc® with hypertensive crisis are not established.

Effect on kidney function

Due to inhibition of RAAS, changes in the function of the kidneys in predisposing patients can be expected. In patients with renal function dependent on RAAS activity (patients with arterial hypertension with renal artery stenosis of one or both kidneys or patients with chronic heart failure III-IV functional class [by classification NYHA]), treatment with other drugs that affect RAAS,was associated with the development of oliguria and / or progressive azotemia and rarely with acute renal failure and / or death. It is impossible to exclude the possibility of such an effect when using APAII, including irbesartan.

Use in elderly patients

Patients who took irbesartan in clinical studies, there was no difference in the efficacy or safety of irbesartan in elderly patients (65 years and older) compared with younger patients.

Use in children

Safety and effectiveness in children have not been established to date.

Double blockade of RAAS with a combination of drug Aprovask® with medicinal products containing aliskiren, and with angiotensin-converting enzyme inhibitors.

Double blockade of RAAS when using a combination of AproVasc® with ACE inhibitors or aliskiren is not recommended, as there is an increased risk of a sharp decrease in blood pressure, hyperkalemia, and renal dysfunction.

In patients with diabetes mellitus or moderately severe and severe renal failure (with GFR <60 mL / min / 1.73 m² surface of the body) application of the drug Aprovask^® in combination with aliskirenom is contraindicated.

Patients with diabetic nephropathy are contraindicated in the use of the drug Aprovask® in combination with ACE inhibitors.

Effect on the ability to drive transp. cf. and fur:The influence of AproVasc® on the ability to drive vehicles or engage in other potentially hazardous activities requiring increased attention has not been studied. However, based on its pharmacodynamic properties, the effect of AproVasc® on this ability is unlikely. But, in case of dizziness, vertigo, weakness, drive vehicles or engage in other potentially hazardous activities is not recommended.

Form release / dosage:Tablets, film-coated 5 mg + 150 mg, 10 mg + 150 mg, 5 mg + 300 mg and 10 mg + 300 mg.

Packaging:

7 tablets per blister PVC / PE / PVDC / Aluminum.

For 2 or 4 blisters together with instructions for use in a cardboard box.

Storage conditions:

Store at a temperature not exceeding 30 ° C.

Keep out of the reach of children.

Shelf life:

3 years.

Do not use the product after the expiration date printed on the package.

Terms of leave from pharmacies:On prescription

Registration number:LP-002695

Date of registration:06.11.2014

Expiration Date:06.11.2019

The owner of the registration certificate: Sanofi-Aventis de Mexico SA de S.V. Sanofi-Aventis de Mexico SA de S.V. Mexico

Manufacturer: & nbsp

SANOFI-AVENTIS DE MEXICO, SA de CV Mexico

Representation: & nbspSanofi Russia, JSCSanofi Russia, JSCRussia

Information update date: & nbsp26.09.2017

Illustrated instructions

Instructions

Aprovask® (Aprovask®)