Aprovel - instructions for use, dose, side effects, contraindications

Excipients: lactose monohydrate 51.0 mg, microcrystalline cellulose 27.0 mg, croscarmellose sodium 12.0 mg, hypromellose 5.0 mg, magnesium stearate 2.5 mg, silicon dioxide 2.5 mg;

film sheath: Deficient white * 10.0 mg, carnauba wax less than 0.05 mg.

Film-coated tablets, 300 mg

One tablet contains:

active substance: irbesartan 300 mg;

Excipients: lactose monohydrate 102.0 mg, cellulose microcrystalline 54.0 mg, croscarmellose sodium 24.0 mg, hypromellose 10.0 mg, magnesium stearate 5.0 mg, silicon dioxide 5.0 mg;

film sheath: Opadrai® white * 20.0 mg, carnauba wax is less than 0.1 mg.

* - Opadrai® white contains lactose monohydrate - 36.00%, hypromellose 28.00%, macrogol-3000 10.00%, titanium dioxide (E 171) 26.00%.

Description:

Tablets, film-coated, 150 mg

Biconvex oval tablets coated with a white or almost white film shell with a heart engraved on one side and number 2872 on the other.

Film-coated tablets, 300 mg

Two-convex oval tablets coated with a white or almost white film shell, with a heart engraving on one side and number 2873 on the other.

Pharmacotherapeutic group:angiotensin II receptor antagonist

ATX: & nbsp

C.09.C.A.04 Irbesartan

Pharmacodynamics:

Irbesartan is a selective angiotensin II receptor antagonist (type AT₁). Irbesartan does not require metabolic activation to acquire pharmacological activity. Angiotensin II is an important component of the renin-angiotensin-aldosterone system (RAAS) and is involved in the pathogenesis of arterial hypertension, as well as sodium homeostasis.

Irbesartan blocks all physiologically significant effects of angiotensin II, regardless of the source or route of its synthesis, including its pronounced vasoconstrictive and aldosterone-secreting effects,realized through receptors of the type AT₁, located on the surface of the smooth muscle cells of the vessels and in the adrenal cortex. He does not have agonistic activity to AT₁-receptors and has a much greater (more than 8500 times) affinity for AT₁receptors than with AT₂- receptors (receptors, not related to the regulation of the cardiovascular system).

Irbesartan does not inhibit RAAS enzymes (such as renin, angiotensin-converting enzyme [ACE]) and does not affect the receptors of other hormones or ion channels involved in the regulation of blood pressure (BP) and sodium homeostasis. Blocking by irbesartan AT₁receptors interrupts the feedback loop in the renin-angiotensin system, which leads to an increase in plasma concentrations of renin and angiotensin II. After taking irbesartan in recommended doses, the plasma concentration of aldosterone decreases without significantly affecting the potassium content in the blood serum (the mean value of its increase is <0.1 mEq / L). Irbesartan has no significant effect on serum concentrations of triglycerides, cholesterol and glucose. Irbesartan does not affect the concentration of uric acid in the blood serum or the rate of excretion of uric acid by the kidneys.

The antihypertensive effect of irbesartan manifests itself after taking its first dose and becomes significant within 1-2 weeks of admission, its maximum antihypertensive effect is reached by 4-6 weeks of treatment. In long-term clinical studies, the antihypertensive effect of irbesartan has been maintained for more than one year.

Antihypertensive effect with once-a-day ingestion of irbesartan in doses up to 900 mg is dose-dependent. Irbesartan at a single dose during the day at doses of 150-300 mg reduces blood pressure, measured in the "lying" or "sitting" position at the end of the inter-dose interval (24 hours after taking the dose of irbesartan, i.e., before taking the next dose of irbesartan) an average of 8-13 / 5-8 mm Hg. Art. (systolic / diastolic blood pressure) compared with placebo. The antihypertensive effect of irbesartan before taking the next dose is 60-70% of the maximum values of the decrease in diastolic and systolic blood pressure. The optimal decrease in blood pressure during 24 hours is achieved with the intake of irbesartan once a day.

Irbesartan approximately in the same degree reduces BP in the "standing" and "lying".Orthostatic effects are rare, however, as with the administration of ACE inhibitors, in patients with hyponatraemia and / or hypovolemia, excessive BP reduction with clinical manifestations is possible.

The antihypertensive effect of irbesartan and thiazide diuretics is additive. In patients with insufficient blood pressure reduction with monotherapy with irbesartan, the addition of low doses of hydrochlorothiazide (12.5 mg) once a day leads to an additional BP reduction of 7-10 / 3-6 mm Hg. Art. (systolic / diastolic) compared with the addition of a placebo.

The effectiveness of irbesartan does not depend on age or sex. As with the use of other drugs that affect RASS, the antihypertensive effect of irbesartan in patients of the Negroid race is much less pronounced, however, when irbesartan is used simultaneously with low doses of hydrochlorothiazide (for example, 12.5 mg per day), the antihypertensive response in patients of the Negroid race is approaching in efficiency to that in patients of the Caucasoid race.

After discontinuing irbesartan, blood pressure returns to the initial level gradually. The syndrome "cancellation" is not observed.

In a multicenter, randomized, controlled active substance (amlodipine) and placebo, a double-blind clinical trial IDNT, in 1715 patients with arterial hypertension and type 2 diabetes mellitus (proteinuria ≥900 mg / day and serum creatinine concentration in the range 1.0-3.0 mg / dl), 20% (p = 0.024) decrease ( compared with placebo) and 23% (p = 0.006) of the relative risk of the first occurrence of any of the following conditions (as compared to amlodipine): a doubling of serum creatinine concentration, development of the terminal stage of renal failure, or death from any of the causes (when a comparable reduction is achieved BP at application rbesartana and amlodipine).

In a multicenter, randomized, placebo-controlled, double-blind clinical study on the effects of irbesartan on microalbuminuria in patients with arterial hypertension and type 2 diabetes mellitus (IRMA 2) performed in 590 patients with arterial hypertension and type 2 diabetes mellitus having microalbuminuria (20-200 μg / min, 30-300 mg / day) and normal kidney function (serum creatinine concentration <1.5 mg / dl in men and <1.1 mg / dl in women),the effect of long-term treatment (over 2 years) on Aprovel on the progression of clinically significant proteinuria was evaluated. When taking the drug at a dose of 300 mg per day, a 70% reduction in the relative risk of developing clinically significant proteinuria (compared with placebo, p = 0.0004) was demonstrated, and at a dose of 150 mg, a 39% reduction in the relative risk of developing clinically significant proteinuria compared with placebo, p = 0.085). The delay in the progression of clinically significant proteinuria was noted after only three months and continued throughout the 2-year period of the clinical study. The decrease in the 24-hour creatinine clearance between the treatment groups did not differ significantly. The regression of microalbuminuria to normal albuminuria (<20 mcg / min, <30 mg / day) was more common in the Aprovel® group at a dose of 300 mg (34%) compared with the placebo group (21%).

Pharmacokinetics:

Absorption

After oral administration irbesartan quickly and completely absorbed, its absolute bioavailability is approximately 60-80%. Simultaneous food intake does not significantly affect the bioavailability of irbesartan.After oral administration, the maximum plasma concentration (C_mOh) irbesartan is achieved after 1.5-2 h.

Distribution

The connection with plasma proteins is approximately 96%. Binding to the cellular components of blood is negligible. The volume of distribution is 53-93 liters.

Metabolism

After ingestion or intravenous administration ¹⁴C-irbesartan 80-85% of the radioactivity circulating in the blood plasma is due to the unchanged irbesartan. Irbesartan metabolized by the liver by oxidation and conjugation with glucuronic acid. The main metabolite in the systemic circulation is irbesartan glucuronide (approximately 6%). Oxidation of irbesartan is carried out, mainly, with the help of cytochrome P450 isoenzyme CYP2C9, the participation of isoenzyme CYP3A4 in the metabolism of irbesartan is insignificant. Irbesartan It is not metabolized by most isoenzymes, which are usually involved in the metabolism of drugs (isoenzymes CYP1A1, CYP1A2, CYP2A6, CYP2B6 CYP2D6 or CYP2E1), and does not cause their inhibition or induction. Irbesartan Does not induce or inhibit isoenzyme CYP3A4.

Excretion

Irbesartan and its metabolites are excreted from the body, both through the intestines (with bile) and the kidneys. After ingestion or intravenous administration ¹⁴C-irbesartan, about 20% of the radioactivity is found in the urine, and the rest is in the feces. Less than 2% of the administered dose is excreted by the kidneys in the form of unchanged irbesartan.

The final half-life of irbesartan (T_1/2) is 11-15 hours. The total clearance of intravenously administered irbesartan is 157-176 ml / min, and its renal clearance is 3-3.5 ml / min. With a daily once-daily irbesartan intake, the equilibrium plasma concentration (Css) is achieved after 3 days, while its limited accumulation in blood plasma (less than + 20%) is observed.

Special patient groups

Influence of sex on the pharmacokinetics of irbesartan

In women (compared with men), slightly higher plasma concentrations of irbesartan were observed. However, sex-related differences in the half-life and accumulation of irbesartan were not detected. Correction of irbesartan dose in women is not required. There were no gender-related differences in the effects of irbesartan.

The pharmacokinetics of irbesartan in elderly patients

Values AUC (area under the pharmacokinetic curve "concentration-time") and C_mOhirbesartan in elderly patients (65-80 years old) with clinically normal renal and hepatic function were approximately 20-50% higher than in younger patients (18-40 years old). The terminal half-lives were comparable. There were no age-related differences in the effects of irbesartan.

The pharmacokinetics of irbesartan in liver function disorder

In patients with mild (functional class A or 5-6 points on the Child-Pugh scale) and moderately expressed (functional class B or 7-9 on the Child-Pugh scale) hepatic insufficiency due to cirrhosis of the liver, the pharmacokinetic parameters of irbesartan do not change significantly.

The pharmacokinetics of irbesartan in renal dysfunction

In patients with impaired renal function or patients undergoing hemodialysis, the pharmacokinetics of irbesartan do not change significantly. Irbesartan is not excreted from the body by hemodialysis.

Influence of race on the pharmacokinetics of irbesartan

In volunteers without hypertension AUC and T_1/2irbesartan in representatives of the Negroid race were approximately 20-25% higher than in the representatives of the Caucasoid race; FROM_mOh irbesartan in them was almost identical with that of representatives of the Caucasoid race.

Indications:

- Arterial hypertension (in monotherapy and in combination with other antihypertensive drugs, for example, thiazide diuretics, beta-blockers, blockers of "slow" calcium channels (BCCC), long-acting);

- Mr.TGF with arterial hypertension and type 2 diabetes mellitus (as part of combined antihypertensive therapy).

Contraindications:

- Hypersensitivity to irbesartan or any of the auxiliary substances of Aprovel®;

- aboutsimultaneous use with medicinal products containing aliskiren, in patients with diabetes mellitus or with moderately severe and severe renal insufficiency (speed glomerular filtering [GFR] <60 ml / min / 1.73 m² body surface);

- aboutsimultaneous use with ACE inhibitors in patients with diabetic nephropathy;

- bVariability;

- PThe period of breastfeeding;

- atozrast to 18 years (efficiency and safety not established);

- Mr.hereditary intolerance to galactose, insufficiency of lactase or glucose-galactose malabsorption;

- PIn severe hepatic insufficiency (functional class C or more than 9 on the Child-Pugh scale) (lack of clinical experience).

Carefully:

- With stenosis of the aortic or mitral valve or hypertrophic obstructive cardiomyopathy (GOKMP);

- PIn hypovolemia, hyponatremia, arising, for example, with intensive diuretic therapy, hemodialysis, adherence to a diet with restricted intake of table salt, diarrhea, vomiting (the risk of excessive blood pressure lowering);

- the patients with kidney function that depends on the activity of RAAS, such as patients with hypertension with bilateral or unilateral stenosis of the renal arteries or patients with chronic heart failure III-IV functional class (according to classification NYHA) (see section "Special instructions");

- Pcoronary heart disease and / or clinically significant atherosclerosis of cerebral vessels (with excessive decrease in blood pressure there is a risk of increasing ischemic disorders, up to the development of acute myocardial infarction and stroke);

- Prenal failure (potassium and creatinine concentrations in the blood are required), recent kidney transplantation (lack of clinical experience);

- Pand the simultaneous use of non-steroidal anti-inflammatory drugs (NSAIDs), including selective inhibitors of cyclooxygenase 2 (COX-2) (increased risk of renal dysfunction, including the possibility of acute renal failure and an increase in serum potassium, especially in elderly patients, hypovolemia [including patients taking diuretics] or in patients with impaired renal function (see section "Interaction with other drugs");

- Pwhen used in combination with ACE inhibitors or aliskiren, as compared to monotherapy with double blockade of RAAS, there is an increased risk of developing excessive blood pressure lowering, hyperkalemia and renal dysfunction (see section "Special instructions").

Pregnancy and lactation:

Pregnancy

Experience with the use of the drug Aprovel® during pregnancy is absent. Taking into account the fact that during the reception of ACE inhibitors by pregnant women in the second and third trimesters of pregnancy, the developing fetus was damaged and died, irbesartan, like any other drug that acts directly on RAAS, can not be used during pregnancy (I, II, III trimesters).

When diagnosing pregnancy during treatment with Aprovel® should be stopped as soon as possible.

Breastfeeding period

It is not known whether the blood is excreted irbesartan or its metabolites into breast milk. During breastfeeding, taking Aprovel® is contraindicated. Therefore, after assessing the relationship between the perceived benefit of taking the drug for the mother and the potential risk to the baby, stop breastfeeding or taking Aprovel®.

Dosing and Administration:

The drug should be taken orally, regardless of the time of ingestion. The tablet is swallowed whole, washed down with water.

Typically, the initial dose of Aprovel® is 150 mg once daily. Patients who, in order to achieve target BP values, require an additional reduction, the dose can be increased to 300 mg once daily.

In the case of an insufficient reduction in BP with monotherapy with Aprovel® to treatment can be added diuretics (for example, hydrochlorothiazide 12.5 mg per day) or other antihypertensive agents (eg, beta-blockers or long-acting BCCC).

In patients with nephropathy in hypertension and type 2 diabetes mellitus, the preferred maintenance dose is 300 mg once daily.

Use in selected patient groups

Children and teens

At the moment, the safety and effectiveness of the drug in patients of childhood and adolescence is not established.

Elderly patients

Usually, elderly patients do not need a dose reduction. In patients who received Aprovel® in clinical studies, overall, there was no difference in efficacy and safety between patients 65 years of age and older and younger patients.

Patients with hepatic insufficiency

Usually, in patients with impaired liver function (mild and moderate severity), dose reduction is not required. The experience of using the drug in patients with severe hepatic insufficiency is absent.

Patients with renal insufficiency

Usually, patients with renal insufficiency (regardless of its severity) do not need to reduce the dose.

Patients with hypovolaemia

In patients with severe hypovolemia and / or hyponatremia, such as patients receiving intensive diuretic therapy, or who are on hemodialysis, hypovolemia and hyponatremia should be corrected before using Aprovel®.

Side effects:

The following undesirable phenomena are presented in accordance with the following grades of their incidence (according to the classification of the World Health Organization (WHO)): very often (≥ 1/10); often (≥ 1/100, <1/10); infrequently (≥ 1/1000, <1/100); rarely (≥ 1/10000, <1/1000); very rarely (<1/10000, including individual messages); unknown frequency (according to available data, it is not possible to determine the frequency of occurrence of an undesirable phenomenon).

The safety of Aprovel® was studied in clinical trials in approximately 5,000 patients, including 1,300 patients with hypertension taking the drug for more than 6 months, and 400 patients taking the drug for one year or more. The adverse events in patients taking Aprovel® were usually mild and transitory, and their frequency was not related to the amount of the dose taken.The incidence of adverse events was independent of sex, age, and race.

In placebo-controlled studies in which 1,655 patients took irbesartan (on average, for 1-3 months), discontinuation of treatment due to the development of any clinical or laboratory adverse events was required in 3.3% of patients taking Aprovel® and 4.5% of patients taking placebo ( the differences were statistically significant).

The adverse events observed in placebo-controlled clinical trials with the use of Aprovel® with hypertension are probably or probably related to its administration, or without the established relationship with the drug administration

The incidence of the following adverse events with irbesartan was statistically not significantly different from that observed with placebo.

Disturbances from the nervous system

Often: dizziness, headache.

Infrequently: orthostatic dizziness.

Heart Disease

Infrequently: edema, tachycardia.

Disturbances from the respiratory system, chest and mediastinal organs

Infrequently: cough.

Disorders from the gastrointestinal tract

Often: nausea, vomiting.

Infrequently: diarrhea, indigestion / heartburn.

Violations of the genitals and mammary gland

Infrequently: sexual dysfunction.

Common violations

Often: increased fatigue.

Infrequently: pain in the chest.

Laboratory and instrumental data

During the controlled clinical trials, patients with hypertension did not show clinically significant changes in laboratory parameters. There is no special monitoring of laboratory parameters for patients with hypertension taking Aprovel®.

Adverse events observed in controlled clinical trials with the use of Aprovel® in patients with nephropathy in hypertension and type 2 diabetes (IDNT and IRMA 2 clinical trials)

Adverse events were similar to those in patients with hypertension, with the exception of orthostatic symptoms (dizziness (10.2%) (with placebo 6%), orthostatic dizziness (5.4%) (with placebo 2.7%) and orthostatic hypotension (5.4%) (when taking placebo 3.2%).

The percentage of discontinuation due to orthostatic symptoms when taking Aprovel® compared with placebo was 0.3% vs. 0.5%, orthostatic dizziness 0.2% vs 0.0%, and orthostatic hypotension 0.0% against 0.0%, respectively.

Violations from laboratory indicators

Hyperkalemia

In a clinical study IDNT the percentage of patients with hyperkalemia (> 6 mEq / L) was 18.6% in the Aprovel® group compared to 6.0% in the placebo group. In a clinical study IRMA 2 percent of patients with hyperkalemia (> 6 mEq / L) were 1.0% in the Aprovel® group, and no placebo hyperkalaemia was observed.

In a clinical study IDNT the frequency of cessation of treatment due to the development of hyperkalemia with the use of Aprovel® and placebo was 2.1% and 0.36%, respectively. In a clinical study IRMA the frequency of cessation of treatment due to the development of hyperkalemia when taking Aprovel® and placebo was 0.5% and 0%, respectively.

Undesirable effects observed during post-marketing use of Aprovel®

Immune system disorders

Rarely: as with all angiotensin II receptor antagonists, very rare cases of allergic reactions such as urticaria, angioedema have been reported. The following undesirable phenomena have been identified with the use of irbesartan from the time of the introduction of the drug Aprovel®.

Disorders from the metabolism and nutrition

Unknown frequency: hyperkalemia.

Disturbances from the nervous system

Unknown frequency: Vertigo.

Disturbances from the liver and bile ducts

Unknown frequency: increased activity of "hepatic" enzymes and bilirubin concentration in the blood, hepatitis, jaundice.

Hearing disorders

Unknown frequency: tinnitus.

Disturbances from musculoskeletal and connective tissue

Unknown frequency: myalgia.

Disorders from the kidneys and urinary tract

Unknown frequency: impaired renal function, including cases of development of renal failure in patients at risk (see section "Special instructions").

Common violations

Unknown frequency: asthenia.

Overdose:

The experience of using the drug in adult patients at doses up to 900 mg / day for 8 weeks showed no toxicity.

There is no specific information regarding the treatment of an overdose of Aprovel®. Constant monitoring of the patient's condition should be established and, if necessary, symptomatic and supportive therapy. In case of overdose, it is recommended to induce vomiting and / or gastric lavage. Irbesartan is not excreted from the body by hemodialysis.

Interaction:

Based on the data of the study in vitro no interaction of irbesartan with drugs metabolized by isoenzymes is expected CYP1A1, CYP1A2, CYP2A6, CYP2B6, CYP2E1 or CYP3A4. Irbesartan, is mainly metabolized by isoenzyme CYP2C9 and, to a lesser extent, undergoes glucuronation. No significant pharmacokinetic and pharmacodynamic interactions were observed with the simultaneous use of irbesartan with warfarin, a drug metabolized by the CYP2C9 isoenzyme.

Irbesartan does not change the pharmacokinetics of digoxin and simvastatin. With the combined use of irbesartan with hydrochlorothiazide or nifedipine, the pharmacokinetics of irbesartan do not change.

With medications containing Aliskiren

Combination of Aprovel® with medications containing aliskiren, is contraindicated in patients with diabetes mellitus or with moderate and severe renal failure (GFR <60 mL / min / 1.73 m² body surface) and is not recommended in other patients (see the sections "Contraindications", "With caution", "Special instructions").

With ACE inhibitors

The use of Aprovel® in combination with ACE inhibitors is contraindicated in patients with diabetic nephropathy and is not recommended in other patients (see the sections "Contraindications", "With caution", "Special instructions").

FROM potassium preparations and potassium-sparing diuretics, heparin

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

With NSAIDs, including selective inhibitors of cyclooxygenase -2 (COX-2)

With the simultaneous use of angiotensin II receptor antagonists and NSAIDs (including selective inhibitors of COX-2), the attenuation of the antihypertensive effect of irbesartan is possible.

In elderly patients, patients with hypovolemia or patients with impaired renal function, the use of NSAIDs, including COX-2 inhibitors, concomitantly with angiotensin II receptor antagonists, including irbesartan, can lead to impaired renal function, including the possible development of acute renal failure. These effects are usually reversible. Periodically monitor kidney function in patients who simultaneously take irbesartan and NSAIDs, including COX-2 inhibitors.

With lithium preparations

An increase in serum lithium concentrations and an increase in its toxicity was reported with the simultaneous use of lithium salts and irbesartan.

With diuretics and other antihypertensive agents

With the simultaneous use of irbesartan and other antihypertensive agents, an increase in antihypertensive action is possible. Irbesartan without any problems used simultaneously with other antihypertensive drugs, such as beta-blockers, long-acting BCCC and thiazide diuretics. Prior treatment with diuretics in high doses can lead to hypovolemia and an increased risk of excessive BP reduction at the beginning of treatment with Aprovel®.

Special instructions:

Excessive BP reduction - patients with hypovolaemia

The use of Aprovel® until now has rarely been accompanied by excessive reduction in blood pressure in patients with hypertension without concomitant diseases. As with the use of ACE inhibitors, excessive blood pressure lowering accompanied by clinical symptoms can develop in patients with hyponatremia / hypovolemia (for example, as a result of intensive diuretic therapy, diarrhea or vomiting, adherence to a diet limiting intake of table salt), as well as in patients, who are on hemodialysis. Before using Aprovel®, it is necessary to correct hypovolemia and / or hyponatraemia.

Patients with renal function, depending on the activity of RAAS

As a consequence of inhibition of RAAS, it is possible to expect a worsening of kidney function in patients predisposed to it. In patients with renal function, depending on the activity of RAAS (patients with arterial hypertension and renal artery stenosis of one or both kidneys, patients with chronic cardiac insufficiency III and IV of the functional class [by classification NYHA]), treatment with drugs that affect RAAS was associated with oliguria and / or progressive azotemia and, rarely, with acute renal failure and / or death. It can not be ruled out that such an effect may arise with the use of angiotensin II receptor antagonists, including irbesartan.

Renal failure and kidney transplantation

When using Aprovel® in patients with renal insufficiency, periodic monitoring of the potassium content and serum creatinine concentration is recommended. There are no clinical data on the use of Aprovel® in patients who have recently undergone a kidney transplant.

Patients with arterial hypertension and type 2 diabetes mellitus with impaired renal function

The favorable effect of Aprovel® on slowing the progression of renal and cardiovascular disorders had varying degrees of severity in different groups of patients, less pronounced in women and in patients not belonging to the Europoid race.

In a clinical study IDNT in patients with arterial hypertension and type 2 diabetes mellitus with proteinuria (≥900 mg / day), in a subgroup of patients with a high risk of renal artery stenosis, no patient who received Aprovel® received an acute early increase in serum creatinine , associated with stenosis of the renal arteries.

Double blockade of RAAS in the combination of Aprovel® with ACE inhibitors or with aliskiren

Double blockade of RAAS with the use of a combination of Aprovel® with ACE inhibitors or aliskiren is not recommended, as compared to monotherapy, there is an increased risk of a sharp decrease in blood pressure, the development of hyperkalemia and renal dysfunction.

The use of Aprovel® in combination with aliskiren is contraindicated in patients with diabetes mellitus or renal insufficiency with GFR <60 mL / min / 1.73 m² body surface) (see the sections "Contraindications", "Interaction with other drugs") and is not recommended in other patients.

The use of Aprovel® in combination with ACE inhibitors is contraindicated in patients with diabetic nephropathy (see "Contraindications", "Interaction with other drugs") and is not recommended in other patients.

Hyperkalemia

As with the use of other drugs that affect RAAS, treatment with Aprovel® can develop hyperkalemia, especially in the presence of kidney failure and / or heart disease. In such patients it is recommended to monitor the potassium content in the blood serum.

Stenosis of the aortic or mitral valve, hypertrophic obstructive cardiomyopathy

As with the use of other vasodilators, care should be taken when taking Aprovel® with patients with aortic or mitral stenosis or with hypertrophic obstructive cardiomyopathy.

Primary hyperaldosteronism

Patients with primary hyperaldosteronism usually do not respond to antihypertensive drugs acting through inhibition of RAAS.Therefore, the use of Aprovel® in such cases is impractical.

Patients with ischemic heart disease and / or clinically significant atherosclerosis of cerebral vessels

As with the use of other antihypertensive drugs, a significant reduction in blood pressure in patients with coronary heart disease and / or severe atherosclerosis of the cerebral vessels can lead to the development of myocardial infarction or stroke. Treatment of such patients should be carried out under the strict control of blood pressure.

Effect on the ability to drive transp. cf. and fur:

The influence of Aprovel® on the ability to drive vehicles or engage in other potentially hazardous activities requiring increased attention and high speed of psychomotor reactions has not been studied. However, based on its pharmacodynamic properties, Aprovel® should not affect the ability to drive vehicles and engage in other potentially hazardous activities (altitude work, air traffic controller work, work with mechanisms, etc.). But, in the case of dizziness and weakness, it is possible to reduce attention and slow the psychomotor reactions.In patients who have such undesirable reactions, the decision on the possibility of engaging in any potentially dangerous activities should be taken by the physician individually.

Form release / dosage:

Film-coated tablets, 150 mg and 300 mg.

Packaging:

For 14 tablets in a blister of PVC / PVDC / aluminum foil.

For 1, 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-001260

Date of registration:22.11.2011 / 23.11.2016

Expiration Date:Unlimited

The owner of the registration certificate:Sanofi-aventis groupSanofi-aventis group France

Manufacturer: & nbsp

SANOFI WINTHROP INDUSTRIE France

Representation: & nbspSanofi Aventis GroupSanofi Aventis Group

Information update date: & nbsp03.11.2015

Illustrated instructions

Instructions

Aprovel® (Aprovel®)