Ramizes Com tablets 10 mg + 12.5 mg blister No. 30

Instructions for Ramizes Com tablets 10 mg + 12.5 mg blister No. 30

Composition

active ingredients: ramipril, hydrochlorothiazide;

1 tablet contains ramipril calculated as 100% dry matter 5 mg and hydrochlorothiazide calculated as 100% dry matter 12.5 mg or ramipril calculated as 100% dry matter 10 mg and hydrochlorothiazide calculated as 100% dry matter 12.5 mg, or ramipril calculated as 100% dry matter 10 mg and hydrochlorothiazide calculated as 100% dry matter 25 mg;

excipients:

5 mg/12.5 mg and 10 mg/25 mg: lactose monohydrate; silicified microcrystalline cellulose; red iron oxide (E 172); crospovidone; hypromellose; magnesium stearate;

10 mg/12.5 mg: lactose monohydrate; silicified microcrystalline cellulose; red iron oxide (E 172); yellow iron oxide (E 172); crospovidone; hypromellose; magnesium stearate.

Dosage form

pills.

Main physicochemical properties:

5 mg/12.5 mg: round tablets, with a flat surface with a bevel and a score on one side, light pink in color. Imperfections on the surface are allowed.

10 mg/12.5 mg: round, biconvex tablets with a score on one side, light orange with a faint pink tint. Irregularities on the surface are allowed.

10 mg/25 mg: round tablets with a flat surface, beveled and scored on one side, light pink in color. Imperfections are allowed on the surface.

Pharmacotherapeutic group

Combined preparations of angiotensin-converting enzyme (ACE) inhibitors. ATC code C09B A05.

Pharmacological properties

Mechanism of action

Ramipril. Ramiprilat, the active metabolite of the prodrug ramipril, is an inhibitor of the enzyme dipeptidylcarboxypeptidase I (also known as ACE or kinase II). In plasma and tissues, this enzyme catalyzes the conversion of angiotensin I to angiotensin II, an active vasoconstrictor, and the cleavage of bradykinin, an active vasodilator. The reduction in the formation of angiotensin II and the inhibition of the cleavage of bradykinin result in vasodilation.

Since angiotensin II also stimulates the release of aldosterone, ramiprilat causes a decrease in aldosterone secretion. In black (Afro-Caribbean) hypertensive patients (a population usually characterized by low renin activity), the response to monotherapy with ACE inhibitors was on average less pronounced than in patients of other races.

Hydrochlorothiazide. Hydrochlorothiazide is a thiazide diuretic. As for thiazide diuretics, the mechanism of their antihypertensive action is not yet fully understood. They inhibit the reabsorption of sodium and chloride ions in the distal tubules. Increased renal excretion of these ions is accompanied by increased diuresis (due to osmotic binding of water). The excretion of potassium and magnesium is also increased, while the excretion of uric acid is reduced. Possible mechanisms of the hypotensive action of hydrochlorothiazide are changes in sodium balance, a decrease in the volume of extracellular fluid and blood plasma, changes in renal vascular resistance, or a decrease in the responses to noradrenaline and angiotensin II.

Pharmacodynamics.

Ramipril. The use of ramipril leads to a significant decrease in peripheral arterial resistance. Usually, there are no significant changes in renal plasma flow or glomerular filtration rate (GFR). In patients with arterial hypertension, the use of ramipril leads to a decrease in blood pressure in both the horizontal and vertical positions, which is not accompanied by a compensatory increase in heart rate.

In most patients, the antihypertensive effect occurs approximately 1-2 hours after a single oral dose of the drug. The maximum effect after a single oral dose usually occurs after 3-6 hours. The antihypertensive effect after a single dose is usually maintained for 24 hours.

With long-term treatment with ramipril, the maximum antihypertensive effect develops after 3-4 weeks. It has been proven that with long-term therapy, the antihypertensive effect persists for 2 years.

Abrupt discontinuation of ramipril does not cause a rapid and excessive increase in blood pressure (rebound phenomenon).

Hydrochlorothiazide. As for hydrochlorothiazide, the onset of the diuretic effect occurs after approximately 2 hours and lasts for 6-12 hours, with the maximum effect being achieved after 4 hours.

The antihypertensive effect occurs after 3-4 days of treatment and may last for 1 week after completion of treatment.

Concomitant use of ramipril and hydrochlorothiazide. In clinical studies, it was found that the use of this combination leads to a greater reduction in blood pressure than the use of each of the active substances separately. The simultaneous use of ramipril and hydrochlorothiazide reduces the loss of potassium that accompanies the diuretic effect, presumably due to inhibition of the activity of the renin-angiotensin-aldosterone system (RAAS). The combination of an ACE inhibitor with a thiazide diuretic has a synergistic effect and also reduces the risk of hypokalemia caused by the use of the diuretic itself.

Clinical efficacy and safety

Mild to moderate hypertension. The efficacy of ramipril and hydrochlorothiazide has been demonstrated in two studies in patients with mild to moderate essential hypertension. The aim of the first study (534 patients) was to find the optimal dose by comparing ramipril (2.5 mg to 10 mg) and hydrochlorothiazide (12.5 mg or 25 mg) used alone and in combination. The study drugs were administered for 6 weeks after a 2-4 week placebo run-in period. Efficacy was assessed by the reduction in supine and standing blood pressure from the end of the placebo run-in period to the endpoint (last measurement for each patient). The effective antihypertensive dose of ramipril was confirmed to be 10 mg. Combination therapy with ramipril and hydrochlorothiazide provided statistically significantly greater reductions in blood pressure compared with ramipril or hydrochlorothiazide alone (p < 0.05 for most comparisons); ramipril 10 mg was more effective when used in combination with hydrochlorothiazide 12.5 mg or 25 mg than as monotherapy. Overall, the greatest mean reductions in systolic blood pressure (SBP) and diastolic blood pressure (DBP) were achieved with ramipril 5 mg or 10 mg in combination with hydrochlorothiazide 12.5 mg or 25 mg.

The second study (192 patients) was a double-blind, randomised, parallel-group study with a 4-week placebo run-in period followed by 12 weeks of active treatment. During the first 6 weeks of the active treatment phase, patients received either ramipril 10 mg or hydrochlorothiazide 50 mg as monotherapy. Efficacy was assessed by measuring supine and standing systolic and diastolic blood pressure. Efficacy was assessed by achieving a supine and standing diastolic blood pressure of ≤ 90 mmHg at the end of the first monotherapy phase. During the second active treatment phase, patients who had not responded to treatment at the end of the 6-week monotherapy phase received a fixed combination of ramipril 10 mg and hydrochlorothiazide 50 mg. At the end of the first 6-week monotherapy phase, the mean reduction in supine SBP was 15.5 mm Hg in the 50 mg hydrochlorothiazide group and 11.1 mm Hg in the 10 mg ramipril group; the corresponding standing SBP values were 14.5 and 8.4 mm Hg. The mean reduction in supine DBP was 10.7 mm Hg in the 50 mg hydrochlorothiazide group and 9.0 mm Hg in the 10 mg ramipril group; the corresponding standing DBP values were 11.3 and 7.9 mm Hg. The response rate after 6 weeks of treatment was 52.1% in the 50 mg hydrochlorothiazide group and 37.7% in the 10 mg ramipril group (Fisher's exact test, p=0.061). Of the 49 patients who did not show a treatment effect at the end of the 6-week phase of monotherapy with 10 mg ramipril, 21 patients (42.9%) showed a treatment effect when 50 mg hydrochlorothiazide was added to this dose of ramipril. Similarly, of the 35 patients who did not respond to treatment at the end of the 6-week phase of monotherapy with 50 mg hydrochlorothiazide, 13 (37.1%) responded when 10 mg ramipril was added to this dose of hydrochlorothiazide.

HOPE study. In addition to its antihypertensive effect, ramipril at a dose of 10 mg exhibits a beneficial protective effect on the cardiovascular system and kidneys, which is independent of blood pressure reduction.

A placebo-controlled study of the preventive properties of the drug (the HOPE study) was conducted, in which ramipril was added to standard therapy in more than 9200 patients. This study included patients at increased risk of cardiovascular disease due to either atherothrombotic cardiovascular disease (history of coronary heart disease, stroke or peripheral vascular disease) or diabetes mellitus with at least one additional risk factor (documented microalbuminuria, hypertension, elevated total cholesterol, low high-density lipoprotein cholesterol or smoking).

Table 1

HOPE study: main results

Dual blockade of the RAAS. Two large randomized controlled trials [ONTARGET (a study of the effects of telmisartan as monotherapy and in combination with ramipril on the overall endpoint) and VA NEPHRON-D (a study of diabetic nephropathy in donors)] have examined the use of a combination of an ACE inhibitor with an angiotensin II receptor antagonist.

The ONTARGET study was conducted in patients with a history of cardiovascular or cerebrovascular disease or with type 2 diabetes mellitus with concomitant signs of target organ damage. The VA NEPHRON-D study included patients with type 2 diabetes mellitus and diabetic nephropathy.

These studies did not demonstrate a significant benefit of combination therapy with respect to renal and/or cardiovascular morbidity and mortality, while there was an increased risk of hyperkalemia, acute renal failure, and/or hypotension compared with monotherapy. Given the similar pharmacodynamic properties of these drugs, these results are also applicable to other ACE inhibitors and angiotensin II receptor antagonists.

In this regard, ACE inhibitors and angiotensin II receptor antagonists should not be used concomitantly in patients with diabetic nephropathy.

The ALTITUDE (Aliskiren in Type 2 Diabetes Cardiovascular and Renal Endpoints Trial) evaluated the benefits of adding aliskiren to standard therapy with an ACE inhibitor or an angiotensin II receptor antagonist in patients with type 2 diabetes and chronic kidney disease, cardiovascular disease, or both. The trial was terminated early due to an increased risk of adverse clinical outcomes. There was a quantitatively higher incidence of cardiovascular death and stroke in the aliskiren group compared with the placebo group, as well as an increased incidence of serious adverse reactions (hyperkalemia, hypotension, and renal dysfunction).

Non-melanoma skin cancer (NMSC). Epidemiological studies have shown an association between cumulative dose of hydrochlorothiazide and the development of NMSC. One study included 71,533 patients with basal cell carcinoma (BCC) and 8,629 patients with squamous cell carcinoma (SCC), matched by 1,430,833 and 172,462 controls, respectively. At high levels of hydrochlorothiazide use (cumulative dose ≥ 50,000 mg), the adjusted odds ratio (OR) was 1.29 (95% CI: 1.23-1.35) for BCC and 3.98 (95% CI: 3.68-4.31) for SCC. A clear cumulative dose-effect relationship was observed for both BCC and SCC. Another study demonstrated a possible association between lip cancer (LC) and hydrochlorothiazide use: 633 patients with lip cancer were identified in 63,067 controls (risk-adjusted sampling strategy was used). The cumulative dose-response effect was demonstrated with an adjusted HR of 2.1 (95% CI: 1.7-2.6). The HR increased to 3.9 (3.0-4.9) at the highest cumulative dose of hydrochlorothiazide (25,000 mg) and to 7.7 (5.7-10.5) at the highest cumulative dose (100,000 mg) (see also section 4.4).

Pharmacokinetics.

Ramipril

Absorption. After oral administration, ramipril is rapidly absorbed from the gastrointestinal tract. Peak plasma concentrations of ramipril are reached within 1 hour. Based on the amount of substance recovered in the urine, absorption is at least 56% and is not significantly affected by the presence of food in the gastrointestinal tract. The bioavailability of the active metabolite ramiprilat after oral administration of 2.5 mg and 5 mg is 45%.

The maximum plasma concentration of ramiprilat, the only active metabolite of ramipril, is reached 2-4 hours after administration of ramipril. After the use of usual doses of ramipril once a day, the equilibrium plasma concentration of ramiprilat is reached after approximately 4 days of treatment.

Metabolism: Ramipril is almost completely metabolized to ramiprilat and to diketopiperazine ester, diketopiperazine acid and glucuronides of ramipril and ramiprilat.

Elimination. Elimination of metabolites occurs mainly by renal excretion. The decline in plasma ramiprilat concentrations is multiphasic. Due to the strong saturable binding to ACE and the slow dissociation from the enzyme, ramiprilat has a prolonged terminal elimination phase at very low plasma concentrations. The effective half-life of ramipril after repeated doses of 5-10 mg ramipril once daily is 13-17 hours and longer at lower doses (1.25-2.5 mg). The difference is due to the saturable capacity of the enzyme to bind ramiprilat. After a single oral dose of ramipril, neither ramipril nor its metabolite were detected in breast milk. However, the effect of repeated doses is unknown.

Patients with renal impairment (see section 4.2). In patients with renal impairment, renal excretion of ramiprilat is reduced and renal clearance of ramiprilat is proportional to creatinine clearance. This results in increased plasma concentrations of ramiprilat, which decrease more slowly than in subjects with normal renal function.

Patients with impaired liver function (see section "Method of administration and dosage"). In patients with impaired liver function, the conversion of ramipril to ramiprilat occurs more slowly due to a decrease in the activity of hepatic esterases. In such patients, an increase in the level of ramipril in the blood plasma is observed. However, the maximum concentration of ramiprilat in the blood plasma of these patients did not differ from that in individuals with normal liver function.

Hydrochlorothiazide

Absorption: After oral administration, 70% of hydrochlorothiazide is absorbed from the gastrointestinal tract. Peak plasma concentrations of hydrochlorothiazide are reached within 1.5-5 hours.

Distribution: For hydrochlorothiazide, plasma protein binding is approximately 40%.

Metabolism: Hydrochlorothiazide is metabolized in the liver to very small extent.

Excretion: Hydrochlorothiazide is excreted by the kidneys almost completely (> 95%) unchanged; 50-70% of a single dose is excreted within 24 hours. The half-life is 5-6 hours.

Patients with renal impairment (see section 4.2). In patients with renal impairment, renal excretion of hydrochlorothiazide is reduced and renal clearance of hydrochlorothiazide is proportional to creatinine clearance. This results in increased plasma concentrations of hydrochlorothiazide, which decrease more slowly than in subjects with normal kidneys.

Patients with hepatic impairment (see section 4.2). The pharmacokinetics of hydrochlorothiazide are not significantly altered in patients with cirrhosis.

No studies have been conducted on the pharmacokinetics of hydrochlorothiazide in patients with heart failure.

Ramipril and hydrochlorothiazide. Concomitant administration of ramipril and hydrochlorothiazide did not affect their bioavailability. The combination product can be considered bioequivalent to the products containing the individual active substances.

Preclinical safety data. In rats and mice, the combination of ramipril and hydrochlorothiazide at doses up to 10,000 mg/kg body weight did not cause acute toxicity. Repeated dose studies in rats and monkeys only showed electrolyte disturbances. Mutagenicity and carcinogenicity studies were not performed with this combination, as studies of the individual components did not reveal any risks. Reproductive toxicity studies showed that the combination was slightly more toxic than either of the active substances taken alone, but none of the studies showed teratogenic effects of this combination.

Indication

Treatment of hypertension. This fixed combination is indicated in patients whose blood pressure is not adequately controlled with ramipril or hydrochlorothiazide monotherapy.

Contraindication

Hypersensitivity to the active substance ramipril or to other ACE inhibitors, hydrochlorothiazide, other thiazide diuretics, sulfonamides or to any of the excipients included in the preparation.

History of angioedema (hereditary, idiopathic or previously experienced while taking ACE inhibitors or angiotensin II receptor antagonists).

Arterial hypotension or hemodynamically unstable conditions.

Concomitant use of ACE inhibitors and extracorporeal treatments that result in contact of blood with negatively charged surfaces, as such use may lead to severe anaphylactoid reactions. Such extracorporeal treatments include dialysis or haemofiltration using certain membranes with high hydraulic permeability (e.g. polyacrylonitrile) and low-density lipoprotein apheresis using dextran sulphate (see section 4.5).

Significant bilateral renal artery stenosis or unilateral renal artery stenosis in the presence of a single functioning kidney.

Severe renal impairment (creatinine clearance <30 ml/min) in patients not undergoing hemodialysis.

Clinically significant electrolyte imbalances, the course of which may worsen during treatment with the drug (see section "Special instructions").

Treatment-resistant hypokalemia or hypercalcemia.

Refractory hyponatremia.

Symptomatic hyperuricemia (gout).

Anury.

Severe liver dysfunction, hepatic encephalopathy.

Pregnancy and planning pregnancy (see section "Use during pregnancy or breastfeeding").

Breastfeeding (see section "Use during pregnancy or breastfeeding").

Concomitant use with aliskiren-containing products in patients with diabetes mellitus or renal dysfunction (GFR < 60 ml/min/1.73 m2) (see sections “Pharmacodynamics” and “Interaction with other medicinal products and other types of interactions”).

Concomitant use with angiotensin II receptor antagonists in patients with diabetic nephropathy.

Interaction with other medicinal products and other types of interactions

Clinical studies have shown that dual blockade of the RAAS through the combined use of ACE inhibitors, angiotensin II receptor antagonists or aliskiren is associated with an increased incidence of adverse reactions such as hypotension, hyperkalemia and renal dysfunction (including the development of acute renal failure) compared with the use of only one drug that affects the RAAS (see sections "Pharmacodynamics", "Contraindications" and "Special Instructions").

Contraindicated combinations

Concomitant use of ACE inhibitors with sacubitril/valsartan is contraindicated as it increases the risk of angioedema (see sections "Contraindications" and "Special warnings and precautions for use"). Ramipril treatment should be initiated no earlier than 36 hours after the last dose of sacubitril/valsartan. Sacubitril/valsartan should be initiated no earlier than 36 hours after the last dose of Ramizes® Com.

Extracorporeal therapy methods that result in contact of blood with negatively charged surfaces, such as dialysis or hemofiltration using certain high flux membranes (e.g. polyacrylonitrile membranes) and low density lipoprotein apheresis using dextran sulfate - due to the increased risk of severe anaphylactoid reactions (see section "Contraindications"). If such treatment is necessary, consideration should be given to using a different type of dialysis membrane or a different class of antihypertensive agent.

Combinations requiring special caution

Potassium salts, heparin, potassium-sparing diuretics and other active substances that increase plasma potassium levels (including angiotensin II antagonists, trimethoprim and fixed-dose combinations with sulfamethoxazole, tacrolimus, ciclosporin). Hyperkalaemia may occur, therefore careful monitoring of plasma potassium levels is necessary.

Antihypertensive drugs (e.g. diuretics) and other active substances that may lower blood pressure (e.g. nitrates, tricyclic antidepressants, anaesthetics, alcohol in high doses, baclofen, alfuzosin, doxazosin, prazosin, tamsulosin, terazosin). The risk of arterial hypotension may be increased (see section "Dosage and administration" for diuretics).

Vasopressor sympathomimetics and other active substances (e.g. epinephrine) that may reduce the antihypertensive effect of ramipril. Regular monitoring of blood pressure is recommended. In addition, hydrochlorothiazide may reduce the effect of vasopressor sympathomimetics.

Allopurinol, immunosuppressants, corticosteroids, procainamide, cytostatics and other substances that may change the blood picture. Increased likelihood of hematological reactions (see section "Special instructions").

Antidiabetic agents, including insulin. Hypoglycaemic reactions may occur. Hydrochlorothiazide may reduce the effect of antidiabetic agents. Therefore, blood glucose levels should be monitored particularly closely at the beginning of concomitant use of these agents.

Non-steroidal anti-inflammatory drugs (NSAIDs) and acetylsalicylic acid. The antihypertensive effect of Ramizes® Com is expected to be reduced. Also, the simultaneous use of ACE inhibitors and NSAIDs may be accompanied by an increased risk of impaired renal function and an increase in blood potassium levels.

Oral anticoagulants: When used simultaneously with hydrochlorothiazide, the anticoagulant effect may be weakened.

Corticosteroids, adrenocorticotropic hormone (ACTH), amphotericin B, carbenoxolone, large amounts of licorice, laxatives (with prolonged use) and other kaliuretic drugs or active substances that reduce the amount of potassium in the blood plasma. Increased risk of hypokalemia.

Digitalis preparations, active substances that can increase the duration of the QT interval, antiarrhythmic agents. In the presence of electrolyte imbalance (e.g. hypokalemia, hypomagnesemia), proarrhythmic effects may be enhanced and antiarrhythmic effects may be attenuated.

Medicinal products affected by changes in serum potassium: Periodic monitoring of serum potassium and ECG is recommended when hydrochlorothiazide is used concomitantly with medicinal products affected by changes in serum potassium (e.g. digitalis glycosides and antiarrhythmic medicinal products) and with the following medicinal products that induce torsades de pointes (including some antiarrhythmic medicinal products), as hypokalaemia is a predisposing factor to torsades de pointes:

Class Ia antiarrhythmics (e.g. quinidine, hydroquinidine, disopyramide);

Class III antiarrhythmics (e.g. amiodarone, sotalol, dofetilide, ibutilide);

some neuroleptics (e.g. thioridazine, chlorpromazine, levomepromazine, trifluoroperazine, cyamemazine, sulpiride, sultopride, amisulpiride, tiapride, pimozide, haloperidol, droperidol);

other medicines (e.g. bepridil, cisapride, diphemanil, intravenous erythromycin, halofantrine, mizolastine, pentamidine, terfenadine, intravenous vincamine).

Methyldopa: Possible hemolysis.

Cholestyramine or other ion exchange resins administered orally. Impaired absorption of hydrochlorothiazide. Sulfonamide diuretics should be taken at least 1 hour before or 4-6 hours after these drugs.

Curare-like muscle relaxants. Possible enhancement and prolongation of the action of muscle relaxants.

Calcium salts and drugs that increase the level of calcium in the blood plasma. When used simultaneously with hydrochlorothiazide, an increase in the concentration of calcium in the blood plasma is possible, therefore it is necessary to carefully monitor the level of calcium in the blood plasma.

Carbamazepine: There is a risk of hyponatremia due to an increase in the effect of hydrochlorothiazide.

Iodinated contrast media: In case of dehydration caused by diuretics, including hydrochlorothiazide, there is an increased risk of developing acute renal failure, especially if large doses of iodinated contrast media are administered.

Penicillin: Excretion of hydrochlorothiazide occurs in the distal tubules of the nephron, which reduces the excretion of penicillin.

Quinine: Hydrochlorothiazide reduces the excretion of quinine.

mTOR (mammalian target of rapamycin) inhibitors or vildagliptin: An increased incidence of angioedema has been observed in patients receiving concomitant ACE inhibitors and mTOR inhibitors (e.g. temsirolimus, everolimus, sirolimus) or vildagliptin. Caution should be exercised when initiating such therapy (see section 4.4).

Heparin: Possible increase in serum potassium concentrations.

Neprilysin inhibitors: An increased risk of angioedema has been reported with the concomitant use of ACE inhibitors and a neprilysin inhibitor, such as racecadotril (see section 4.4).

Salicylates: When using high doses of salicylates, hydrochlorothiazide may enhance their toxic effects on the central nervous system.

Cyclosporine: Concomitant use of cyclosporine may increase hyperuricemia and increase the risk of complications such as gout.

Alcohol: Ramipril may lead to increased vasodilation and thus potentiate the effects of alcohol.

Alcohol, barbiturates, narcotics, or antidepressants. May increase orthostatic hypotension.

Salt. The antihypertensive effect of the drug may be weakened with increased salt intake.

Beta-blockers and diaxozide: Concomitant use of thiazide diuretics, including hydrochlorothiazide, with beta-blockers increases the risk of hyperglycemia. Thiazide diuretics, including hydrochlorothiazide, may potentiate the hyperglycemic effect of diaxozide.

Amantadine: Thiazides, including hydrochlorothiazide, increase the risk of adverse reactions caused by amantadine.

Antigout agents (probenecid, sulfinpyrazone and allopurinol). Dose adjustment of uricosuric agents may be necessary, as hydrochlorothiazide may increase serum uric acid levels. Increased doses of probenecid or sulfinpyrazone may be necessary. Concomitant use of thiazides may increase the incidence of hypersensitivity reactions to allopurinol.

Anticholinergics (e.g. atropine, biperiden): Bioavailability of thiazide-type diuretics increases due to decreased gastrointestinal motility and decreased gastric emptying rate.

The effect of drugs on laboratory test results

Due to their effect on calcium metabolism, thiazides may interfere with the results of parathyroid function tests (see section 4.4).

Specific hyposensitization. ACE inhibition increases the likelihood and severity of anaphylactic and anaphylactoid reactions to insect venom. It is believed that this effect may also be observed for other allergens.

Application features

Special patient groups

Pregnancy: Treatment with ACE inhibitors or angiotensin II receptor antagonists should not be initiated during pregnancy. Unless continued ACE inhibitor/angiotensin II receptor antagonist therapy is considered essential, patients planning pregnancy should be changed to alternative antihypertensive treatments which have an established safety profile for use in pregnancy. When pregnancy is diagnosed, treatment with ACE inhibitors/angiotensin II receptor antagonists should be stopped immediately, and, if appropriate, alternative therapy should be started (see sections 4.3 and 4.8).

Dual blockade of the RAAS. There is evidence that the concomitant use of ACE inhibitors, angiotensin II receptor antagonists or aliskiren increases the risk of hypotension, hyperkalemia and renal dysfunction (including the development of acute renal failure). Therefore, dual blockade of the RAAS through the combined use of ACE inhibitors, angiotensin II receptor antagonists or aliskiren is not recommended (see sections 5.1 and 5.5).

If such dual blockade therapy is considered absolutely necessary, it should only be used under specialist supervision and with frequent and careful monitoring of renal function, electrolytes and blood pressure.

ACE inhibitors and angiotensin II receptor antagonists should not be used concomitantly in patients with diabetic nephropathy.

Patients at high risk of hypotension

Patients with increased RAAS activity. Patients with increased RAAS activity are at risk of a sudden significant decrease in blood pressure and renal function impairment due to ACE inhibition. This is particularly true when an ACE inhibitor or concomitant diuretic is prescribed for the first time or when the dose is increased for the first time. Increased RAAS activity, which requires medical supervision, including constant monitoring of blood pressure, can be expected, for example, in patients:

with severe arterial hypertension;

with decompensated congestive heart failure;

with hemodynamically significant obstruction of the inflow or outflow tracts of blood from the left ventricle (for example, with aortic or mitral valve stenosis);

with unilateral renal artery stenosis in the presence of a second functioning kidney;

with existing or possible fluid or electrolyte depletion (including patients receiving diuretics);

with liver cirrhosis and/or ascites;

who are undergoing major surgical procedures or during anesthesia with drugs that can cause arterial hypotension.

Correction of dehydration, hypovolemia, or electrolyte depletion is usually recommended before initiating treatment (however, in patients with heart failure, such corrective measures should be carefully weighed against the risk of volume overload).

In the patient