Rasilez (Aliskiren, Aliskiren) 300 mg tablet. No. 28

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Manufacturers: Novartis Pharmaceuticals Corporation

Active ingredients

Aliskiren

Disease class

Essential [primary] hypertension
Secondary hypertension

Clinical and pharmacological group

Not indicated. See instructions

Pharmacological action

Antihypertensive

Pharmacological group

Renin inhibitors

Pharmacological properties of the drug Rasilez

Pharmacodynamics. Aliskiren is an orally active, non-peptide, potent selective renin inhibitor in humans. Aliskiren specifically reaches the renin-angiotensin system (RAS), thereby blocking the conversion of angiotensin to angiotensin I (Ang I) and reducing the level of activity of plasma renin (Ang I) and angiotensin II (Ang II). Renin is released by the kidneys in response to a decrease in blood volume and renal perfusion. This initiates a cycle involving the RAS and homeostatic feedback. Renin breaks down angiotensinogen to form the inactive decapeptide Ang I. Ang I is converted into the active octapeptide Ang II with the help of ACE. Ang II is a powerful vasoconstrictor and releases catecholamines from the adrenal medulla and presynaptic nerve endings. It also enhances the secretion of aldosterone and the readsorption of sodium ions. At the same time, these effects lead to an increase in blood pressure. A constant increase in the level of Ang II leads to the expression of markers and mediators of inflammation and fibrosis, which result in organ damage. Ang II also inhibits the release of renin, which has a negative feedback effect on the system. An increase in plasma renin activity to varying degrees leads to an increase in cardiovascular risk in patients with normo- or hypotension. All agents that inhibit this system, including renin inhibitors, suppress negative feedback, leading to a compensatory increase in plasma renin concentrations. When such an increase occurs during treatment with ACE inhibitors and angiotensin receptor blockers, it is accompanied by an increase in the level of plasma renin activity. Exposure to aliskiren neutralizes the feedback effect. As a result, when aliskiren is used as monotherapy or in combination with other antihypertensive drugs, the level of plasma renin activity, Ang I and Ang II decreases. Treatment with Rasilez reduces plasma renin activity in patients with hypertension (arterial hypertension). In clinical trials, the decrease in plasma renin activity was 50–80%. A similar reduction was found when aliskiren was combined with other antihypertensive drugs. Hypertension (arterial hypertension) In patients, Rasilez causes a dose-dependent long-term decrease in systolic and diastolic blood pressure. Administration of Rasilez in doses of 150 and 300 mg once a day provides an effective reduction in blood pressure over 24 hours (the advantage of the effect persists in the early morning), with an average peak of the required ratio for diastolic response of about 98% at a dose of 300 mg. After 2 weeks, 85–90% of the maximum effect of lowering blood pressure is noted. The effect of lowering blood pressure persists in patients treated for a year, which was established in randomized studies. After cessation of treatment, blood pressure gradually returns to baseline levels over several weeks without any adverse effect on blood pressure or plasma renin activity. In controlled studies, first dose hypotension and no effect on pulse level were observed in treated patients. In patients with uncomplicated hypertension (arterial hypertension) receiving monotherapy with Rasilez, excessive hypotension was rarely observed (0.1%). Hypotension was also not common (≤1%) during combination therapy with other antihypertensive drugs. In controlled studies, the blood pressure lowering effect of Rasilez in combination with hydrochlorothiazide or ramipril was additive and the combination was well tolerated. For the combination of Rasilez with the ACE inhibitor ramipril, a decrease in the severity of cough (as a side effect) was noted compared to ramipril (aliskiren/ramipril - 1.8% compared to ramipril - 4.7%). Aliskiren at a dose of 150 mg also has an additive blood pressure lowering effect and is well tolerated in patients with an inadequate response to the calcium channel blocker amlodipine at a dose of 5 mg. Efficacy was similar to that of amlodipine 10 mg, but the effect of reducing edema was greater with aliskiren (aliskiren/amlodipine - 2.1% compared with amlodipine - 11.2%). Tolerability when combined with the angiotensin receptor blocker valsartan was good. In terms of its effectiveness in lowering blood pressure, Rasilez is similar to antihypertensive drugs of other classes, including ACE inhibitors, angiotensin receptor blockers and calcium channel blockers. The antihypertensive effects of Rasilez and hydrochlorothiazide were compared in a 26-week, randomized, double-blind, parallel group study (with targeted addition of amlodipine). After 12 weeks of monotherapy with aliskiren at a dose of 300 mg/day and monotherapy with hydrochlorothiazide 25 mg/day, the decrease in blood pressure (systolic/diastolic) compared to baseline was 17.0/12.3 mm Hg. Art. for aliskiren and 14.4/10.5 mmHg. Art. for hydrochlorothiazide. At the end of the study, the decrease in blood pressure (systolic/diastolic) compared to baseline was 19.6/14.2 mm Hg. st for aliskiren and 17.9/13.0 mmHg. Art. for hydrochlorothiazide. In patients with hypertension (arterial hypertension) on the background of diabetes mellitus, monotherapy with Rasilez was effective and safe. In combination with ramipril, Rasilez provides additional reduction in blood pressure. In patients with hypertension (arterial hypertension) due to obesity, in whom treatment with hydrochlorothiazide was ineffective, the introduction of Rasilez into the treatment regimen provides an additional reduction in blood pressure compared with the use of irbesartan or amlodipine in the combination therapy regimen. The antihypertensive effect of Rasilez does not depend on the age, gender, body weight and race of patients. Pharmacokinetics. After oral administration of aliskiren, the maximum concentration in the blood plasma is reached after 1–3 hours. The absolute bioavailability of aliskiren is 2.6%. Food reduces the maximum concentration and exposure (AUC) of aliskiren, but has minimal effect on pharmacodynamics, so the drug can be used regardless of food intake. The equilibrium concentration in the blood plasma is achieved within 5–7 days after the start of dosing once a day, the equilibrium level is approximately 2 times higher than at the initial dose. After oral administration, aliskiren is usually distributed systemically. After IV administration, the mean volume of distribution at steady state is approximately 135 L, indicating that aliskiren is extensively distributed into the extravascular space. The binding of aliskiren to plasma proteins is moderate (47–51%) and does not depend on concentration. The average half-life is approximately 40 hours (34–41 hours). Aliskiren is excreted mainly unchanged in the feces (91%). About 1.4% of the total oral dose is metabolized by the CYP3A4 enzyme. Approximately 0.6% of the oral dose is excreted in the urine. After intravenous administration, the average plasma clearance is about 9 l/h. Maximum concentrations and exposure (AUC) of aliskiren increase linearly with increasing doses in the range of 75–600 mg. Features of pharmacokinetics in patients with impaired renal function . The pharmacokinetics of aliskiren was assessed in patients with varying degrees of renal failure. The relative maximum concentration and AUC of aliskiren in patients with impaired renal function are 0.8–2 times higher than those in healthy individuals after 1 dose and at steady state. On the other hand, such changes do not correlate with the severity of renal dysfunction. For patients with mild to severe renal impairment, no dose adjustment is required, but the use of the drug in patients with severe renal impairment should be carried out with extreme caution and under strict supervision.

Rasilez (Aliskiren, Aliskiren) 300 mg tablet. No. 28 - Instructions

Dosage form

Film-coated tablets, 28 pieces per package.

Release form, packaging and composition of Rasilez

Brownish-pink, oval, biconvex, film-coated tablets, without a score, imprinted “IU” on one side and “NVR” on the other.

1 tab.
aliskiren hemifumarate	331.5 mg,
which corresponds to the content of aliskiren	300 mg

Clinical and pharmacological group

Renin secretion inhibitor. Antihypertensive drug.

Pharmacotherapeutic group

Renin inhibitor.

pharmachologic effect

Antihypertensive drug, selective renin inhibitor of non-peptide structure. Secretion of renin by the kidneys and activation of the renin-angiotensin-aldosterone system (RAAS) occurs with a decrease in blood volume and renal blood flow through a feedback mechanism. Renin acts on angiotensinogen, resulting in the formation of an inactive decapeptide - angiotensin I (ATI), which, with the help of ACE and, partly, without its participation, is converted into the active octapeptide angiotensin II (ATII). ATII is a powerful vasoconstrictor, stimulates the release of catecholamines from the adrenal medulla and presynaptic nerve endings, and also enhances the secretion of aldosterone and the reabsorption of sodium ions, which ultimately leads to an increase in blood pressure.

A prolonged increase in ATII concentration stimulates the production of mediators of inflammation and fibrosis, which leads to damage to target organs.

With an increase in the concentration of ATII in the blood plasma, a decrease in renin secretion is observed via a negative feedback mechanism.

All drugs that inhibit the RAAS (including renin inhibitors) suppress negative feedback, leading to a compensatory increase in plasma renin concentration, which, when treated with ACE inhibitors and angiotensin II receptor antagonists, leads to an increase in plasma renin activity, but when treated with aliskiren, the effects of negative feedback connections are neutralized, as a result of which plasma renin activity (in patients with arterial hypertension by an average of 50-80%), AT I and AT II decreases, both with aliskiren monotherapy and when combined with other antihypertensive drugs.

An increase in plasma renin activity is directly associated with an increase in the risk of cardiovascular diseases both in patients with normal blood pressure and in patients with arterial hypertension.

In patients with arterial hypertension, when using the drug Rasilez at a dose of 150 and 300 mg 1 time / day, a dose-dependent long-term decrease in both systolic and diastolic blood pressure is observed over 24 hours, including the early morning hours. When taking Rasilez at a dose of 300 mg/day, the ratio of the residual effect of the drug to the maximum or target for diastolic blood pressure is 98%.

After 2 weeks of regular use of the drug, a decrease in blood pressure by 85-90% of the maximum is observed, the hypotensive effect remains at the achieved level during long-term (up to 1 year) use.

After cessation of treatment with Rasilez, a gradual return of blood pressure to the initial level is observed over several weeks, without the development of withdrawal syndrome and an increase in plasma renin activity. After 4 weeks from the moment of discontinuation of the drug Rasilez, blood pressure levels remained significantly lower compared to placebo.

When using the drug for the first time, there is no hypotensive reaction (the effect of the first dose) and a reflex increase in heart rate in response to vasodilation.

When Rasilez is used as monotherapy and in combination with other antihypertensive drugs, an excessive decrease in blood pressure is observed in 0.1% and 1% of cases, respectively.

Combination therapy with Rasilez with ACE inhibitors, angiotensin II receptor antagonists, slow calcium channel blockers (SCBCs) and diuretics is well tolerated by patients and allows for an additional reduction in blood pressure.

The incidence of dry cough was significantly lower in patients receiving the combination of Rasilez with the ACE inhibitor ramipril compared to ramipril monotherapy (1.8% and 4.7%, respectively). When using the drug Rasilez in combination with the BMCC amlodipine at a dose of 10 mg, the incidence of peripheral edema is reduced compared to amlodipine monotherapy (2.1% and 11.4%, respectively).

Monotherapy with Rasilez for concomitant diabetes mellitus allows achieving an effective and safe reduction in blood pressure. In patients with concomitant diabetes mellitus, the use of the drug Rasilez in combination with ramipril leads to a more pronounced decrease in blood pressure compared to that during monotherapy with each drug separately.

In patients with arterial hypertension, obesity and insufficient blood pressure control during monotherapy with hydrochlorothiazide, additional administration of the drug Rasilez provides a decrease in blood pressure comparable to the combination of hydrochlorothiazide with irbesartan or amlodipine.

The severity of the antihypertensive effect of the drug does not depend on age, gender, race and body mass index.

In patients with existing (or a history of) arterial hypertension and compensated chronic heart failure (CHF) of a stable course, receiving standard therapy for CHF (ACE inhibitors or angiotensin II receptor antagonists, beta-blockers and for a third of patients - aldosterone antagonists), inclusion of the drug Rasilez in standard therapy at a dose of 150 mg/day is well tolerated. The level of brain natriuretic peptide was reduced by 25% in the group of patients receiving Rasilez compared to the placebo group.

In patients with arterial hypertension, type 2 diabetes mellitus and nephropathy receiving losartan at a dose of 100 mg and optimized antihypertensive concomitant therapy, the addition of Rasilez at a dose of 300 mg / day leads to a clinically significant decrease in the urinary albumin-creatinine ratio by 20% compared to with placebo, i.e. from 58 mg/mmol to 46 mg/mmol. The percentage of patients with a decrease in urinary albumin-creatinine ratio of at least 50% compared to baseline was 24.7% and 12.5% in the Rasilez and placebo groups, respectively.

Pharmacokinetics

Suction

After oral administration, the time to reach Cmax of aliskiren in blood plasma is 1-3 hours, absolute bioavailability is 2.6%. Concomitant food intake reduces the Cmax and AUC of aliskiren, but this does not have a significant effect on the pharmacodynamics of the drug. Therefore, aliskiren can be used regardless of food intake.

The increase in Cmax and AUC of aliskiren has a linear dependence on the dose of the drug in the range from 75 to 600 mg.

Css of aliskiren in blood plasma is achieved between days 5 and 7 with daily dosing once a day and remains constant when the initial dose is doubled.

Distribution

After oral administration, aliskiren is evenly distributed in the body. After intravenous administration, the average Vd at steady state is about 135 L, which indicates a significant extravascular distribution of aliskiren. Aliskiren is moderately bound to plasma proteins (47-51%), regardless of concentration.

Metabolism and excretion

The average T1/2 of aliskiren is 40 hours (varies from 34 to 41 hours).

It is excreted mainly unchanged through the intestines (91%). About 1.4% of the ingested dose is metabolized with the participation of the CYP3A4 isoenzyme. After oral administration, about 0.6% of aliskiren is excreted by the kidneys. After intravenous administration, the average plasma clearance is about 9 l/h.

Pharmacokinetics in special clinical situations

When using aliskiren in patients over 65 years of age, no dose adjustment is required.

The pharmacokinetics of aliskiren have been studied in patients with renal failure of varying severity. The AUC and Cmax of aliskiren in patients with renal failure after a single dose and after reaching Css increased by 0.8-2 times compared to healthy individuals. However, no correlation was found between the above changes and the degree of renal dysfunction.

The pharmacokinetics of aliskiren does not change significantly in patients with mild to moderate liver dysfunction (5-9 points on the Child-Pugh scale).

Indications for the drug Rasilez

- arterial hypertension.

Dosage regimen

Rasilez can be used regardless of food intake, both as monotherapy and in combination with other antihypertensive drugs.

The recommended starting dose of Rasilez is 150 mg 1 time/day. The development of the antihypertensive effect is observed 2 weeks after the start of therapy at a dose of 150 mg 1 time / day. If blood pressure control is insufficient, the dose of the drug can be increased to 300 mg 1 time / day.

In patients with impaired renal function (with a glomerular filtration rate > 30 ml/min) and liver (5-9 points on the Child-Pugh scale), mild to moderate dose adjustment is not required.

In patients over 65 years of age, no dose adjustment is required.

Side effect

The safety of Rasilez was assessed in more than 7,800 patients. The incidence of adverse reactions was not associated with gender, age, body mass index, or race.

When using the drug in doses up to 300 mg, the overall frequency of adverse reactions was similar to that when using placebo. Adverse reactions were generally moderate, temporary, and rarely required discontinuation of drug therapy. The most common symptom observed in patients when using Rasilez was diarrhea.

When using the drug, there was no increase in the incidence of dry cough, characteristic of ACE inhibitors. The incidence of dry cough during treatment with Rasilez (0.9%) was similar to that when taking placebo (0.6%).

During clinical trials, the incidence of angioedema in the Rasilez group was similar to that in the placebo or hydrochlorothiazide group.

Determination of the frequency of adverse reactions likely associated with the use of the drug: very often (≥1/10); often (≥1/100, <1/10); sometimes (≥1/1000, <1/100), rarely (≥1/10,000, <1/1000), including isolated reports. Within each group, adverse reactions are presented in order of decreasing importance.

From the digestive system: often - diarrhea.

Dermatological reactions: sometimes - skin rash.

From the laboratory parameters: rarely - during monotherapy, a slight decrease in the concentration of hemoglobin and hematocrit was observed (on average by 0.05 mmol/l and 0.16%, respectively), which did not require discontinuation of treatment (a decrease in the concentration of hemoglobin and hematocrit is also observed when using other drugs that affect RAAS, in particular ACE inhibitors and angiotensin II receptor antagonists), a slight increase in serum potassium concentration (0.9% compared to 0.6% when taking placebo).

There were no clinically significant changes in fasting total cholesterol, HDL cholesterol, triglycerides, glucose or uric acid.

Allergic reactions: in some cases - angioedema.

Contraindications for use

severe renal impairment (serum creatinine >150 µmol/L for women and >177 µmol/L for men and/or glomerular filtration rate <30 ml/min);
nephrotic syndrome;
renovascular hypertension;
regular hemodialysis procedures;
severe liver dysfunction (more than 9 points on the Child-Pugh scale);
children and adolescents up to 18 years of age;
hypersensitivity to the components of the drug.

The drug should be prescribed with caution to patients with unilateral or bilateral renal artery stenosis or stenosis of the artery of a single kidney, diabetes mellitus, reduced blood volume, hyponatremia, hyperkalemia, or patients after kidney transplantation. The safety of using Rasilez in patients with bilateral renal artery stenosis or stenosis of the artery of a single kidney has not been established.

Use during pregnancy and breastfeeding

There is insufficient data on the safety of Rasilez use during pregnancy. The use of drugs that have a direct effect on the RAAS during pregnancy can cause the development of pathology in the fetus and newborn, as well as lead to their death. Rasilez, like other drugs that have a direct effect on the RAAS, should not be used during pregnancy or in women planning pregnancy.

Before prescribing drugs that affect the RAAS, the doctor should inform patients of childbearing age about the possibility of a potential risk to the fetus when using these drugs during pregnancy. If pregnancy occurs during treatment with Rasilez, the drug should be stopped immediately.

It is not known whether aliskiren is excreted into breast milk in humans. If therapy is necessary during lactation, breastfeeding should be stopped while taking the drug.

Use for liver dysfunction

The drug is contraindicated in severe liver dysfunction (more than 9 points on the Child-Pugh scale).

In patients with impaired liver function (5-9 points on the Child-Pugh scale) from mild to severe, no dose adjustment is required.

Use for renal impairment

The drug is contraindicated in severe renal impairment (serum creatinine >150 µmol/l for women and >177 µmol/l for men and/or glomerular filtration rate <30 ml/min); nephrotic syndrome; renovascular hypertension; the need for regular hemodialysis procedures.

The drug should be prescribed with caution to patients with unilateral or bilateral stenosis of the renal arteries or stenosis of the artery of a single kidney (the safety of Rasilez has not been established), and to patients after kidney transplantation.

In patients with impaired renal function (with a glomerular filtration rate of more than 30 ml/min), no dose adjustment is required.

Use in children

Since the safety and effectiveness of Rasilez in children and adolescents under 18 years of age have not yet been established, the drug should not be used in this category of patients.

Use in elderly patients

In patients over 65 years of age, no dose adjustment is required.

special instructions

The effectiveness and safety of the drug Rasilez have not been established: in patients with severely impaired renal function (serum creatinine >150 µmol/l for women and >177 µmol/l for men and/or glomerular filtration rate less than 30 ml/min), with nephrotic syndrome , renovascular hypertension and during regular hemodialysis procedures, as well as in patients with severe liver dysfunction (more than 9 points on the Child-Pugh scale).

The drug should be stopped immediately if there are signs of allergic reactions (for example, difficulty breathing or swallowing, swelling of the face, limbs, lips, tongue).

During therapy with Rasilez, it is possible to increase the concentration of potassium, creatinine, and blood urea nitrogen, which is characteristic of drugs that affect the RAAS.

At the beginning of treatment with Rasilez in patients with reduced blood volume and/or hyponatremia (including against the background of high doses of diuretics), symptomatic arterial hypotension is possible. Before using the drug, correction of water-salt imbalance should be carried out. In patients with reduced blood volume and/or hyponatremia, treatment should be carried out under close medical supervision.

Use in pediatrics

Since the safety and effectiveness of Rasilez in children and adolescents under 18 years of age have not yet been established, the drug should not be used in this category of patients.

Impact on the ability to drive vehicles and operate machinery

The effect of Rasilez on the ability to drive vehicles and operate machinery has not been studied.

Overdose

There are limited data on drug overdose.

Symptoms: the most likely and main symptom is a pronounced decrease in blood pressure.

Treatment: maintenance therapy.

Drug interactions

The likelihood of interaction between aliskiren and other drugs is low.

There were no clinically significant interactions between aliskiren and acenocoumarol, atenolol, celecoxib, fenofibrate, pioglitazone, allopurinol, isosorbide 5-mononitrate, irbesartan, digoxin, ramipril and hydrochlorothiazide.

When using aliskiren with one of the following drugs, its Cmax or AUC may change: valsartan (28% decrease), metformin (28% decrease), amlodipine (29% increase), cimetidine (19% increase).

Since, when used together, aliskiren does not have a significant effect on the pharmacokinetics of atorvastatin, valsartan, metformin, amlodipine, no changes in the doses of Rasilez or the above drugs are required when administered simultaneously.

Aliskiren does not inhibit the isoenzymes of the cytochrome P450 system (CYP1A2, 2C8, 2C9, 2C19, 2D6, 2E1 and CYP3A) and does not induce the CYP3A4 isoenzyme. Since aliskiren is to a small extent metabolized with the participation of isoenzymes of the cytochrome P450 system, a clinically significant effect of Rasilez on the bioavailability of drugs that are inducers or inhibitors of isoenzymes of the cytochrome P450 system or metabolized with its participation is unlikely.

Interaction at the level of P-glycoprotein (Pgp), encoded by the MDR1/ Mdr 1a/ 1b genes. Since experimental studies have established that P-glycoprotein (a membrane transporter of molecules) plays an important role in regulating the absorption and distribution of aliskiren, the pharmacokinetics of the latter may change when used simultaneously with substances that inhibit Pgp (depending on the degree of inhibition). No significant interaction of aliskiren with weakly or moderately active Pgp inhibitors, such as atenolol, digoxin, amlodipine and cimetidine, has been established.

When used simultaneously with the active Pgp inhibitor atorvastatin (at a dose of 80 mg/day), at steady state there is an increase in the AUC and Cmax of aliskiren (dose 300 mg/day) by 50%.

With simultaneous administration of the active Pgp inhibitor ketoconazole (200 mg) and aliskiren (300 mg), an increase in the plasma concentration of the latter (AUC and Cmax) by 80% is observed. In experimental studies, simultaneous administration of aliskiren with ketoconazole led to an increase in absorption of the latter from the gastrointestinal tract and a decrease in its excretion in bile. Changes in plasma concentrations of aliskiren when administered concomitantly with ketoconazole or atorvastatin are expected within the concentration range determined by doubling the aliskiren dose. In controlled clinical studies, the safety of the drug was demonstrated at a dose of 600 mg and an increase in the maximum recommended therapeutic dose by 2 times. When using aliskiren together with ketoconazole or atorvastatin, no dose adjustment of aliskiren is required.

When used with such a highly active Pgp inhibitor as cyclosporine (200 and 600 mg), healthy individuals showed an increase in Cmax and AUC of aliskiren (75 mg) by 2.5 and 5 times, respectively. In this regard, it is not recommended to use Rasilez simultaneously with cyclosporine.

With simultaneous use of aliskiren with furosemide, a decrease in the AUC and Cmax of furosemide was observed by 28% and 49%, respectively. To prevent possible fluid retention when prescribing aliskiren together with furosemide at the beginning and during treatment, it is necessary to adjust the dose of furosemide depending on the clinical effect.

Given the experience with the use of other drugs that affect the RAAS, aliskiren should be prescribed with caution along with potassium salts, potassium-sparing diuretics, potassium-containing table salt substitutes, or any other drugs that can increase the concentration of potassium in the blood.

Storage conditions Rasilez

The drug should be stored out of the reach of children at a temperature not exceeding 30°C.

Best before date

2 years.

Terms of sale

The drug is available with a prescription.

Use of the drug Rasilez

AH (arterial hypertension) The initial recommended dose of Rasilez is 150 mg 1 time per day. For patients whose blood pressure is not adequately controlled, the dose may be increased to 300 mg once daily. A significant antihypertensive effect develops within 2 weeks (85–90%) after the start of therapy at a daily dose of 150 mg. Rasilez can be used as monotherapy or in combination with other antihypertensive drugs. The drug is used regardless of food intake. Elderly patients For elderly patients (over 65 years of age), no adjustment of the initial dose is required. Patients with impaired renal function In patients with impaired renal function, regardless of severity, no adjustment of the initial dose is required. Patients with impaired liver function Patients with impaired liver function, regardless of severity, do not require adjustment of the initial dose.

Side effects of the drug Rasilez

The safety of Rasilez was assessed in 7800 patients, of which 2300 patients received treatment for 6 months, and about 1200 for 1 year. The severity of adverse reactions is not related to gender, age, body weight or race. Treatment with Rasilez at a dose of up to 300 mg/day was well tolerated with the overall severity of side effects close to placebo. Side effects are usually mild and transient and rarely require discontinuation of therapy. Among them, the most common is diarrhea. Rasilez is not characterized by the appearance of a dry cough, which is typical for ACE inhibitors. The severity of cough is similar in patients receiving placebo (0.6%) and Rasilez (0.9%). During treatment with Rasilez, the appearance of angioedema was noted. In controlled clinical trials, angioedema occurred rarely with Rasilez treatment, at levels comparable to placebo or hydrochlorothiazide treatment. Patients should stop treatment and inform the doctor of any allergic manifestations (especially difficulty breathing and swallowing, swelling of the face, limbs, eyes, lips, tongue). Adverse reactions are arranged in decreasing order of frequency using the following classification: very common (≥1/10); often (≥1/100, ≤1/10); sometimes (≥1/1000, 1/100); rare (≥1/10,000, ≤1/1000); very rare (≤1/10,000), including isolated reports. Gastrointestinal disorders : often - diarrhea. From the skin and subcutaneous tissues : sometimes - skin rash. Laboratory indicators. Controlled clinical trials using Rasilez rarely showed significant changes in standard laboratory parameters. In clinical trials in patients with hypertension (arterial hypertension), Rasilez did not have a clinically significant effect on total cholesterol, HDL, TG (fasting), glucose (fasting) or uric acid. Hemoglobin and hematocrit. A slight decrease in hemoglobin and hematocrit was noted (mean decrease of approximately 0.05 mmol/L or 0.16 vol.%, respectively). None of the patients discontinued treatment due to anemia. This effect has also been observed with other drugs acting on the RAS, such as ACE inhibitors and angiotensin receptor blockers. Serum potassium. In patients with essential hypertension (arterial hypertension) who received a course of monotherapy with Rasilez, the increase in serum potassium levels was minimal and rare (0.9% compared to 0.6% for placebo). However, in one study in which Rasilez was used in combination with an ACE inhibitor in patients with diabetes mellitus, increases in serum potassium levels were more common (5.5%). Therefore, as with any other drug that affects the RAS, regular monitoring of electrolyte levels and renal function is recommended for patients with diabetes taking Rasilez.

Oral tablets Rasilez (Rasilez)

Instructions for medical use of the drug

Description of pharmacological action

Antihypertensive drug, selective renin inhibitor of non-peptide structure.

Indications for use

Arterial hypertension.

Release form

film-coated tablets 150 mg; blister 7 cardboard pack 1. film-coated tablets 150 mg; blister 7 cardboard pack 4. film-coated tablets 150 mg; blister 7 cardboard pack 8. film-coated tablets 150 mg; blister 7 cardboard pack 12. film-coated tablets 150 mg; blister 7 cardboard pack 14. film-coated tablets 150 mg; blister 7 cardboard pack 40. film-coated tablets 300 mg; blister 7 cardboard pack 40. film-coated tablets 300 mg; blister 7 cardboard pack 1. film-coated tablets 300 mg; blister 7 cardboard pack 4. film-coated tablets 300 mg; blister 7 cardboard pack 8. film-coated tablets 300 mg; blister 7 cardboard pack 12. film-coated tablets 300 mg; blister 7 cardboard pack 14. film-coated tablets 150 mg; blister 7 cardboard pack 2. film-coated tablets 300 mg; blister 7 cardboard pack 2.

Pharmacodynamics

A selective renin inhibitor of non-peptide structure with pronounced activity. Secretion of renin by the kidneys and activation of the RAAS occurs with a decrease in blood volume and renal blood flow. Renin acts on angiotensinogen, resulting in the formation of angiotensin I, which is converted by ACE into active angiotensin II. Angiotensin II is a powerful vasoconstrictor, stimulating the release of catecholamines, enhancing aldosterone secretion and Na+ reabsorption, which leads to an increase in blood pressure. A prolonged increase in angiotensin II stimulates the production of mediators of inflammation and fibrosis, which leads to target organ damage. Angiotensin II reduces renin secretion through a negative feedback mechanism. Drugs that inhibit the RAAS suppress negative feedback, leading to a compensatory increase in plasma renin. Aliskiren inhibits the RAAS at the rate-limiting stage of the reaction, in contrast to ACE inhibitors and angiotensin receptor blockers, which block the system at later stages. That. Aliskiren reduces plasma renin activity in contrast to ACE and angiotensin receptor antagonists. Aliskiren neutralizes the suppression of negative feedback, resulting in a decrease in renin activity (by 50-80% in patients with arterial hypertension), as well as the concentration of angiotensin I and angiotensin II. When taken at a dose of 150 mg and 300 mg 1 time per day, a dose-dependent decrease in systolic and diastolic blood pressure is observed within 24 hours. A sustained hypotensive clinical effect (reduction in blood pressure by 85-90% of the maximum) is achieved 2 weeks after the start of therapy at a dose of 150 mg 1 time per day. The hypotensive effect persists during long-term (up to 1 year) use. When taking 300 mg/day, the ratio of the residual effect of the drug to the maximum or target for diastolic blood pressure is 98%. After cessation of treatment, blood pressure returns to its original value within several weeks, without the development of the syndrome or increase in renin activity. When aliskiren was combined with ramipril, the incidence of cough was significantly lower compared to motor therapy with ramipril (1.8% and 4.7%, respectively). When aliskiren is combined with amlodipine (10 mg), the incidence of peripheral edema is significantly reduced compared to amlodipine monotherapy (2.1% and 11.4%, respectively). Monotherapy for diabetes mellitus allows you to achieve an effective and safe reduction in blood pressure; when combined with ramipril, it leads to a more pronounced decrease in blood pressure compared to monotherapy with each drug separately. In patients with arterial hypertension, obesity and poor blood pressure control during hydrochlorothiazide therapy, the additional use of aliskiren provides a reduction in blood pressure comparable to the combination of hydrochlorothiazide with irbesartan or amlodipine.

Pharmacokinetics

Absorption. After oral administration, Tmax of aliskiren in blood plasma is 1–3 hours, absolute bioavailability is 2.6%. Concomitant food intake reduces the Cmax and AUC of aliskiren, but this does not have a significant effect on the pharmacodynamics of the drug. Therefore, aliskiren can be used regardless of food intake. The increase in Cmax and AUC of aliskiren has a linear dependence on the dose of the drug in the range from 75 to 600 mg. CSS of aliskiren in blood plasma is achieved between the 5th and 7th day when taken once a day daily and remains constant when the initial dose is doubled. Distribution. After oral administration, aliskiren is evenly distributed in the body. After IV administration, the mean apparent volume of distribution (VSS) at steady state is approximately 135 L, indicating a significant extravascular distribution of aliskiren. Aliskiren is moderately bound to plasma proteins (47–51%), regardless of concentration. Metabolism and excretion. The average T1/2 of aliskiren is 40 hours (varies from 34 to 41 hours). It is excreted mainly unchanged through the intestines (91%). About 1.4% of the ingested dose is metabolized with the participation of the CYP3A4 isoenzyme. After oral administration, about 0.6% of aliskiren is excreted by the kidneys. After intravenous administration, the average plasma clearance is about 9 l/h. Pharmacokinetics in special groups of patients When using aliskiren in patients over 65 years of age, no dose adjustment is required. Patients with impaired renal function. The pharmacokinetics of aliskiren have been studied in patients with renal failure of varying severity. The AUC and Cmax of aliskiren in patients with renal failure after a single dose and after reaching CSS increased by 0.8-2 times compared to healthy individuals. However, no correlation was found between the above changes and the degree of renal dysfunction. Patients with liver dysfunction. The pharmacokinetics of aliskiren does not change significantly in patients with mild to moderate hepatic impairment (Child-Pough score 5–9). Pharmacodynamics Selective renin inhibitor of non-peptide structure. Secretion of renin by the kidneys and activation of the renin-angiotensin-aldosterone system (RAAS) occurs with a decrease in blood volume and renal blood flow through a feedback mechanism. Renin acts on angiotensinogen, resulting in the formation of an inactive decapeptide - angiotensin I (ATI), which, with the help of ACE and, partly without its participation, is converted into the active octapeptide angiotensin II (ATII). ATII is a powerful vasoconstrictor, stimulates the release of catecholamines from the adrenal medulla and presynaptic nerve endings, and also enhances the secretion of aldosterone and sodium reabsorption, which ultimately leads to an increase in blood pressure. A prolonged increase in ATII concentration stimulates the production of mediators of inflammation and fibrosis, which leads to damage to target organs. With an increase in the concentration of ATII in the blood plasma, a decrease in renin secretion is observed via a negative feedback mechanism. All drugs that inhibit the RAAS (including renin inhibitors) suppress negative feedback, leading to a compensatory increase in plasma renin concentrations, which, when treated with ACE inhibitors and angiotensin II receptor antagonists (APA II), leads to an increase in plasma renin activity, however, with treatment With aliskiren, the effects of negative feedback are neutralized, as a result of which plasma renin activity (in patients with arterial hypertension - by an average of 50–80%), ATI and ATII is reduced, both with aliskiren monotherapy and when combined with other antihypertensive drugs. An increase in plasma renin activity is directly associated with an increase in the risk of cardiovascular diseases both in patients with normal blood pressure and in patients with arterial hypertension (AH). In patients with arterial hypertension, when using the drug Rasilez at a dose of 150 and 300 mg 1 time / day, a dose-dependent long-term decrease in both SBP and DBP is observed over 24 hours, including the early morning hours. When taking the drug Rasilez at a dose of 300 mg/day, the ratio of the residual effect of the drug to the maximum or target for DBP is 98%. After 2 weeks of regular use of the drug, a decrease in blood pressure by 85–90% of the maximum is observed, the hypotensive effect remains at the achieved level during long-term (up to 1 year) use. After cessation of treatment with Rasilez, a gradual return of blood pressure to the initial level is observed over several weeks, without the development of a withdrawal syndrome and an increase in plasma renin activity. After 4 weeks from the moment of discontinuation of the drug Rasilez, blood pressure levels remained significantly lower compared to placebo. When using the drug for the first time, there is no hypotensive reaction (the “first dose” effect) and a reflex increase in heart rate in response to vasodilation. When using the drug Rasilez as monotherapy and in combination with other antihypertensive drugs, an excessive decrease in blood pressure is observed in 0.1 and 1% of cases, respectively. Combination therapy with Rasilez with ACE inhibitors, angiotensin II receptor antagonists, calcium channel blockers (CCBs) and diuretics is well tolerated by patients and allows for an additional reduction in blood pressure. The incidence of dry cough was significantly lower in patients receiving the combination of the drug Rasilez with the ACE inhibitor ramipril, compared with motor therapy with ramipril (1.8 and 4.7%, respectively). When using the drug Rasilez in combination with the CCB amlodipine at a dose of 10 mg, the incidence of peripheral edema is reduced compared to amlodipine monotherapy (2.1 and 11.4%, respectively). Monotherapy with Rasilez for diabetes mellitus allows you to achieve an effective and safe reduction in blood pressure. In patients with concomitant diabetes mellitus, the use of the drug Rasilez in combination with ramipril leads to a more pronounced decrease in blood pressure compared to that during monotherapy with each drug separately. In patients with hypertension, obesity and insufficient blood pressure control during monotherapy with hydrochlorothiazide, additional administration of the drug Rasilez provides a decrease in blood pressure comparable to the combination of hydrochlorothiazide with irbesartan or amlodipine. The severity of the antihypertensive effect of the drug does not depend on age, gender, race and body mass index. In patients with existing (or a history of) hypertension and compensated chronic heart failure (CHF) of a stable course, receiving standard therapy for CHF (ACE inhibitors or APA II, beta-blockers and for a third of patients - aldosterone antagonists), inclusion in the standard Therapy with the drug Rasilez at a dose of 150 mg/day is well tolerated. Brain natriuretic peptide (BNP) levels were reduced by 25% in the group of patients receiving Rasilez compared to the placebo group. In patients with hypertension, type 2 diabetes mellitus and nephropathy receiving losartan 100 mg and optimized antihypertensive concomitant therapy, the addition of Rasilez at a dose of 300 mg/day leads to a clinically significant decrease in the urinary albumin-creatinine ratio by 20% compared with placebo, i.e. from 58 to 46 mg/mmol. The percentage of patients with a decrease in the albumin-cretinin ratio in urine by at least 50% compared to baseline was 24.7 and 12.5% in the Rasilez and placebo groups, respectively.

Use during pregnancy

There is insufficient data on the safety of using the drug Rasilez during pregnancy. The use of drugs that have a direct effect on the RAAS during pregnancy can cause the development of pathology in the fetus and newborn, as well as lead to their death. The drug Rasilez, like other drugs that have a direct effect on the RAAS, should not be used during pregnancy or in women planning pregnancy. Before prescribing drugs that affect the RAAS, the doctor should inform patients of childbearing age about the possibility of a potential risk to the fetus when using these drugs during pregnancy. If pregnancy occurs during treatment with Rasilez, the drug should be stopped immediately. It is not known whether aliskiren is excreted into breast milk in humans. If therapy is necessary during lactation, breastfeeding should be stopped while taking the drug.

Contraindications for use

Hypersensitivity, history of angioedema when using aliskiren, severe liver failure (more than 9 points on the Child-Pug scale), severe chronic renal failure (creatinine more than 150 µmol/l for women, more than 177 µmol/l for men and/or glomerular filtration less than 30 ml/min), nephrotic syndrome, renovascular hypertension, hemodialysis, simultaneous use of cyclosporine, pregnancy, lactation, children (up to 18 years).

Side effects

Frequency: very often (more than 1/10), often (more than 1/100 and less than 1/10), infrequently (more than 1/1000 and less than 1/100), rarely (more than 1/10000 and less than 1/1000). From the digestive system: often - diarrhea. From the skin: infrequently - skin rash. Laboratory parameters: decrease in Hb and hematocrit by 0.05 mmol/l and 0.16%, respectively; hyperkalemia (0.9% versus 0.6% with placebo). Other: dry cough (0.9% compared to 0.6% with placebo), angioedema. When using aliskiren as monotherapy and in combination with other antihypertensive drugs, an excessive decrease in blood pressure is observed in 0.1% and 1% of cases, respectively.

Directions for use and doses

Orally, regardless of food intake, both as monotherapy and in combination with other antihypertensive drugs. The recommended starting dose of Rasilez is 150 mg once a day. The development of the antihypertensive effect is observed 2 weeks after the start of therapy at a dose of 150 mg 1 time per day. If blood pressure control is insufficient, the dose of the drug can be increased to 300 mg 1 time / day. In patients over 65 years of age, no dose adjustment is required. Use in children and adolescents under 18 years of age. Since the effectiveness and safety of the drug Rasilez in children and adolescents (under 18 years of age) have not yet been established, the drug is not recommended for use in this category of patients. In patients with impaired renal function (with a glomerular filtration rate of more than 30 ml/min) and mild to moderate liver dysfunction (Child-Pough points 5–9), no dose adjustment is required.

Overdose

There are limited data on drug overdose. Symptoms: the most likely and main symptom is a pronounced decrease in blood pressure. Treatment: maintenance therapy.

Interactions with other drugs

Valsartan and metformin reduce the Cmax and AUC of aliskiren by 28%; amlodipine and cimetidine increase the Cmax and AUC of aliskiren by 29% and 19%, respectively. Since P-glycoprotein plays an important role in the regulation of absorption and distribution of aliskiren. When aliskiren is used together with P-glycoprotein inhibitors, its pharmacokinetics changes (depending on the degree of inhibition). No clinically significant interaction of aliskiren with weak or moderate P-glycoprotein inhibitors (atenolol, digoxin, amlodipine, cimetidine) has been established. When using aliskiren (300 mg/day) with the active P-glycoprotein inhibitor atorvastatin (80 mg/day), there is an increase in the AUC and Cmax of aliskiren by 50%. When using aliskiren (300 mg/day) with the active P-glycoprotein inhibitor ketoconazole (200 mg/day), there is an increase in the AUC and Cmax of aliskiren by 80%, an increase in the absorption of ketoconazole in the gastrointestinal tract and a decrease in its excretion in bile. Changes in plasma concentrations of aliskiren when used simultaneously with ketoconazole and atorvastatin are expected in the concentration range determined by doubling the aliskiren dose, however, no dose adjustment of aliskiren is required. When using aliskiren (75 mg) with the active P-glycoprotein inhibitor cyclosporine (200 and 600 mg), the Cmax and AUC of aliskiren increase by 2.5 and 5 times, respectively, and therefore their simultaneous use is not recommended. Reduces the AUC and Cmax of furosemide by 28% and 49%, respectively, which requires dose adjustment of furosemide depending on the clinical effect. Simultaneous intake of K+ salts, potassium-sparing diuretics and other drugs that increase the concentration of K+ in the blood, potassium-containing table salt substitutes can lead to hyperkalemia, and therefore caution is required when using them simultaneously with aliskiren.

Special instructions for use

In patients with diabetes mellitus, during therapy with aliskiren in combination with an ACE inhibitor, an increase in the frequency of hyperkalemia was observed (5.5%). When using the drug Rasilez and other drugs that affect the RAAS in patients with diabetes, it is necessary to regularly monitor the electrolyte composition of the blood plasma and renal function. The drug should be stopped immediately if there are signs of allergic reactions (for example, difficulty breathing or swallowing, swelling of the face, limbs, lips, tongue). During therapy with Rasilez, it is possible to increase the concentration of potassium, creatinine, and blood urea nitrogen, which is characteristic of drugs that affect the RAAS. At the beginning of treatment with Rasilez in patients with reduced blood volume and/or hyponatremia (including against the background of high doses of diuretics), symptomatic arterial hypotension is possible. Before using the drug, correction of water-salt imbalance should be carried out. In patients with reduced blood volume and/or hyponatremia, treatment should be carried out under close medical supervision.

Storage conditions

At a temperature not exceeding 30 °C.

Best before date

12 months

ATX classification:

C Cardiovascular system

C09 Drugs affecting the renin-angiotensin system

C09X Other drugs affecting the renin-angiotensin system

C09XA Renin secretion inhibitors

C09XA02 Aliskiren

Special instructions for the use of the drug Rasilez

Patients with decreased sodium levels and/or decreased intravascular volume . In patients with significant salt deficiency and/or intravascular volume depletion (for example, when using high doses of diuretics), symptomatic hypotension may occur after starting Rasilez. Before starting the administration of Rasilez, this condition should be corrected or treatment should be started under strict medical supervision. Renal dysfunction. In clinical studies, the effect of Rasilez was not studied in patients with hypertension (arterial hypertension) and severe renal impairment (creatinine ≥150 µmol/l for women and ≥177 µmol/l for men and/or an established intraglomerular filtration rate of 30 ml/min), in patients on hemodialysis with nephrotic syndrome or renovascular hypertension. Due to the limited information on the safety of Rasilez in such patients, caution is required when using it in patients with hypertension (arterial hypertension) and severe renal impairment. Taking drugs that affect the RAS may increase potassium levels, serum creatinine and blood urea nitrogen in such patients, therefore, a similar effect can be expected as a result of the use of Rasilez. Renal artery stenosis. There are no data on the use of Rasilez in patients with unilateral or bilateral renal artery stenosis or with stenosis of the artery of a single kidney. Use during pregnancy or breastfeeding. Since no specific clinical studies have been conducted, aliskiren is not recommended for use during pregnancy or for women planning pregnancy. Physicians prescribing any drugs that affect RAS should warn women of reproductive age about the potential risk of exposure to these drugs during pregnancy. If pregnancy is established, the use of Rasilez should be discontinued immediately. It has not been established whether aliskiren passes into breast milk. Due to the potential negative effect on the newborn, the use of Rasilez is not recommended in women during breastfeeding. Children. The safety and effectiveness of Rasilez in children and adolescents (under 18 years of age) have not been studied, therefore Rasilez is not recommended for use in children. The ability to influence reaction speed when driving vehicles or working with other mechanisms. No studies have been conducted on the effect on the ability to drive vehicles and technical devices.

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Interactions of the drug Rasilez

Rasilez has little potential for interaction with other drugs. Clinical pharmacokinetic interaction studies were conducted with acenocoumarol, atenolol, celecoxib, fenofibrate, pioglitazone, allopurinol, isosorbide-5-mononitrate, irbesartan, digoxin, ramipril and hydrochlorothiazide - no interaction with these drugs was established. When combined with the following drugs, aliskiren leads to a 20-30% change in the maximum concentration or AUC of aliskiren: with valsartan - a decrease of 28%, metformin - a decrease of 28%, amlodipine - an increase of 29%, or cimetidine - an increase of 19%. Co-administration of aliskiren does not significantly affect the pharmacokinetics of atorvastatin, valsartan, metformin or amlodipine. Thus, when aliskiren is combined with the latter of these drugs, no dose adjustment is required. CYP 450 interactions. Aliskiren does not inhibit CYP 450 isoenzymes (CYP 1A2, 2C8, 2C9, 2C29, 2D6, 2E1 and CYP 3A). Aliskiren does not induce CYP 3A4. The drug is minimally metabolized by cytochrome P450 enzymes and is therefore not expected to interact with substances that inhibit, induce, or are metabolized by these enzymes. P-glycoprotein interactions. P-glycoprotein (Pgp) multidrug resistance gene 1/1a/1b (MDR1/Mdr1a/1b) has been identified as a major system involved in the absorption and disposition of aliskiren in preclinical studies. The potential for substance interactions with Pgp may depend on the degree of inhibition of this transporter. P-glycoprotein substrates and mild inhibitors. No interactions were noted with atenolol, digoxin, amlodipine and cimetidine. P-glycoprotein is a powerful inhibitor. When aliskiren (300 mg) is administered with atorvastatin (80 mg), the steady-state maximum concentration or AUC of aliskiren increases by 50%. The combined use of ketoconazole (200 mg) with aliskiren (300 mg) resulted in an 80% increase in aliskiren plasma levels (AUC and maximum concentration). Preclinical studies show that concomitant use of aliskiren and ketoconazole increases gastrointestinal absorption of aliskiren and reduces biliary excretion. The change in plasma levels of aliskiren in the presence of atorvastatin or ketoconazole was expected to be within the level that would be achieved if the dose of aliskiren was doubled. Aliskiren at doses up to 600 mg, or twice the recommended therapeutic dose, was determined to be well tolerated in controlled clinical studies. As a result, there is no need to adjust the dose of aliskiren. P-glycoprotein is a very powerful inhibitor. A single-dose interaction study in healthy volunteers showed that cyclosporine (200 and 600 mg) increased the maximum concentration of aliskiren (75 mg) by approximately 2.5-fold and the AUC by approximately 5-fold. Therefore, the combined use of cyclosporine and aliskiren is not recommended. Furosemide. With simultaneous administration of aliskiren with furosemide, the AUC and maximum concentration of furosemide are reduced by 28 and 49%, respectively. Therefore, at the beginning of the use and correction of furosemide therapy, it is recommended to monitor the excretory function in order to exclude a possible decrease in the excretion of aliskiren in clinical situations associated with volume overload. Potassium and potassium-sparing diuretics . Based on experience with other drugs that affect the RAS, concomitant use of aliskiren with the following drugs may lead to an increase in serum potassium levels: potassium-sparing diuretics, potassium-containing dietary supplements or salt substitutes containing potassium. If concomitant use of this combination is necessary, caution should be exercised and serum potassium levels should be monitored.