Rasilez^® (Tablets) Instructions for Use

Marketing Authorization Holder

Novartis Pharma AG (Switzerland)

Manufactured By

Novartis Farma S.p.A. (Italy)

ATC Code

C09XA02 (Aliskiren)

Active Substance

Aliskiren (Rec.INN registered by WHO)

Dosage Forms

	Rasilez^®	Film-coated tablets, 150 mg: 7, 14, 28, 56, 84, 98 or 280 pcs.
		Film-coated tablets, 300 mg: 7, 14, 28, 56, 84, 98 or 280 pcs.

Dosage Form, Packaging, and Composition

Film-coated tablets light pink in color, round, biconvex, with a bevel, without a score, with the imprint “IL” on one side and “NVR” on the other.

	1 tab.
Aliskiren hemifumarate	165.75 mg,
Equivalent to aliskiren content	150 mg

Excipients: microcrystalline cellulose, crospovidone, povidone, magnesium stearate, colloidal anhydrous silicon dioxide, titanium dioxide (E171), red iron oxide (E172), black iron oxide (E172), macrogol (polyethylene glycol 4000), talc, hypromellose (hydroxypropyl methylcellulose).

7 pcs. – blisters (1) – cardboard packs.
7 pcs. – blisters (2) – cardboard packs.
7 pcs. – blisters (4) – cardboard packs.
7 pcs. – blisters (8) – cardboard packs.
7 pcs. – blisters (12) – cardboard packs.
7 pcs. – blisters (14) – cardboard packs.
7 pcs. – blisters (40) – cardboard packs.

Film-coated tablets brownish-pink in color, oval, biconvex, without a score, with the imprint “IU” on one side and “NVR” on the other.

	1 tab.
Aliskiren hemifumarate	331.5 mg,
Equivalent to aliskiren content	300 mg

Film-coated tablets light pink in color, round, biconvex, with a bevel, without a score, with the imprint “IL” on one side and “NVR” on the other.

	1 tab.
Aliskiren hemifumarate	165.75 mg,
Equivalent to aliskiren content	150 mg

Film-coated tablets brownish-pink in color, oval, biconvex, without a score, with the imprint “IU” on one side and “NVR” on the other.

	1 tab.
Aliskiren hemifumarate	331.5 mg,
Equivalent to aliskiren content	300 mg

Clinical-Pharmacological Group

Renin secretion inhibitor. Antihypertensive drug

Pharmacotherapeutic Group

Renin inhibitor

Pharmacological Action

An antihypertensive drug, a selective non-peptide renin inhibitor. Renin secretion by the kidneys and activation of the renin-angiotensin-aldosterone system (RAAS) occurs when blood volume and renal blood flow decrease via a feedback mechanism. Renin acts on angiotensinogen, resulting in the formation of an inactive decapeptide – angiotensin I (ATI), which is converted into the active octapeptide angiotensin II (ATII) with the help of ACE and, partially, without its participation. ATII is a potent 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.

Long-term increase in ATII concentration stimulates the production of inflammatory and fibrotic mediators, leading to target organ damage.

When plasma ATII concentration increases, a decrease in renin secretion via a negative feedback mechanism is observed.

All drugs that inhibit the RAAS (including renin inhibitors) suppress negative feedback, leading to a compensatory increase in plasma renin concentration, which, during treatment with ACE inhibitors and angiotensin II receptor antagonists, leads to an increase in plasma renin activity. However, during treatment with aliskiren, the effects of negative feedback are neutralized, resulting in a decrease in plasma renin activity (by an average of 50-80% in patients with arterial hypertension), AT I, and AT II, both during aliskiren monotherapy and in combination with other antihypertensive drugs.

Increased plasma renin activity is directly associated with an increased risk of cardiovascular diseases in both patients with normal blood pressure and those with arterial hypertension.

In patients with arterial hypertension, the use of Rasilez^® at doses of 150 and 300 mg once daily results in a dose-dependent, prolonged reduction in both systolic and diastolic blood pressure over 24 hours, including the early morning hours. When taking Rasilez^® at a dose of 300 mg/day, the trough-to-peak ratio for diastolic blood pressure is 98%.

After 2 weeks of regular use of the drug, blood pressure reduction reaches 85-90% of the maximum; the antihypertensive effect is maintained at the achieved level during long-term (up to 1 year) use.

After discontinuation of Rasilez^® treatment, a gradual return of blood pressure to baseline levels is observed over several weeks, without the development of withdrawal syndrome and without an increase in plasma renin activity. Four weeks after discontinuation of Rasilez^®, blood pressure levels remain significantly lower compared to placebo.

No first-dose hypotensive reaction or reflex increase in heart rate in response to vasodilation is observed upon initial use of the drug.

Excessive blood pressure reduction is observed in 0.1% and 1% of cases with Rasilez^® monotherapy and in combination with other antihypertensive agents, respectively.

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

The incidence of dry cough is 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 Rasilez^® in combination with the CCB amlodipine at a dose of 10 mg, the frequency of peripheral edema is reduced compared to amlodipine monotherapy (2.1% and 11.4%, respectively).

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

In patients with arterial hypertension, obesity, and insufficient blood pressure control on hydrochlorothiazide monotherapy, the additional prescription of Rasilez^® provides a blood pressure reduction 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, or body mass index.

In patients with existing (or history of) arterial hypertension and stable compensated chronic heart failure (CHF) receiving standard therapy for CHF (ACE inhibitors or angiotensin II receptor antagonists, beta-blockers, and for one-third of patients – aldosterone antagonists), the inclusion of Rasilez^® at a dose of 150 mg/day into standard therapy is well tolerated. Brain natriuretic peptide levels decreased 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 concomitant antihypertensive therapy, the addition of Rasilez^® at a dose of 300 mg/day leads to a clinically significant 20% reduction in the urine albumin-to-creatinine ratio compared to placebo, i.e., from 58 mg/mmol to 46 mg/mmol. The percentage of patients with a reduction in the urine albumin-to-creatinine ratio of at least 50% from baseline was 24.7% and 12.5% in the Rasilez^® and placebo groups, respectively.

Pharmacokinetics

Absorption

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

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

Steady-state plasma concentration (C_ss) of aliskiren is reached between days 5 and 7 with daily once-daily administration and remains constant when the initial dose is doubled.

Distribution

After oral administration, Aliskiren is evenly distributed in the body. After intravenous administration, the mean V_d at steady state is about 135 L, indicating significant extravascular distribution of aliskiren. Aliskiren is moderately bound to plasma proteins (47-51%), independent of concentration.

Metabolism and Excretion

The mean T_1/2 of aliskiren is 40 hours (ranging from 34 to 41 hours).

It is excreted mainly unchanged through the intestine (91%). About 1.4% of the orally administered dose is metabolized via the CYP3A4 isoenzyme. After oral administration, about 0.6% of aliskiren is excreted by the kidneys. After intravenous administration, the mean plasma clearance is about 9 L/h.

Pharmacokinetics in Special Clinical Situations

No dose adjustment of aliskiren is required in patients over 65 years of age.

The pharmacokinetics of aliskiren have been studied in patients with varying degrees of renal impairment. The AUC and C_max of aliskiren in patients with renal impairment after single administration and after reaching C_ss increased by 0.8-2 times compared to healthy individuals. However, no correlation was found between these changes and the degree of renal function impairment.

The pharmacokinetics of aliskiren are not significantly altered in patients with mild to moderate hepatic impairment (5-9 points on the Child-Pugh scale).

Indications

Arterial hypertension.

ICD codes

Open the list of ICD codes

ICD-10 code	Indication
I10	Essential [primary] hypertension

ICD-11 code	Indication
BA00.Z	Essential hypertension, unspecified

Dosage Regimen

The method of application and dosage regimen for a specific drug depend on its form of release and other factors. The optimal dosage regimen is determined by the doctor. It is necessary to strictly adhere to the compliance of the dosage form of a specific drug with the indications for use and dosage regimen.

Rasilez^® can be taken regardless of meals, either as monotherapy or in combination with other antihypertensive agents.

The recommended initial dose of Rasilez^® is 150 mg once daily. The development of the antihypertensive effect is observed 2 weeks after starting therapy at a dose of 150 mg once daily. If blood pressure control is insufficient, the drug dose may be increased to 300 mg once daily.

In patients with mild to moderate renal impairment (with glomerular filtration rate > 30 ml/min) and hepatic impairment (5-9 points on the Child-Pugh scale), no dose adjustment is required.

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

Adverse Reactions

The safety of Rasilez^® has been evaluated in more than 7800 patients. The frequency of adverse reactions was not associated with gender, age, body mass index, or race.

When using the drug at doses up to 300 mg, the overall frequency of adverse reactions was similar to that with placebo use. Adverse reactions were generally mild to moderate, temporary, and rarely required discontinuation of therapy with the drug. Diarrhea was most frequently observed in patients using Rasilez^®.

No increase in the frequency of dry cough, characteristic of ACE inhibitors, was noted with the use of the drug. The frequency of dry cough during treatment with Rasilez^® (0.9%) was similar to that with placebo (0.6%).

During clinical studies, the frequency of angioedema in the Rasilez^® group was similar to that in the placebo or hydrochlorothiazide group.

Definition of frequency of adverse reactions probably related to drug use: very common (≥1/10); common (≥1/100, <1/10); uncommon (≥1/1000, <1/100), rare (≥1/10,000, <1/1000), including isolated reports. Within each group, adverse reactions are presented in order of decreasing significance.

From the digestive system: common – diarrhea.

Dermatological reactions: uncommon – skin rash.

From laboratory parameters rare – during monotherapy, a slight decrease in hemoglobin and hematocrit concentration was observed (on average by 0.05 mmol/L and 0.16%, respectively), which did not require treatment discontinuation (a decrease in hemoglobin and hematocrit concentration is also observed with the use of other drugs affecting the RAAS, in particular ACE inhibitors and angiotensin II receptor antagonists), a slight increase in serum potassium concentration (0.9% compared to 0.6% with placebo).

No clinically significant changes in total cholesterol, HDL, triglycerides, fasting glucose, or uric acid levels were observed.

Allergic reactions in isolated cases – angioedema.

Contraindications

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 procedure;
Severe hepatic impairment (more than 9 points on the Child-Pugh scale);
Children and adolescents under 18 years of age;
Hypersensitivity to the components of the drug.

Caution should be exercised when prescribing the drug to patients with unilateral or bilateral renal artery stenosis or stenosis of the artery to a solitary kidney, diabetes mellitus, reduced blood volume, hyponatremia, hyperkalemia, or patients after kidney transplantation. The safety of Rasilez^® in patients with bilateral renal artery stenosis or stenosis of the artery to a solitary kidney has not been established.

Use in Pregnancy and Lactation

Data on the safety of Rasilez^® use during pregnancy are insufficient. The use during pregnancy of drugs that have a direct effect on the RAAS may cause the development of fetal and neonatal pathology and also lead to their death. Rasilez^®, like other agents that have a direct effect on the RAAS, should not be used during pregnancy and in women planning pregnancy.

Before prescribing drugs that affect the RAAS, the physician should inform women of childbearing potential about the potential risk to the fetus when using these drugs during pregnancy. If pregnancy occurs during treatment with Rasilez^®, the drug should be discontinued immediately.

It is not known whether Aliskiren is excreted in human breast milk. If therapy is necessary during lactation, breastfeeding should be discontinued during the drug intake.

Use in Hepatic Impairment

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

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

Use in 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 procedure.

Caution should be exercised when prescribing the drug to patients with unilateral or bilateral renal artery stenosis or stenosis of the artery to a solitary kidney (safety of Rasilez^® not established), patients after kidney transplantation.

In patients with renal impairment (with glomerular filtration rate greater than 30 ml/min), no dose adjustment is required.

Pediatric Use

Since the safety and efficacy 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.

Geriatric Use

In patients over 65 years of age, dose adjustment of the drug is not required.

Special Precautions

The efficacy and safety of Rasilez^® have not been established: in patients with severe renal impairment (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 undergoing regular hemodialysis procedure, as well as in patients with severe hepatic impairment (more than 9 points on the Child-Pugh scale).

In patients with diabetes mellitus, an increased incidence of hyperkalemia (5.5%) was observed during therapy with aliskiren in combination with an ACE inhibitor. When using Rasilez^® and other drugs affecting the RAAS in patients suffering from diabetes mellitus, it is necessary to regularly monitor plasma electrolyte levels and renal function.

Administration of the drug should be stopped immediately if signs of allergic reactions occur (e.g., difficulty breathing or swallowing, swelling of the face, extremities, lips, tongue).

During therapy with Rasilez^®, an increase in the concentration of potassium, creatinine, and blood urea nitrogen, characteristic of drugs affecting the RAAS, is possible.

At the beginning of treatment with Rasilez^®, symptomatic arterial hypotension may occur in patients with reduced circulating blood volume and/or hyponatremia (including due to high doses of diuretics). Correction of water and electrolyte balance disorders should be carried out before using the drug. In patients with reduced circulating blood volume and/or hyponatremia, treatment should be carried out under careful medical supervision.

Use in Pediatrics

Since the safety and efficacy 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.

Effect on 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 is limited data on drug overdose.

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

Treatment supportive therapy should be administered.

Drug Interactions

The likelihood of interaction of aliskiren with other drugs is low.

No clinically significant interaction of aliskiren with acenocoumarol, atenolol, celecoxib, fenofibrate, pioglitazone, allopurinol, isosorbide 5-mononitrate, irbesartan, digoxin, ramipril, and hydrochlorothiazide was identified.

When using aliskiren with one of the drugs listed below, a change in its C_max or AUC is possible: valsartan (decrease by 28%), metformin (decrease by 28%), amlodipine (increase by 29%), cimetidine (increase by 19%).

Since co-administration of Aliskiren does not have a significant effect on the pharmacokinetics of atorvastatin, valsartan, metformin, amlodipine, no dose adjustments of Rasilez^® or the aforementioned drugs are required when used concomitantly.

Aliskiren does not inhibit the cytochrome P450 system isoenzymes (CYP1A2, 2C8, 2C9, 2C19, 2D6, 2E1, and CYP3A) and does not induce the CYP3A4 isoenzyme. Since Aliskiren is minimally metabolized with the participation of cytochrome P450 system isoenzymes, a clinically significant effect of Rasilez^® on the bioavailability of drugs that are inducers or inhibitors of cytochrome P450 system isoenzymes or metabolized with their 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, a change in the pharmacokinetics of the latter is possible when used concomitantly with substances that inhibit Pgp (depending on the degree of inhibition). No significant interaction of aliskiren with weak or moderately active Pgp inhibitors, such as atenolol, digoxin, amlodipine, and cimetidine, has been established.

When used concomitantly with the potent Pgp inhibitor atorvastatin (at a dose of 80 mg/day) at steady state, an increase in the AUC and C_max of aliskiren (dose 300 mg/day) by 50% was noted.

When the potent Pgp inhibitor ketoconazole (200 mg) and aliskiren (300 mg) are taken concomitantly, an 80% increase in the plasma concentration of the latter (AUC and C_max) is observed. In experimental studies, concomitant administration of aliskiren with ketoconazole led to increased absorption of the latter from the gastrointestinal tract and reduced its biliary excretion. Changes in the plasma concentration of aliskiren when used concomitantly with ketoconazole or atorvastatin are expected to be within the range of concentrations determined when the dose of aliskiren is doubled. In controlled clinical studies, the safety of the drug at a dose of 600 mg and doubling the maximum recommended therapeutic dose has been demonstrated. When using aliskiren together with ketoconazole or atorvastatin, no dose adjustment of aliskiren is required.

When used with such a highly potent Pgp inhibitor as cyclosporine (200 and 600 mg) in healthy individuals, an increase in the C_max and AUC of aliskiren (75 mg) by 2.5 and 5 times, respectively, was noted. Therefore, it is not recommended to use Rasilez^® concomitantly with cyclosporine.

When aliskiren is used concomitantly with furosemide, a decrease in the AUC and C_max of furosemide by 28% and 49%, respectively, is observed. To prevent possible fluid retention when prescribing aliskiren together with furosemide at the beginning and during treatment, the dose of furosemide should be adjusted depending on the clinical effect.

Given the experience with other drugs affecting the RAAS, Aliskiren should be prescribed with caution together with potassium salts, potassium-sparing diuretics, potassium-containing salt substitutes, or any other drugs that can increase the concentration of potassium in the blood.

Storage Conditions

The drug should be stored out of the reach of children at a temperature not exceeding 30°C (86°F).

Shelf Life

Shelf life is 2 years.

Dispensing Status

The drug is dispensed by prescription.

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.

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