Composition, form of production and packaging
The tablets covered with a film cover of light pink color, round, biconcave, with a facet, without risks, with an overprint "IL" on one side and "NVR" - on another.
1 tab.
aliskiren hemifumarate 165.75 mg,
which corresponds to the content of aliskiren 150 mg
[PRING] microcrystalline cellulose, crospovidone, povidone, magnesium stearate, silicon dioxide, colloidal anhydrous, titanium dioxide (E171), iron oxide red (E172), iron oxide black (E172), macrogol (polyethylene glycol 4000), talc, hypromellose (hydroxypropylmethylcellulose) .
7 pcs. - blisters (1) - packs of cardboard.
7 pcs. - blisters (2) - packs of cardboard.
7 pcs. - blisters (4) - packs of cardboard.
7 pcs. - blisters (8) - packs of cardboard.
7 pcs. - blisters (12) - packs of cardboard.
7 pcs. - blisters (14) - packs of cardboard.
7 pcs. - blisters (40) - packs of cardboard.
The tablets covered with a film membrane brownish-pink color, oval, biconcave, without risks, with an overprint "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
[PRING] microcrystalline cellulose, crospovidone, povidone, magnesium stearate, silicon dioxide, colloidal anhydrous, titanium dioxide (E171), iron oxide red (E172), iron oxide black (E172), macrogol (polyethylene glycol 4000), talc, hypromellose (hydroxypropylmethylcellulose) .
7 pcs. - blisters (1) - packs of cardboard.
7 pcs. - blisters (2) - packs of cardboard.
7 pcs. - blisters (4) - packs of cardboard.
7 pcs. - blisters (8) - packs of cardboard.
7 pcs. - blisters (12) - packs of cardboard.
7 pcs. - blisters (14) - packs of cardboard.
7 pcs. - blisters (40) - packs of cardboard.
The tablets covered with a film cover of light pink color, round, biconcave, with a facet, without risks, with an overprint "IL" on one side and "NVR" - on another.
1 tab.
aliskiren hemifumarate 165.75 mg,
which corresponds to the content of aliskiren 150 mg
[PRING] microcrystalline cellulose, crospovidone, povidone, magnesium stearate, silicon dioxide, colloidal anhydrous, titanium dioxide (E171), iron oxide red (E172), iron oxide black (E172), macrogol (polyethylene glycol 4000), talc, hypromellose (hydroxypropylmethylcellulose) .
7 pcs. - blisters (1) - packs of cardboard.
7 pcs. - blisters (2) - packs of cardboard.
7 pcs. - blisters (4) - packs of cardboard.
7 pcs. - blisters (8) - packs of cardboard.
7 pcs. - blisters (12) - packs of cardboard.
7 pcs. - blisters (14) - packs of cardboard.
7 pcs. - blisters (40) - packs of cardboard.
The tablets covered with a film membrane brownish-pink color, oval, biconcave, without risks, with an overprint "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
[PRING] microcrystalline cellulose, crospovidone, povidone, magnesium stearate, silicon dioxide, colloidal anhydrous, titanium dioxide (E171), iron oxide red (E172), iron oxide black (E172), macrogol (polyethylene glycol 4000), talc, hypromellose (hydroxypropylmethylcellulose) .
7 pcs. - blisters (1) - packs of cardboard.
7 pcs. - blisters (2) - packs of cardboard.
7 pcs. - blisters (4) - packs of cardboard.
7 pcs. - blisters (8) - packs of cardboard.
7 pcs. - blisters (12) - packs of cardboard.
7 pcs. - blisters (14) - packs of cardboard.
7 pcs. - blisters (40) - packs of cardboard.
INSTRUCTION FOR THE SPECIALIST.
Description of the drug approved by the manufacturer for the printed edition of 2011.
PHARMACHOLOGIC EFFECT
Antihypertensive drug, selective inhibitor of renin of non-peptide structure. Renin secretion by the kidneys and activation of the renin-angiotensin-aldosterone system (RAAS) occurs with a decrease in bcc and renal blood flow by the feedback mechanism. Renin acts on angiotensinogen, resulting in the formation of an inactive decapeptide - angiotensin I (ATI), which with ACE and, partially, without its participation, is converted to the active octapeptide angiotensin II (ATII). ATII is a potent vasoconstrictor, stimulates the release of catecholamines from the adrenal medulla and presynaptic nerve endings, and enhances the secretion of aldosterone and the reabsorption of sodium ions, which ultimately leads to an increase in blood pressure.
A prolonged increase in the concentration of ATII stimulates the production of mediators of inflammation and fibrosis, which leads to the defeat of target organs.
When the concentration of ATII in the blood plasma increases, there is a decrease in renin secretion by the mechanism of negative feedback.
All preparations inhibiting RAAS (including renin inhibitors) inhibit negative feedback, leading to a compensatory increase in renin plasma concentration, which, when treated with ACE inhibitors and angiotensin II receptor antagonists, leads to an increase in plasma renin activity, however, in the treatment with aliskiren, the effects of negative feedback bonds are neutralized, as a result of which plasma renin activity (in patients with arterial hypertension, on average 50-80%), AT I and AT II decreases, both with monotherapy with aliskiren and and its combination with other antihypertensive drugs.
Increased renin activity of blood plasma is directly associated with an increased risk of cardiovascular disease in both patients with normal blood pressure and in patients with hypertension.
In patients with arterial hypertension with the use of Racileus 150 and 300 mg once a day, a dose-dependent prolonged decrease in both systolic and diastolic blood pressure is observed within 24 hours, including the early morning hours. When taking Racilez 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 intake of the drug, blood pressure drops by 85-90% of the maximum, the hypotensive effect remains at the achieved level during long (up to 1 year) use.
After discontinuation of treatment with Racileus, a gradual return of blood pressure to the baseline is observed for several weeks, without the development of a withdrawal syndrome and an increase in renin activity of the blood plasma. In 4 weeks after the withdrawal of Racileus, the blood pressure level remains significantly lower in comparison with placebo.
When using the drug for the first time, there is no hypotensive reaction (first-dose effect) and a reflex increase in heart rate in response to vasodilation.
In the application of Racilez in the form of monotherapy and in combination with other antihypertensive agents, an excessive decrease in blood pressure is observed in 0.1% and 1% of cases, respectively.
Combination therapy with racemose with ACE inhibitors, angiotensin II receptor antagonists, slow calcium channel blockers (BCCI), and diuretics is well tolerated by patients and allows an additional reduction in blood pressure.
The frequency of development of dry cough was significantly lower in patients who received combination of Racileza with an inhibitor of ACE ramipril compared with ramipril monotherapy (1.8% and 4.7%, respectively). With the use of the drug Racilez in combination with BCCK amlodipine at a dose of 10 mg, the incidence of peripheral edema decreases compared with amlodipine alone (2.1% and 11.4%, respectively).
Monotherapy Racilez with concomitant diabetes mellitus allows to achieve an effective and safe reduction in blood pressure. In patients with concomitant diabetes, the use of the drug Racilez in combination with ramipril leads to a more pronounced decrease in blood pressure compared with that in the background of monotherapy with each drug alone.
In patients with arterial hypertension, obesity and insufficient control of blood pressure with monotherapy with hydrochlorothiazide, the addition of Racileus medication provides a reduction in blood pressure comparable to a combination of hydrochlorothiazide with irbesartan or amlodipine.
The severity of the antihypertensive effect of the drug does not depend on age, sex, race and body mass index.
In patients with an existing (or history) arterial hypertension and compensated chronic heart failure (CHF) of stable course who received standard therapy in connection with CHF (ACE inhibitors or angiotensin II receptor antagonists, beta-adrenoblockers and for a third of patients - aldosterone antagonists), Inclusion in standard therapy of the drug Racilez in a dose of 150 mg / day is well tolerated. The level of the brain natriuretic peptide is reduced by 25% in the group of patients receiving Racilez compared with the placebo group.
In patients with hypertension, type 2 diabetes and nephropathy receiving losartan at a dose of 100 mg and optimized antihypertensive concomitant therapy, the addition of the drug Racilez at a dose of 300 mg / day leads to a clinically significant decrease in the albumin-creatinine ratio in urine by 20% with placebo, i.e. from 58 mg / mmol to 46 mg / mmol. The percentage of patients with a decrease in the albumin-creatinine ratio in urine by at least 50% compared with the baseline is 24.7% and 12.5% ​​in the Racile and placebo groups, respectively.
PHARMACOKINETICS
Suction
After oral administration, the time to achieve C max aliskiren in blood plasma is 1-3 hours, absolute bioavailability is 2.6%. Simultaneous food intake reduces C maxand AUC 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 C max and AUC of aliskiren has a linear dependence on the dose of the drug in the range of 75 to 600 mg.
C ss aliskiren in blood plasma is achieved between 5 and 7 in the day with a daily intake of 1 time / day and remains constant with an increase in the initial dose of 2 times.
Distribution
Once ingested, aliskiren is evenly distributed in the body. After intravenous administration, the average V d in the equilibrium state is about 135 liters, indicating a significant extravascular distribution of aliskiren. Aliskiren moderately binds to blood plasma proteins (47-51%), regardless of concentration.
Metabolism and excretion
The average T 1/2 aliskiren is 40 hours (varies from 34 to 41 hours).
It is excreted mainly unchanged through the intestine (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 iv introduction, the average plasma clearance is about 9 l / h.
Pharmacokinetics in special clinical cases
When using aliskiren in patients older than 65 years, dose adjustment is not required.
The pharmacokinetics of aliskiren has been studied in patients with renal insufficiency of varying severity. The values ​​of AUC and C max aliskiren in patients with renal insufficiency after a single application and after reaching C ss increased by 0.8-2 times in comparison with healthy individuals. However, no correlation was found between the above changes and the degree of renal function impairment.
The pharmacokinetics of aliskiren does not change significantly in patients with mild and moderate impairment of liver function (5-9 on the Child-Pugh scale).
INDICATIONS
- arterial hypertension.
DOSING MODE
Racial can be used regardless of food intake, either as a monotherapy or in combination with other antihypertensive drugs.
The recommended initial dose of Racileza is 150 mg 1 time / day. Development of antihypertensive effect is observed in 2 weeks after the beginning of therapy in a dose of 150 mg 1 time / day. With insufficient control of blood pressure, the dose of the drug can be increased to 300 mg 1 time / day.
In patients with impaired renal function (at a glomerular filtration rate> 30 ml / min) and liver (5-9 points on the Child-Pugh scale), mild to moderatedosage adjustment is not required.
Patients over 65 years of age are not required to adjust the dose.
SIDE EFFECT
The safety of the use of Racileza was evaluated in more than 7800 patients. The frequency of adverse reactions was not related to gender, age, body mass index or race.
When the drug was administered in a dose of up to 300 mg, the overall incidence of adverse reactions was similar to that of placebo. Unwanted reactions were generally moderately expressed, were temporary and rarely required discontinuation of therapy with the drug. Most often, with the use of Racileza, patients experienced diarrhea.
When using the drug, there was no increase in the incidence of dry cough, characteristic of ACE inhibitors. The frequency of development of dry cough in the background of treatment with Racileus (0.9%) was similar to that of placebo (0.6%).
In clinical studies in the Racileza group, the frequency of angioedema development was similar to that in the placebo group or hydrochlorothiazide.
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 individual messages. Within each group, adverse reactions are presented in order of decreasing significance.
From the digestive system: often - diarrhea.
Dermatological reactions: sometimes - skin rash.
From the laboratory: rarely - against a background of monotherapy, there was a slight decrease in the concentration of hemoglobin and hematocrit (an average of 0.05 mmol / L and 0.16%, respectively), which did not require the withdrawal of treatment (a decrease in the hemoglobin and hematocrit concentration is also observed with other drugs affecting RAAS, in particular ACE inhibitors and angiotensin II receptor antagonists), a slight increase in serum potassium concentration (0.9% versus 0.6% with placebo).
There were no clinically significant changes in total cholesterol, HDL cholesterol, or triglycerides, glucose or uric acid on an empty stomach.
Allergic reactions: in some cases - angioedema.
CONTRAINDICATIONS
- severe renal dysfunction (serum creatinine> 150 Ојmol / l for women and> 177 Ојmol / l for men and / or glomerular filtration rate <30 ml / min);
- nephrotic syndrome;
- Renovascular hypertension;
- regular hemodialysis procedure;
- violations of liver function of a serious degree (more than 9 points on the Child-Pugh scale);
- children and adolescence under 18;
- Hypersensitivity to the components of the drug.
Caution should be given to patients with unilateral or bilateral stenosis of the renal arteries or stenosis of the artery of a single kidney, diabetes mellitus, reduced bcc, hyponatremia, hyperkalemia or patients after kidney transplantation. Safety of the use of Racileza in patients with bilateral stenosis of the renal arteries or stenosis of the artery of a single kidney is not established.
PREGNANCY AND LACTATION
Data on the safety of the use of Racileza in pregnancy is not enough. The use of drugs that directly affect RAAS during pregnancy can cause the development of fetal and newborn pathologies, as well as lead to their death. Racilus, like other drugs that have a direct effect on RAAS, should not be used in pregnancy and in women planning pregnancy.
Before prescribing drugs that affect RAAS, the physician should inform the patient of childbearing age about the potential risk to the fetus when using these medicines during pregnancy. At the onset of pregnancy during the treatment with Racilez, the drug should be stopped immediately.
It is not known whether aliskiren is excreted in human milk. If it is necessary to perform therapy during lactation, breastfeeding should be stopped for the time of taking the drug.
APPLICATION FOR FUNCTIONS OF THE LIVER
The drug is contraindicated in cases of severe impairment of renal function (serum creatinine> 150 Ојmol / l for women and> 177 Ојmol / l for men and / or glomerular filtration rate <30 ml / min); nephrotic syndrome; Renovascular hypertension; the need for regular hemodialysis.
Caution should be given to patients with unilateral or bilateral stenosis of the renal arteries or stenosis of the artery of a single kidney (safety of Racileus not established), to patients after kidney transplantation.
In patients with impaired renal function (at a glomerular filtration rate of more than 30 ml / min), dose adjustment is not required.
APPLICATION FOR VIOLATIONS OF THE FUNCTION OF KIDNEYS
The drug is contraindicated in violations of liver function of a serious degree (more than 9 points on the Child-Pugh scale).
In patients with impaired hepatic function (5-9 points on the Child-Pugh scale), mild to severe dose adjustment is not required.
APPLICATION FOR CHILDREN
Since the safety and effectiveness of Racilez in children and adolescents under the age of 18 years have not yet been established, the drug should not be used in this category of patients.
APPLICATION IN ELDERLY PATIENTS
Patients over 65 years of age are not required to adjust the dose.
SPECIAL INSTRUCTIONS
The efficacy and safety of Racilez have not been established: in patients with severe impaired renal function (serum creatinine> 150 Ојmol / l for women and> 177 Ојmol / l for men and / or glomerular filtration rate less than 30 ml / min), with nephrotic syndrome , Renovascular hypertension and regular hemodialysis procedure, as well as in patients with severe hepatic dysfunction (more than 9 on the Child-Pugh scale).
In patients with diabetes mellitus, an increase in the frequency of hyperkalemia (5.5%) was noted with aliskiren in combination with an ACE inhibitor. When using Racileza and other drugs that affect RAAS, patients with diabetes mellitus should regularly monitor the electrolyte composition of the blood plasma and kidney function.
The drug should be stopped immediately if signs of allergic reactions (eg, difficulty breathing or swallowing, swelling of the face, extremities, lips, tongue).
Against the background of therapy with Racileus, an increase in the concentration of potassium, creatinine, blood urea nitrogen, characteristic for preparations that affect RAAS, is possible.
At the beginning of treatment with ratsilezom in patients with reduced BCC and / or hyponatremia (including against a background of high doses of diuretics), symptomatic arterial hypotension is possible. Before applying the drug, correction of the water-salt balance should be carried out. In patients with reduced BCC and / or hyponatremia, treatment should be performed under close medical supervision.
Use in Pediatrics
Since the safety and effectiveness of Racilez in children and adolescents under the age of 18 years have not yet been established, the drug should not be used in this category of patients.
Impact on the ability to drive vehicles and manage mechanisms
Rasileza influence on the ability to road management and operation mechanisms have not been studied.
OVERDOSE
There are limited data on drug overdose.
Symptoms: The most likely and the main symptom - marked reduction of blood pressure.
Treatment: maintenance therapy.
DRUG INTERACTION
The probability of interaction of aliskiren with other drugs is low.
There were no clinically significant interaction with aliskiren acenocoumarol, atenolol, celecoxib, fenofibrate, pioglitazone, allopurinol, isosorbide 5-mononitrate, irbesartan, digoxin, ramipril and hydrochlorothiazide.
In the application of aliskiren with one of the following drugs may change its C max or AUC: valsartan (reduced by 28%), metformin (a decrease of 28%), amlodipine (increase 29%), cimetidine (19% increase).
Since the combined use of aliskiren has no significant effect on the pharmacokinetics of atorvastatin, valsartan, metformin, amlodipine, while appointing change doses Rasileza or above preparations are required.
Aliskiren does not inhibit the cytochrome P450 system isozymes (CYP1A2, 2S8, 2S9, 2S19, 2 D6, 2E1 and CYP3A) and does not induce isoenzyme CYP3A4. Since aliskiren is metabolized to a minor extent, with the participation of cytochrome P450 isoenzymes, Rasileza clinically significant effect on the bioavailability of drugs which are inducers, or inhibitors of the cytochrome P450 or metabolized with his participation is unlikely.
Interaction at the level of P-glycoprotein (Pgp), encoded by the genes MDR1 / Mdr 1a / 1b.As in experimental studies it has been found that P-glycoprotein (membrane transporter molecules) plays an important role in regulating the absorption and distribution of aliskiren may alter the pharmacokinetics of the latter while the use of substances inhibiting Pgp (depending on the degree of inhibition). Not identified significant interaction aliskiren with weakly or moderately active Pgp-inhibitors, such as atenolol, digoxin, amlodipine and cimetidine.
When applied simultaneously with the active Pgp-inhibitor atorvastatin (80 mg / day) in the equilibrium state marked increase in AUC and C max of aliskiren (dosage of 300 mg / day) of 50%.
When simultaneous administration of the active Pgp-inhibitor ketoconazole (200 mg) and aliskiren (300 mg) observed elevated plasma concentration of the latter (AUC and C max) 80%. In experimental studies, concomitant use of aliskiren with ketoconazole resulted in an increase in the absorption of the latter from the gastrointestinal tract and reduce its excretion in the bile. Changes in plasma concentrations of aliskiren in the plasma while the use of ketoconazole or atorvastatin concentrations are expected in the range defined with increasing doses of aliskiren to 2 times. In controlled clinical studies have demonstrated safety of the drug at a dose of 600 mg, and increasing the maximum recommended therapeutic dose 2 times. In applying aliskiren together with ketoconazole or atorvastatin dose adjustment of aliskiren is not required.
When applied to such highly active inhibitor of Pgp-like cyclosporin (200 and 600 mg) in healthy individuals showed an increase in C maxand AUC aliskiren (75 mg) in 2.5 and 5 times, respectively. Therefore, Rasilez should not be used simultaneously with cyclosporine.
With simultaneous use of aliskiren with furosemide marked decrease AUC and C max of furosemide at 28% and 49% respectively. To prevent a possible delay in the appointment liquid aliskiren together with furosemide in the beginning and during the treatment to adjust the dose of furosemide is necessary depending on the clinical effect.
Given the experience of other drugs affecting the RAAS should be used with caution aliskiren together with potassium salts, potassium-sparing diuretics, potassium-containing edible salt substitutes or any other agents which are capable of increasing the concentration of potassium in the blood.
TERMS OF RELEASE FROM PHARMACY
The drug is released by prescription.
TERMS AND CONDITIONS OF STORAGE
The drug should be stored out of reach of children at a temperature of no higher than 30 В° C. Shelf life - 2 years.
