Composition, form of production and packaging
The tablets covered with a film cover of light pink color, round, slightly biconcave.
1 tab.
aliskiren in the form of a substance-granules 150 mg
[PRING] cellulose microcrystalline 84.75 mg, crospovidone 21.25 mg, silicon dioxide colloid 2.5 mg, magnesium stearate 10 mg.
Composition of the film coat: Opaprai pink OY-S-24900 15 mg, including hypromellose (66%), macrogol (6.6%), titanium dioxide (27%), iron dye oxide yellow (0.15%), iron oxide dye red (0.15%).
7 pcs. - packings of cellular contour (1) - packs cardboard.
7 pcs. - packings cellular planimetric (2) - packs cardboard.
7 pcs. - packings cellular planimetric (4) - packs cardboard.
7 pcs. - packings cellular planimetric (8) - packs cardboard.
7 pcs. - packings cellular planimetric (12) - packs cardboard.
7 pcs. - packings cellular planimetric (14) - packs cardboard.
7 pcs. - packings cellular planimetric (40) - packs cardboard.
The tablets covered with a film cover of light pink color, round, slightly biconcave.
1 tab.
aliskiren in the form of a substance-granules 300 mg
[PRING] microcrystalline cellulose 169.5 mg, crospovidone 42.5 mg, silicon dioxide colloid 5 mg, magnesium stearate 20 mg.
Composition of the film coat: Opaprai pink OY-S-24900 15 mg, including hypromellose (66%), macrogol (6.6%), titanium dioxide (27%), iron dye oxide yellow (0.15%), iron oxide dye red (0.15%).
7 pcs. - packings of cellular contour (1) - packs cardboard.
7 pcs. - packings cellular planimetric (2) - packs cardboard.
7 pcs. - packings cellular planimetric (4) - packs cardboard.
7 pcs. - packings cellular planimetric (8) - packs cardboard.
7 pcs. - packings cellular planimetric (12) - packs cardboard.
7 pcs. - packings cellular planimetric (14) - packs cardboard.
7 pcs. - packings cellular planimetric (40) - packs cardboard.
INSTRUCTION FOR THE SPECIALIST.
Description of the drug approved by the manufacturer for the printed edition of 2014.
PHARMACHOLOGIC EFFECT
Aliskiren is a selective inhibitor of renin of a non-peptide structure. Renin secretion by the kidneys and the activation of the renin-angiotensin-aldosterone system (RAAS) occur with a decrease in the volume of circulating blood (BCC) and renal blood flow by the feedback mechanism. Renin acts on angiotensinogen with the formation of an inert decapeptide - apyotensin I (AT I ), which under the action of angiotensin-converting enzyme (ACE) and, partially, without its participation, turns into active octapeptide-angiotensin II (AT II ). AT II 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, leading to an increase in blood pressure.
A prolonged increase in AT II activity in the blood plasma stimulates the formation of mediators of inflammation and fibrosis with further damage to target organs.
When the activity of AT II in the blood plasma increases, the secretion of renin decreases through the mechanism of "negative" feedback. All preparations that inhibit RAAS (including renin inhibitors) inhibit "negative" feedback, causing a compensatory increase in renin activity in the blood plasma. ACE inhibitors and angiotensin II receptor antagonists (APA II) increase the activity of renin in the blood plasma, whereas the use of aliskiren in monotherapy or in combination with other antihypertensive drugs neutralizes the effects of suppressing the reverse "negative" connection, causing a decrease in plasma renin activity (on average 50-80% in patients with arterial hypertension). The activity of AT I and AT II in blood plasma also decreases, as with monotherapy with aliskiren, and when combined with other antihypertensive drugs. Increased plasma renin activity leads to an increased risk of developing cardiovascular diseases.
The use of aliskiren in a dose of 150 mg and 300 mg once a day in patients with hypertension leads to a prolonged dose-dependent decrease in systolic and diastolic blood pressure within 24 hours, including the early morning hours. If aliskiren is used at a dose of 300 mg per day, the ratio of the residual antihypertensive effect of the drug to the maximum for diastolic blood pressure is 98%.
After 2 weeks of regular use of aliskiren, blood pressure is reduced by 85-90% of the maximum value, the antihypertensive effect remains at the level reached with long-term (up to 1 year) use.
After discontinuation of aliskiren therapy, blood pressure gradually returns to baseline within a few weeks without the development of a withdrawal syndrome and an increase in renin plasma activity.
After 4 weeks after discontinuation of aliskiren, blood pressure remains significantly lower in comparison with placebo.
At the beginning of aliskiren therapy, there is no excessive decrease in blood pressure (the effect of the "first" dose) and a reflex increase in the heart rate (heart rate) in response to vasodilation.
Excessive decrease in blood pressure is observed in 0.1% and 1% of patients taking aliskiren in monotherapy and simultaneously with other antihypertensive agents, respectively. The simultaneous use of aliskiren with ACE inhibitors, ARA II, 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 a "dry" cough is significantly lower in patients taking aliskiren simultaneously with an inhibitor of ACE-ramipril, compared with ramipril monotherapy (1.8% and 4.7%, respectively). When aliskiren is used simultaneously with BCCA-amlodipine at a dose of 10 mg, the incidence of peripheral edema decreases in comparison with amlodipine monotherapy (2.1% and 11.4%, respectively).
Aliskiren monotherapy with concomitant diabetes mellitus (DM) provides a safe and effective reduction in blood pressure. The simultaneous use of aliskiren with ramipril in patients with diabetes leads to a greater reduction in blood pressure in comparison with the monotherapy of each of the drugs alone.
The additional use of aliskiren in patients with arterial hypertension, obesity and inadequate control of blood pressure along with monotherapy with hydrochlorothiazide, provides an additional reduction in blood pressure, comparable to a combination of hydrochlorothiazide with irbesartan or amlodipine. The severity of the antihypertensive effect of aliskiren does not depend on the age, sex, ethnicity and body mass index of the patient.
In patients with an existing (or anamnesis) hypertension and compensated chronic heart failure (CHF) of stable course who received standard therapy in connection with CHF (ACE inhibitors or ARA II, beta-blockers and (or) for a third of patients - aldosterone antagonists) , the inclusion in standard therapy of aliskiren at a dose of 150 mg per day is well tolerated. The concentration of brain natriuretic peptide (MNI) is reduced by 25% in the group of patients receiving aliskiren, compared with the placebo. In patients with arterial hypertension, type 2 diabetes and nephropathy receiving losartan at a dose of 100 mg per day and optimized concomitant antihypertensive therapy, the addition of aliskiren at a dose of 300 mg per day leads to a clinically significant decrease in the albumin / creatinine ratio in urine by 20% with placebo and 50% compared with baseline (24.7% and 12.5% ​​in groups receiving aliskiren and placebo, respectively).
PHARMACOKINETICS
Suction
The time to reach (TC max ) after ingestion is 1-3 hours, the absolute bioavailability is 2.6%. The intake of aliskiren in combination with fat-rich foods reduces the maximum concentration in the blood plasma (C max ) and the area under the concentration-time curve (AUC), however, this does not have a significant effect on the pharmacodynamics of aliskiren. Therefore, aliskiren can be taken regardless of the time of ingestion. The pharmacokinetics (C max and AUC) of aliskiren are linear in the dose range from 75 to 600 mg. The equilibrium concentration of aliskiren in blood plasma is reached between the 5th and the 7th day with daily intake once a day.In this case, the concentration of aliskiren in blood plasma is 2 times higher than that after a single oral intake.
Distribution
Once ingested, aliskiren is evenly distributed in the body. The average volume of distribution after intravenous administration in the equilibrium state is about 135 liters, which confirms the significant extravascular distribution of aliskiren. Aliskiren moderately binds to blood plasma proteins (47 - 51%) regardless of concentration.
Metabolism and excretion
T 1/2 aliskiren is 40 hours (varies from 34 to 41 hours). About 1.4% of the ingested dose is metabolized with the participation of the CYP3A4 isofermeptide. Aliskiren is excreted, in the main, unchanged through the intestine (78%). After ingestion about 0.6% aliskiren is excreted by the kidneys. The average plasma clearance after intravenous administration is about 9 l / h.
Pharmacokinetics in specific patient groups
Impaired renal function
The values ​​of AUC and C max aliskiren in patients with impaired renal function after a single oral intake and after reaching an equilibrium concentration are 0.8-2 times higher than the values ​​in healthy volunteers. However, there was no correlation between the above changes and the degree of renal dysfunction.
Correction of the initial dose in patients with mild and moderate renal dysfunction is not required. Patients with severe renal failure (glomerular filtration rate (GFR) <30 ml / min / 1.73 m 2 ) use of aliskiren is contraindicated. The simultaneous use of aliskiren with ARA II or ACE inhibitors in patients with renal insufficiency (GFR <60 ml / min / 1.73 m 2 ) is contraindicated.
In patients on hemodialysis, a single oral intake of aliskiren at a dose of 300 mg was accompanied by minor changes in the pharmacokinetics of aliskiren (an increase in C max of less than 1.2, an increase in AUC of 1.6 times) compared with healthy volunteers. The duration of hemodialysis did not have a significant effect on the pharmacokinetics of aliskiren in patients with terminal renal insufficiency. If it is necessary to use aliskiren in patients with terminal renal failure who are on hemodialysis, dose adjustment is not required. However, the use of aliskiren is contraindicated in patients with severe renal failure.
Impaired liver function
The pharmacokinetics of aliskiren does not change significantly in patients with mild, moderate and severe impairment of liver function, so there is no need to adjust the initial dose.
Patients of advanced age (over 65 years)
Dose adjustments in patients over 65 years of age are not required.
INDICATIONS
- arterial hypertension.
DOSING MODE
Inside, take with a small amount of food once a day, preferably at the same time. Do not drink grapefruit juice.
The drug Rixila can be used both in monotherapy and in combination with other antihypertensive agents, except for ACE inhibitors or ARA II in patients with diabetes and impaired renal function (GFR <60 ml / min / 1.73 m 2 ).
The recommended initial dose of Rixil is 150 mg (1 tablet) once a day. The maximum antihypertensive effect (85-90%) develops within 2 weeks after the beginning of application in a dose of 150 mg once a day. With insufficient control of blood pressure, the dose can be increased to 300 mg once a day.
The use in elderly patients (over 65 years)
Correction of the initial dose in patients older than 65 years is not required. In elderly patients with increasing doses up to 300 mg / day there is no clinically significant additional decrease in blood pressure.
Patients under the age of 18 years
Rixil should not be used in patients younger than 18 years of age (safety and efficacy not established).
Patients with impaired renal function
In patients with impaired renal function (GFR> 30 ml / min / 1.73 m 2 ), correction of the initial dose is not required.
Rixil should not be given to patients with severe renal dysfunction (GFR <30 ml / min / 1.73 m 2 ).
The simultaneous use of Rixila with APA II and ACE inhibitors in patients with impaired renal function (GFR <60 ml / min / 1.73 m 2 ) is contraindicated (see section "Contraindications").
Patients with impaired hepatic function
In patients with mild, moderate and severe impairment of liver function, correction of the initial dose is not required.
SIDE EFFECT
The safety of aliskiren was assessed in patients, including patients treated with aliskiren for a long time, more than 6 months - 1 year.
Severe adverse reactions include anaphylactic reactions and Quincke's edema, which were rare (less than 1 case per 1000 patients) with post-marketing aliskiren. The most common side effect is diarrhea.
Classification of the frequency of development of side effects of the World Organization
Health (WHO):
Often ? 1/10
often from? 1/100 to <1/10
infrequently from? 1/1000 to <1/100
rarely from? 1/10000 to <1/1000
very rarely <1/10000
the frequency of the unknown can not be estimated from the available data.
Within each group, the incidence of adverse reactions is presented in order of decreasing significance.
Immune system disorders:
rarely: hypersensitivity reactions and anaphylactic reactions.
Impaired nervous system:
often: dizziness.
Heart Disease:
infrequent: a feeling of palpitations.
Vascular disorders:
infrequent: marked decrease in blood pressure.
Disturbances from the respiratory system, chest and mediastinal organs:
infrequently: cough.
Disorders from the digestive tract:
often: diarrhea.
Disturbances from the skin and subcutaneous tissues:
infrequent: skin rash, toxic epidermal necrolysis, Stevens-Johnson syndrome and reactions from the oral mucosa, urticaria, skin itching;
rarely: angioedema, erythema.
Disturbances from the musculoskeletal and connective tissue:
often: arthralgia.
Disorders from the kidneys and urinary tract:
infrequently: acute renal failure, impaired renal function.
General disorders and disorders at the site of administration:
infrequent: peripheral edema.
Laboratory and instrumental data:
often: hyperkalemia;
infrequently: increased activity of "liver" enzymes;
rarely: a decrease in hemoglobin and hematocrit, an increase in the concentration of creatinine in the blood plasma.
Description of some side effects
Laboratory data
Clinically significant changes in standard laboratory parameters are not often associated with the use of Rixil.
In the application of aliskiren in patients with arterial hypertension, no clinically significant changes in the concentration of total cholesterol, high-density lipoproteins (HDL cholesterol), triglycerides, glucose or uric acid in fasting blood plasma were noted.
Against the backdrop of aliskiren therapy, a slight decrease in hemoglobin and hematocrit (an average of 0.05 mmol / L and 0.16% by volume, respectively) was rarely observed, which did not require discontinuation of the drug. Reduction of hemoglobin and hematocrit is also observed when using other drugs that affect RAAS, in particular, ACE inhibitors and ARA II.
An increase in potassium in the blood serum against the background of aliskiren is more pronounced with the simultaneous use of other drugs acting on RAAS, or when taking NSAIDs. If it is necessary to combine therapy, it is recommended to periodically determine the kidney function, including the content of serum electrolytes. The simultaneous use of aliskiren with ACE inhibitors or ARA II is contraindicated in patients with diabetes or renal dysfunction (GFR <60 mL / min / 1.73 m2).
CONTRAINDICATIONS
- hypersensitivity to aliskiren or any component of the drug;
- anuria, severe renal dysfunction (creatinine clearance less than 30 ml / min and / or plasma creatinine concentration of 150 Ојmol / l for women and 177 Ојmol / l for men);
- age under 18 years (effectiveness and safety not established);
- hereditary and / or idiopathic angioedema;
- angioedema with aliskiren (in history);
- simultaneous use with strong inhibitors of P-glycoprotein - cyclosporine or itraconazole;
- simultaneous use of aliskiren with APA II or ACE inhibitors in patients with diabetes mellitus or renal dysfunction (GFR <60 ml / min / 1.73 m 2 );
- Pregnancy and the period of breastfeeding.
With caution: unilateral and / or bilateral stenosis of the renal artery, or stenosis of the artery of a single kidney, a decrease in BCC (eg, due to blood loss, severe and prolonged diarrhea, prolonged vomiting, etc.), cardiovascular disease, liver disease, sugar diabetes, kidney disease, hyponatremia, hyperkalemia, condition after kidney transplantation, CHF III-IV functional class according to NYHA classification, simultaneous application of furosemide in patients with CHF, simultaneous use of drugs capable of amb content of potassium in blood serum (including nonsteroidal anti-inflammatory drugs (NSAIDs), ACE inhibitors or angiotensin II).simultaneous application of moderate inhibitors of P-glycoprotein (ketoconazole, verapamil, clarithromycin, telithromycin, erythromycin, amiodarone), inducers of P-glycoprotein (rifampicin) and grapefruit juice.
PREGNANCY AND LACTATION
There is no data on the use of Rixila in pregnant women; nevertheless, it is known that the use of drugs that directly affect RAAS can cause fetal and newborn pathologies, as well as lead to their death. Therefore, do not use the drug Ricksila in the first trimester of pregnancy and women planning a pregnancy. The drug Rixila is contraindicated in II and III trimesters of pregnancy. Before using drugs that affect RAAS, the doctor should inform the patient of reproductive age about the possible risk to the fetus. When pregnancy occurs, the use of Rixil should be stopped immediately.
It is not known whether aliskiren is excreted in breast milk. Aliskiren is excreted in breast milk from lactating rats. During the treatment, breastfeeding should be discontinued.
Fertility
Pre-clinical studies of reproductive toxicity in rats showed no adverse effects of aliskiren on fertility.
Data on the effects of aliskiren on fertility in humans.
APPLICATION FOR FUNCTIONS OF THE LIVER
The values of AUC and C max of aliskiren in patients with impaired renal function after single oral administration and after reaching equilibrium concentration at 0.8-2 times higher than the values in healthy volunteers. However, the correlation between the above changes and the degree of renal function is not revealed.
Correcting the initial dose in patients with mild and moderate renal impairment is required. For patients with severe renal failure (glomerular filtration rate (GFR) <30 ml / min / 1.73 m 2 ) application of aliskiren contraindicated. The simultaneous use of aliskiren with ARA II or ACE inhibitors in patients with renal failure (GFR <60 mL / min / 1.73 m 2 ) is contraindicated.
In patients undergoing hemodialysis, single ingestion of aliskiren 300 mg accompanied by minor modifications pharmacokinetics of aliskiren (increase C max less than 1.2 times, the increase in AUC 1.6 fold) compared to healthy volunteers. The duration of hemodialysis has no significant effect on the pharmacokinetics of aliskiren in patients with end-stage renal failure. If necessary, the use of aliskiren in patients with end-stage renal failure on hemodialysis, dose adjustment is not required. However, the use of aliskiren is contraindicated in patients with severe renal insufficiency.
APPLICATION FOR VIOLATIONS OF THE FUNCTION OF KIDNEYS
In patients with mild, moderate and severe impairment of liver function initial correction dose is not required.
APPLICATION FOR CHILDREN
The drug is contraindicated in children under 18 years (effectiveness and safety have been established).
APPLICATION IN ELDERLY PATIENTS
Dose adjustment in patients older than 65 years are required.
SPECIAL INSTRUCTIONS
General
In the event of severe and persistent diarrhea therapy with Rix should be discontinued.
In patients with chronic heart failure III-IV functional class NYHA classification Ricks drug should be used with caution.
Should be used with caution in patients with CHF patients receiving furosemide (cm. 'Interaction with other drugs "section).
Dual blockade of the RAAS
in patients with concomitant use of drugs acting on the RAAS may develop hypotension, syncope, stroke, hyperkalemia, and renal dysfunction (including acute renal failure). In this regard, the dual blockade of the RAAS (simultaneous application of aliskiren and ACE inhibitors or angiotensin II) is not recommended.
The simultaneous use of ARA II or ACE inhibitors in patients with diabetes or impaired renal function (GFR <60 mL / min / 1.73 m 2 ) is contraindicated.
Anaphylactic reactions and angioedema
As with other drugs acting on the RAAS, angioneurotic edema (swelling of face, mouth, throat and / or tongue) was observed in patients treated with aliskiren. Some of these patients had a history of events described angioedema or symptoms suggestive of angioedema, when applied drugs, including ACE inhibitors or angiotensin II. The post-marketing application angioedema was recorded while applying aliskiren with ACE inhibitors and / or angiotensin II. Patients with a history of angioedema, aliskiren should be used with care, the patient should be carefully monitored, especially at the beginning of therapy. The drug should be stopped immediately when signs of allergic reactions (e.g., difficulty breathing or swallowing,swelling of the face, lips, tongue, limbs). In the case of swelling of the tongue and throat should enter epinephrine solution (adrenaline). It is necessary to ensure a patent airway.
Renal dysfunction
not examined the use of aliskiren in patients with hypertension and severe renal failure (creatinine concentration in the serum? 150 pmol / L or 1.70 mg / dL in women and? 177 mmol / l or 2.00 mg / dl in male and / or GFR <30 mL / min / 1.73 m 2 ), patients on dialysis, patients with nephrotic syndrome or renovascular hypertension. For patients with severe renal failure (GFR <30 mL / min / 1.73 m 2 ), using the product Rix contraindicated.
In the application of aliskiren, as well as other drugs acting on the RAAS, caution should be exercised in the presence of conditions that predispose to the development of renal dysfunction such as hypovolemia (e.g., due to loss of blood, severe and prolonged diarrhea, prolonged vomiting and t. D.) , cardiovascular disease, liver disease, kidney disease or diabetes. The simultaneous use of aliskiren with ACE inhibitors or angiotensin II contraindicated in patients with diabetes or impaired renal function (GFR <60 mL / min / 1.73 m 2 ). At-risk patients on
treatment with aliskiren observed the development of acute renal failure, reversible upon discontinuation of therapy. If signs of renal failure should immediately cease the use of aliskiren.
Against the background of Rix drug may increase the content of potassium in blood serum which may be increased while the use of drugs acting on the RAAS or NSAIDs. If necessary, such a combination is recommended to periodically monitor renal function, including serum electrolytes.
Hyponatremia and / or reduction bcc
At the beginning of therapy with Rix in patients with reduced BCC and / or hyponatremia (including hyponatremia caused by high doses of diuretics) may develop symptomatic hypotension. Before using the product should carry out the correction of violations of water-electrolyte balance. In patients with reduced BCC and / or hyponatremia treatment should be under close medical supervision.
Renal artery stenosis
No application experience in patients with unilateral or bilateral renal artery stenosis or stenosis of a solitary kidney. However, as the use of other drugs acting at the RAAS, such patients are at increased risk of renal insufficiency, including acute renal failure. Therefore, caution should be exercised in these cases. In renal insufficiency, the development of treatment should be stopped.
Effect of PA's ability to drive vehicles and other complex mechanisms
Not studied the effect of the drug Ricks on ability to drive vehicles and use machines. However, the possible development of dizziness or fatigue, as well as when taking any antihypertensive drugs. Ricks drug has little effect on the ability to drive and operate machinery.
OVERDOSE
Symptoms
Data on aliskiren overdose is limited. The most likely manifestation of overdose is a marked reduction in blood pressure.
Treatment
In marked decrease in blood pressure is needed symptomatic therapy. In patients with end-stage renal failure on hemodialysis, dialysis clearance of aliskiren was low (<2% of the clearance of aliskiren by ingestion). Therefore dialysis is not effective when aliskiren overdose.
DRUG INTERACTION
The simultaneous use is contraindicated
dual blockade of the RAAS
simultaneous use of ARA II or ACE inhibitors in patients with diabetes or impaired renal function (GFR <60 mL / min / 1.73 m 2 ) is contraindicated.
Strong inhibitors of P-glycoprotein (P-gp)
In the study on the interaction in the application of a single dose (75 mg) and cyclosporine aliskiren (in doses of 200 mg and 600 mg) in healthy volunteers, C max and AUC aliskiren increased by 2.5 times and 5 times, respectively. Increasing C max and AUC may be higher with higher doses of aliskiren.
In healthy volunteers the application of aliskiren (150 mg) simultaneously with itraconazole (100 mg) showed an increase in Cmax and AUC aliskiren in 6.5 and 5.8 times, respectively.
Therefore, the simultaneous use of the drug with potent inhibitors Ricks P-gp is contraindicated.
The simultaneous use is not recommended
Grapefruit juice
With simultaneous use of aliskiren 150 mg and 300 mg and grapefruit juice reduced aliskiren AUC by 61% and 38%, respectively, and also decreases its C max . This is probably due to the inhibition mediated by transport polypeptides, organic anions (TPOA) aliskiren absorption in the gastrointestinal tract when using grapefruit juice.
The simultaneous use with caution
Interaction at the level of P-gp
The invitro studies revealed that P-gp (MDR1 / Mdr1a / 1b) - a membrane transporter, which is important in the regulation of absorption and excretion into the intestine in bile aliskiren. Rifampicin is an inductor of P-gp, however while applying it with aliskiren bioavailability is reduced by about 50%. When applied simultaneously with other inducers of P-gp (e.g., drugs Hypericum perforatum), the bioavailability of aliskiren may be also reduced.
It is known that P-gp also controls distribution in the body. P-gp inhibitors can increase the concentration in the tissues of aliskiren with respect to its plasma concentration. Intensity of drug interaction on the level of P-gp inhibition depends on the conveyor.
Moderate inhibitors of P-gp
Simultaneous application of moderate inhibitor of P-gp - ketoconazole (200 mg) or verapamil (240 mg) and aliskiren (300 mg) AUC Aliskiren increases by 76% and 97%, respectively. Changing aliskiren concentration in blood plasma, while the use of ketoconazole or verapamil should correspond to a range of concentrations, which is achieved by increasing the dose of aliskiren 2 times. Proved safety of aliskiren 600 mg that is longer than the recommended dose of 2 times. Experimental studies show that the simultaneous use of aliskiren and ketoconazole enhances the absorption of aliskiren in the digestive tract and reduce its excretion in the bile through the intestines. Caution should be exercised while the use of ketoconazole, verapamil and other moderate P-gp inhibitors (e.g., clarithromycin,telithromycin, erythromycin, amiodarone).
Potassium-sparing diuretics, kalisodergaszczye substitutes edible salt, potassium or any other means of salt capable of increasing the content of potassium in blood serum
If necessary, the simultaneous application of potassium salts, potassium-sparing diuretics, potassium-containing substitutes for dietary salt or any other means capable of increase the content of potassium in blood serum NSAIDs and, given the experience of the use of other drugs that affect the RAAS, caution should be exercised. The simultaneous use of ARA II or ACE inhibitors in patients with diabetes or impaired renal function (GFR <60 mL / min / 1.73 m 2 ) is contraindicated.
Nonsteroidal anti-inflammatory drugs, including selective inhibitors of cyclooxygenase-2 (COX-2)
With simultaneous application of aliskiren, as well as other drugs acting on the RAAS with NSAID may decrease the antihypertensive effect of aliskiren. In some patients with impaired renal function (patients with hypovolemia or elderly patients) aliskiren with simultaneous use of NSAIDs may result in further deterioration of renal function, including acute renal failure (usually reversible). In this connection, use aliskiren simultaneously with NSAIDs with caution, especially in elderly patients.
Furosemide
With simultaneous use of aliskiren (300 mg / d) with furosemide (20 mg / day) in healthy volunteers AUCi marked decline in C max of furosemide at 28% and 49%, respectively.
Given the possible reduction in systemic bioavailability furosemide, when using aliskiren together with furosemide in the beginning and during therapy is necessary to adjust the dose of furosemide depending on clinical effect.
Warfarin
effect of aliskiren on warfarin pharmacokinetics have not been studied.
Admission as poor
fat meal significantly reduces the absorption of aliskiren.
No drug interaction
on the results of clinical pharmacokinetic studies showed no interaction with aliskiren acenocoumarol, atenolol, celecoxib, pioglitazone, allopurinol, isosorbide 5-mononitrate, hydrochlorothiazide, fenofibrate, irbesartan, ramipril, hypoglycemic agents for oral and insulin.
Simultaneous application aziskirena metformin (v 28%), amlodipine (~ 29%) or cimetidine (~ 19%) in equilibrium increases parameters AUC and C max for aliskiren 20% - 30% with atorvastatin - 50%. In this case, the simultaneous application has no significant effect on the pharmacokinetics of these drugs, however correction dose Ricks or simultaneously apply the above formulations is not required.
While the use of digoxin and verapamil bioavailability of aliskiren may be slightly reduced.
Interaction with isozymes CYP450 system
Aliskiren does not inhibit cytochrome P450 isozymes (CYP1A2, 2S8, 2S9, 2C19, 2D6, 2E1, and WA) and does not induce isoenzyme CYP3A4. Since aliskiren is metabolized slightly CYP450 isozymes, a clinically significant effect on the bioavailability of drugs which are inducers or inhibitors of CYP450 isozymes or metabolized with his participation is unlikely.
However, inhibitors of CYP3A4 isoenzyme may influence the P-gp. Therefore, it may increase systemic exposure (AUC and C max ) of aliskiren, while the use of inhibitors of isoenzyme CYP3A4, which inhibit P-gp (cm. "Substrates and weak inhibitors of P-gpВ»).
Substrates and weak inhibitors of P-gp
No clinically significant interaction with such weakly active inhibitors of P-gp, as atenolol, digoxin, amlodipine or cimetidine, have been identified. The simultaneous use of active inhibitor of P-gp - atorvastatin (80 mg) in the equilibrium state causes an increase in AUC and C mah aliskiren (300 mg) 50%.
Inhibitors of organic anions transport polypeptides
according to preclinical studies aliskiren may be a substrate TPOA. There is potential interaction while the use of TPOA inhibitors (see. The interaction with grapefruit juice).
TERMS OF RELEASE FROM PHARMACY
The drug is released by prescription.
TERMS AND CONDITIONS OF STORAGE
At a temperature
