Simultaneous use is contraindicated
Double blockade of RAAS
Simultaneous application with ARA II or ACE inhibitors in patients with diabetes or impaired renal function (GFR <60 mL / min / 1.73 m2) is contraindicated.
Strong P-glycoprotein inhibitors (P-gp)
In a study on the interaction with a single dose (75 mg) of aliskiren and cyclosporine (in doses of 200 mg and 600 mg) in healthy volunteers CmOh and AUC aliskiren increased by 2.5 times and 5 times, respectively. Increase in CmOh and AUC may be higher with higher doses of aliskiren.
In healthy volunteers, when using aliskiren (at a dose of 150 mg) simultaneously with itraconazole (at a dose of 100 mg) there was an increase in CmOh and AUC aliskiren in 6.5 and 5.8 times, respectively.
Therefore, the simultaneous use of Rixila® with strong inhibitors P-gp it is contraindicated.
Simultaneous use is not recommended
Grapefruit juice
With the simultaneous use of aliskiren in a dose of 150 mg and 300 mg and grapefruit juice decreases AUC aliskiren by 61% and 38% %, respectively, and also decreases its CmOh. This is probably due to the inhibition of transport-mediated organic anion (TBAA) mediated absorption of aliskiren in the gastrointestinal tract when grapefruit juice is used.
Use with caution at the same time
Interaction at the level P-gp
In studies in vitro determined that P-gp (MDRl/Mdrla/lb) - Membrane transporter, which is important in the regulation of absorption in the intestine and the removal of aliskiren with bile. Rifampicin is an inductor P-gp, therefore, with simultaneous application with it, the bioavailability of aliskiren is reduced by about 50%. When used simultaneously with other inducers P-gp (eg, preparations of St. John's wort perfumed), the bioavailability of aliskiren may also decrease.
It is known that P-gp also controls the distribution in the body. Inhibitors P-gp can increase the concentration of aliskiren in tissues in relation to its plasma concentration. Severity of drug interaction at the level of P-gp depends on the degree of inhibition of the conveyor.
Moderate inhibitors P-gp
Simultaneous application of a moderate inhibitor P-gp - ketoconazole (200 mg) or verapamil (240 mg) and aliskiren (300 mg) increases AUC aliskiren by 76% and 97%, respectively. The change in the concentration of aliskiren in blood plasma, when used simultaneously with ketoconazole or verapamil, should correspond to the concentration range, which is achieved by increasing the dose of aliskiren by 2 times.
The safety of using aliskiren in a dose of 600 mg is proven, which is twice the maximum recommended dose. Experimental studies show that the simultaneous use of aliskiren and ketoconazole increases the absorption of aliskiren in the gastrointestinal tract and reduces its excretion with bile through the intestine. Care must be taken when using ketoconazole, verapamil and other mild inhibitors P-gp (eg, clarithromycin, telithromycin, erythromycin, amiodarone).
Potassium-sparing diuretics, potassium-containing substitutes for edible salt, potassium salts or any other means capable of increasing the serum potassium content
When simultaneous application with potassium salts, potassium-sparing diuretics, potassium-containing substitutes for edible salt, or any other means capable of increasing serum potassium levels, NSAIDs and, taking into account the experience of other drugs that affect RAAS, Care should be taken. Simultaneous application with ARA II or ACE inhibitors in patients with diabetes or impaired renal function (GFR <60 mL / min / 1.73 m2) is contraindicated.
Non-steroidal anti-inflammatory drugs, including selective inhibitors of cyclooxygenase-2 (COX-2)
With the simultaneous use of aliskiren, like others drugs acting on RAAS, with NSAIDs it is possible to reduce the antihypertensive effect of aliskiren. In some patients with impaired renal function (patients with hypovolemia or elderly patients) simultaneous application of aliskiren with NSAIDs can lead to further deterioration in kidney function, including the development of acute renal failure (usually reversible). In this regard, apply aliskiren at the same time with NSAIDs with caution, especially in elderly patients.
Furosemide
With the simultaneous use of aliskiren (300 mg / day) with furosemide (20 mg / day) in healthy volunteers there is a decrease in indicators AUC and CmOh furosemide by 28% and 49%, respectively.
Given the possible reduction in systemic bioavailability furosemide, when aliskiren is used simultaneously with furosemide at the beginning and during the therapy it is necessary to adjust the dose furosemide depending on the clinical effect.
Warfarin
Effect of aliskiren on pharmacokinetics warfarin not studied.
Food intake
Fatty food significantly reduces the absorption of aliskiren.
No drug interaction
According to the results of clinical pharmacokinetic studies, no interaction of aliskiren with acenocoumarol, atenolol, celecoxib, pioglitazone, allopurinol, isosorbide 5-mononitrate, hydrochlorothiazide, fenofibrate, irbesartan, ramipril, hypoglycemic agents for ingestion and insulin.
The simultaneous use of aliskiren with metformin (↓ 28 %), amlodipine (↑ 29 %) or cimetidine (↑ 19%) increases in the equilibrium state AUC and CmOh for aliskiren by 20% - 30 %, from atorvastatin - by 50%.In this case, the simultaneous application has no significant effect on the pharmacokinetics of these drugs, however correction dose Riksila® or simultaneously apply the above formulations is not required.
When used simultaneously with digoxin and verapamil the bioavailability of aliskiren may decrease slightly.
Interactions with isoenzymes of the system CYP450
Aliskiren does not inhibit cytochrome P450 isoenzymes (CYP1A2, 2С8, 2С9, 2С19, 2D6, 2E1 and 3A) and does not induce isoenzyme CYP3A4. Because the aliskiren is slightly metabolized by isoenzymes CYP450, clinically significant effect on the bioavailability of drugs that are inducers or inhibitors of isoenzymes CYP450 or metabolized with his participation, is unlikely.
But, inhibitors of isoenzyme CYP3A4 may affect P-gp. Therefore, it is possible to increase the system exposure (AUC and CmOh) aliskiren with simultaneous application with inhibitors of isoenzyme CYP3A4, which suppress P-gp (cm. "Substrates and weak inhibitors P-gp").
Substrates and weak inhibitors P-gp
Clinically significant interaction with such weakly active inhibitors P-gp, as atenolol, digoxin, amlodipine or cimetidine, not found. Simultaneous application with active inhibitor P-gp - atorvastatin (at a dose of 80 mg), in the equilibrium state causes an increase AUC and CmOh aliskiren (at a dose of 300 mg) by 50%.
Inhibitors of transport polypeptides of organic anions
According to preclinical research aliskiren can be a substrate TREA. There is a potential for interaction when used simultaneously with inhibitors of TPOA (see the interaction with grapefruit juice).