Clinical tests have demonstrated that the drug does not have a pharmacokinetic interaction with the following substances: celecoxib with acenocoumarol, as well as allopurinol and atenolol with pioglitazone and hydrochlorothiazide with isosorbide-5-mononitrate.
Individual drugs in combination with aliskiren can change its peak level (within 20-30%) or AUC. Among those - metformin (reduces the peak value by 28%), amlodipine (a decrease of 29%) and cimetidine (increases by 19%).
The combination with atorvastatin resulted in an increase in peak values and a drug AUC level of 50%. Racilus does not have a significant effect on the pharmacokinetic characteristics of metformin, atorvastatin, and amlodipine. As a result, when these drugs are combined with aliskiren, correction of their dosage is not required.
Admission with Racileus may slightly lower the level of bioavailability of the digoxin substance.
Preliminary information indicates that irbesartan is capable of decreasing the peak values and AUC of the drug.
Interaction with the CYP450 element.
The active substance does not inhibit the isoenzymes CYP450 (also CYP1A2 with 2C8, as well as 2C9 and 2C19 with 2D6, 2E1 with 3A). In addition, it does not induce the element CYP3A4. As a consequence, there is no reason to expect that aliskiren will affect the AUC of drugs that are induced, slowed down or metabolized with the participation of these enzymes.
Aliskiren undergoes minimal metabolism with the help of enzymes of the hemoprotein P450, which is why interaction is not expected after the inhibition or stimulation of isoenzymes CYP450. But inhibitors of the element CYP3A4 quite often affect P-gp. This allows one to expect an increase in the AUC of aliskiren during the period of combined use with inhibitors of the CYP3A4 element, which slow down the effect of P-gp.
Interaction with the P-gp element.
With preclinical testing, MDR1 / Mdr1a / 1b (P-gp) was found to be the main efflux system for intestinal absorption, as well as biliary excretion of aliskiren. Clinical tests have shown that rifampicin (an inductor of the P-gp element) reduces the level of bioavailability of aliskiren by approximately 50%. Other inducers of P-gp substance (such as St. John's Wort) are also able to lower the bioavailability of the drug.
Although such studies have not been carried out with aliskiren, it is known that the P-gp element also plays a major role in the capture of various substrates by tissues, and substances that slow P-gp are capable of increasing the tissue-plasma ratio. This allows the inhibitors of the P-gp component to more strongly influence the indices of the drug inside the tissues (increasing them) than the plasma values. The potential for drug interaction in the P-gp region will most likely depend on the level of suppression of this vector.
Substrates or drugs that slow P- gp (with poor efficacy).
There is no significant interaction with substances digoxin, cimetidine, as well as amlodipine or atenolol. After combining with atorvastatin (at a dose of 80 mg), the steady-state values of peak indices and the level of AUC of aliskiren (at a dose of 300 mg) were increased by 50%. Animal tests have demonstrated that P-gp is the main determining factor that allows you to know the level of bioavailability of Racileuse.
Medications with a moderate retardation effect on P- gp.
The combination of the drug (300 mg) with ketoconazole (200 mg) or verapamil (240 mg) caused an increase in its peak plasma values (by 97%) and AUC (by 76%). It should be expected that the values of aliskiren inside the plasma in combination with verapamil or ketoconazole will vary within the same limits as due to the use of a double dose of Racilease. Clinical tests showed that aliskiren in dosages of up to 600 mg (2 times the recommended value) was tolerated without adverse consequences.
Preclinical tests demonstrated that the combination of drugs with ketoconazole enhances the absorption of aliskiren from the gastrointestinal tract, and also weakens the biliary excretion of the substance. But it is expected that the use of P-gp inhibitors will increase the concentration of the substance inside the tissues more than the plasma. In this regard, it is necessary to carefully mix the drug with ketoconazole or other P-gp (moderate effect) inhibitors such as telithromycin, amiodarone, and erythromycin with clarithromycin.
Medications that slow down P- gp (with a powerful effect).
Tests on the interaction of single doses in volunteers demonstrated that cyclosporine (in dosages of 200 and 600 mg) increased the peak level of aliskiren (75 mg) approximately 2.5-fold, and the AUC-value approximately 5-fold. An increase can also occur with higher doses of aliskiren.
Itraconazole at a dose of 100 mg increased the peak values of the drug (150 mg) by 5.8 times, as well as the level of its AUC (by 6.5 times) in volunteers. Because of this, the reception of Racilez in combination with powerful inhibitors of P-gp is prohibited.
Inhibitors of polypeptide carriers of organic anions.
Preclinical testing makes it clear that aliskiren can become a TPOA substrate, which suggests that there is a potential for its interaction with TPAO inhibitors when combining these drugs.
Torasemide with furosemide.
Combined ingestion of furosemide and aliskiren does not affect the pharmacokinetic characteristics of the latter, but the effect of furosemide is weakened by about 20-30% (studies on the effect of aliskiren on furosemide administered in / or in / m were not performed).
With repeated use of furosemide (60 mg daily) in combination with aliskiren (300 mg daily), the excretion of sodium in urine decreased in the first 4 hours, and in addition, urine volume (by 31% and 24% ) in comparison with the situations when only furosemide was used. The average weight of people taking aliskiren (300 mg) with furosemide exceeded the weight values of people taking only furosemide (84.6 / 83.4 kg).
When using the drug at a dose of 150 mg, there were insignificant changes in the efficacy and pharmacokinetic indices of furosemide.
In existing clinical information, there is no information on the combination of aliskiren with torasemide in high doses. It is known that the excretion of torasemide through the kidney occurs with the indirect participation of carriers of organic anions. Minimal doses of aliskiren are excreted through the kidneys, and only 0.6% of the dosage of the substance can be observed in the urine when ingestion is given. But, since it is revealed that aliskiren is a substrate for the polypeptide carrier of organic anions 1A2 (OATP1A2), it is potentially possible to lower the plasma level of torasemide under the influence of aliskiren (it affects the absorption process).
In patients who use aliskiren with torasemide or furosemide (orally), it is required to carefully monitor the effects of these substances at the beginning of treatment or when adjusting the doses of the above drugs. This is necessary to avoid changes in the volume of intercellular fluids, as well as possible volume overload.
Use in combination with NSAIDs.
As with the use of other drugs that affect the function of PAC, in the case of NSAIDs, it is possible to weaken the hypotensive properties of aliskiren.
In some people with disorders in the work of the kidneys (elderly patients, dehydration) a combination of such drugs can contribute to a subsequent deterioration in the work of the kidneys (for example, acute insufficiency, often this pathology is reversible). Therefore, it is required to combine the drug data with caution (especially for the elderly).
Medicines affecting serum potassium levels.
With the simultaneous use of Racileuse with potions such as potassium-sparing diuretics, dietary potassium supplements, salt substitutes, which contain calcium, and other substances that can affect potassium levels (eg heparin), potassium may increase. If this treatment is necessary, it should be done with great care.
With a double blockade of the function of RAAS BRA, aliskiren or ACE inhibitors.
The results of clinical tests demonstrated that with double blockade of the function of RAAS by the combined use of aliskiren with ARB or ACE inhibitors, the incidence of side effects (such as stroke, pressure decrease, renal function impairment (eg acute kidney failure) and hyperkalemia ) compared with monotherapy with the use of only ARBs.
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