There have been no studies of the interaction of the drug Racilam with other drugs, so the section presents information on known interactions with other drugs for aliskiren and amlodipine.
The simultaneous use of aliskiren and amlodipine does not cause significant changes in AUC and Cmah of each component in healthy volunteers.
Aliskiren
Contraindicated combinations
Strong P-glycoprotein inhibitors
When used with such a highly active inhibitor of P-glycoprotein, both ciclosporin (200 and 600 mg), in healthy volunteers there was an increase in Cmah and AUC aliskiren (75 mg) in 2.5 and 5 times, respectively. In healthy volunteers, with the use of aliskiren (at a dose of 150 mg) with itraconazole (at a dose of 100 mg), there was an increase in AUC and Cmah aliskiren in 6.5 and 5.8 times, respectively. In this regard, it is not recommended to apply aliskiren simultaneously with strong inhibitors of P-glycoprotein cyclosporine and itraconazole.
Double blockade of RAAS
Contraindicated simultaneous use of the drug with ACE inhibitors and angiotensin II receptor antagonists (APA II) in patients with type 2 diabetes mellitus and / or moderate or severe renal dysfunction (glomerular filtration rate less than 60 ml / min / 1.73 m2).
Unsupported combinations
Grapefruit juice
Since there is no data on the possible interaction of aliskiren with grapefruit juice, the Racilam preparation should not be taken simultaneously with grapefruit juice.
Combinations that require caution
Double blockade of RAAS
The simultaneous use of aliskiren with other drugs that affect RAAS, including those with ACE inhibitors and ARA II,leads to an increase in the incidence of severe depression of blood pressure, hyperkalemia, renal dysfunction (including acute renal failure). It is necessary to monitor blood pressure, kidney function, and the content of plasma electrolytes when using the preparation Racilam with other drugs that affect the PAAS.
Interaction at the level of P-glycoprotein, encoded by MDR1 genes
Since it has been established in in vitro studies that the P-glycoprotein (membrane transporter of molecules) plays an important role in regulating the absorption and distribution of aliskiren, it is possible to alter the pharmacokinetics of the latter when used simultaneously with drugs inhibiting P-glycoprotein (depending on the degree of inhibition).
Moderate inhibitors of P-glycoprotein
With simultaneous application of a moderate inhibitor of P-glycoprotein ketoconazole (200 mg) and aliskiren (300 mg), an increase in plasma concentration of the latter (AUC and Cmah) by 80%. In experimental studies, the simultaneous use of aliskiren with ketoconazole led to an increase in the absorption of aliskiren in the gastrointestinal tract and a decrease in its excretion through the intestine with bile.With a single use of verapamil (240 mg) with aliskiren (300 mg dose), there was an increase in AUC and Cmah aliskiren in 2 times.
Changes in the plasma concentration of aliskiren with simultaneous use with ketoconazole or verapamil are expected in the range of concentrations determined with an increase in the aliskiren dose by a factor of 2. In controlled clinical trials, the safety of the drug at a dose of 600 mg was demonstrated, that is, with an increase in the maximum recommended therapeutic dose by a factor of 2. Therefore, when aliskiren is used together with ketoconazole or verapamil, dose adjustment of aliskiren is not required.
Potassium and potassium-sparing diuretics
Considering the experience of using other agents that affect RAAS, caution should be exercised aliskiren with preparations containing potassium, potassium-sparing diuretics, potassium-containing substitutes for edible salt, or any other medicines capable of increasing the content of potassium ions in the blood.
Furosemide
With the simultaneous use of aliskiren (300 mg / day) with furosemide (20 mg / day) in healthy volunteers, a decrease in AUC and Cmfurosemide by 28% and 49%, respectively.
In patients with heart failure, simultaneous use of aliskiren (300 mg / day) with furosemide (60 mg / day) resulted in a decrease in AUC and Cmax furosemide by 17% and 27%, respectively, and by a 29% decrease in furosemide excretion by the kidneys within 24 hours after administration. In addition, the excretion of sodium by the kidneys and the volume of urine were reduced during the first 4 hours after admission by 31% and 24% respectively, but compared with the use of furosemide in monotherapy.
To prevent possible fluid retention when using aliskiren with furosemide, it is necessary to adjust the dose of furosemide at the beginning and during treatment, depending on the clinical effect.
Non-steroidal anti-inflammatory drugs (NSAIDs), including selective inhibitors of cyclooxygenase-2 (COX-2)
In elderly patients, patients with reduced BCC (including caused by taking diuretics), patients with impaired renal function, the simultaneous use of NSAIDs with drugs that affect RAAS can lead to impaired renal function, up to the development of acute renal failure, in most cases reversible.As with the simultaneous use of NSAIDs with other agents that affect RAAS, the antihypertensive effect of aliskiren may decrease with the use of NSAIDs.
Unlikely interactions
The likelihood of interaction of aliskiren with other drugs is low. Because the aliskiren has no significant effect on the pharmacokinetics of acenocumarol, atenolol, celecoxib, fenofibrate, inoglitazone, allopurinol, isosorbide mononitrate, irbesartan, digoxin. ramipril, valsartan, metformin, amlodipine, atorvastatin, cimetidine and hydrochlorothiazide dose adjustment of aliskiren or the above preparations, while not simultaneously required.
Interaction at the level of the cytochrome P450 system
Aliskiren nc inhibits the isoenzymes of the cytochrome P450 system (CYP1A2, 2C8, 2C9, 2C19, 2D6, 2E1 and CYP3A) and does not induce the isozyme CYP3A4. Because the aliskiren is slightly metabolized by isoenzymes of the cytochrome P450 system, the clinically significant effect of aliskiren on the bioavailability of drugs that are inducers or inhibitors of the cytochrome P450 system, or metabolized with its participation, is unlikely.
Substrates and weak inhibitors of P-glycoprotein
There is no significant interaction of aliskiren with weak P-glycoprotein inhibitors, such as atenolol, digoxin, amlodipine and cimetidine. With simultaneous use with atorvastatin (at a dose of 80 mg), AUC and Cmaliskiren in the equilibrium state by 50% (300 mg dose).
Amlodipine
Combinations that require caution
Simvastatin
Simultaneous long-term use of simvastatin at a dose of 80 mg / day and amlodipine at a dose of 10 mg / day leads to a 77% increase in the exposure of simvastatin. It is recommended to reduce the dose of simvastatin in patients taking amlodipine, up to 20 mg / day.
Inhibitors of the isoenzyme CYP3A4
When amlodipine with diltiazem is used in elderly patients, amlodipine metabolism slows down, probably due to inhibition of the CYP3A4 isoenzyme, which leads to an increase in the concentration of amlodipine in the blood plasma by approximately 50% and an increase in its systemic exposure. When using amlodipine with potent inhibitors of the isoenzyme CYP3A4 (for example, ketoconazole, itraconazole and ritonavir) a marked increase in the systemic exposure of amlodipine.
Inductors of the isoenzyme CYP3A4
Since the use of amlodipine together with inducers of the isoenzyme CYP3A4 (for example, carbamazepine, phenobarbital, phenytoin, phosphenytoin, primidon, rifampicin, grapefruit juice, herbal preparations containing Hypericum perforated) can lead to a marked decrease in its concentration in the blood plasma with the use of amlodipine with inducers of the isoenzyme CYP3A4, it should monitor its concentration in the blood plasma.
Unlikely interactions
With monotherapy with amlodipine, there is no clinically significant interaction with thiazide diuretics, beta adrenoblockers, ACE inhibitors, long-acting nitrates, nitroglycerin for sublingual use, digoxin, warfarin, atorvastatin, sildenafil, simethicone, antacids (magnesium hydroxide, aluminum hydroxide gel), cimetidine, NSAIDs, antibiotics and hypoglycemic agents for oral administration.
Amlodipine does not affect the pharmacokinetics of ethanol.