DRUG INTERACTIONS
No drug interaction studies have been conducted with Valturna and other drugs, although studies with the individual aliskiren and valsartan components are described below.
Aliskiren
Effects
of Other Drugs
on Aliskiren
Based on in vitro studies, aliskiren is metabolized by CYP 3A4.
Irbesartan: Coadministration of irbesartan reduced aliskiren Cmax up to 50% after multiple dosing.
P-glycoprotein Effects: Pgp (MDR1/Mdr1a/1b) was found to be the major efflux system involved in absorption and disposition of aliskiren in preclinical studies. The potential for drug interactions at the Pgp site will likely depend on the degree of inhibition of this transporter.
Atorvastatin: Coadministration of atorvastatin resulted in about a 50% increase in aliskiren Cmax and AUC after multiple dosing.
Ketoconazole: Coadministration of 200 mg twice-daily ketoconazole with aliskiren resulted in approximate 80% increase in plasma levels of aliskiren. A 400-mg once-daily dose was not studied but would be expected to increase aliskiren blood levels further.
Itraconazole: Coadministration of 100 mg itraconazole with 150 mg aliskiren resulted in approximately 5.8-fold increase in Cmax and 6.5-fold increase in AUC of aliskiren. Concomitant use of aliskiren with itraconazole is not recommended.
Cyclosporine: Coadministration of 200 mg and 600 mg cyclosporine with 75 mg aliskiren resulted in an approximately 2.5-fold increase in Cmax and 5-fold increase in AUC of aliskiren. Concomitant use of aliskiren with cyclosporine is not recommended.
Verapamil: Coadministration of 240 mg of verapamil with 300 mg aliskiren resulted in an approximately 2-fold increase in Cmax and AUC of aliskiren. However, no dosage adjustment is necessary.
Drugs with no clinically significant effects: Coadministration of lovastatin, atenolol, warfarin, furosemide, digoxin, celecoxib, hydrochlorothiazide, ramipril, valsartan, metformin and amlodipine did not result in clinically significant increases in aliskiren exposure.
Effects of Aliskiren on Other Drugs
Aliskiren does not inhibit the CYP450 isoenzymes (CYP1A2, 2C8, 2C9, 2C19, 2D6, 2E1, and CYP 3A) or induce CYP 3A4.
Furosemide: When aliskiren was coadministered with furosemide, the AUC and Cmax of furosemide were reduced by about 30% and 50%, respectively. Patients receiving furosemide could find its effect diminished after starting aliskiren.
Drugs with no clinically significant effects: Coadministration of aliskiren did not significantly affect the pharmacokinetics of lovastatin, digoxin, valsartan, amlodipine, metformin, celecoxib, atenolol, atorvastatin, ramipril or hydrochlorothiazide.
Warfarin
: The effects of aliskiren on warfarin pharmacokinetics have not been evaluated.
Valsartan
No clinically significant pharmacokinetic interactions were observed when valsartan was coadministered with aliskiren, amlodipine, atenolol, cimetidine, digoxin, furosemide, glyburide, hydrochlorothiazide, or indomethacin. The valsartan-atenolol combination was more antihypertensive than either component, but it did not lower the heart rate more than atenolol alone.
Warfarin
: Coadministration of valsartan and warfarin did not change the pharmacokinetics of valsartan or the time-course of the anticoagulant properties of warfarin.
CYP 450 Interactions: In vitro metabolism studies have indicated that CYP450 mediated drug interactions between valsartan and coadministered drugs are unlikely because of low extent of metabolism (s
ee Pharmacokinetics — Valsartan
(
12.3).
Transporters: The results from an in vitro study with human liver tissue indicate that valsartan is a substrate of the hepatic uptake transporter OATP1B1 and the hepatic efflux transporter MRP2. Coadministration of inhibitors of the uptake transporter (rifampin, cyclosporine) or efflux transporter (ritonavir) may increase the systemic exposure to valsartan.
As with other drugs that block angiotensin II or its effects, concomitant use of potassium sparing diuretics (e.g., spironolactone, triamterene, amiloride), potassium supplements, or salt substitutes containing potassium may lead to increases in serum potassium and in heart failure patients to increases in serum creatinine.
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