Tasigna Drug Interactions

Nilotinib is mainly metabolized in the liver, and is also a substrate for the multi-drug efflux pump, P-glycoprotein (P-gp). Therefore, absorption and subsequent elimination of systemically absorbed nilotinib may be influenced by drugs that affect CYP3A4 and/or P-gp.
Drugs that may increase nilotinib serum concentrations: In a Phase I study of nilotinib given in combination with imatinib (a substrate of P-gp and CYP3A4), both drugs had a slight inhibitory effect on CYP3A4 and/or P-gp. When the two drugs were administered concomitantly, the AUC of imatinib was increased by 18% to 39%, and the AUC of nilotinib was increased by 18% to 40%.
The bioavailability of nilotinib in healthy subjects was increased by 3-fold when co-administered with the strong CYP3A4 inhibitor ketoconazole. Concurrent treatment with strong CYP3A4 inhibitors should therefore be avoided (including but not limited to ketoconazole, itraconazole, voriconazole, ritonavir, clarithromycin, and telithromycin) (see Dosage & Administration and QT Prolongation under Precautions). Alternative concomitant medications with no or minimal CYP3A4 inhibition should be considered.
Drugs that may decrease nilotinib serum concentrations: In healthy subjects receiving the CYP3A4 inducer, rifampicin, at 600 mg daily for 12 days, systemic exposure (AUC) to nilotinib was decreased approximately 80%.
Inducers of CYP3A4 activity could increase the metabolism of nilotinib and thereby decrease plasma concentrations of nilotinib. The concomitant administration of medications that induce CYP3A4 (e.g. phenytoin, rifampicin, carbamazepine, phenobarbital, and St. John's Wort) may reduce exposure to nilotinib. In patients for whom CYP3A4 inducers are indicated, alternative agents with less enzyme induction potential should be considered.
Nilotinib has pH-dependent solubility, with lower solubility at higher pH. In healthy subjects receiving esomeprazole at 40 mg once daily for 5 days, gastric pH was markedly increased, but nilotinib absorption was only decreased modestly (27% decrease in C_max and 34% decrease in AUC_0-∞). Tasigna may be used concurrently with esomeprazole or other proton pump inhibitors as needed.
In a healthy subjects study, no significant change in nilotinib pharmacokinetics was observed when a single 400 mg dose of Tasigna was administered 10 hours after and 2 hours before famotidine. Therefore, when the concurrent use of an H2 blocker is necessary, it may be administered approximately 10 hours before and approximately 2 hours after the dose of Tasigna.
In the same study as previously mentioned, administration of an antacid (aluminum hydroxide/magnesium hydroxide/simethicone) 2 hours before or after a single 400 mg dose of Tasigna also did not alter nilotinib pharmacokinetics. Therefore, if necessary, an antacid may be administered approximately 2 hours before or approximately 2 hours after the dose of Tasigna.
Drugs that may have their systemic concentration altered by nilotinib: In vitro nilotinib is identified as a competitive inhibitor of CYP3A4, CYP2C8, CYP2C9, CYP2D6 and UGT1A1, with Ki value being lowest for CYP2C9 (Ki=0.13 microM).
In CML patients, nilotinib administered at 400 mg twice daily for 12 days increased the systemic exposure of oral midazolam (a substrate of CYP3A4) 2.6-fold. Nilotinib is a moderate CYP3A4 inhibitor. As a result, the systemic exposure of other drugs primarily metabolized by CYP3A4 (e.g. certain HMG-CoA reductase inhibitors) may be increased when co-administered with nilotinib. Appropriate monitoring and dose adjustment may be necessary for drugs that are CYP3A4 substrates and have a narrow therapeutic index (including but not limited to alfentanil, cyclosporine, dihydroergotamine, ergotamine, fentanyl, sirolimus and tacrolimus) when co-administered with nilotinib.
In healthy subjects, nilotinib at clinically relevant concentrations was not found to alter the pharmacokinetics or pharmacodynamics of warfarin, a sensitive CYP2C9 substrate. Tasigna can be used concurrently with warfarin without increasing the anticoagulant effect.
Antiarrhythmic medicines and other drugs that may prolong the QT interval: Concomitant use of anti-arrhythmic medicines (including, but not limited to amiodarone, disopyramide, procainamide, quinidine and sotalol) and other drugs that may prolong the QT interval (including, but not limited to chloroquine, halofantrine, clarithromycin, haloperidol, methadone, moxifloxacin, bepridil and pimozide) should be avoided (see Precautions).
Food interactions: The absorption and the bioavailability of nilotinib are increased if it is taken with food, resulting in higher serum concentration (see Dosage & Administration, Precautions and Pharmacology under Actions).
Grapefruit juice and other foods that are known to inhibit CYP3A4 should be avoided at any time.