Imatinib

Concomitant use of moderate CYP3A4 inhibitors (such as amprenavir, aprepitant, atazanavir, ciprofloxacin, crizotinib, darunavir/ritonavir, diltiazem, erythromycin, fluconazole, fosamprenavir, imatinib, verapamil) has not been studied, but concomitant use with lomitapide is contraindicated since lomitapide exposure will likely increase significantly in the presence of these inhibitors. Coadministration of lomitapide with P-gp substrates (such as aliskiren, ambrisentan, colchicine, dabigatran etexilate, digoxin, everolimus, fexofenadine, imatinib, lapatinib, maraviroc, nilotinib, posaconazole, ranolazine, saxagliptin, sirolimus, sitagliptin, talinolol, tolvaptan, topotecan) may increase the absorption of P-gp substrates.

Warfarin should not be used in patients requiring anticoagulation; use low-molecular weight or standard heparin instead due to CYP2C9 and CYP3A4 metabolism interactions.

Enzyme-inducing anti-epileptic drug that decreases imatinib AUC by 73%, significantly reducing imatinib exposure.

Enzyme-inducing anti-epileptic drug that decreases imatinib AUC by 73%, significantly reducing imatinib exposure.

( 7.5 ) 7.1 Agents Inducing CYP3A Metabolism Concomitant administration of Gleevec and strong CYP3A4 inducers may reduce total exposure of imatinib; consider alternative agents [see Clinical Pharmacology (12.3)]. 7.2 Agents Inhibiting CYP3A Metabolism Concomitant administration of Gleevec and strong CYP3A4 inhibitors may result in a significant imatinib exposure increase. Grapefruit juice may also increase plasma concentrations of imatinib; avoid grapefruit juice [see Clinical Pharmacology (12.3)] .

Antineoplastics irinotecan axitinib, dabrafenib, dasatinib, ibrutinib, nilotinib, sunitinib bortezomib, busulphan, docetaxel, erlotinib, imatinib, ixabepilone, lapatinib, ponatinib, trimetrexate, vinca alkaloids Irinotecan: The potential increase in plasma concentrations of irinotecan when coadministered with itraconazole may increase the risk of potentially fatal adverse events.

Eletriptan: Eletriptan should be used with caution with ketoconazole, and specifically, should not be used within at least 72 hours of treatment with ketoconazole Antineoplastics irinotecan dasatinib, lapatinib, nilotinib bortezomib, busulphan, docetaxel, erlotinib, imatinib, ixabepilone, paclitaxel, trimetrexate, vinca alkaloids Irinotecan: The potential increase in plasma concentrations of irinotecan when coadministered with ketoconazole tablets may increase the risk of potentially fatal adverse events.

Enzyme-inducing anti-epileptic drug that significantly decreases imatinib exposure.

Enzyme-inducing anti-epileptic drug that decreases imatinib AUC by 73%, significantly reducing imatinib exposure.

Enzyme-inducing anti-epileptic drug that decreases imatinib AUC by 73%, significantly reducing imatinib exposure.

Enzyme-inducing anti-epileptic drug that decreases imatinib AUC by 73%, significantly reducing imatinib exposure.

Strong CYP3A4 inducer that significantly decreases imatinib Cmax and AUC by 3.8-fold, reducing therapeutic exposure.

BCRP substrate whose exposure may be altered by velpatasvir and voxilaprevir inhibition. Coadministration is not recommended.

Mild or Moderate CYP3A Inhibitors, such as: antibiotics (e.g., erythromycin), calcium channel blockers (e.g., verapamil, diltiazem, nifedipine, nicardipine), amiodarone, danazol, ethinyl estradiol, cimetidine, lansoprazole and omeprazole, azole antifungals (e.g., clotrimazole, fluconazole, isavuconazole), imatinib, nilotinib, letermovir May increase tacrolimus whole blood trough concentrations and increase the risk of serious adverse reactions (e.g., neurotoxicity, QT prolongation) [see Warnings and Precautions (5.6 , 5.9 , 5.10) ].

Caution is recommended when administering imatinib mesylate tablets with strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, and voriconazole).

Imatinib increases plasma concentration of dihydropyridine calcium channel blockers; use caution with drugs having narrow therapeutic window.

Caution is recommended when administering imatinib mesylate tablets with strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, and voriconazole).

Increases cyclosporine concentrations. Dosage adjustment essential.

CYP3A4 inducers may decrease imatinib C max and AUC; consider alternative agents.

7.2 Transporters Use caution when concomitantly administering eltrombopag and drugs that are substrates of OATP1B1 (e.g., atorvastatin, bosentan, ezetimibe, fluvastatin, glyburide, olmesartan, pitavastatin, pravastatin, rosuvastatin, repaglinide, rifampin, simvastatin acid, SN-38 [active metabolite of irinotecan], valsartan) or breast cancer resistance protein (BCRP) (e.g., imatinib, irinotecan, lapatinib, methotrexate, mitoxantrone, rosuvastatin, sulfasalazine, topotecan).

7.2 Transporters Use caution when concomitantly administering PROMACTA and drugs that are substrates of OATP1B1 (e.g., atorvastatin, bosentan, ezetimibe, fluvastatin, glyburide, olmesartan, pitavastatin, pravastatin, rosuvastatin, repaglinide, rifampin, simvastatin acid, SN-38 [active metabolite of irinotecan], valsartan) or breast cancer resistance protein (BCRP) (e.g., imatinib, irinotecan, lapatinib, methotrexate, mitoxantrone, rosuvastatin, sulfasalazine, topotecan).

Grapefruit juice may increase plasma concentrations of imatinib; avoid concomitant use.

Caution is recommended when administering imatinib mesylate tablets with strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, and voriconazole).

Concurrent use may cause hypothyroidism. Closely monitor TSH levels in patients receiving this tyrosine-kinase inhibitor.

Imatinib increases plasma concentration of certain HMG-CoA reductase inhibitors; use caution with drugs having narrow therapeutic window.

Caution is recommended when administering imatinib mesylate tablets with strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, and voriconazole).

Chemotherapy agent metabolized by CYP3A4; systemic exposure can increase with AKYNZEO; caution and monitoring advised.

Caution is recommended when administering imatinib mesylate tablets with strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, and voriconazole).

Caution is recommended when administering imatinib mesylate tablets with strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, and voriconazole).

CYP3A4 inducer that reduces imatinib AUC by 30%; consider alternative therapeutic agents.

The recommended dose of BELSOMRA is 5 mg in subjects receiving moderate CYP3A inhibitors (e.g., amprenavir, aprepitant, atazanavir, ciprofloxacin, diltiazem, erythromycin, fluconazole, fosamprenavir, grapefruit juice, imatinib, verapamil).

Tafamidis inhibits BCRP, increasing imatinib exposure and toxicity risk. Monitor for toxicities and adjust dosage if needed.

Caution is recommended when administering imatinib mesylate tablets with strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, and voriconazole).

Imatinib increases plasma concentration of triazolo-benzodiazepines; use caution with drugs having narrow therapeutic window.

Caution is recommended when administering imatinib mesylate tablets with strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, and voriconazole).

7.8 Tyrosine-Kinase Inhibitors Concurrent use of tyrosine-kinase inhibitors such as imatinib may cause hypothyroidism.

Interactions with Drugs Metabolized by CYP2D6 Imatinib mesylate tablets increased the mean C max and AUC of metoprolol by approximately 23% suggesting that imatinib mesylate tablets have a weak inhibitory effect on CYP2D6-mediated metabolism.

Interactions with Drugs Metabolized by CYP3A4 Imatinib mesylate tablets increase the mean C max and AUC of simvastatin (CYP3A4 substrate) 2- and 3.5-fold, respectively, suggesting an inhibition of the CYP3A4 by imatinib mesylate tablets.

Table 2: Examples of CYP450 Interactions with Warfarin Enzyme Inhibitors Inducers CYP2C9 amiodarone, capecitabine, cotrimoxazole, etravirine, fluconazole, fluvastatin, fluvoxamine, metronidazole, miconazole, oxandrolone, sulfinpyrazone, tigecycline, voriconazole, zafirlukast aprepitant, bosentan, carbamazepine, phenobarbital, rifampin CYP1A2 acyclovir, allopurinol, caffeine, cimetidine, ciprofloxacin, disulfiram, enoxacin, famotidine, fluvoxamine, methoxsalen, mexiletine, norfloxacin, oral contraceptives, phenylpropanolamine, propafenone, propranolol, terbinafine, thiabendazole, ticlopidine, verapamil, zileuton montelukast, moricizine, omeprazole, phenobarbital, phenytoin, cigarette smoking CYP3A4 alprazolam, amiodarone, amlodipine, amprenavir, aprepitant, atorvastatin, atazanavir, bicalutamide, cilostazol, cimetidine, ciprofloxacin, clarithromycin, conivaptan, cyclosporine, darunavir/ritonavir, diltiazem, erythromycin, fluconazole, fluoxetine, fluvoxamine, fosamprenavir, imatinib, indinavir, isoniazid, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, nilotinib, oral contraceptives, posaconazole, ranitidine, ranolazine, ritonavir, saquinavir, telithromycin, tipranavir, voriconazole, zileuton armodafinil, amprenavir, aprepitant, bosentan, carbamazepine, efavirenz, etravirine, modafinil, nafcillin, phenytoin, pioglitazone, prednisone, rifampin, rufinamide 7.3 Drugs that Increase Bleeding Risk Examples of drugs known to increase the risk of bleeding are presented in Table 3 .