Drug interactions with the tyrosine kinase inhibitors imatinib, dasatinib and nilotinib Table from the following article: Haouala A, Widmer N, Duchosal MA, Montemurro M, Buclin T, Decosterd LA. Drug interactions with the tyrosine kinase inhibitors imatinib, dasatinib, and nilotinib. Blood 2010. http://dx.doi.org/10.1182/blood-2010-07-294330 Legend: The Table (in 17 parts) summarizes observed or potential drug interactions between TKIs and commonly concomitantly prescribed drugs or classical interacting agents (lines) sorted according to the ATC classification. The arrows and indicate an increase or decrease of drug concentration respectively. Boldface text outlines interactions reported in the literature (reference number), whereas standard characters represent potential interactions predicted from theoretical considerations (but not yet reported in the literature). Absence of interaction means that a clinical study concluded to the absence of interaction (reference number), and a box shaded in grey means that no interaction is either reported or theoretically expected Disclaimer: This table summarizes potential drug interactions between some commonly prescribed drugs (lines) and three tyrosine kinase inhibtors (columns). Each cell indicates the type of interaction expected when the drug is taken together with the corresponding tyrosine kinase inhibitor. The data presented are however only indicative and do not replace clinical judgment necessary when treating patients with multiple drugs. Not all interactions are expected to have clinical significance and/or to imply dosage adjustment. It is also of importance to check regularly for updated literature on this topic. References: See full article.
Alimentary tract and metabolism Omeprazole Inhibition of Pgp by omeprazole : dasatinib absorption PPI Esomeprazole Inhibition of Pgp by esomeprazole : dasatinib absorption Pantoprazole Inhibition of Pgp by pantoprazole: dasatinib absorption H2-antagonists Cimetidine Ranitidine Inhibition of CYP 3A4 and Pgp by cimetidine : Inhibition of hoct1 by cimetidine : Inhibition of Pgp by ranitidine : Inhibition of hoct1 by ranitidine : dasatinib absorption dasatinib absorption cimetidine : Antiemetics Metoclopramide Insulin Metformin Inhibition of hoct1 by metformin : Glibenclamide 2C9 by glibenclamide exposure Inhibition of Pgp by glibenclamide : glibenclamide exposure Inhibition of Pgp by glibenclamide : 2C9 by glibenclamide exposure Antidiabetic drugs Acarbose Rosiglitazone Pioglitazone rosiglitazone exposure 2C9 by pioglitazone exposure pioglitazone exposure rosiglitazone exposure 2C9 by pioglitazone exposure Nateglinide 2C9 by nateglinide exposure nateglinide exposure 2C9 by nateglinide exposure Repaglinide pioglitazone exposure 2C8 by pioglitazone exposure 2C8 by pioglitazone exposure 2
Blood and blood forming organs Antiplatelet drug a Clopidogrel 2C19 by clopidogrel exposure clopidogrel bioactivation clopidogrel exposure clopidogrel bioactivation Thrombocytopenic effect of risk of bleeding clopidogrel exposure clopidogrel bioactivation Acenocoumarol anticoagulation monitor PT/INR Thrombocytopenic effect of risk of bleeding anticoagulation monitor PT/INR Phenprocoumon anticoagulation monitor PT/INR Thrombocytopenic effect of risk of bleeding anticoagulation monitor PT/INR Warfarin anticoagulation monitor PT/INR Thrombocytopenic effect of risk of bleeding anticoagulation monitor PT/INR Anticoagulants a Heparin Inhibition of Pgp by heparin: Thrombocytopenic effect of risk of bleeding Inhibition of Pgp by heparin: Enoxaparin Thrombocytopenic effect of risk of bleeding Nadroparin Thrombocytopenic effect of risk of bleeding Dalteparin Thrombocytopenic effect of risk of bleeding 3
Cardiovascular system Calcium channel blockers Verapamil Diltiazem Nifedipine Amlodipine verapamil exposure verapamil: diltiazem exposure diltiazem: nifedipine exposure amlodipine exposure verapamil exposure verapamil: diltiazem exposure diltiazem: nifedipine exposure amlodipine exposure verapamil exposure verapamil: diltiazem exposure diltiazem: Inhibition of CYP3A4 by nifedipine exposure amlodipine exposure Molsidomine NO precursors Isosorbid mononitrate (ISMN) Isosorbid dinitrate (ISDN) ISMN exposure ISDN exposure ISMN exposure ISDN exposure ISMN exposure ISMN exposure Nitroglycerine HMG-CoA reductase inhibitors Simvastatin Pravastatin Atorvastatin Rosuvastatin simvastatin exposure Inhibition of Pgp by simvastatin: atorvastatin exposure Inhibition of Pgp by atorvastatin: simvastatin exposure Inhibition of Pgp by simvastatin: atorvastatin exposure Inhibition of Pgp by atorvastatin: Inhibition of CYP 3A4 by simvastatin exposure atorvastatin exposure Antiarrhythmic drugs Amiodarone Quinidine amiodarone exposure Inhibition of CYP3A4 and Pgp by amiodarone: Inhibition of hoct1 by amiodarone : quinidine exposure Inhibition of Pgp by quinidine: Inhibition of hoct1 by quinidine : amiodarone exposure amiodarone: quinidine exposure Inhibition of Pgp by quinidine: Inhibition of Pgp and CYP 3A4 by amiodarone exposure amiodarone: QT interval => monitor ECG quinidine exposure 4
Furosemide Absence of interaction Diuretics Torasemide Hydrochlorothiazide torasemide exposure torasemide exposure Spironolactone Inhibition of Pgp by spironolactone: Inhibition of Pgp by spironolactone: Metoprolol metoprolol exposure Inhibition of Pgp by metoprolol: metoprolol exposure Beta blockers Bisoprolol Carvedilol bisoprolol exposure Inhibition of CYP 2C9 and 2D6 by carvedilol exposure Inhibition of Pgp by carvedilol: bisoprolol exposure Inhibition of Pgp by carvedilol: bisoprolol exposure Inhibition of CYP 2C9 and 2D6 by carvedilol exposure Atenolol Absence of interaction Captopril captopril exposure Inhibition of Pgp by captopril: Inhibition of Pgp by captopril: captopril exposure ACE inhibitors Enalapril Ramipril enalapril exposure Inhibition of Pgp by enalapril: Inhibition of Pgp by enalapril: dasatinib exposure enalapril exposure Lisinopril Inhibition of Pgp by lisinopril exposure Inhibition of Pgp by lisinopril: Inhibition of Pgp by lisinopril: AT II receptor blockers Losartan Candesartan Inhibition of CYP 2C9 and 3A4 by losartan exposure and losartan bioactivation Inhibition of Pgp by losartan: losartan exposure Inhibition of Pgp by losartan: Inhibition of CYP 2C9 and 3A4 by losartan exposure and losartan bioactivation Cardiac glycosides Digoxin digoxin absorption (unknown mechanism) Inhibition of Pgp by digoxin exposure 5
Hormonal preparations Prednisone Corticosteroids Dexamethasone dexamethasone : dexamethasone : dexamethasone : Betamethasone Thyroid therapy Levothyroxine Induction of UGTs by imatinib : levothyroxine levothyroxine: levothyroxine: levothyroxine: Carbimazole Antineoplastic agents Cyclophosphamide Inhibition of CYP 2D6 and 3A4 by cyclophosphamide exposure cyclophosphamide bioactivation cyclophosphamide exposure cyclophosphamide bioactivation Induction of CYP 2B6 by cyclophosphamide exposure cyclophosphamide bioactivation Antiestrogen agent Tamoxifen Inhibition of CYP 2D6 and 3A4 by tamoxifen exposure tamoxifen bioactivation tamoxifen exposure tamoxifen bioactivation Inhibition of CYP 2D6 and 3A4 by tamoxifen exposure tamoxifen bioactivation 6
Anti-infectives Penicillins Amoxicillin Flucloxacillin Cephalosporins Céfuroxime Cefpodoxime Ceftriaxone Macrolides Clarithromycin Azithromycin Erythromycin Pgp by clarithromycin: Pgp by erythromycin: Pgp by clarithromycin: Pgp by erythromycin: Inhibition of CYP 3A4 by clarithromycin: Inhibition of CYP 3A4 by erythromycin: Tertracyclines Doxycyclin Ciprofloxacin Inhibition of Pgp by ciprofloxacin: Inhibition of Pgp by ciprofloxacin: Quinolones Levofloxacin Inhibition of Pgp by levofloxacin: Inhibition of hoct1 by levofloxacine : Inhibition of Pgp by levofloxacin: Norfloxacin Sulfonamides Co-trimoxazole co-trimoxazole Inhibition of CYP 2C9 by co-trimoxazole 7
Itraconazole Pgp by itraconazole: itraconazole: itraconazole: Azoles Fluconazole Voriconazole Pgp by fluconazole: voriconazole: fluconazole: voriconazole: fluconazole: voriconazole: Ketoconazole Pgp by ketoconazole: ketoconazole: ketoconazole: Allylamine Terbinafine 2C9 by terbinafine exposure terbinafine exposure 2C9 by terbinafine exposure Nitroimidazole Metronidazole Aciclovir Absence of interaction Antiviral/Nucleoside analog Valaciclovir Ganciclovir Valganciclovir Absence of interaction Inhibition of hoct1 by ganciclovir : imatinib intracellular exposure Inhibition of hoct1 by ganciclovir : imatinib intracellular exposure Antimycobacterials Rifampicine Isoniazide Ethambutol rifampicine: rifampicine: rifampicine: 8
Ritonavir ritonavir: ritonavir: Saquinavir saquinavir exposure Inhibition of hoct1 by saquinavir : saquinavir exposure saquinavir exposure Protease inhibitors Darunavir Atazanavir Tipranavir darunavir: atazanavir exposure tipranavir exposure tipranavir: darunavir: atazanavir exposure tipranavir exposure tipranavir: darunavir: atazanavir exposure tipranavir exposure tipranavir: Indinavir indinavir exposure Inhibition of hoct1 by indinavir : indinavir exposure indinavir exposure Nucleoside and nucleotide reverse transcriptase inhibitors Lamivudine Emtricitabine Zidovudine Inhibition of hoct1 by lamivudine : Non-nucleoside reverse transcriptase inhibitors Efavirenz Nevirapine Etravirine efavirenz exposure efavirenz: nevirapine exposure nevirapine: Inhibition of CYP 2C9 and 3A4 by etravirine exposure etravirine: efavirenz exposure efavirenz: nevirapine exposure nevirapine: etravirine exposure etravirine: efavirenz exposure efavirenz: nevirapine exposure nevirapine: Inhibition of CYP 2C9 and 3A4 by etravirine exposure etravirine: 9
Quinine quinidine exposure Inhibition of CYP 2D6 and Pgp by quinidine: Inhibition of hoct1 by quinine : quinidine exposure quinidine exposure quinidine exposure Chloroquine Inhibition of Pgp by chloroquine: Inhibition of hoct1 by chloroquine : Inhibition of Pgp by chloroquine: Antimalarial drugs Mefloquine mefloquine exposure Inhibition of Pgp by mefloquine: mefloquine exposure Inhibition of Pgp by mefloquine: Ppg by mefloquine exposure Proguanil Inhibition of CYP 2C19 and Pgp by proguanil exposure proguanil bioactivation Atovaquone Doxycycline 10
Immunomodulating agents Ciclosporin ciclosporin exposure Inhibition of Pgp and CYP 3A4 by ciclosporin: ciclosporin exposure Inhibition of CYP3A4 and Pgp by ciclosporin: Inhibition of CYP 3A4 and Pgp by ciclosporin exposure Inhibition of CYP3A4 by ciclosporin: Tacrolimus tacrolimus exposure Inhibition of Pgp by tacrolimus: tacrolimus exposure Inhibition of Pgp by tacrolimus: Pgp by tacrolimus exposure Immunosuppressants Sirolimus Everolimus sirolimus exposure everolimus exposure sirolimus exposure everolimus exposure Pgp by sirolimus exposure Pgp by everolimus exposure Mycophenolate mofetil Methotrexate Azathioprine 11
Musculo-skeletal system Aspirin Thrombocytopenic effect of risk of bleeding Ibuprofen ibuprofen exposure Inhibition of CYP 2C8 by ibuprofen exposure Inhibition of CYP 2C8 and 2C9 by ibuprofen exposure NSAIDs Mefenacid mefenacid exposure Inhibition of CYP 2C8 by mefenacid exposure Inhibition of CYP 2C8 and 2C9 by mefenacid exposure Metamizole metamizole: metamizole : metamizole : Diclofenac diclofenac exposure Inhibition of Pgp by diclofenac: Inhibition of CYP 2C8 by diclofenac exposure Inhibition of Pgp by diclofenac: Inhibition of CYP 2C8 and 2C9 and by diclofenac exposure Antigout preparations Allopurinol 12
Nervous system Fluoxetine fluoxetine exposure Fluvoxamine fluvoxamine exposure fluvoxamine exposure SSRI Paroxetine paroxetine exposure paroxetine exposure Citalopram 2D6 by citalopram exposure citalopram exposure 2D6 by citalopram exposure SSNRI Sertraline Venlafaxine 2D6 by sertraline exposure 2D6 by venlafaxine exposure sertraline exposure venlafaxine exposure 2D6 by sertraline exposure 2D6 by venlafaxine exposure Duloxetine duloxetine exposure duloxetine exposure Tetracyclic agent Mirtazapine 2D6 by mirtazapine exposure mirtazapine exposure 2D6 by nilotinib : mirtazapine exposure Tricyclic agents Trimipramine Amitriptyline trimipramine exposure 2D6 by amitriptyline exposure amitriptyline exposure trimipramine exposure 2D6 by amitriptyline exposure Phenothiazines Levomepromazine levomepromazine exposure levomepromazine exposure 13
Zolpidem zolpidem exposure zolpidem exposure zolpidem exposure Z-drugs Zaleplon zaleplon exposure zaleplon exposure zaleplon exposure Zopiclon zopiclon exposure zopiclon exposure zopiclon exposure Alprazolam alprazolam exposure alprazolam exposure alprazolam exposure Bromazepam bromazepam exposure bromazepam exposure bromazepam exposure Clonazepam clonazepam exposure clonazepam exposure clonazepam exposure Benzodiazepines Oxazepam Lorazepam Diazepam Midazolam diazepam exposure midazolam exposure Inhibition of Pgp by midazolam: Inhibition of hoct1 by midazolam : diazepam exposure midazolam exposure Inhibition of Pgp by midazolam: diazepam exposure midazolam exposure Barbiturates Phenobarbital Inhibition of CYP 2C9 and 2C19 by phenobarbital exposure phenobarbital: phenobarbital: phenobarbital exposure phenobarbital: 14
Antipsychotic agents Haloperidol Clozapine Olanzapine 2D6 by haloperidol exposure 2D6 by clozapine exposure haloperidol exposure clozapine exposure 2D6 by clozapine exposure Risperidone risperidone exposure Phenytoin phenytoin : phenytoin : phenytoin : Antiseizure drugs Valproic acid Carbamazepine Lamotrigine Inhibition of CYP 2C9 and 2C19 by valproic acid exposure valproic acid: Induction of CYP 3A4 and Pgp by carbamazepine: valproic acid : Induction of CYP 3A4 and Pgp by carbamazepine: valproic acid exposure valproic acid : carbamazepine: Gabapentin Topiramate topiramate : topiramate : topiramate : Levetiracetam Antimaniac drug Lithium Aminoketone Bupropion Induction of CYP 2B6 by bupropion exposure bupropion bioactivation 15
Morphine Tramadol 2D6 by imatinib : tramadol exposure tramadol bioactivation dasatinib : tramadol exposure 2D6 by nilotinib : tramadol exposure tramadol bioactivation Opioids Methadone imatinib : methadone exposure Inhibition of Pgp by methadone:. dasatinib : methadone exposure Inhibition of Pgp by methadone:. nilotinib : methadone exposure Induction of CYP 2B6 by methadone exposure Hydromorphone Oxycodone 2D6 by imatinib : oxycodone exposure oxycodone bioactivation dasatinib : oxycodone exposure 2D6 by nilotinib : oxycodone exposure oxycodone bioactivation Buprenorphine imatinib : buprenorphine exposure buprenorphine exposure buprenorphine exposure Other Acetaminophen Inhibition of o- glucuronidation by imatinib : acetaminophen exposure Antimigraine preparations Dihydroergotamine Sumatriptan dihydroergotamine exposure dihydroergotamine exposure dihydroergotamine exposure 16
Respiratory system Cetirizin Inhibition of Pgp by cetirizin exposure H1-antagonists Levocetirizin Loratadin imatinib : loratadin exposure loratadin exposure Inhibition of Pgp by cetirizin exposure Inhibition of Pgp by loratadin exposure Fexofenadin Anti asthma drugs Salbutamol Theophylline 17
Miscellaneous St John s wort St John s wort: St John s wort: St John s wort: Grapefruit Pgp by grapefruit: Pgp by grapefruit: grapefruit: Licorice licorice: licorice: licorice: a TKIs in general can cause thrombocytopenia, which is usually of no clinical relevance, please take that into consideration when coadministrating with anticoagulant medication. 18