1 Drug/Drug and Drug/Food Interactions with Target-Specific Oral Anticoagulants Sara R. Vazquez, PharmD, BCPS, CACP Clinical Pharmacist University of Utah Health Care Thrombosis Service Nothing to disclose
3 Drug Absorption: Food Take with or without food High-fat meal delays time to C max from 1 hour to 3 hours 10-mg dose: Take with or without food 15-mg and 20-mg doses: Take WITH food (enhances bioavailability) Take with or without food Pradaxa prescribing information. Boehringer-Ingelheim, Xarelto prescribing information. Janssen, Stampfuss J, et al. Int J Clin Pharmacol Ther 2013, Epub ahead of print. Eliquis prescribing information. Bristol-Myers Squibb, Frost C, et al. Br J Clin Pharmacol 2013;75:
4 Drug Absorption: Gastric ph Absorption independent of gastric ph No change in drug exposure when given with antacids, ranitidine, omeprazole Absorption independent of gastric ph No interaction identified when coadministered with famotidine Xarelto prescribing information. Janssen, Moore KT. J Cardiovasc Pharmacol 2011; 58: Eliquis prescribing information. Bristol-Myers Squibb, Upreti W, et al. Clin Pharmacol 2013; 5:
5 Dabigatran Etexilate Dabigatran etexilate coating Tartaric acid core renders the extent of absorption of dabigatran etexilate independent of variations in gastric ph The concomitant use of proton pump inhibitors nor H2 antagonists did not appreciably change the trough concentration of dabigatran. Overall drug exposure (Cmax and AUC) is reduced by 20-25% if dabigatran-treated patients are given proton pump inhibitors although this is not considered clinically relevant. Acidic microenvironment Stangier J. Clin Pharmacokinet 2008; 47: Pradaxa prescribing information. Boehringer-Ingelheim, 2012.
6 Drug-Drug Interactions: P-glycoprotein Gut Gut Gut P-gp inducer P-gp inhibitor Bloodstream Bloodstream Bloodstream
7 Dabigatran Drug-Drug Interactions: P-glycoprotein Strong P-glycoprotein Inhibitors Strong P-glycoprotein Inducers Alfentanil Indinavir Quinidine Barbiturates Amiodarone Itraconazole Ritonavir Carbamazepine Bepridil Ketoconazole Saquinavir Dexamethasone Carvedilol Lapatinib Tacrolimus Phenytoin Clarithromycin Lovastatin Tamoxifen Rifampin Conivaptan Mefloquine Telaprevir St John s Wort Cyclosporine Mifepristone Telithromycin Diltiazem Nelfinavir Testosterone Dronedarone Nicardipine Ticagrelor Duloxetine Posaconazole Verapamil Fenofibrate Propafenone U.S. Food and Drug Administration, Drug Development and Drug Interactions: Table of Substrates, Inhibitors, and Inducers. Hansten PD, Horn JR. The Top 100 Drug Interactions 2012 Edition. Pradaxa prescribing information. Boehringer-Ingelheim, 2012.
8 Dabigatran etexilate Prescribing Information The concomitant use of dabigatran with P-gp inducers (e.g., rifampin) reduces exposure to dabigatran and should generally be avoided. The use of P-gp inhibitors (verapamil, amiodarone, quinidine, and clarithromycin) does not require a dose adjustment of dabigatran. These results should not be extrapolated to other P-gp inhibitors. Pradaxa prescribing information. Boehringer-Ingelheim, 2012.
9 Dabigatran Drug-Drug Interactions: P-glycoprotein Strong P-glycoprotein Inhibitors Strong P-glycoprotein Inducers Alfentanil Indinavir Quinidine Barbiturates Amiodarone Itraconazole Ritonavir Carbamazepine Bepridil Ketoconazole Saquinavir Dexamethasone Carvedilol Lapatinib Tacrolimus Phenytoin Clarithromycin Lovastatin Tamoxifen Rifampin Convipatan Mefloquine Telaprevir St John s Wort Cyclosporine Mifepristone Telithromycin Diltiazem Nelfinavir Testosterone Dronedarone Nicardipine Ticagrelor Duloxetine Posaconazole Verapamil Fenofibrate Propafenone U.S. Food and Drug Administration, Drug Development and Drug Interactions: Table of Substrates, Inhibitors, and Inducers. Hansten PD, Horn JR. The Top 100 Drug Interactions 2012 Edition. Pradaxa prescribing information. Boehringer-Ingelheim, 2012.
10 Drug Interactions: Rivaroxaban and Apixaban Rivaroxaban Avoid concomitant use of rivaroxaban with combined P-gp and strong CYP 3A4 inhibitors (e.g., ketoconazole, itraconazole, lopinavir/ritonavir, indinavir/ritonavir, and conivaptan). Apixaban The dose of apixaban should be decreased to 2.5 mg twice daily when it is coadministered with drugs that are strong dual inhibitors of CYP3A4 and P-gp (e.g., ketoconazole, itraconazole, ritonavir, or clarithromycin). Avoid concomitant use of rivaroxaban with drugs that are combined P-gp and strong CYP3A4 inducers (e.g., carbamazepine, phenytoin, rifampin, St John s wort). Avoid concomitant use of apixaban with strong dual inducers of CYP3A4 and P-gp (e.g., rifampin, carbamazepine, phenytoin, St John s wort) because such drugs will decrease exposure to apixaban. Xarelto prescribing information. Janssen, Eliquis prescribing information. Bristol-Myers Squibb, 2012.
11 Drug-Drug Interactions: CYP3A4 CYP3A4 Inhibitors CYP3A4 Inducers amiodarone cyclosporine fluvoxamine nelfinavir voriconazole aminoglutethimide nafcillin amprenavir dalfopristin fosamprenavir posaconazole zafirkulast armodafinil nevirapine aprepitant danazol imatinib propoxyphene artemether phenobarbital atazanavir darunavir indinavir quinupristin barbiturates phenytoin basiliximab dasatinib isoniazid ritonavir bexarotene primidone boceprevir delavirdine itraconazole saquinavir bosentan rifabutin chlorampehnicol diltiazem ketoconazole tamoxifen carbamazepine rifampin ciprofloxacin dronedarone lapatinib telaprevir dexamethasone rifapentine clarithomycin erythromycin miconazole telithromycin efavirenz St John's wort conivaptan ethinyl estradiol mifepristone troleandomycin etravirine vemurafenib crizotinib fluconazole nefazodone verapamil modafinil U.S. Food and Drug Administration, Drug Development and Drug Interactions: Table of Substrates, Inhibitors, and Inducers. Hansten PD, Horn JR. The Top 100 Drug Interactions 2012 Edition.
12 Drug-Drug Interactions: P-glycoprotein AND CYP3A4 Combined Strong P-glycoprotein AND CYP3A4 Inhibitors Combined Strong P-glycoprotein AND CYP3A4 Inducers amiodarone nelfinavir barbiturates clarithromycin posaconazole carbamazepine conivaptan ritonavir dexamethasone cyclosporine saquinavir phenytoin indinavir tamoxifen rifampin itraconazole telaprevir St John's wort ketoconazole mifepristone telithromycin U.S. Food and Drug Administration, Drug Development and Drug Interactions: Table of Substrates, Inhibitors, and Inducers. Hansten PD, Horn JR. The Top 100 Drug Interactions 2012 Edition. Xarelto prescribing information. Janssen, Eliquis prescribing information. Bristol-Myers Squibb, 2012.
20 Drug-Drug Interactions: Antiplatelet Agents TSOAC + Low-dose ASA (eg, 81 mg daily) All major TSOAC clinical trials have allowed concomitant low-dose ASA bleeding rates when TSOACs combined with low-dose ASA TSOAC + dual antiplatelet therapy (eg, ASA + clopidogrel) For all TSOACs: significant in major bleeding when used concomitantly with dual antiplatelet therapy
21 Drug-Drug Interactions: NSAIDS GIB NSAIDS allowed in all clinical trials Per manuf PI, no interactions with diclofenac Post-hoc pooled analysis of 3 TKA/THA trials showed no risk of bleeding with concomitant NSAIDs GIB Chronic NSAID treatment an EXCLUSION criterion in clinical trials General statement about potential increased bleeding risk with concomitant NSAIDs Pre-specified pooled analysis of RECORD 1-4 trials showed no risk of bleeding with concomitant NSAIDs NSAIDS allowed in all clinical trials Per manuf PI, no interaction and no dose adjustment required with concomitant naproxen use General statement about potential increased bleeding risk with concomitant NSAIDs Pradaxa prescribing information. Boehringer-Ingelheim, Friedman RJ, et al. Thromb Haemost 2012; 108: Xarelto prescribing information. Janssen, Eriksson BI, et al. Thromb Res 2012; 130: Eliquis prescribing information. Bristol-Myers Squibb, 2012.
22 Drug-Food Interactions: Grapefruit Strong P-gp AND intestinal CYP3A4 inhibitor No current US package labeling guidance for TSOACs Health Canada (rivaroxaban prescribing information): Grapefruit juice is a moderate CYP3A4 inhibitor. Therefore, an increase in rivaroxaban exposure following grapefruit juice consumption is not expected to be clinically relevant. Hansten PD, Horn JR. The Top 100 Drug Interactions 2012 Edition. Xarelto prescribing information. Health Canada, 2012.
23 Sneak Peak Edoxaban Absorption unaffected by food can be administered with or without food Half-life 10 hours 35-40% renal clearance P-gp substrate CYP3A4 substrate Camm AJ, Bounameaux H. Drugs 2011; 71:
24 New Paradigm of Drug Interaction Management Warfarin TSOACs Warfarin + Interacting Drug Many reported drug interactions Much published literature and clinical expertise to guide management INR monitoring Warfarin dose adjustment TSOAC + Interacting Drug Few reported drug interactions Little published literature or clinical expertise to guide management No established laboratory monitoring method TSOAC dose adjustment???
25 TSOAC Drug Interactions Exist How do we manage them? Prevention/Education to patients/providers How are interactions with non-anticoagulant drugs handled? Dose reduction/increase of target drug Change interacting drug to non-interacting drug Consider duration of interacting drug: short-term vs long-term and level of risk/toxicity Importance of anticoagulation specialist/ pharmacist involvement and follow-up! Specific management strategies
26 Clarithromycin/TSOAC Interaction Dabigatran Rivaroxaban Apixaban U.S. FDA Health Canada EMA Do not use if CrCl <30 ml/min No precautions necessary unless renally impaired (do not use if CrCl <50 ml/min) Reduce apixaban dose to 2.5 mg BID, or avoid if already on apixaban 2.5 mg BID No dose adjustment is recommended; use with caution may increase the risk of bleeding particularly in patients with underlying disease conditions, and elderly. Caution is required. Not specifically addressed a clinically relevant interaction cannot be excluded close monitoring should be exercised notably in patients having mild to moderate renal impairment No clinically relevant interaction Not specifically addressed
27 Amiodarone/TSOAC Interaction Dabigatran Rivaroxaban Apixaban U.S. FDA Health Canada EMA Do not use if CrCl <30 ml/min No precautions necessary unless renally impaired (do not use if CrCl <50 ml/min) Not specifically addressed No dose adjustment is recommended; use with caution Not specifically addressed Similar effect to diltiazem; no dose adjustment required; use with caution Caution should be exercised Not specifically addressed Considers amiodarone a less potent CYP3A4 inhibitor; no dose adjustment required
28 Good Rule of Thumb If not otherwise specifically described, close clinical surveillance (looking for signs of bleeding or anemia), along with a sense of caution is required when dabigatran is co-administered with P-glycoprotein inhibitors, especially in the elderly, i.e., >75 years of age. Consideration should be given to avoiding use of strong P-gp inhibitors with dabigatran, unless deemed medically essential. Pradaxa prescribing information. Health Canada, 2012.
29 TSOACS Drug-Drug and Drug-Food Interactions Summary Dabigatran Concomitant P-gp inhibitors/inducers Renal function Elderly (age >75 years) Concomitant antiplatelet agents/nsaids Rivaroxaban Take with food Concomitant strong P-gp inhibitors/ inducers AND CYP3A4 inhibitors/ inducers Renal function Elderly (age >75 years) Concomitant antiplatelet agents/ NSAIDs Apixaban Concomitant strong P-gp inhibitors/inducers AND CYP3A4 inhibitors/inducers Combination of older age, renal dysfunction, and low body weight Concomitant antiplatelet agents/nsaids
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