Slide 1. Slide 2. Slide 3. Disclosures. Objectives DRUG INTERACTIONS WITH NEW ORAL ANTICOAGULANTS. None

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1 Slide 1 DRUG INTERACTIONS WITH NEW ORAL ANTICOAGULANTS Michelle Friedman, B.S., Pharm.D. PGY-2 Internal Medicine Pharmacy Resident Kingsbrook Jewish Medical Center Chanie Wassner, Pharm.D. PGY-2 Critical Care Pharmacy Resident Kingsbrook Jewish Medical Center January 18 th, 2015 Lake Placid, New York Slide 2 Disclosures 2 None Slide 3 Objectives 3 Provide an overview of the pharmacology and pharmacokinetics of rivaroxaban, apixaban, and dabigatran Identify the bleeding profile of the new oral anticoagulants (NOACs) Compare and contrast the drug-drug interactions (DDIs) of warfarin, rivaroxaban, apixaban, and dabigatran Describe the implications of pharmacogenomics on NOACs

2 Slide 4 Anticoagulant Medications Available on the US Market 1943 Heparin Approved by FDA 1954 Warfarin Approved by FDA 1993 Enoxaparin Approved by FDA 2000 Argatroban approved by FDA 2001 Fondaparinux approved by FDA 2010 Dabigatran Approved by FDA 2011 Rivaroxaban Approved by FDA 2012 Apixaban approved by FDA Slide 5 5 Advantages and Disadvantages of NOACs Advantages Disadvantages Fast onset/offset of action No routine monitoring Standardized dosing Fewer drug interactions Short half-life No routine monitoring No coagulation assay specific to anticoagulation effect Lack of antidote Cost Circulation 2012;125: Slide 6 Oral Anticoagulant Pharmacology 6 Vitamin K Antagonists Warfarin Oral Factor Xa Inhibitors Rivaroxaban Apixaban Direct Thrombin Inhibitor Dabigatran Anesthesia UK

3 Slide 7 NOAC Agents 7 Dabigatran (Pradaxa ) Rivaroxaban (Xarelto ) Apixaban (Eliquis ) Mechanism Direct thrombin inhibitor Factor Xa inhibitor Factor Xa inhibitor Onset of action Fast Fast Fast Atrial Fibrillation CrCl > 50 ml/min CrCl > 30 ml/min CrCl ml/min Treatment of DVT/PE Reduction in DVT/PE Recurrence DVT Prophylaxis After Hip or Knee Replacement Surgery 5 PO BID 150 PO BID 20 PO once daily IF >2 of the following: 150 PO BID 15 PO once daily 80 years Body weight 60 kg 75 PO BID (not 15 PO once daily SCr 1.5 /dl studied) 2.5 PO BID 15 PO BID X21 days 10 PO BID X7 days, 150 PO BID Then 20 PO once then 5 PO BID daily 150 PO BID 20 PO once daily 2.5 PO BID Hip: 10 PO once daily X35 days N/A 2.5 PO BID Knee: 10 PO once daily X12 days Pradaxa [package insert]. Ridgefield, CT: Boehringer Ingelheim Pharmaceuticals, Inc; Revised September 2014 Eliquis [package insert]. Princeton, NJ: Bristol-Myers Squibb Company; Revised August 2014 Xarelto [package insert]. Titusville, NJ: Janssen Pharmaceuticals, Inc; Revised August 2014 Slide 8 NOAC Pharmacokinetics 8 Bioavailability 3-7% Bioavailability: 66% (without food) >80% (with food) Bioavailability 50% Europace 2013;15: Slide 9 Risk of Any Anticoagulant 9 BLEEDING! BLEEDING! BLEEDING!

4 Slide Rivaroxaban Bleeding Profile Review Event ROCKET-AF Atrial Fibrillation Rivaroxaban N = 7111 n (%) Warfarin N = 7125 n (%) EINSTEIN DVT and PE DVT/PE Treatment Rivaroxaban N = 4130 n (%) Enoxaparin/ VKA N = 4116 n (%) RECORD 1-3 Hip/Knee Replacement Rivaroxaban N = 3281 n (%) Enoxaparin N = 3298 n (%) Major Bleeding 395 (5.6) 386 (5.4) 40 (1.0)* 72 (1.7)* 7 (0.2) 3 (0.1) Fatal Bleeding 27 (0.4)* 55 (0.8)* 3 (<0.1) 8 (0.2) 1 (<0.1) 0 Gastrointestinal Bleeding Intracranial Bleeding * = statistically significant 221 (3.1)* 140 (2.0) * 1 (<0.1) 4 (<0.1) (0.77)* 84 (1.18)* 3 (<0.1) 8 (<0.2) Thrombosis Journal 2013;11:1-10 N Engl J Med 2011; 365: Xarelto [package insert]. Titusville, NJ: Janssen Pharmaceuticals, Inc; Revised August 2014 Slide 11 Apixaban Bleeding Profile Review 11 ARISTOTLE AVERROES ADVANCE 1-3 Event Atrial Fibrillation Atrial Fibrillation Hip/Knee Replacement Apixaban Warfarin Apixaban Aspirin Apixaban Enoxaparin N = 9088 N = 9052 N = 2808 N = 2791 N = 5770 N = 5755 n (%/year) n (%/year) n (%/year) n (%/year) n (%) n (%) 11 (0.69) 22 (1.39) 14 (0.93) Major Bleeding 327 (2.13)* 462 (3.09)* 44 (1.4) 39 (1.2) 9 (0.60) 22 (0.82) 18 (0.68) Fatal Bleeding 10 (0.06) 37 (0.24) 4 (0.1) 6 (0.2) Gastrointestinal 105 (0.76) 119 (0.86) 12 (0.4) 14 (0.4) Bleeding Intracranial 52 (0.33)* 122 (0.80)* 11 (0.4) 13 (0.4) Bleeding * = statistically significant Eliquis [package insert]. Princeton, NJ: Bristol-Myers Squibb Company; Revised August 2014 N Engl J Med 2011;365: N Engl J Med 2011;364: Slide 12 Dabigatran Bleeding Profile Review RE-MEDY RELY RE-COVER I and II Event VTE Secondary Atrial Fibrillation DVT/PE Treatment Prevention Dabigatran Warfarin Dabigatran Warfarin Dabigatran Warfarin N = 6076 N =6022 N = 2553 N = 2554 N =1430 N = 1426 n (%/yr) n (%/yr) n (%) n (%) n (%) n (%) Major Bleeding Event 375 (3.1) 397 (3.4) 37 (1.4) 51 (2) 13 (0.9) 25 (1.8) (MBE) Fatal Bleeding (0.04) 2 (0.1) 0 1 (0.1) Bleeding Sites for MBE Intracranial 36 (0.3)* 87 (0.74)* 2 (0.1) 5 (0.2) 2 (0.1) 4 (0.3) Gastrointestinal 182 (1.51)* 120 (1.02)* 15 (0.6) 14 (0.5) 4 (0.3) 8 (0.6) Any GI Bleeding (3.1) 61 (2.4) 44 (3.1) 31 (2.2) Any Bleeding 1977 (16.42)* 2142 (18.15)* 411 (16.1)* 567 (22.7)* 278 (19.4)* 374 (26.2)* * = statistically significant Pradaxa [package insert]. Ridgefield, CT: Boehringer Ingelheim Pharmaceuticals, Inc; Revised September 2014 N Engl J Med 2009;361(12)

5 Slide 13 Rivaroxaban and Apixaban Slide 14 Slide 15

6 Slide Drug Metabolism and Interactions Cytochrome P450 P-glycoprotein Slide 17 Cytochrome P450 Enzymes 17 Heme-containing enzymes bound to membranes within a cell Essential for metabolism of chemicals and many medications Six subtypes metabolize 90% of drugs 1A2, 2C9, 2C19, 2D6, 3A4, 3A5 2 most significant: 3A4, 2D6 Clinically significant drug interactions Induction of enzymes Decreased level of substrate drug Inhibition of enzymes Increased level of substrate drug Genetic polymorphisms may occur Alter metabolism of chemicals and medications American Family Physician 2007;76:391-6 Slide 18 CYP3A4 Agents 18 Substrates Inhibitors Inducers Alprazolam Clarithromycin Carbamazepine Amlodipine Diltiazem Phenobarbital Apixaban Erythromycin Phenytoin Atorvastatin Grapefruit juice Rifampicin, rifampin Cyclosporine Itraconazole St John s Wort Diazepam Estradiol Rivaroxaban Simvastatin Sildenafil Verapamil Zolpidem Ketoconazole Nefazodone Ritonavir Telithromycin Verapamil American Family Physician 2007;76:391-6

7 Slide 19 P-Glycoprotein (P-gp) 19 Plasma membrane efflux transporter located in the intestinal lumen and kidneys Involved with metabolism in enterocytes and hepatocytes Involved with elimination in kidneys Pumps drug back into intestinal lumen, reducing the bioavailability of orally administered drugs DDIs P-gp inhibitors Increased drug bioavailability P-gp inducers Decreased drug bioavailability P-gp competitors Increased drug bioavailability CMAJ 2004;170: Slide 20 P-gp Inducers and Inhibitors Inducers Inhibitors Carbamazepine Amiodarone Nelfinavir Doxorubicin Atorvastatin Nicardipine Dexamethasone Clarithromycin Nifedipine Nefazodone Cyclosporine Progesterone Paclitaxel Diltiazem Propranolol Phenytoin Dipyridamole Quinidine/quinine Prazosin Erythromycin Ritonavir Rifampin Hydrocortisone Saquinavir St. John s Wort Itraconazole Tacrolimus Tenofovir Ketoconazole Tamoxifen Trazodone Lovastatin Verapamil Ann Pharmacother 2013;47: Slide 21 Dual CYP3A4 and P-gp Metabolism 21 CMAJ 2004;170:1531-2

8 Slide 22 Dual 3A4/P-gp Agents 22 Substrates Inhibitors Inducers Apixaban Amiodarone Carbamazepine Atorvastatin Cimetidine Phenobarbital Cyclosporine Clarithromycin Rifampicin Docetaxel Erythromycin St John s Wort Paclitaxel Fluconazole Rivaroxaban Ketoconazole Tacrolimus Itraconazole Nifedipine Ritonavir Saquinavir Verapamil Voriconazole Can J Cardiol 2013;29:S24-33 Slide 23 Rivaroxaban Metabolism 23 Bioavailability: 66% (without food) >80% (with food) Europace 2013;15: Slide Rivaroxaban Pharmacokinetic Interactions Strong CYP3A4/P-gp inhibitors Bioavailability increased by ~2.5 times May increase risk of hemorrhage Management Avoid combination with strong inhibitors Consider therapy modification with moderate inhibitors Strong CYP3A4/P-gp inducers Bioavailability decreased by about 50% May decrease efficacy Management Avoid combination with strong inducers Monitor therapy with moderate inducers Xarelto [package insert]. Titusville, NJ: Janssen Pharmaceuticals, Inc; Revised August 2014 Thromb Haemost 2010;103:572-85

9 Slide Rivaroxaban Pharmacokinetic Interactions Europace 2013;15: Slide Rivaroxaban Pharmacokinetic Interactions Europace 2013;15: Slide Pharmacokinetic Interactions: Drugs Affecting Gastric ph Absorption and bioavailability of rivaroxaban not affected by gastric ph No significant changes in AUC and C max when given together with ranitidine or an aluminummagnesium hydroxide antacid No significant changes when given with omeprazole Annals of Pharmacotherapy 2013;47(11):

10 Slide Pharmacodynamic Interactions: Rivaroxaban and Antiplatelets/NSAIDs Aspirin ROCKET-AF warfarin versus rivaroxaban Concomitant aspirin in 36.3% Independent risk factor for major bleeding Clopidogrel Concomitant administration in healthy subjects Increase in bleeding time by 30-45% NSAIDS No clinically relevant effect of naproxen on bleeding time and clotting parameters in one pharmacokinetic study Possible may increase bleeding risk Package insert: Avoid concomitant antiplatelet and NSAID use unless the risk outweighs the benefit Annals of Pharmacotherapy 2013;47(11): Xarelto [package insert]. Titusville, NJ: Janssen Pharmaceuticals, Inc; Revised August 2014 Slide Pharmacodynamic Interactions: Antiplatelet Therapy ATLAS ACS 2-TIMI 51 Trial Recent acute coronary syndrome > 98% on aspirin, > 90% on thienopyridine Rivaroxaban death from cardiovascular causes Bleeding rate 2.1% vs 0.6% N Engl J Med 2012;366:9-19 Annals of Pharmacotherapy 2013;47: Xarelto [package insert]. Titusville, NJ: Janssen Pharmaceuticals, Inc; Revised August 2014 Slide Rivaroxaban and Prolonged Coagulation Markers in Elderly Woman on Multiple Medications Case report of 88-year old female on rivaroxaban 15 daily for atrial fibrillation Concomitant medications: mirtazapine, nebivolol, digitoxin, lisinopril, gliclazide, amlodipine, valproate Day of Admission INR PT, % (70-130) aptt, sec (<33) Anti- Factor Xa (U/mL) Day 1 NA NA Day Heart & Lung 2014;43:262-3

11 Slide 31 Rivaroxaban and Prolonged Coagulation Markers in Elderly Woman on Multiple Medications 31 Overestimation of renal function Potential drug interactions Authors used MDRD to calculate renal function CrCl of ~27 ml/min according to Cockroft-Gault method CrCl of <30 ml/min was exclusion criterion for ROCKET-AF Weak CYP3A4 Inhibitors: Mirtazapine, amlodipine, valproate Elderly Median age 73 in ROCKET-AF Little data about metabolism in elderly patients Heart & Lung 2014;43:262-3 Slide Rivaroxaban and Gastrointestinal Bleed in HIV Patient on HAART Therapy Right malleolus fracture requiring surgery Rivaroxaban 10 daily for six weeks for VTE prophylaxis HIV specialist concerned about surgeon s choice because of concurrent darunavir/rito navir Case DDI ADE 52 y/o male on rivaroxaban 10 PO daily Rivaroxaban plasma level 253 mcg/l and patient told to take half dose Rivaroxabanritonavir Patient traveled abroad to Mexico GI bleed A few weeks later patient abroad and has bloody diarrhea Swiss Med Wkly 2014;144:w13906 Slide 33 Fatal Pulmonary Emboli in Patient on Rivaroxaban and Rifampicin 33 Case DDI ADE 67 year old female on rivaroxaban 20 once daily Rivaroxaban-rifampicin Fatal PE Patient presents short of breath, diaphoretic, tachycardic PE not highly suspected Rivaroxaban therapy Prolonged PT of 21.6 sec 12 hours later patient deteriorated and died Autopsy: extensive central pulmonary emboli Haemotologica 2014;99:e26-7

12 Slide 34 Patient with Hemopericardium on Rivaroxaban and Saw Palmetto 34 Case DDI ADE 76 year old male on rivaroxaban Rivaroxaban-saw palmetto Hemopericardium Spontaneous hemopericardium occurs in % of patients receiving anticoagulation First reported published case occurring with rivaroxaban Mechanism likely due to inhibition of metabolism by saw palmetto Pharmacotherapy 2014;34:e Slide 35 Apixaban Metabolism 35 Bioavailability 50% Europace 2013;15: Slide 36 Apixaban Drug-Drug Interactions 36 Strong CYP3A4/P-gp Inhibitors May increase risk of hemorrhage Management In patients taking >2.5 dose, reduce dose by 50% In patients already taking the 2.5 dose, avoid combination Strong CYP3A4/P-gp Inducers May decrease efficacy Management Avoid combination Eliquis [package insert]. Princeton, NJ: Bristol-Myers Squibb Company; Revised August 2014

13 Slide Apixaban Pharmacokinetic Interactions Europace 2013;15: Slide Apixaban Pharmacokinetic Interactions Europace 2013;15: Slide Pharmacokinetic Interactions: Drugs Affecting Gastric ph Absorption and bioavailability of apixaban not affected by gastric ph No significant changes in AUC and C max when given together with famotidine Annals of Pharmacotherapy 2013;47(11):

14 Slide Pharmacodynamic Interactions: Apixaban and Antiplatelets Apixaban for the Prevention of Acute Ischemic Events (APPRAISE-2) Concurrent antiplatelets according to clinician 97% on ASA 81% on ASA + P2Y2- receptor antagonist Trial terminated early Increased incidence of bleeds reported with little efficacy Package insert: Avoid antiplatelets when possible N Engl J Med 2011;365: Eliquis [package insert]. Princeton, NJ: Bristol-Myers Squibb Company; Revised August 2014 Slide Pharmacodynamic Interactions: Apixaban and NSAIDs NSAIDs Naproxen has been reported to produce 50% increase in apixaban AUC and 60% increase in C max No clinically relevant increase in bleeding time seen Eliquis [package insert]. Princeton, NJ: Bristol-Myers Squibb Company; Revised August 2014 Slide 42 A patient comes to refill her rivaroxaban prescription and is also purchasing a bottle of St John s Wort. You become concerned about the St John s Wort because: 42 A. St. John s Wort is a strong CYP3A4 inhibitor and may cause bleeding B. St. John s Wort is a strong CYP2J2 inducer and rivaroxaban therapy may fail C. St. John s Wort is a strong CYP3A4 inducer and rivaroxaban therapy may fail D. You are not concerned about this combination

15 Slide 43 Dabigatran Metabolism Bioavailability 3-7% Europace 2013;15: Pradaxa [package insert]. Ridgefield, CT: Boehringer Ingelheim Pharmaceuticals, Inc; Revised September 2014 Slide Dabigatran Pharmacokinetic Interactions P-gp inducers dabigatran concentration P-gp inhibitors dabigatran concentration P-gp competitors dabigatran concentration Acid suppression therapy dabigatran absorption and bioavailability Pradaxa [package insert]. Ridgefield, CT: Boehringer Ingelheim Pharmaceuticals, Inc; Revised September 2014 Ann Pharmacother 2013;47(11): Drug Safety. 2005;29: Slide 45 Dabigatran and P-gp Inducers Avoid concomitant use of dabigatran and strong P-gp inducers Package Insert: Avoid rifampin 66% decrease in AUC and 67% decrease in Cmax if given after 7 days of rifampin No interaction 7 days after rifampin discontinuation Additional P-gp inducers that may interact Carbamazepine Prazosin Doxorubicin St John s Wort Dexamethasone Tenofovir Nefazodone Trazodone Paclitaxel Vinblastine Phenytoin Pradaxa [package insert]. Ridgefield, CT: Boehringer Ingelheim Pharmaceuticals, Inc; Revised September 2014 Ann Pharmacother 2013;47: Am J Health-Syst Pharm 2011;68:

16 Slide 46 Dabigatran and P-gp Inhibitors CrCl (ml/min) Recommendation >50 May coadminister P-gp inhibitors No dose adjustment required Dronedarone and ketoconazole: - dabigatran dose to 75 BID Verapamil, amiodarone, quinidine, clarithromycin, and ticagrelor: -No dose adjustment required -Interaction with verapamil may be avoided by administering both drugs at same time <30 Avoid dabigatran use with P-gp inhibitors Pradaxa [package insert]. Ridgefield, CT: Boehringer Ingelheim Pharmaceuticals, Inc; Revised September 2014 Ann Pharmacother 2013;47: Slide 47 Dabigatran and P-gp Competitors P-gp substrates: Clopidogrel, digoxin Phase I studies: 30-40% dabigatran exposure with clopidogrel load No change in dabigatran concentration at steady state Pradaxa [package insert]. Ridgefield, CT: Boehringer Ingelheim Pharmaceuticals, Inc; Revised September 2014 Ann Pharmacother 2013;47: Slide Dabigatran and Drugs Affecting Gastric ph Low ph required for dabigatran absorption Capsules contain dabigatran-coated pellets with tartaric acid core Phase I Trials PPIs: 30% in bioavailability H2RAs: no effect on bioavailability Phase III RE-LY Trial PPIs: 12.5% in bioavailability H2RAs: no effect on bioavailability Interaction not clinically significant Pradaxa [package insert]. Ridgefield, CT: Boehringer Ingelheim Pharmaceuticals, Inc; Revised September 2014 Ann Pharmacother 2013;47: N Engl J Med 2009;361:

17 Slide Dabigatran Pharmacodynamic Interactions Major Bleeding Increased bleeding risk if used with other drugs that have bleeding risk Examples: antiplatelet agents, NSAIDs, anticoagulants RE-LY Trial: Increased bleeding risk when used with aspirin or clopidogrel Similar bleeding rate with warfarin + antiplatelet vs. dabigatran + antiplatelet Bleeding Rate by Antiplatelet Use Dabigatran Antiplatelet HR=2.14 (95% CI:1.75,2.61) HR=1.87 (95% CI:1.54,2.27) Event Rate (% per year) Dabigatran 150 Warfarin + Antiplatelet Warfarin Circulation 2013;127: Slide Dabigatran and Dronedarone Interaction- Induced Bleeding: Study Overview Background: Dronedarone increases dabigatran concentration via P-gp inhibition Clinical significance of interaction not established Objective: Compare bleeding rate of dabigatran alone vs. dabigatran + dronedarone Methods: Design: Retrospective, data mining analysis Database: FDA Adverse Event Reporting System (FAERS) 217,362 cases evaluated for presence of bleeding based on use of: Dabigatran alone Dronedarone alone Dabigatran + dronedarone Neither dabigatran or dronedarone J Am Pharm Assoc. 2013;53: Slide 51 Dabigatran and Dronedarone Interaction- Induced Bleeding: Study Results Percentage (%) of Patients Rate of Bleeding Events Dabigatran + Dronedarone Dabigatran Dronedarone No Dabigatran or Dronedarone 0 J Am Pharm Assoc. 2013;53:414-19

18 Slide 52 Dabigatran and Dronedarone Interaction- Induced Bleeding: Study Conclusions Conclusion: Similar likelihood of reporting bleeding events to FAERS among patients using dabigatran alone vs. dabigatran + dronedarone Limitations: Data from FAERS limited by reporting Renal function not reported dosing cannot be evaluated Applicability to Practice: Trial limited by reporting follow package insert recommendations J Am Pharm Assoc. 2013;53: Slide 53 Dabigatran and Amiodarone Interaction- Induced Coagulopathy Case: 82 year old female presents with nausea, vomiting, dizziness, and weakness Medications: dabigatran (150 BID), amiodarone, carvedilol, simvastatin, furosemide Basic Metabolic Panel: SCr 1.78 /dl increased from 1 /dl 1-week prior BUN 40 /dl increased from 20 /dl 1-week prior Coagulation Panel: INR: 7.25 (1) PTT: 135 seconds (25-35 seconds) Fibrinogen: 80 /dl ( /dl) Thrombin Time: 120 seconds (<20 seconds) Indicates acute kidney injury possibly due to dehydration Indicates excess anticoagulation secondary to dabigatran N Z Med J Mar 1;126:110-2 Slide 54 Dabigatran and Amiodarone Interaction- Induced Coagulopathy Continued Possible cause of excess anticoagulation: Acute kidney injury (SCr increase to >1.5 times baseline) Concomitant amiodarone use Result: clearance and exposure to dabigatran Evidence of excess dabigatran exposure: Abnormal INR, PTT, fibrinogen level, and thrombin time Thrombin time and ecarin clotting time are most sensitive clotting assays for dabigatran activity in blood N Z Med J Mar 1;126:110-2

19 Slide A 58 year old male patient (CrCl 42 ml/min) will be started on anticoagulation for atrial fibrillation. He is also on phenytoin for seizures and enalapril for hypertension. His physician asks you to recommend a dose for dabigatran. You would respond the following: A. Start the patient on dabigatran 150 by mouth twice daily B. Start the patient on dabigatran 75 by mouth twice daily since the CrCl <50 ml/min C. Rivaroxaban or apixaban would be a better choice since phenytoin is a P-gp inducer and may cause dabigatran therapy to fail D. All NOACs should be avoided with phenytoin due to risk for anticoagulant therapy failure since phenytoin induces both CYP3A4 and P-gp Slide 56 A physician would like to prescribe pantoprazole to a patient on rivaroxaban. She calls you to confirm that it is okay to use a proton pump inhibitor (PPI) or H2 receptor antagonist (H2RA) with NOACs. You tell her: 56 A. It is safe to use H2RAs with NOACs but PPIs should not be used B. Both PPIs and H2RAs should be avoided with NOACs C. PPIs and H2RAs must be avoided with dabigatran only D. PPIs and H2RAs have not been shown to significantly decrease NOAC absorption and may be used with NOACs Slide 57 Drug Interactions: Warfarin vs. New Oral Anticoagulants

20 Slide 58 Drug Interactions: Warfarin vs. NOACs CYP450 Substrate P-gp Substrate Food Interactions Warfarin Dabigatran Rivaroxaban Apixaban Primary: None CYP3A4/5 and Primary: CYP2C9 CYP2J2 CYP3A4/5 Secondary: Secondary: CYP2C8, 2C18, CYP1A2, 2C8, 2C19, 1A2, and 2C9, 2C19, and 3A4 2J2 No Yes Yes Yes Many None Minimal Minimal (foods with high (food delays (grapefruit (grapefruit juice vitamin K time to peak juice may may increase content inhibit concentration increase concentration anticoagulant but may concentration via CYP3A4 effect) administer via CYP3A4 inhibition) without regard inhibition) to meals) Clinic Pharmac Ther 2014;96(1): Slide 59 Drug Interactions: Warfarin vs. NOACs Warfarin Dabigatran Rivaroxaban Apixaban PROS Not a P-gp substrate Stable and predictable pharmacokinetics if INR monitoring may make use no significant DDIs safe and effective despite Set dosing recommendations despite DDIs interactions and can be used to Less DDIs than warfarin monitor adherence Dabigatran: Not a CYP450 substrate Can be given with aspirin in some patients Ability to reverse warfarin effect Genomic dosing allows for tailored therapy CONS Many food interactions Monitoring difficult in presence of DDIs Many DDIs Renal elimination may complicate dosing Conflicting dosing (e.g. renal impairment + DDI) recommendations in management One-size-fits-all dosing not appropriate for of DDIs everyone Not recommended with aspirin for some patients Inability to reverse agents in cases of bleeding Clinic Pharmac Ther 2014;96:17-19 Slide 60 Effect of Pharmacogenomics on NOAC Therapy

21 Slide 61 Introduction to Pharmacogenomics 61 Slide 62 Pharmacogenomics and Pharmacogenetics 62 People may respond differently to drugs due to genetic variability Pharmacogenomics Study of effect of multiple genes on drug Pharmacogenetics Study of effect of a single gene on drug response Goal: Provide PERSONALIZED medicine to produce optimal patient response Am J Health-Syst Pharm 2009;66: Slide Role of Pharmacogenomics in Warfarin Therapy Pharmacogenomics have known important role CYP2C9 primary enzyme that metabolizes warfarin Vitamin K epoxide reductase complex subunit 1 (VKORC1) site of warfarin action Polymorphisms present to different extent among ethnic groups Pharmacogenetic dosing algorithms available Pharmacogenetic testing available Pharmacogenetic testing and dosing not routinely recommended Am J Health-Syst Pharm 2009;66: Coumadin [package insert]. Princeton, NJ: Bristol-Myers Squibb; Revised October 2011

22 Slide Role of Pharmacogenetics in Warfarin Therapy VKORC1 GG - Wild type AG Small in VKORC1 expression AA - Large VKORC presence CYP2C9 CYP2C9*1*1 Wild type CYP2C9*2 30% in enzyme activity CYP2C9*3 80% in enzyme activity VKORC1 GG AG AA CYP2C9 *1/*1 *1/*2 *1/*3 *2/*2 *2/*3 *3/* P T. Aug 2009; 34: Clinic Pharmac Ther 2014;96:17-19 Coumadin [package insert]. Princeton, NJ: Bristol-Myers Squibb; Revised October 2011 Slide Role of Pharmacogenomics in NOAC Therapy Limited data regarding role of pharmacogenomics Potential for pharmacogenetic variability exists May impact safe and effective use Pharmacotherapy. 2011; 31:1-26 Slide 66 Pharmacogenetics of NOACs NOACs are P-gp substrates ABCB1 gene encodes for P-gp Single nucleotide polymorphisms (SNPs) in ABCB1 promoter and exon regions may affect concentrations of P-gp substrates ABCB1 genotype may influence NOAC concentration Pharmacotherapy. 2011; 31:1-26 Circulation. 2013;127:

23 Slide 67 Pharmacogenetics of Rivaroxaban 67 Metabolized via CYP3A4/5 and CYP2J2 Variations in CYP450 enzymes may affect PK Factor Xa inhibitor Variations at site of action may affect PD Pharmacotherapy December ; 31(12) Circulation. 2013;127: Slide 68 Genetic Testing for NOACs Genetic Testing Availability Primarily used for research purposes Available commercially to guide medication selection First available test: Amplichip CYP450 test thru Roche Diagnostics Now offered by multiple companies (e.g. Iverson Genetics, Advanced Genomics) Insurances often approve when appropriate Cost: ~$500 Role of Genetic Testing for NOACs May help ensure appropriate therapy No recommendations available for use of genotyping data Lack of data regarding benefit Currently not recommended for warfarin or NOACs AAFP. 2007;76(3): Slide 69 Conclusions NOACs commonly used for anticoagulation in atrial fibrillation, DVT, and PE NOACs have less drug-drug and drug-food interactions than warfarin Some significant NOAC interactions may affect safe and effective use Pharmacokinetic interactions of NOACs: Rivaroxaban and apixaban should be avoided with strong CYP3A4/P-gp inhibitors or inducers such as phenytoin Dabigatran should be avoided with strong P-gp inducers such as rifampin Dabigatran s dose should be adjusted if used with strong P-gp inhibitors such as ketoconazole in patients with renal impairment

24 Slide 70 Conclusions Continued 70 Pharmacodynamic Interactions: NOACs have risk of bleeding if taken with other drugs that increase bleeding risk Due to lack of available lab monitoring vigilance in management of DDIs essential Pharmacogenetics may affect NOAC concentration and effect Pharmacogenetics may play a greater role in NOAC management in future Slide 71 DRUG INTERACTIONS WITH NEW ORAL ANTICOAGULANTS Michelle Friedman, B.S., Pharm.D. PGY-2 Internal Medicine Pharmacy Resident Kingsbrook Jewish Medical Center Chanie Wassner, Pharm.D. PGY-2 Critical Care Pharmacy Resident Kingsbrook Jewish Medical Center January 18 th, 2015 Lake Placid, New York

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