Safety Considerations for TSOACs (Target Specific Oral Anticoagulants): An Overview Christopher Malabanan, Pharm.D., BCPS, CACP Jenny Park, Pharm.D. St. Joseph’s Regional Medical Center

Learning Objectives After the presentation, pharmacists will be able to Describe basic principles in changing to/from anticoagulants Define appropriate dosing for idarucizumab to reverse dabigatran After the presentation, pharmacy technicians will be able to Name four TSOACs used in the outpatient setting Describe safe packaging and handling of the TSOACs

Patient Case AB is a 65 year old female on dabigatran 150 mg po BID as an outpatient for non-valvular AF. She is admitted to the ICU for severe sepsis secondary to pneumonia. She is intubated and is receiving enteral feeding and medication through a nasogastric tube. The following are options regarding anticoagulant administration, Scr 1.0, Wt 76 kg Open capsules and administer dabigatran through NGT Discontinue dabigatran and initiate IV UFH protocol Discontinue dabigatran and convert to apixaban 5 mg po BID Either B or C

Target Specific Oral Anticoagulants Warfarin (Vitamin K antagonist) has been conventional anticoagulant agent TSOACs are classes of “newer” anticoagulant agents Anticoagulants = “Blood Thinners” Indications Atrial fibrillation Venous thromboembolism (VTE) Treatment Prophylaxis https://www.boehringer-ingelheim.com/products/prescription_medicines/pradaxa/static/images/nonbranded_logo.png http://smp.businesswire.com/sites/smp.newshq.businesswire.com/files/logo/image/1588216_ELIQUIS_Promo_Logo_US_4c.jpg https://jnswire.s3.amazonaws.com/jns-media/04/c8/39301/large_savaysa.jpg Images retrieved on March 28, 2016 from: https://www.boehringer-ingelheim.com/products/prescription_medicines/pradaxa/static/images/nonbranded_logo.png http://smp.businesswire.com/sites/smp.newshq.businesswire.com/files/logo/image/1588216_ELIQUIS_Promo_Logo_US_4c.jpg https://jnswire.s3.amazonaws.com/jns-media/04/c8/39301/large_savaysa.jpg

Target Specific Oral Anticoagulants Advantages Fixed dose No INR monitoring No food interactions Fewer drug interactions (vs warfarin) Disadvantages Cost No antidote for FXa inhibitors Assessment of compliance Renal monitoring/dose adjustment

High Risk Medications Institute for Safe Medication Practices (ISMP) All TSOACs are listed as high risk medication High alert medications ↑ risk of causing significant harm when they are used in error ADE can be significant Bleeding Limited reversal agent Variable indication and dosing Administration/dosing is not simple! Ways to reduce the risk of errors Standardize the ordering/storage Auxiliary labels Limit access to high-alert medication Pradaxa® Plavix

TJC National Patient Safety Goal 03.05.01 Reduce the likelihood of patient harm associated with the use of anticoagulant therapy Use approved protocols Use authoritative resources to manage potential food and drug interactions for patients receiving warfarin Written policy addressing baseline and ongoing laboratory tests Evaluate anticoagulation safety practices, take action to improve practices, and measure Provide education to prescribers, staff, patients, and families. Patient/family education includes: Importance of follow-up monitoring Compliance Drug-food interactions Adverse drug reactions and interactions

Mechanism of action Rivaroxaban Dabigatran Apixaban Edoxaban Clotting Cascade Intrinsic (Damaged surface) Extrinsic (Trauma) XII XIIa VIIa VII XI XIa Rivaroxaban Apixaban Edoxaban IX IXa Dabigatran X Xa X Harter K, Levine M, Henderson SO. Anticoagulation drug therapy: a review. West J Emerg Med. 2015; 16(1):11-17. Prothrombin (II) Thrombin (IIa) Fibrinogen (I) Fibrin (Ia) Cross-linked fibrin clot Harter K, et al..West J Emerg Med. 2015; 16(1):11-17.

Comparison of TSOACs Apixaban Rivaroxaban Dabigatran Edoxaban Brand name Available strength Eliquis® 2.5, 5 Xarelto® 10,15,20 Pradaxa® 75,110,150 Savaysa® 15,30,60 Indication/Dose NVAF 5mg BID 20mg QD 150mg BID 60mg QD VTE treatment 10mg BID x 7D  5mg BID 15mg BID x21D  20mg QD Reduction of risk of VTE recurrence 2.5mg BID X DVT Prophylaxis (hip/knee surgery) 10mg QD 220mg QD Parenteral lead-in 5 – 10 days Reversal agent Praxbind® Package insert of pradaxa, rivaroban, apixaban, endoxaban Pradaxa® [package insert]. Ridgefield, CT: Boehringer Ingelheim Pharmaceuticals; 2015. Xarelto® [package insert]. Titusville, NJ: Janssen Pharmaceuticals; 2015. Eliquis® [package insert]. Princeton, NJ: Bristol-Myers Squibb Company; 2015. Savaysa® [package insert]. Parsippany, NJ: Daiichi Sankyo Co., LTD; 2015. NVAF: nonvalvular atrial fibrillation; VTE: venous thromboembolism; DVT: Deep venous thrombosis Pradaxa®, Xarelro®, Eliquis®, Savaysa® [package insert]. 2015. Adapted from SJHMC TSOAC Protocol by Shannon Tellier, Pharm.D.

Comparison of TSOACs Apixaban Rivaroxaban Dabigatran Edoxaban Renal Dose Adjustment NVAF 2.5mg: Scr >1.5 + Age ≥ 80 or ≤ 60kg 15mg: CrCl 15-50 75mg: CrCl 15-30 Dronedarone Ketoconazole Avoid use: CrCl 15-30 + P-gp inhibitor 30mg: CrCl 15-50 CrCl >95 CrCl < 15 VTE None CrCl < 30 CrCl ≤ 30 CrCl < 50 + P-gp inhibitor Extreme Weight Not affected Affected Unknown APS X Package insert of pradaxa, rivaroban, apixaban, endoxaban Pradaxa® [package insert]. Ridgefield, CT: Boehringer Ingelheim Pharmaceuticals; 2015. Xarelto® [package insert]. Titusville, NJ: Janssen Pharmaceuticals; 2015. Eliquis® [package insert]. Princeton, NJ: Bristol-Myers Squibb Company; 2015. Savaysa® [package insert]. Parsippany, NJ: Daiichi Sankyo Co., LTD; 2015. Pradaxa®, Xarelro®, Eliquis®, Savaysa® [package insert]. 2015. Adapted from SJHMC TSOAC Protocol by Shannon Tellier, Pharm.D.

Comparison of TSOACs Apixaban Rivaroxaban Dabigatran Edoxaban Pregnancy B C Lactation X Split/Crush O Unknown GI tolerability Dyspepsia Storage Original container Discard after 4 months Co-pay assistance & patient assistance programs (PAP) $10 savings card for eligible patients PAP available via BMS $0 savings card for eligible patients PAP available via J&J PAP available via Boehringer Ingelheim $4 savings card for eligible patients Package insert of pradaxa, rivaroban, apixaban, endoxaban Pradaxa® [package insert]. Ridgefield, CT: Boehringer Ingelheim Pharmaceuticals; 2015. Xarelto® [package insert]. Titusville, NJ: Janssen Pharmaceuticals; 2015. Eliquis® [package insert]. Princeton, NJ: Bristol-Myers Squibb Company; 2015. Savaysa® [package insert]. Parsippany, NJ: Daiichi Sankyo Co., LTD; 2015. Pradaxa®, Xarelro®, Eliquis®, Savaysa® [package insert]. 2015. Adapted from SJHMC TSOAC Protocol by Shannon Tellier, Pharm.D.

TSOACs- Drug interactions Dabigatran Rivaroxaban Apixaban Edoxaban ↑ drug effect Other AC Antiplatelets NSAIDS P-gp inhibitors CYP3A4 inhibitors ↓ drug effect P-gp inducers Antacids? CYP3A4 inducers Pradaxa®, Xarelro®, Eliquis®, Savaysa® [package insert]. 2015.

Safe Medication Handling: Pradaxa® Blue-white capsule Cannot open capsule Increases AUC by 75% Available Blister packs Plastic medication bottle Cannot remove Pradaxa capsules Unit-dosing from bottle is unsafe Medication stability Medication efficacy Image retrieved from https://www.publichealthwatchdog.com/wp-content/uploads/2014/02/Pradaxa-Bleeding-Risks.jpg

Importance of Accurate Medication Reconciliation Increased prescriptions for TSOACs Pharmacist or pharmacy technician driven medication reconciliation There can be change in the choice of anticoagulation Warfarin  TSOAC TSOAC  TSOAC TSOAC  Warfarin Important to identify duplicate therapy! Obtaining the accurate medication and dose is crucial Medication error can cause severe adverse event

Dabigatran (Pradaxa®) PLAVIX® PRADAXA® Anticoagulation Antiplatelet Used to prevent stroke/heart attack

Anticoagulation conversion Warfarin LMWH UFH Apixaban D/C warfarin Start when INR is < 2.0 D/C LMWH Start when next LMWH is due D/C infusion Start at same time Dabigatran Start 0-2 hours prior to next scheduled evening LMWH Edoxaban Start when INR is < 2.5 Start 4 hours later Rivaroxaban Start when INR is < 3.0 Start 0-2 hours prior to next scheduled evening administration Now that we know what agents are more optimal for specific population – we also need to take the conversion method into consideration Pradaxa®, Xarelro®, Eliquis®, Savaysa® [package insert]. 2015.

Anticoagulation conversion From To Dabigatran Warfarin CrCl 50 mL/min, start warfarin 3 days before discontinuing dabigatran. CrCl 30-50 mL/min, start warfarin 2 days before discontinuing dabigatran. CrCl 15-30 mL/min, start warfarin 1 day before discontinuing dabigatran. CrCl <15 mL/min, no recommendations can be made. LMWH/UFH CrCl >30 mL/min, wait 12 hours after last dose of dabigatran to initiate parenteral anticoagulant CrCl <30 mL/min, wait 24 hours after last dose of dabigatran to initiate parenteral anticoagulant Now that we know what agents are more optimal for specific population – we also need to take the conversion method into consideration Hellerslia V, et al. Transition of Anticoagulants 2014. Hospital Pharmacy

Anticoagulation conversion From To Rivaroxaban LMWH/UFH Wait 24 hours after rivaroxaban (treatment dose) discontinuation to initiate parenteral anticoagulant. Warfarin Initiate warfarin when next dose of rivaroxban is due Consider use of parenteral anticoagulant until INR is therapeutic Apixaban Wait 12 hours after last dose of apixaban to initiate parenteral anticoagulant. Initiate warfarin when next dose of apixaban is due Now that we know what agents are more optimal for specific population – we also need to take the conversion method into consideration Hellerslia V, e al. Transition of Anticoagulants 2014. Hospital Pharmacy

Anticoagulation conversion From To Edoxaban Warfarin Oral option edoxaban 60 mg/day reduce dose to 30 mg/day and begin warfarin at the same time edoxaban 30 mg/day reduce dose to 15 mg/day and begin warfarin at the same time INR must be measured at least weekly When INR ≥2, discontinue edoxaban and continue warfarin Parenteral option Discontinue edoxaban and administer a parenteral anticoagulant and warfarin at the time of the next scheduled edoxaban dose When INR ≥2 , discontinue the parenteral anticoagulant and continue warfarin LMWH/UFH Discontinue edoxaban and start the parenteral anticoagulant at the time of the next dose of edoxaban Now that we know what agents are more optimal for specific population – we also need to take the conversion method into consideration Savaysa® [package insert]. 2015..

Example: Anticoagulation Algorithm Is patient at ↑ risk of bleed? (HAS-BLED score = ____) No Yes Consider apixaban Only TSOAC superior to warfarin for major bleeding event Alternative: rivaroxaban Renal impairment? Yes No Consider apixaban Portion of renal elimination: Dabigatran>rivaroxaban>edoxaban>apixaban Is CrCl > 95 ml/min? Yes No Consider apixaban Edoxaban should NOT be used if CrCl>95 Does patient have dyspepsia? Yes Consider apixaban, rivaroxaban, or edoxaban Dabigatran is associated with dyspepsia No Yes Is patient > 75 y/o? Consider apixaban Edoxaban should NOT be used if CrCl>95 No Consider apixaban Alternatives: rivaroxaban, dabigatran, or edoxaban Adapted from SJHMC TSOAC Protocol by Shannon Tellier, Pharm.D.

Back to our patient! AB is a 65 year old female on dabigatran 150 mg po BID as an outpatient for non-valvular AF. She is admitted to the ICU for severe sepsis secondary to pneumonia. She is intubated and is receiving enteral feeding and medication through a nasogastric tube. The following are options regarding anticoagulant administration, Scr 1.0, Wt 76 kg Open capsules and administer dabigatran through NGT Discontinue dabigatran and initiate IV UFH protocol Discontinue dabigatran and convert to apixaban 5 mg po BID Either B or C

Reversal agents for TSOACs Four factor PCC not FDA approved for reversal of TSOACs Idarucizumab (Praxbind®) FDA approved for urgent reversal of dabigatran No current reversal agent for Factor Xa inhibitors Andexanet (ANNEXA-R, ANNEXA-A, ANNEXA-4)- biologics license application filed in early 2016 Aripazine (PER977, ciraparantag)- broad activity among many anticoagulants Ansell J, et al. NEJM 2014; 371:2141-2142 Siegal DM, et al. NEJM 2015; 373:2413-2424 Pollack CV, et al. NEJM 2015; 373: 511-520 Praxbind® [package insert]. 2015.

Idarucizumab (Praxbind®) Humanized monoclonal antibody fragment, reversal of dabigatran for emergent/urgent surgery or life-threatening/uncontrolled bleeding Dosed as 5 grams IV (given as 2 separate infusions of 2.5 grams/50ml) Interim analysis of REVERSE-AD Almost complete reversal of anticoagulant effect based on dTT or ECT LASA: Idarubicin (ISMP alert) Image retrieved from http://www.praxbind.com/storage-handling Pollack CV, et al. NEJM 2015; 373: 511-520 Praxbind® [package insert]. 2015.

Question 1 True or false When converting dabigatran (Pradaxa®) to warfarin, one has to consider patient’s creatinine clearance. True False Pharmacists

Question 2 Which of the following is NOT a TSOAC used in outpatient setting? Dabigatran Rivaroxaban Apixaban Enoxaparin Edoxaban

Question 3 What is the appropriate dose of idarucizumab (Praxbind®) to administer for reversal of dabigatran (Pradaxa®)? Administer 2.5mg IV x1, repeat if bleeding persists Administer 2.5mg IV x2 (more than 15 minutes apart) Administer 2.5mg IV x2 (no more than 15 minutes apart) Administer 5mg IV

Question 4 Which of the following TSOACs cannot be removed from original container for storage? Dabigatran Rivaroxaban Apixaban Edoxaban

References Ansell J, Bakhru SH, Laulicht BE, et al. Use of PER977 to Reverse to Anticoagulant Effect of Edoxaban. N Engl J Med. 2014;371:2141-2142 Eliquis® [package insert]. Princeton, NJ: Bristol-Myers Squibb Company; 2015 Harter K, Levine M, Henderson SO. Anticoagulation drug therapy: a review. West J Emerg Med. 2015; 16(1):11-17. Hellerslia V, et al. Transition of Anticoagulants 2014. Hospital Pharmacy Pollack CV, Reilly PA, Eikelbloom J, et al. Idarucizumab for dabigatran reversal. N Engl J Med. 2015;373:511-20 Pradaxa® [package insert]. Ridgefield, CT: Boehringer Ingelheim Pharmaceuticals; 2015. Praxbind® [package insert]. Ridgefield, CT: Boerhinger Ingelheim Pharmaceuticals; 2015 Savaysa® [package insert]. Parsippany, NJ: Daiichi Sankyo Co., LTD; 2015. Siegal DM, et al. "Andexanet alfa for the reversal of factor Xa inhibitor activity". N Engl J Med. 2015. 373:2413-2424 Xarelto® [package insert]. Titusville, NJ: Janssen Pharmaceuticals; 2015.