TABLE 1. Initial Rivaroxaban Dosing Indication Renal Function a (CrCL ml/min) Recommended Dose b

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1 U N C H E A L T H C A R E G U I D E L I N E Mngement of Rivroxn in Adults Rivroxn (Xrelto ) is n orl nticogulnt tht cts s fctor X inhiitor. It is pproved y the FDA s n lterntive to wrfrin for the prevention of stroke nd systemic emolism in ptients with nonvlvulr tril firilltion nd for prophylxis of deep vein thromosis (DVT) nd pulmonry emolism (PE) in ptients undergoing hip or knee replcement surgery. Rivroxn is not FDA-pproved for the tretment of DVT or PE t this time. Key phrmcokinetic dt for rivroxn include pek onset of nti-x ctivity within 2-4 hours fter orl dministrtion nd hlf-life of 5-9 hours in ptients with norml heptic nd renl function. Approximtely 51% of rivroxn undergoes heptic metolism nd 66% is excreted in the urine (36% s unchnged prent drug). I N I T I A T I O N O F T H E R A P Y Ptient-specific considertions for initition of rivroxn therpy include the following: Indiction for therpy. (1) For prevention of stroke or systemic emolism in tril firilltion: ptients must hve non-vlvulr tril firilltion nd risk fctors tht wrrnt therpeutic nticogultion (i.e., CHADS 2 score > 1); (2) For prevention of DVT nd PE: ptients must hve undergone knee or hip replcement surgery; rivroxn is not indicted for the prevention of DVT nd PE in medicl or other surgicl ptients. Renl nd heptic function. A seline serum cretinine is required for rivroxn use nd pproprite dosing (see Tle 1). Assessment of heptic function should lso e performed, s rivroxn should e voided in moderte (Child-Pugh B) nd severe (Child-Pugh C) heptic impirment or ny degree of heptic impirment ssocited with cogulopthy. Dosing nd dministrtion. Dosing recommendtions re provided in Tle 1. When using rivroxn for prevention of DVT nd PE fter knee or hip replcement surgery, the first dose should e given t lest 6-10 hours fter surgery once hemostsis hs een chieved. Rivroxn is optimlly sored in the gstric environment; therefore, if dministrtion vi feeding tue is required, the tue should e dvnced no further thn the stomch. Higher doses of rivroxn (15-20 mg) should e given with food to enhnce iovilility (see ptient eduction). For ptients with tril firilltion tking doses of mg, it is recommended tht rivroxn e given with the evening mel, s this is how the drug ws studied in this popultion. Doses dministered t other times of the dy hve not een studied, so it is unknown whether they would confer the sme degree of stroke protection s evening dministrtion. Cost of therpy. Whether ptients cn fford rivroxn t dischrge must lso e considered, s costs my exceed $200 per month. TABLE 1. Initil Rivroxn Dosing Indiction Renl Function (CrCL ml/min) Recommended Dose Atril Firilltion c,d (Stroke Prevention) Knee Replcement Hip Replcement > mg once dily with evening mel mg once dily with evening mel < 15 Do not use > mg once dily for 12 dys < 30 Do not use > mg once dily for 35 dys < 30 Do not use Pge 1 of 6

2 For the purpose of rivroxn dosing, renl function should e estimted y the Cockcroft-Gult method. It is not pproprite to use the CrCL (MDRD method) utomticlly reported in the WeCIS l section. Cockcroft-Gult eqution: CrCL= [ (140-ge) x weight (kg) ] / (SCr x 72) (x 0.85 if femle) Co-dministrtion with p-glycoprotein nd strong CYP3A4 inducers (i.e., crmzepine, phenytoin, rifmpin) my wrrnt dose increse. Doses > 10 mg should e tken with food. c The medin ody mss index of ptients in ROCKET-AF 1 ws pproximtely 28 ± 3 kg/m 2. No informtion is ville on its sfety nd efficcy in overweight or oese ptients nd nti-x levels hve not een evluted for guiding drug dosing. d In ROCKET-AF 1, rivroxn ws not studied in ptients with CrCL < 30 ml/min, so recommendtions in ptients with CrCL ml/min re sed on the FDA-pproved leling. C O N V E R S I O N T O R I V A R O X A B A N TABLE 2. Converting to Rivroxn Agent Heprin Enoxprin Digtrn Fondprinux Conversion Instructions Discontinue the heprin infusion when the first evening dose of rivroxn is dministered. Strt rivroxn t the time the next evening dose of enoxprin ws to e dministered (my overlp y up to 2 hours). If enoxprin ws djusted for renl function, rivroxn my lso require dose djustment or e voided ltogether, depending on its indiction for use (see Tle 1). Strt rivroxn 12 hours fter the lst morning dose of digtrn. Discontinue fondprinux. Strt rivroxn in the evening on the following dy. Wrfrin Discontinue wrfrin nd strt rivroxn in the evening when the INR is < 3.0. C O N V E R S I O N F R O M R I V A R O X A B A N In clinicl tril of ptients with non-vlvulr tril firilltion 1, discontinution of rivroxn ws ssocited with n incresed risk of thromotic events (primrily driven y n incresed risk of stroke). If rivroxn must e discontinued for resons other thn leeding, dministrtion of n lterntive nticogulnt should e strongly considered. If it is deemed tht ongoing nticogultion is pproprite, ptients should e ridged to the new nticogulnt (i.e., wrfrin or digtrn) using the recommendtions outlined on the following pge. Strtegies for converting ptients to or from rivroxn hve not een evluted in clinicl trils. The pproved leling for rivroxn recommends the initition of n lterntive nticogulnt t the time the next dose of rivroxn ws to e dministered. However, sed on the phrmcokinetics of the drug, inititing n lterntive nticogulnt s erly s 12 hours fter the lst dose of rivroxn my e considered in ptients who re t incresed risk of thromosis (e.g., recent crdioversion or ltion procedure, higher CHADS 2 scores, conditions tht my increse seline risks of thromoemolism). Pge 2 of 6

3 TABLE 3. Converting Rivroxn to Wrfrin Tking into considertion the risk of stroke nd emolism in ech individul ptient (i.e., CHADS 2 score, recent crdioversion), it my e resonle to continue rivroxn until the INR is 2 3., Renl Function Strtegy Conversion Instructions (CrCL ml/min) Strtegy 1 (Prenterl) Strtegy 2 (Orl) > 50 < 50 > < 15 Strt prenterl nticogulnt hours fter the lst rivroxn dose (consider 12 hours in ptients t greter risk of stroke). Strt wrfrin t the next stndrd dministrtion time. Strt prenterl nticogulnt 24 hours fter the lst rivroxn dose. Strt wrfrin t the next stndrd dministrtion time. Strt wrfrin nd overlp with rivroxn for t lest 5 dys. Discontinue rivroxn on dy 5 or when INR is 2 3. Strt wrfrin nd overlp for t lest 3 dys with rivroxn. Discontinue rivroxn on dy 3 or when INR is 2 3. Sme s for ptients with CrCL ml/min; however, this ptient should not resume rivroxn. Exmples of incresed stroke risk include recent crdioversion or ltion, higher CHADS 2 score, nd conditions tht my increse seline risks of thromoemolism (e.g., mediclly ill). Rivroxn my contriute to n elevted INR for up to 2 dys fter discontinution. c Limited dt exist in ptients with CrCL < 30 ml/min or in ptients on hemodilysis. Recommendtions re extrpolted from phrmcokinetic dt nd comprison of reltive risks nd enefits. TABLE 4. Converting Rivroxn to Prenterl Anticogulnts (Heprin, Enoxprin, or Fondprinux) Renl Function Conversion Instructions (CrCL ml/min) > 50 Strt prenterl nticogulnt hours fter the lst rivroxn dose (consider 12 hours in ptients t greter risk of stroke). < 50 Strt prenterl nticogulnt 24 hours fter lst rivroxn dose. Methods for converting rivroxn to prenterl nticogulnts hve not een studied nd re sed on the pproved product leling nd phrmcokinetics of the drug. Clinicl decisions should e mde sed on ptient-specific risk of leeding vs. thromoemolism. Converting Rivroxn to Digtrn The pproved leling for rivroxn recommends giving the first digtrn dose t the time the next evening dose of rivroxn ws to e dministered. For ptients who re trnsitioning from rivroxn in the community setting, strting digtrn the following evening my e cceptle. However, for ptients with norml renl function (CrCL > 50 ml/min) who re t greter risk of stroke (e.g., recent crdioversion or ltion procedure, higher CHADS 2 scores, other conditions tht my increse seline risks of thromoemolism), strting digtrn 12 hours fter the lst dose of rivroxn my e considered. For ptients with impired renl function (CrCL < 50 ml/min), digtrn my e strted 24 hours fter the lst digtrn dose. Pge 3 of 6

4 P E R I O P E R A T I V E M A N A G E M E N T TABLE 5. Discontinution Prior to Inptient or Outptient Procedures 2, 3 Renl Function (CrCL ml/min) Hlf-life (hours) Timing of Discontinution Prior to Procedure (Minimum) Stndrd Risk of Bleeding High Risk of Bleeding c > hours 1 2 dys < 50 > hours > 2 dys Heptic Function (Child-Pugh Score) Mild Impirment (Child-Pugh A) Moderte Impirment (Child-Pugh B) Severe Impirment (Child-Pugh C) Hlf-life (hours) Stndrd Risk of Bleeding High Risk of Bleeding c 8 24 hours 1 2 dys > 48 hours > 4 dys Unknown hours > 1 week No pulished dt exist on optiml periopertive mngement of rivroxn, so the recommendtions here hve een extrpolted from the phrmcokinetics nd phrmcodynmics of the drug. Exmples: electrophysiology procedures, crdic ctheteriztions, no dditionl ptient-specific risk fctors. c Exmples: surgery involving mjor orgns, procedures requiring complete hemostsis (e.g., spinl nesthesi), or when dditionl ptient-specific risk fctors re present. Bridging to Procedures with Prenterl Anticogulnts For ptients t high risk of thromoemolic events in whom inptient procedures re plnned, some clinicins my wish to ridge with prenterl nticogulnts (e.g., unfrctionted heprin, enoxprin). The necessity for this depends on ptient s risk for thromoemolism while off nticogultion, nd for leeding if on nticogulnts. This my e performed y (1) converting rivroxn to the desired prenterl nticogulnt s descried in Tle 4, nd (2) continuing to hold rivroxn for the minimum mount of time recommended in Tle 5, sed on n individul ptient s renl function nd risk of leeding. Prenterl nticogultion my then e discontinued prior to the plnned procedure ccording to usul stndrds of cre. Dentl Procedures Mny dentl procedures cn e sfely performed on full-dose nticogultion, nd this is lso likely true with rivroxn. Consider risk of leeding versus risk of thromoemolism when deciding to hold doses of rivroxn for dentl procedure. A D V E R S E E F F E C T S Rivroxn is ssocited with similr rtes of overll leeding events compred to wrfrin nd enoxprin. Rtes of intrcrnil hemorrhge nd ftl leeding events re lower with rivroxn, wheres gstrointestinl (GI) leeding is more common. The most common non-hemorrhgic dverse effects re GI-relted disturnces (e.g., nuse, vomiting, nd constiption), epistxis, peripherl edem, dizziness, nd nsophryngitis. 1,4,5 The following section outlines strtegies for the mngement of rivroxn-relted leeding events. Pge 4 of 6

5 M A N A G E M E N T O F B L E E D I N G E V E N T S Currently, no ville evidence exists to guide clinicins in the mngement of rivroxn-ssocited leeding events. While in vitro dt nd studies in nimls nd helthy humn volunteers indicte some phrmcologic gents (e.g., fctor products) my hve n impct on the nticogulnt effects of rivroxn, these hve not een evluted for the mngement of leeding events in ptients nd should not e used for clinicl decision-mking. 6 An outline for supportive mngement of rivroxn-relted leeding events sed on leeding severity is provided in Tle 6. If ptients require phrmcologic therpy to mnge hemorrhgic complictions, Hemtology/Cogultion consult is lso required. TABLE 6. Mngement of Rivroxn-Relted Bleeding Events Bleeding Severity Mild Moderte Mngement Recommendtions Dely next dose or discontinue rivroxn. Consider ny of the following sed on leeding severity: Symptomtic tretment Mechnicl compression Surgicl intervention Fluid replcement nd hemodynmic support Blood product trnsfusion Orl ctivted chrcol (if previous dose ingested within 2 hours) Dose: Liquid chrcol with soritol 50 g PO x 1 dose If hemostsis is not chieved with the strtegies outlined ove, proceed to the steps elow nd otin Hemtology/Cogultion consult for further recommendtions. Consider ny of the strtegies outlined ove sed on leeding severity. No gent currently ville in the US hs een shown to successfully reverse the nticogulnt effects of rivroxn or tret rivroxn-relted leeding events. Therefore, the phrmcologic interventions elow my e considered ut re not required in the mngement of rivroxn-relted leeding. Severe or Lifethretening A Hemtology/Cogultion consult must e otined prior to the following: 1. Prothromin Complex Concentrte (PCC). Low risk for thromotic complictions: Consider ctivted prothromin complex concentrte (PCC) (FEIBA ) 50 units/kg x 1.. High-risk for thromotic complictions: Consider non-ctivted prothromin complex concentrte (PCC) (Profilnine ) 50 units/kg x If () is chosen ove nd dequte hemostsis is not chieved, consider lso giving recominnt fctor VII (NovoSeven ) mcg/kg IV x 1. After severl hours, consider using PCC (FEIBA ) 50 units/kg (with Hemtology/Cogultion guidnce) sed on leeding severity nd degree of hemostsis chieved. To investigte potentil cuses of the leeding event, otin the following: serum cretinine, PTT, PT/INR, CBC (pltelets), nti-x level (send-out l; write ptient on rivroxn ). Both ctivted PCC (FEIBA ) nd recominnt fctor VII (NovoSeven ) re ssocited with thromotic complictions, so the risk of leeding versus thromosis must e considered. A strting dose of mcg/kg ws chosen sed review of clinicl trils nd cse series s well s dose-relted risk of thromoemolic complictions. 7,8 Pge 5 of 6

6 P A T I E N T E D U C A T I O N Rivroxn Discontinution Ptients who re tking rivroxn for the prevention of stroke nd systemic emolism in the setting of tril firilltion should e dvised tht discontinution of therpy my plce them t n incresed risk of thromotic events (primrily stroke). Ptients who experience dverse effects (including rivroxnrelted leeding events) should contct their provider immeditely, ut should not discontinue therpy until instructed to do so. An lterntive mens of nticogultion my e required. Dosing & Orl Administrtion The solute iovilility of rivroxn is dose-dependent. For ptients tking rivroxn 10 mg for the prevention of DVT nd PE fter hip or knee replcement surgery, the drug my e tken once dily with or without food (iovilility out %). However, for ptients tking mg of rivroxn for the prevention of stroke or systemic emolism in tril firilltion, doses should e tken once dily with the evening mel (fsting iovilility out 66%; men AUC nd C mx is incresed y 39% nd 76%, respectively, with food). Mngement of Missed Doses If dose of rivroxn is not tken t the scheduled time, the dose should e tken s soon s possile, unless it is within 12 hours of the next dose. The dose of rivroxn should not e douled to mke up for missed dose. Mngement of Douled Dose No specific strtegy hs een recommended y the mnufcturer for ptients who tke douled dose of rivroxn. However, sed on the phrmcokinetics of the drug, ptients with norml heptic nd renl function should e le to resume their usul dose t the next scheduled time without skipping dose (i.e., 24 hours lter fter the douled dose). Additionl Informtion For dditionl informtion on lood clots nd nticogultion therpy, ptients (nd helth cre providers) my visit the University of North Crolin Clot Connect wesite t R E F E R E N C E S 1. Ptel MR, Mhffey KW, Cliff RM, et l; for the ROCKET AF Investigtors. Rivroxn versus wrfrin in nonvlvulr tril firilltion. N Engl J Med Sep 8;365(10): Kreutz R. Fundm Clin Phrmcol. Phrmcodynmic nd phrmcokinetic sics of rivroxn Fe;26(1): Kuitz D, Beck M, Bruck H et l. Effects of renl impirment on the phrmcokinetics, phrmcodynmics nd sfety of rivroxn, n orl, direct Fctor X inhiitor. Br J Clin Phrmcol Nov;70(5): Lssen MR, Ageno W, Turpie AG, et l; for the RECORD3 Investigtors. Rivroxn versus enoxprin for thromoprophylxis fter totl knee rthroplsty. N Engl J Med Jun 26;358(26): Eriksson BI, Borris LC, Geerts W, et l; for the RECORD1 Study Group. Rivroxn versus enoxprin for thromoprophylxis fter hip rthroplsty. N Engl J Med Jun 26;358(26): Eerenerg ES, Kmphuisen PW, Levi M, et l. Reversl of rivroxn nd digtrn y prothromin complex concentrte: rndomized, plceo-controlled, crossover study in helthy sujects. Circultion Oct 4;124(14): Levi M, et l. Sfety of recominnt ctivted fctor VII in rndomized clinicl trils. N Engl J Med Nov 4;363(19): Vvr KA, et l. Recominnt fctor VII to mnge mjor leeding from newer prenterl nticogulnts.ann Phrmcother Apr;44(4): Pge 6 of 6