Quick Reference for Direct Oral Anticoagulants
QUICK REFERENCE FOR DIRECT ORAL ANTICOAGULANTS
(Amr A. Soliman, PharmD, BCPS, CGP) (Updated L. Kelly PharmD PhC CACP (10/11/2016)
Directoral anti-coagulant name / APIXABAN (ELIQUIS®) / DABIGATRAN (PRADAXA®) / EDOXABAN (SAVAYSA®) / RIVAROXABAN (XARELTO®)Mechanism of action / factor Xa inhibitor / thrombin inhibitor / factor Xa inhibitor / factor Xa inhibitor
FDA-approved indication(s) / • Thromboembolism/stroke prevention in non-valvular afib
• VTE prevention post hip or knee repl.
• DVT/PE treatment; prevention of recurrence / Thromboembolism/stroke prevention in non-valvular afib
VTE prevention post hip or knee repl.
DVT/PE treatment; prevention of recurrence / Systemic embolism/stroke prevention in non-valvular afib
DVT/PE treatment following 5-10 days of initial therapy with parenteral anticoagulant / Thromboembolism/stroke prevention in non-valvular afib
VTE prevention post hip or knee repl.
DVT/PE treatment; prevention of recurrence
Off-label use(s) / . / • VTE prevention post knee repl / VTE (DVT) prophylaxis in hosp’d medical patients, stroke prevention in cardiac ablation
DOSING: NO RENAL / HEPATIC DISEASE or DRUG INTERACTIONS
thromboembolism/stroke prevention in non-valvular afib / 5mg BID(with or w/out food) / 150mg BID(with or w/out food) / 60mg daily (CrCl 51-95)(with or without food)
DO NOT use if CrCl >95 due to increased risk of ischemic stroke; assess CrCl prior to initiation of treatment / 20mg daily with evening meal
VTE prevention post hip or knee repl / 2.5mg BID (hip: 35 days; knee: 12 days; start 12-24hrs post-op) / (Hip only)110mg once on the first day (1-4 hours post op) then 220mg dailyfor 28-35 days / (off label) 30mg daily (with or without food)starting 6 to 24 hours after surgery and continuing for 11-14 days (dose used in study) / 10mg daily (with or without food) start at least 6-10 hrs after surgery 35 days for hip, 12 days for knee
DVT/PE treatment; prevention of recurrence / Initial treatment 10mg bid for 7 days then 5mg bid
VTE prevention after at least 6 months of full dose anticoagulant treatment: 2.5mg BID / VTE treatment & prevention of recurrence: 150mg BID after 5-10 days of parenteral anticoagulant / 60mg daily (with or without food)beginning 5 to 10 days after initiating therapy with a parenteral anticoagulant
30mg daily (with or without food)in patients weighing <60kg / 15mg BID w/food x 21days, then 20mg daily with food
VTE (DVT) prophylaxis in hosp’d med pts / (n/a) / (n/a) / (n/a) / (off label): 10mg daily (for up to 35 days)
Catheter Ablation/Cardioversion / (off label): 20mg daily pre and post ablation/cardioversion
DOSING: RENAL DISEASE
thromboembolism/stroke prevention in non-valvular afib / Hemodialysis: 5mg bid, reduce to
2.5mg BID if has at least 2 of the following:
age = 80+, weight 60kg, SCr 1.5 / CrCl 15-30: 75mg BID
CrCl <15: AVOID USE
(Pts with CrCl 30 excluded from RE-LY trial) / Assess CrCl before initiating therapy
CrCl >95: Do Not Use
CrCl 51-95: 60mg daily
CrCl 15-50: 30mg daily
CrCl <15: Use not recommended / Periodically assess renal function.
(Use actual body weight to calculate CrCl)
CrCl 15-50: 15mg daily w/evening meal
CrCl <15: AVOID USE (D/C in acute renal failure)
VTE prevention post hip or knee repl / 2.5mg BID (pts with CrCl < 30ml/min excluded from trials ) / (Hip only)CrCl <30: AVOID USE / (off –label): Pts with CrCl < 30 excluded from trials / (Use actual body weight to calculate CrCl)
CrCl<30: AVOID USE
DVT/PE treatment; prevention of recurrence / VTE treatment and prevention after initial treatment: no adjustment needed-study excluded pt with SCr more than 2.5 or CrCl less than 25 / CrCl <30: AVOID USE) / CrCl 15-50: 30mg daily
CrCl <15: Use not recommended / (Use actual body weight to calculate CrCl)
CrCl<30: AVOID USE
VTE (DVT) prophylaxis in hosp’d med pts / (n/a) / (n/a) / (n/a) / (off label):7.5-10mg daily (for up to 35 days)
Catheter Ablation/Cardioversion / (off label): Cardioversion: 15mg daily CrCl 30-49
DOSING: HEPATIC DISEASE*
dosing adjustments based on hepatic disease / mild: no dose adjustment is requiredmoderate: dosing not provided
severe: not recommended / moderate hepatic impairment (Child-Pugh B): no dosing adjustment needed
advanced liver disease: not recommended / Mild: no dose adjustment is required
Moderate or severe: not recommended / Avoid in Child-Pugh B & C, hepatic impairment or with any degree of hepatic coagulopathy
DOSING: DRUG INTERACTIONS
dosing adjustments based on drug interactions / Reduce dose by 50% when given with strong dual inhibitors of CYP3A4 & P-gp (e.g., ketoconazole, itraconazole, ritonavir, clarithromycin); avoid if already taking a reduced dose for another reason before adding interacting drug
Avoid concomitant use of ELIQUIS with strong dual inducers of CYP3A4 and P-gp / CrCl 30-50 mL/minuteconcomitant P-gp inhibitors (dronedarone, oral ketoconazole):75 mg BID
CrCl 15-30 mL/minute concomitant P-gp inhibitors:avoid concurrent use / Avoid use with rifampin(P-gp Inducer).
Concomitant use of P-gp inhibitors may increase serum concentrations of edoxaban; no dose reduction is recommended for atrial fibrillation
Reduce dose to 30mg daily for VTE indication / Avoid with combined P-gp, strong CYP3A4inhibitors (ketoconazole, itracon-azole, ritonavir, conivaptan)
Avoid with combined P-gp, strong CYP3A4 inducers (carbamaz-epine, phenytoin, rifampin, St. John’swort)
*Hyperlink to Child-Pugh Classification Score
Direct oral anti-coagulant name / APIXABAN (ELIQUIS®) / DABIGATRAN (PRADAXA®) / EDOXABAN (SAVAYSA®) / RIVAROXABAN (XARELTO®)Administration via tube / May be crushed, suspended in 60 ml D5W & given via any GI tubes / Cannot be given via tube; breaking, chewing or opening capsule = 75% in absorption = adverse reactions likely / No data available / Needs acidic pH; may be crushed, mixed in 50ml of water & given via GI tubes that end in stomach, but not in intestines
Epidural catheter / Catheter removal no sooner than 24h post last apixaban dose, restart apixaban at least 5 hours post removal
For traumatic punctures, delay administration of apixaban for 48 hours / No information provided by manuf. except for info above regarding surgery (ie, d/c dabigatran > 3-5 days before epidural catheter insertion or removal) / Catheter cannot be removed <12hrs after last edoxaban dose; next dose cannot be <2hrs after catheter removal / Catheter cannot be removed <18hrs after last rivaroxaban dose; next dose cannot be <6hrs after catheter removal; traumatic puncture: delay rivaroxaban dose x 24hrs
Pregnancy & lactation / Pregnancy: category B; no studies in pregnant patients – treatment likely to increase risk of hemorrhage during pregnancy & delivery; should be used only if potential benefit outweighs potential risk to mother & fetus
lactation: not compatible with breastfeeding (d/c breastfeeding or d/c apixaban) / Pregnancy: category C: no studies in pregnant patients; safety/effectiveness during labor & delivery not studied; Consider risks of bleeding and of stroke in this setting
lactation: not known whether excreted in human milk; caution should be exercised / Pregnancy: category C; no studies in pregnant women – weigh potential benefits vs risks; safety/effectiveness during labor & delivery not studied – weigh risk of bleeding vs thrombotic events in this setting
lactation: no known if edoxaban is excreted in human milk; recommend to d/c breastfeeding or d/c edoxaban (edoxaban is excreted milk in animal studies) / Pregnancy: category C; no studies in pregnant patients – dosing not established; use with caution – potential for hemorrhage &/or emergent delivery with an anti-coagulant that is not readily reversible.
lactation: infant risk cannot be ruled out (not compatible with breastfeeding in Canadian labeling)
Miscellaneous information / --- Not dialyzable; activated charcoal within 6 hours of dose will remove some of the drug
--- Missed dose: take as soon as possible; two doses CANNOT be taken together / --- Approx 60% dialyzed out, activated charcoal may be considered
--- Missed dose with BID dosing: take late dose only if within 6hrs after dose was due
--- Must store in original package / --- Not dialyzable.
--- Missed dose: take as soon as possible; two doses CANNOT be taken together / --- Not dialyzable.
--- Missed dose with 15mg BID: ensure 30mg/day; two 15mg tabs may be taken
Approximate retail price per month / $325-350 / $325-350 / $300 / $325-350
CONVERSIONS
from warfarin to … / apixaban: d/c warfarin; start apixaban when INR is < 2 / dabigatran: d/c warfarin; start dabigatran when INR is < 2 / edoxaban: discontinue warfarin and start edoxaban when the INR is ≤ 2.5 / rivaroxaban: d/c warfarin; start rivaroxaban when INR is < 3
to warfarin from … / apixaban: apixaban will falsely INR, so INRs not useful for dosing warfarin while on apixaban; d/c apixaban & begin both a parenteral anti-coagulant & warfarin at time of next apixaban dose / dabigatran: CrCl 50: start warfarin 3 days before d/c’ing dabigatran
CrCl 30-50: start warfarin 2 days before
CrCl 15-30: start warfarin 1 day before
CrCl <15: no recommendations made / edoxaban (oral): pt receiving 60mg should reduce 60mg dose to 30mg and begin warfarin concomitantly; for pt receiving 30mg, reduce 30mg dose to 15mg and begin warfarin concomitantly. Measure INR weekly just prior to daily dose of edoxaban to minimize the influence of edoxaban on INR measurements. Once stable INR ≥ 2.0 is achieved, d/c edoxaban / rivaroxaban: rivaroxaban will falsely elevate INR, so INRs not useful for dosing warfarin while on rivaroxaban; d/c rivaroxaban & begin both a parenteral anti-coagulant & warfarin at time of next rivaroxaban dose
from non-warfarin anti-coagulant to … / apixaban: d/c non-warfarin anti-coagulant & begin the apixaban at the next scheduled dose of the non-warfarin anti-coagulant / dabigatran: start 0 to 2 hours before the time of the next dose of the non-warfarin anti-coagulant or at time of discontinuation of continuously administered parenteral anti-coagulant (ie, heparin infusion) / edoxaban:
non-warfarin oral anti-coagulant: d/c the non-warfarin oral anti-coagulant & begin edoxaban at the time of the next scheduled dose of the other oral anticoagulant
LMWH: d/c LMWH & begin edoxaban
at the time of the next scheduled administration of LMWH
unfractionated heparin: d/c unfractionated heparin infusion & begin edoxaban / rivaroxaban: d/c the non-warfarin anti-coagulant & begin the rivaroxaban at the next scheduled dose of the non-warfarin anti-coagulant. From heparin continuous infusion to rivaroxaban: stop heparin infusion & start rivaroxaban at same time
to non-warfarin anti-coagulant from … / apixaban: d/c apixaban & begin the non-warfarin anti-coagulant at the next scheduled dose of the apixaban / dabigatran: wait 12 hrs (CrCl ≥30) or 24 hrs (CrCl <30) after last dose of dabigatran before initiating non-warfarin anti-coagulant / edoxaban: d/c edoxaban & begin the other non-warfarin oral anticoagulant at the time of the next dose of edoxaban / rivaroxaban d/c rivaroxaban & begin the non-warfarin anti-coagulant at the next scheduled dose of the rivaroxaban
References:
Eliquis [package insert]. Bristol-Myers Squibb Co., Princeton, NJ; September 2015.
Pradaxa [package insert] Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, CT; November 2015.
Savaysa [package insert]. Daiichi Sankyo, Inc., Parsippany, NJ; September 2015.
Xarelto [package insert].Jassen Pharmaceuticals, Inc., Titusville, NJ; May 2016.