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Monograph Review: Apixaban, Dabigatran, Edoxaban, Rivaroxaban Supplementary Handout

PHARMACOKINETICS:

Rivaroxaban Apixaban Dabigatran Edoxaban

Absorption 2-4 hours, 92% protein bound

Cmax: 3-4 hours Cmax: 1 hour (fasted) Cmax prolonged with high-fat meals

Cmax: 1-2 hours 55% protein bound

Metabolism CYP3A4/A5 25% urine and feces as metabolites

CYP3A4 Pgp substrate

Pgp substrate Minimal metobalism via hydrolysis, conjugation, and oxidation by CYP3A4

Excretion 66% in the urine 27% renally excreted 80% renally cleared 50% renally cleared Remaining: biliary/intestinal

Hepatic Impairment Major site of metabolism

Avoid use in moderate to severe hepatic impairment (Child-Pugh B or C

Mild impairment: no dose adjustment

Moderate impairment: no recommendations

Severe: not recommended

No dosage adjustments No dosage adjustments in mild to moderate hepatic impairment No data in severe heapticl impairment

Renal Impairment Nonvalvular A.fib: Crcl <15ml/min: avoiduse

Post-op prophylaxis of DVT/Treatment and prevention of DVT/PE: Crcl <30ml/min: avoid use

CrCl 15-80mL/min + Pgp inhibitors and moderate CYP3A4 inhibitors: avoid use

Recommended to discontinue in acute renal failure

Reduce dose for 2 or more characteristics:

o > 80 years o < 60 kg o SrCr >1.5

mg/dL Dialysis or Crcl

<15ml/min: avoid use

DVT/PE Crcl <50mL/min + concomitant Pgp

inhibitors: avoid use Crcl <30mL/min: no data for use Hemodialysis: no data for use A.FIB CrCl 30-50 mL/min + dronedarone or

po ketoconazole : reduced dose (75mg BID)

CrCl 15-30 mL/min: 75 mg BID CrCl 15-30 mL/min + Pgp inhibitor:

avoid use CrCl <15mL/min: use not

recommended

Do not use in CrCl <15mL/min

Geriatric Patients No dose adjustments necessary

Refer to adult dosing Age >65: refer to adult dosing Age> 80: use with caution (case reports of hemorrhaging, etc)

Refer to adult dosing

Pediatric Patients Safety and effectiveness have not been established in this population

Safety and effectiveness have not been established in this population



Pregnancy Pregnancy category C Pregnancy category B Pregnancy category C Pregnancy category C


ADVERSE DRUG EFFECTS:

Rivaroxaban Apixaban Dabigatran Edoxaban

Adverse Event

Bleeding General incidence of bleeding: Hip/knee replacement, 5.8%; DVT

Major bleeding: A.fib: 5.6%, hip/knee replacement: 0.3%, DVT/PE: 1%

General incidence of bleeding: A.fib: 2.08%/year DVT prophylaxis

2.88% to 4.83%

Major bleeding: 0.1% to 2.13%

General incidence of bleeding: DVT/PE: 10.5%, A.fib: 16.6%

Major bleed: DVT/PE: 0.3%-1.4%

A.fib: 3.3%

Anemia: A.fib: 9.6%, DVT/PE 1.7%

Bleeding, Clinically relevant, non major: A.fib: 9.4%, DVT/PE 7.2%

Gastrointestinal Not common Not common Esophagitis, gastritis, GERD (A.fib, 5.5%), GI ulcer, indigestion (DVT and PE, 7.5%).

Not common

Other Syncope: 1.2% Bleeding gums: <0.1% to 1.4%

Epistaxis: DVT/PE: 1.5% to 3.6%

Abnormal LFTs: A.fib:

4.8%, DVT/PE: 7.8%


DOSING AND ADMINISTRATION:

Drug How Supplied

(mg)

Prevention of stroke in nonvalvular A.Fib

Treatment of DVT/PE DVT/PE prophylaxis

DVT/PE prophylaxis post hip/knee replacement

Rivaroxaban 10, 15, 20 CrCl>50mL/min: 20mg qd w/ evening meal

CrCl 15-50mL/min: 15mg qd w/ evening meal

15mg BID w/ food x 21 days 20mg qd with food

20mg qd w/ food Hip: 10mg qd x 35 days Knee: 10mg qd x 12 days

Apixaban 2.5, 5 5mg BID 2.5mg BID with 2 of the

following: o > 80 years of

age o < 60kg o SrCr > 1.5mg/dL

10mg BID x 7 days 5mg BID

2.5mg BID Hip: 2.5mg BID x 35 days Knee: 2.5mg BID x 12 days

Dabigatran 75, 150 CrCl >30 mL/min: 150 mg twice daily

CrCl 15 to 30 mL/min: 75

mg twice daily CrCl <15 mL/min or on

dialysis: no dosing recommendations

CrCl 30-50mL/min +

dronedarone or ketoconazole: 75mg BID

CrCl <30 mL/min + Pgp

inhibitors: avoid use

CrCl >30 mL/min: 150 mg twice daily

CrCl < 30 mL/min

or dialysis: no dosing recommendations

CrCl <50 mL/min

+ Pgp inhibitors: avoid use

CrCl >30 mL/min: 150 mg twice daily

CrCl < 30

mL/min or dialysis: no dosing recommendations

CrCl <50

mL/min + Pgp inhibitors: avoid use

Not indicated

Edoxaban 15, 30, 60 60mg qd in CrCL >50 to <95 mL/min

CrCl > 95mL/min: avoid use

CrCl 15-50mL/min: 30mg qd

60mg qd

CrCl 15-50mL/min, <60kg, or use of Pgp inh ( verapamil, quinidine, dronedarone): 30mg qd

Not indicated Not indicated


BUDGET IMPACT:

Medication Dosage Range (mg) Acquisition Cost

(per day)

Apixaban 2.5,5 $7.50

Dabigatran 75,150 $7.78

Rivaroxaban 10,15,20 $8.89

Edoxaban 15,30,60 $8.79

SUBSTITUTION TABLE

Practitioner Order Pharmacy Dispense

Apixaban Apixaban

Rivaroxaban Rivaroxaban

Dabigatran Apixaban (Pharmacy to renally adjust)


SUMMARY AND RECOMMENDATIONS:

Efficacy: Apixaban is the only new oral anticoagulant to show superiority over warfarin in 3 major areas in patients with atrial fibrillation:

prevention of strokes, major bleeds, and deaths. No other new oral anticoagulant has shown superiority in death over warfarin. Dabigatran showed

superiority over warfarin in preventing strokes with a lower rate of hemorrhagic stroke but higher rate of GI bleeding. Rivaroxaban was no better or

worse than warfarin in preventing stroke or systemic embolism. It had comparable major bleeding, lower rate of hemorrhagic stroke but a higher

rate of major GI bleed. Edoxaban showed non-inferiority to warfarin in prevention of stroke or systemic embolism, hemorrhagic stroke, and rate of

death from CV causes. Only Edoxaban 60mg showed non-inferiority to warfarin in ischemic stroke, Edoxaban 30mg showed a higher rate of

ischemic stroke compared to warfarin. All regimens are comparable to warfarin in the prevention of recurrent VTE.

Dosing adjustments: In patients with Atrial Fibrillation Edoxaban cannot be used in patients with CrCl >95ml/min. Apixaban is less renally cleared

among all of the anticoagulants. Apixaban doesn’t have a strict CrCL cut-off in which dose needs to be adjusted it is based off of patient

characteristics that my suggest decrease in renal function: age> 80, SrCr > 1.5mg/dL, < 60kg. All anticoagulants have interactions with dual p-

glycoprotein and CYP3A4 inhibitors/inducers. For all, strong inhibitors/inducers should be avoided. As far as moderate inhibitors, Apixaban is the

only medication that doesn’t have a recommendation for a reduce dose.

Other considerations: Rivaroxaban has to be taken with food. Rivaroxaban is the only medication dosed once daily, the rest are dose BID. Rivaroxaban and Apixaban are the only two anticoagulants that have a full range of indications. Dabigatran and Edoxaban are only indicated in the prevention of stroke in patients with atrial fibrillation and the treatment of DVT/PE. Dabigatran has to be kept in its original packaging and has to be used in 4 months once opened.

Patient analysis at Marion General Hospital: Rivaroxaban and Apixaban were the most utilized anticoagulants. Apixaban was the most

common drug initiated in patients who required anticoagulation in the hospital. All patients on Dabigatran were continued from home and not

started in the hospital. Rivaroxaban use was mainly attributed to continuation of home medications versus new start. The most common indication

for all three of the drugs was Atrial Fibrillation. Most patients on Rivaroxaban were concomitantly on Diltiazem which is a moderate P-glycoprotein

inhibitor. Concomitant use with Rivaroxaban and moderate P-glycoprotein inhibitors use is cautioned in patients with CrCl between 15-80mL/min

and is recommended to be used only when benefits outweigh the risks. 3 out of 4 patients on concomitant Rivaroxaban and Diltiazem had CrCl

that fell into this range. Concomitant use of moderate P-glycoprotein inhibitors such as Diltiazem and Amiodarone (which is commonly utilized in

atrial fibrillation patients) is cautioned with Dabigatran and Rivaroxaban. Apixaban doesn’t carry the same warning. Apixaban is cautioned only

with strong dual CYP3A4 and P-glycoprotein inhibitors. With Apixaban, dosing discrepancies occurred around the 3 criteria for reduced dosage:

age> 80, SrCr > 1.5mg/dL, < 60kg. 2 patients had a reduced dose when either 1 or no criteria were met. No dosing discrepancies were identified

with Dabigatran or Rivaroxaban.

Recommendation: Keep Apixaban and Rivaroxaban on formulary with Apixaban having preferred status.


References:

1. PL Detail-Document, Comparison of Oral Anticoagulants. Pharmacist’s Letter/Prescriber’s Letter. June 2014.

2. Apixaban. Lexi-Comp OnlineTM, Lexi-Drugs Online, Hudson, Ohio: Lexi-Comp, Inc.; Accessed April 16, 2015.

3. Apixaban. In: DRUGDEX® System [Internet database]. Greenwood Village, Colo: Thomson Reuters (Healthcare) Inc. Updated

periodically.

4. Edoxaban. Lexi-Comp OnlineTM, Lexi-Drugs Online, Hudson, Ohio: Lexi-Comp, Inc.; Accessed April 21, 2015.

5. Edoxaban. In: DRUGDEX® System [Internet database]. Greenwood Village, Colo: Thomson Reuters (Healthcare) Inc. Updated

periodically.

6. Dabigatran. Lexi-Comp OnlineTM, Lexi-Drugs Online, Hudson, Ohio: Lexi-Comp, Inc.; Accessed April 16, 2015.

7. Dabigatran. In: DRUGDEX® System [Internet database]. Greenwood Village, Colo: Thomson Reuters (Healthcare) Inc. Updated

periodically.

8. Rivaroxaban. Lexi-Comp OnlineTM, Lexi-Drugs Online, Hudson, Ohio: Lexi-Comp, Inc.; Accessed April 16, 2015.

9. Rivaroxaban. In: DRUGDEX® System [Internet database]. Greenwood Village, Colo: Thomson Reuters (Healthcare) Inc. Updated

periodically.

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