rivaroxaban (Xarelto)

Dosing and uses of Xarelto (rivaroxaban)

• Adult
• Pediatric

 

Adult dosage forms and strengths

tablet

• 10mg
• 15mg
• 20mg

 

DVT Prophylaxis (Orthopedic Surgery)

Indicated for prophylaxis of deep vein thrombosis (DVT), which may lead to pulmonary embolism (PE) in patients undergoing knee or hip replacement surgery

Knee replacement: 10 mg PO qDay for 12 days; may take with or without food

Hip replacement: 10 mg PO qDay for 35 days; may take with or without food

Administer initial dose at least 6-10 hr after surgery once hemostasis has been established

 

Nonvalvular Atrial Fibrillation

Indicated to reduce the risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation

20 mg/day PO with the evening meaL

 

DVT or PE Treatment

Indicated for treatment of DVT and Pe

15 mg PO q12hr for 21 days with food, THEN 20 mg PO qDay for 6 months

Reduce risk for recurrent DVT or Pe

• Indicated to reduce the risk of recurrence of DVT and PE following initial 6 months treatment for DVT and/or PE
• 20 mg PO qDay following initial 6 months of treatment for DVT and/or PE

 

Dosage modifications

Renal impairment (risk reduction of recurrent DVT/PE)

• Moderate (CrCl 30 to <50 mL/min): Observe closely and promptly evaluate any signs or symptoms of blood loss in patients with moderate renal impairment
• Severe (CrCl <30 mL/min): Avoid use, due to expected increase in rivaroxaban exposure and pharmacodynamic effects
• If acute renal failure develops while on rivaroxaban, discontinue treatment

Renal impairment (nonvalvular AF)

• CrCl 30-50 mL/min: 20 mg/day
• CrCl 15-50 mL/min: 15 mg/day
• ESRD on intermittent renal dialysis: 15 mg/day
• Periodically assess renal function as clinically indicated (i.e., more frequently in situations in which renal function may decline) and adjust therapy accordingly; consider dose adjustment or discontinuation in patients who develop acute renal failure while on therapy

Renal impairment (postoperative thromboprophylaxis)

• CrCl >50 mL/min: Dose adjustment not necessary
• CrCl 30-50 mL/min: Use with caution; dose adjustment not necessary
• CrCl <30 mL/min: Avoid use

Hepatic impairment

• Moderate impairment: Not studied
• Avoid use in patients with moderate-to-severe impairment (Child-Pugh B) or severe (Child-Pugh C) hepatic impairment or with any hepatic disease associated with coagulopathy

 

Dosing Considerations

Discontinuation for surgery or other procedures

• Stop rivaroxaban at least 24 hours before procedure
• Restart rivaroxaban after surgery/procedure as soon as adequate hemostasis is established
• If unable to take oral medication following surgical intervention, consider administering a parenteral drug

Switching to rivaroxaban

• From warfarin to rivaroxaban: Discontinue warfarin and start rivaroxaban as soon as INR is below 3.0
• From anticoagulant other than warfarin to rivaroxaban: Start rivaroxaban 0 to 2 hours prior to next scheduled evening administration of the drug and omit administration of the other anticoagulant
• From unfractionated heparin continuous infusion to rivaroxaban: Stop infusion and start rivaroxaban at the same time

Switching from rivaroxaban

• From rivaroxaban to warfarin: No clinical trial data are available; INR measurements made during coadministration with warfarin may not be useful for determining the appropriate dose of warfarin; one approach is to discontinue rivaroxaban and begin both a parenteral anticoagulant and warfarin at the time the next dose of rivaroxaban would have been taken
• From rivaroxaban and transitional to rapid-onset anticoagulant: Discontinue rivaroxaban and five first dose of other anticoagulant at the time the next rivaroxaban dose would have been taken

 

Administration

10 mg tablets: May take with or without food

15 mg and 20 mg tablets: Take with food

Patients unable to swallow whole tablets

• 10 mg, 15 mg, or 20 mg tablets may be crushed and mixed with applesauce immediately prior to use
• After administration of a crushed 15 mg or 20 mg tablet, the dose should be immediately followed with food
• Stable in applesauce for up to 4 hr

Feeding tube administration

• 10 mg, 15 mg, or 20 mg tablets may be crushed and suspended in 50 mL of water and administered via NG or gastric feeding tube
• Absorption dependent on site of drug release in the gastrointestinal tract (gastric vs small intestine); avoid administrating distal to the stomach which can result in reduced absorption and thereby, reduced drug exposure
• When administering as a crushed tablet via a feeding tube, confirm gastric placement of the tube
• After administration of a crushed 15 mg or 20 mg tablet, the dose should be immediately followed by enteral feeding
• Stable in water for up to 4 hr

Missed dose

• If a dose is not taken at the scheduled time, take as soon as possible on the same day and continue on the following day with the once-daily regimen as recommended
• If taking 15 mg q12hr: Take immediately to ensure intake of 30 mg/day; in this instance, two 15 mg tablets may be taken at once; continue with regular 15 mg q12hr on the following day
• If taking 10, 15, or 20 mg qDay: Take the missed dose immediately

 

Pediatric dosage forms and strengths

Safety and efficacy not established

 

Xarelto (rivaroxaban) adverse (side) effects

Incidence of adverse effects was found not to differ significantly from that of enoxaparin

 

1-10%

Abdominal pain (<2%)

Back pain (<4%)

Blister (1%)

Bruising (3%)

Constipation (<3%)

Diarrhea (<5%)

Dizziness (<6%)

Dyspepsia (<2%)

Epistaxis (4-10%)

Fatigue (<3%)

Headache (3-5%)

Nausea (1-3%)

Hematuria (<4%)

Muscle spasm (1%)

Oropharyngeal pain (≤1%)

Osteoarthritis (<2%)

Peripheral edema (<6%)

Pruritus (<2%)

Pyrexia (1-3%)

Rash (2%)

Syncope (<2%)

Toothache (≤1%)

Urinary tract infection (≤1%)

Vomiting (<2%)

Wound secretion (<3%)

Bleeding

• Atrial fibrillation (21%; major bleeding 6%)
• DVT prophylaxis (5-6%; major bleeding <1%)
• DVT treatment (6-10%; major bleeding 1%)
• Hematoma (<3%)

 

<1%

Agranulocytosis

Hepatitis

Dysuria

Fatal bleeding

Hematoma

Hemiparesis

Hemorrhage

Hypotension

Increased amylase

Increased BUn

Jaundice

Menorrhagia

Retroperitoneal bleeding

Stevens-Johnson syndrome

Thrombocytopenia

Urticaria

Xerostomia

 

Warnings

Black box warnings

Epidural or spinal hematomas

• May occur in patients who are anticoagulated and are receiving neuraxial anesthesia or undergoing spinal puncture; consider the benefits and risks in anticoagulated patients who are candidates for neuraxial intervention; optimal timing between therapy administration and neuraxial procedures is not known
• These hematomas may result in long-term or permanent paralysis; consider these risks when scheduling patients for spinal procedures
• Factors increasing risk: Indwelling epidural catheters, coadministration with other drugs that affect hemostasis, such as non-steroidal anti-inflammatory drugs (NSAIDs), platelet inhibitors, other anticoagulants, history of traumatic or repeated epidural or spinal punctures, history of spinal deformity or spinal surgery
• Monitor patients frequently for signs and symptoms of neurologic impairment; if neurologic compromise is noted, urgent treatment is necessary
• Epidural catheters should not be removed earlier than 18 hr after the last administration of rivaroxaban; the next dose is not to be administered earlier than 6 hr after the removal of the catheter; if traumatic puncture occurs, delay rivaroxaban administration for 24 hr

Discontinuing use for atrial fibrillation

• Premature discontinuation of anticoagulants, including rivaroxaban, places patients at increased risk for thrombotic events
• If anticoagulation with rivaroxaban must be discontinued for a reason other than pathologic bleeding, consider administering another anticoagulant

 

Contraindications

Hypersensitivity

Active, major bleeding

 

Cautions

Neuraxial anesthesia (see Black box warnings)

Risk for thrombotic events increased with premature discontinuation (see Black box warnings)

Safety and efficacy not established in patients with prosthetic heart valves

Increases risk of bleeding and can cause serious and fatal bleeding; reports of major hemorrhages, including epidural hematomas, adrenal bleeding, and intracranial, gastrointestinal, and retinal hemorrhages; promptly evaluate S/S of blood loss and consider the need for blood replacement; discontinue with active pathological hemorrhage

Not recommended acutely as an alternative to unfractionated heparin in patients with pulmonary embolism who present with hemodynamic instability or who may receive thrombolysis or pulmonary embolectomy

An indwelling epidural or intrathecal catheter should not be removed before at least 2 half-lifes have elapsed (i.e., 18 hours in young patients aged 20 to 45 years and 26 hours in elderly patients aged 60 to 76 years), after last administration; next dose should not be administered earlier than 6 hr after removal of catheter. if traumatic puncture occurs, delay administration for 24 hr

Use with caution in pregnant women and only if the potential benefit justifies the potential risk to the mother and fetus (see Pregnancy and lactation)

Avoid in patients with moderate-to-severe hepatic impairment (Child-Pugh classes B and C) or in patients with any hepatic disease associated with coagulopathy

Drug interaction overview

• Avoid concomitant use of P-gp and strong CYP3A4 inhibitors (eg, ketoconazole, itraconazole, lopinavir/ritonavir, ritonavir, indinavir/ritonavir, conivaptan)
• Caution with concomitant use of P-gp and weak or moderate CYP3A4 inhibitors (eg, erythromycin, azithromycin, diltiazem, verapamil, quinidine, ranolazine, dronedarone, amiodarone, felodipine, citalopram, escitalopram, fluoxetine, fluvoxamine, desvenlafaxine, venlafaxine)
• Avoid concomitant use of P-gp and strong CYP3A4 inducers (eg, carbamazepine, phenytoin, rifampin, St. John’s wort ); these drugs may decrease the systemic effects and efficacy of rivaroxaban
• Concomitant use of other drugs that impair hemostasis increases risk of bleeding; these include aspirin, P2Y12 platelet inhibitors, other antithrombotic agents, fibrinolytic therapy, non-steroidal anti-inflammatory drugs (NSAIDs), selective serotonin reuptake inhibitors, and serotonin norepinephrine reuptake inhibitors
• Clopidogrel: Avoid concomitant use unless the benefit outweighs the bleeding risk; change in bleeding time was found to be approximately twice the maximum increase seen with either drug alone

 

Pregnancy and lactation

Pregnancy category: C

Use with caution in pregnant women and only if the potential benefit justifies the potential risk to the mother and fetus

Dosing in pregnancy has not been studied

The anticoagulant effect cannot be monitored with standard laboratory testing nor readily reversed

Promptly evaluate any signs or symptoms suggesting blood loss (eg, decreased hemoglobin and/or hematocrit, hypotension, or fetal distress)

Lactation: Unknown whether distributed in human breast milk; not recommended; a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother

 

Pregnancy categories

A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

NA: Information not available.

 

Pharmacology of Xarelto (rivaroxaban)

Mechanism of action

Factor Xa inhibitor that inhibits platelet activation by selectively blocking the active site of factor Xa without requiring a cofactor (eg, antithrombin III) for activity

Blood coagulation cascade is dependent on the activation of factor X to factor Xa via the intrinsic and extrinsic pathways plays a central role in the blood coagulation cascade

Dose-dependent inhibition of factor Xa activity observed; antifactor Xa activity is also influenced by rivaroxaban; prolongs PT and aPTT and HepTest

 

Absorption

Bioavailability: 80-100%

Peak plasma time: 2-4 hr

AUC: 29-56% decrease when released in proximal small intestine compared with gastric absorption

 

Distribution

Protein bound: 92-95% (mainly albumin)

Vd: 50 L

 

Metabolism

Metabolized by oxidative degradation catalyzed by CYP3A4/5 and CYP2J2; also metabolized by hydrolysis

Unchanged rivaroxaban is the predominant moiety in plasma with no major or active circulating metabolites (50% higher in patients of Japanese descent)

Substrate of P-gp and ABCG2 (Bcrp) efflux transporter proteins

 

Elimination

Half-life: 5-9 hr; 11-13 hr (elderly)

Total body clearance: 10 L/hr (following IV administration)

Excretion: feces (21% as metabolites; 28% unchanged), urine (30% as metabolites; 36% unchanged)