Dosing & Uses
Dosage Forms & Strengths
tablet
- 2.5mg
- 10mg
- 15mg
- 20mg
Deep Vein Thrombosis 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
Hip replacement: 10 mg PO qDay for 35 days
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 PO qDay 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
Reduction in risk of recurrence of DVT or PE
- Indicated for reduction in risk of recurrence of DVT and/or PE in patients at continued risk for recurrent DVT and/or PE after completion of initial treatment lasting ≤6 months
- 10 mg PO qDay with or without food, after at least 6 months of standard anticoagulant treatment
Reduction of Risk of Major Cardiovascular Events
In combination with aspirin, is indicated to reduce the risk of major cardiovascular events (cardiovascular [CV] death, myocardial infarction [MI] and stroke) in patients with chronic coronary artery disease (CAD) or peripheral artery disease (PAD)
2.5 mg PO BID, plus aspirin (75-100 mg) qDay with or without food
Dosage Modifications
Renal impairment (risk reduction of major cardiovascular events)
- No dose adjustment needed based on CrCl
- ESRD, not on dialysis: 2.5 mg BID is expected to give an exposure similar to that in patients with moderate renal impairment, whose efficacy and safety outcomes were similar to those with preserved renal function
- ESRD on dialysis: No clinical outcome data available for use with aspirin; in patients with ESRD maintained on intermittent hemodialysis, administration of 2.5 mg BID resulted in concentrations and pharmacodynamic activity similar to those observed in moderate renal impaired patients in the COMPASS study
Renal impairment (treatment, risk reduction of recurrent DVT/PE, prophylaxis of DVT)
- Moderate (CrCl ≥30 mL/min): No dosage adjustment
- Severe (CrCl <30 mL/min) and ESRD on dialysis: Avoid use
Renal impairment (nonvalvular AF)
- CrCl >50 mL/min: Dose adjustment not necessary
- CrCl 15-50 mL/min: 15 mg/day
- ESRD on intermittent renal dialysis: 15 mg/day
Hepatic impairment
- Moderate (Child-Pugh B): AUC increases of 127% were observed
- Moderate-to-severe (Child-Pugh B or C) or with any hepatic disease associated with coagulopathy: Avoid use
Dosing Considerations
Discontinuation for surgery or other procedures
- Stop rivaroxaban at least 24 hr 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 <3
- From anticoagulant other than warfarin (eg, low molecular weight heparin) to rivaroxaban: Start rivaroxaban 0-2 hr prior to next scheduled evening administration 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 give first dose of other anticoagulant (PO or parenteral) at the next scheduled rivaroxaban dose
Safety and efficacy not established
Interactions
Interaction Checker
No Results
Contraindicated
Serious - Use Alternative
Significant - Monitor Closely
Minor
Adverse 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
Drug reaction with eosinophilia and systemic symptoms (DRESS)
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 frequently for signs and symptoms of neurologic impairment; if neurologic compromise is noted, urgent treatment is necessary
Premature discontinuation increases the risk of thrombotic events
- 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 pathological 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 PE who present with hemodynamic instability or who may receive thrombolysis or pulmonary embolectomy
Do not remove an indwelling epidural or intrathecal catheter before at least 2 half-lives have elapsed (ie, 18 hr in patients aged 20-45 years and 26 hr in patients aged 60-76 years), after last administration; do not administer next dose earlier than 6 hr after removal of catheter; if traumatic puncture occurs, delay administration for 24 hr
Periodically assess renal function as clinically indicated (ie, more frequently in situations in which renal function may decline) and adjust therapy accordingly; consider dose adjustment or discontinuation of therapy in patients who develop acute renal failure while on therapy
Concomitant use of other drugs that impair hemostasis increases risk of bleeding including, aspirin, P2Y12 platelet inhibitors, dual antiplatelet therapy, other antithrombotic agents, fibrinolytic therapy, non-steroidal anti-inflammatory drugs (NSAIDs), selective serotonin reuptake inhibitors, and serotonin norepinephrine reuptake inhibitors
Use with caution in pregnant women and only if the potential benefit justifies the potential risk to the mother and fetus (see Pregnancy)
Reversing anticoagulant effect
- Use of procoagulant reversal agents, including prothrombin complex concentrate (PCC), activated prothrombin complex concentrate or recombinant factor VIIa, may be considered when reversal of anticoagulation is needed because of life-threatening or uncontrolled bleeding; but, clinical efficacy and safety has not been evaluated; monitoring for anticoagulation effect of rivaroxaban using a clotting test (PT, INR or aPTT) or anti-factor Xa (FXa) activity not recommended
Drug interaction overview
- Avoid concomitant use of P-gp and strong CYP3A4 inhibitors (eg, ketoconazole, itraconazole, lopinavir/ritonavir, ritonavir, indinavir/ritonavir, conivaptan); may increase risk of bleeding
- 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 and may increase risk of thromboembolic events
- 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 & Lactation
Pregnancy
Limited available data in pregnant women are insufficient to inform a drug-associated risk of adverse developmental outcomes
Use with caution in pregnant patients because of the potential for pregnancy related hemorrhage and/or emergent delivery; anticoagulant effect cannot be reliably monitored with standard laboratory testing
Consider benefits and risks for the mother and possible risks to the fetus when prescribing to a pregnant woman
Females of reproductive potential requiring anticoagulation should discuss pregnancy planning
Clinical considerations
- Pregnancy is a risk factor for VTE and risk increases in women with inherited or acquired thrombophilias; pregnant women with thromboembolic disease have an increased risk of maternal complications (eg, pre-eclampsia); maternal thromboembolic disease increases the risk for intrauterine growth restriction, placental abruption, and early and late pregnancy loss
- Based on pharmacologic activity of Factor Xa inhibitors and the potential to cross the placenta, bleeding may occur at any site in the fetus and/or neonate
- All patients receiving anticoagulants, including pregnant women, are at risk for bleeding and this risk may be increased during labor or delivery; risk of bleeding should be balanced with the risk of thrombotic events when considering the use in this setting
Lactation
Drug detected in human milk
Insufficient data available to determine effects on breastfed child or on milk production; drug and/or its metabolites were present in milk of rats
Consider developmental and health benefits of breastfeeding along with mother’s clinical need for therapy and any potential adverse effects on breastfed infant from therapy or from underlying maternal condition
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
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, which play 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)
Administration
Oral Administration
2.5 mg or 10 mg tablets: May take with or without food (bioavailability not significantly affected in fasted state)
15 mg or 20 mg tablets: Take with food (bioavailability improves when taken with food)
Patients unable to swallow whole tablets
- Rivaroxaban 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
- Rivaroxaban 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 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
- 2.5 mg PO BID: If a dose is missed, take a single 2.5-mg dose as recommended at the next scheduled time
- 15 mg PO BID: 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 PO qDay: Take missed dose immediately; do not double dose within the same day to make up for a missed dose
Storage
Tablets: Store at room temperature, 25°C (77°F); excursions permitted to 15-30°C (59-86°F)
Crushed tablets in water or applesauce: Store at room temperature, 25°C (77°F) for up to 4 hr
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Formulary
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