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Rivaroxaban

Pronunciation

Pronunciation

(riv a ROX a ban)

Index Terms

  • BAY 59-7939

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Tablet, Oral:

Xarelto: 10 mg, 15 mg, 20 mg

Tablet Therapy Pack, Oral:

Xarelto Starter Pack: 15 mg (42s) and 20 mg (9s) (51 ea)

Brand Names: U.S.

  • Xarelto
  • Xarelto Starter Pack

Pharmacologic Category

  • Anticoagulant
  • Anticoagulant, Factor Xa Inhibitor
  • Direct Oral Anticoagulant (DOAC)

Pharmacology

Inhibits platelet activation and fibrin clot formation via direct, selective and reversible inhibition of factor Xa (FXa) in both the intrinsic and extrinsic coagulation pathways. FXa, as part of the prothrombinase complex consisting also of factor Va, calcium ions, factor II and phospholipid, catalyzes the conversion of prothrombin to thrombin. Thrombin both activates platelets and catalyzes the conversion of fibrinogen to fibrin.

Absorption

Rapid

Distribution

Vdss: ~50 L

Metabolism

Hepatic via CYP3A4/5 and CYP2J2

Excretion

Urine (66% primarily via active tubular secretion [~36% as unchanged drug; 30% as inactive metabolites]); feces (28% [7% as unchanged drug; 21% as inactive metabolites])

Time to Peak

Plasma: 2 to 4 hours

Half-Life Elimination

Terminal: 5 to 9 hours; Elderly: 11 to 13 hours

Protein Binding

~92% to 95% (primarily to albumin)

Special Populations: Renal Function Impairment

Rivaroxaban exposure is increased by 44% in patients with mild impairment (CrCl 50 to 79 mL/minute) and by 52% in patients with moderate impairment (CrCl 30 to 49 mL/minute). In patients with moderate renal impairment, a 1.86-fold increase in the AUC for factor Xa inhibition and a 2.16-fold increase in PT prolongation was observed (Kubitza 2010).

Special Populations: Hepatic Function Impairment

Significant increases in rivaroxaban exposure were observed in subjects with moderate hepatic impairment (Child-Pugh class B). Increases in pharmacodynamic effects were also observed. No clinical data are available for patients with severe hepatic impairment.

Special Populations: Elderly

Elderly patients exhibit higher plasma concentrations than younger patients, with mean AUC values being ~50% higher, mainly because of reduced (apparent) total body and renal clearance.

Special Populations: Race

Healthy Japanese subjects were found to have 20% to 40% higher exposures compared with other ethnicities, including Chinese subjects.

Use: Labeled Indications

Deep vein thrombosis prophylaxis: Postoperative thromboprophylaxis of deep vein thrombosis (DVT) which may lead to pulmonary embolism in patients undergoing knee or hip replacement surgery.

Deep vein thrombosis treatment: Treatment of DVT.

Nonvalvular atrial fibrillation: Prevention of stroke and systemic embolism in patients with nonvalvular atrial fibrillation (AF).

Note: The 2014 American Heart Association/American College of Cardiology/Heart Rhythm Society guidelines for the management of AF recommend oral anticoagulation for patients with nonvalvular AF or atrial flutter with prior stroke, TIA, or a CHA2DS2-VASc score ≥2. As an alternative to warfarin, rivaroxaban may also be used for 3 weeks prior and 4 weeks after cardioversion in patients with AF or atrial flutter of ≥48 hours duration or when the duration is unknown. (January 2014).

Pulmonary embolism treatment: Treatment of pulmonary embolism.

Reduction in the risk (secondary prevention) of recurrent deep vein thrombosis and/or pulmonary embolism: Reduction in the risk of recurrence of DVT and pulmonary embolism following initial 6 months of treatment for DVT and/or pulmonary embolism.

Contraindications

Severe hypersensitivity to rivaroxaban or any component of the formulation; active pathological bleeding

Canadian labeling: Additional contraindications (not in U.S. labeling): Hepatic disease (including Child-Pugh classes B and C) associated with coagulopathy and clinically relevant bleeding risk; lesions or conditions at increased risk of clinically significant bleeding (eg, hemorrhagic or ischemic cerebral infarction, spontaneous or acquired impairment of hemostasis, active peptic ulcer disease with recent bleeding); concomitant systemic treatment with strong CYP3A4 and P-glycoprotein (P-gp) inhibitors (eg, ketoconazole, itraconazole, posaconazole, ritonavir); concomitant use with any other anticoagulant including unfractionated heparin (except at doses used to maintain central venous or arterial catheter patency), low molecular weight heparins (eg, enoxaparin, dalteparin) or heparin derivatives (eg, fondaparinux); concomitant use with warfarin, dabigatran, or apixaban except when switching therapy to or from rivaroxaban; pregnancy; lactation

Dosing: Adult

Note: Extremes of body weight (<50 kg or >120 kg) do not significantly influence rivaroxaban exposure (Kubitza 2007).

Deep vein thrombosis (DVT), pulmonary embolism (PE) treatment: Oral: Initial: 15 mg twice daily with food for 21 days followed by 20 mg once daily with food. Note: The American College of Chest Physicians (ACCP) recommends anticoagulant treatment for 3 months in patients with provoked DVT or ≥3 months with unprovoked DVT (duration depends on bleeding risk) (Guyatt 2012). Canadian labeling recommends continuation of treatment for at least 3 months if first episode of DVT is secondary to transient risk factors (eg, recent trauma, surgery, immobilization) and an extended duration of treatment if patient has permanent risk factors or idiopathic DVT/PE.

Reduction in the risk (secondary prevention) of recurrent DVT/PE after an initial 6 months of treatment: Oral: 20 mg once daily with food; duration of treatment in the EINSTEIN-Extension Study was 6 to 12 months in addition to the initial treatment duration of 6 to 12 months (EINSTEIN Investigators 2010).

Postoperative DVT thromboprophylaxis: Oral: Note: Initiate therapy after hemostasis has been established, 6 to 10 hours postoperatively.

Knee replacement: 10 mg once daily; recommended total duration of therapy: 12 days; ACCP recommendation: Minimum of 10 to 14 days; extended duration of up to 35 days suggested (Guyatt 2012).

Hip replacement: 10 mg once daily; total duration of therapy: 35 days; ACCP recommendation: Minimum of 10 to 14 days; extended duration of up to 35 days suggested (Guyatt 2012).

Nonvalvular atrial fibrillation (to prevent stroke and systemic embolism): Oral: 20 mg once daily with the evening meal.

Conversion:

Conversion from warfarin: Discontinue warfarin and initiate rivaroxaban as soon as INR falls to <3.0 (U.S. labeling) or ≤2.5 (Canadian labeling)

Conversion to warfarin: Note: Rivaroxaban affects INR; therefore, initial INR measurements after initiating warfarin may be unreliable.

U.S. labeling: Discontinue rivaroxaban and initiate both warfarin and a parenteral anticoagulant at the time the next dose of rivaroxaban would have been taken (other approaches to this conversion may be acceptable).

Canadian labeling: Continue rivaroxaban concomitantly with warfarin until INR ≥2.0 and then discontinue rivaroxaban. Note: Caution must be employed with this strategy given the lack of an antidote for rivaroxaban reversal. During the first 2 days of concomitant therapy, usual doses of warfarin may be given without INR testing. Thereafter, while on concomitant therapy, measure INR daily just prior to the next scheduled rivaroxaban dose, as appropriate. After rivaroxaban has been discontinued, INR testing may be done at least 24 hours after the last rivaroxaban dose.

Conversion from continuous infusion unfractionated heparin: Initiate rivaroxaban at the time of heparin discontinuation

Conversion to continuous infusion unfractionated heparin: Discontinue rivaroxaban and initiate continuous infusion unfractionated heparin at the time the next dose of rivaroxaban would have been taken.

Conversion from anticoagulants (other than warfarin and continuous infusion unfractionated heparin):

U.S. labeling: Discontinue current anticoagulant and initiate rivaroxaban ≤2 hours prior to the next regularly scheduled evening dose of the discontinued anticoagulant.

Canadian labeling: Discontinue current anticoagulant and initiate rivaroxaban ≤2 hours prior to the next regularly scheduled evening dose of the discontinued anticoagulant; patients previously receiving prophylactic doses of anticoagulant may initiate rivaroxaban ≥6 hours after last prophylactic dose.

Conversion to other anticoagulants (other than warfarin): Discontinue rivaroxaban and initiate the anticoagulant at the time the next dose of rivaroxaban would have been taken

Dosing: Geriatric

Refer to adult dosing. In older adults with CrCl between 30 to 50 mL/minute, reduce dose (specific dosage adjustment not provided). In older adults with CrCl <30 mL/minute, avoid use due to increased risk of bleeding (Beers Criteria [AGS 2015])

Dosing: Renal Impairment

Note: Clinical trials evaluating safety and efficacy utilized the Cockcroft-Gault formula with the use of actual body weight (weight range of patients enrolled in clinical trials: 33 to 209 kg) (data on file; Janssen Pharmaceuticals Inc 2012).

DVT, PE, reduction of the risk of recurrent DVT/PE:

US labeling:

CrCl ≥30 mL/minute: There are no dosage adjustments provided in the manufacturer’s labeling. The Beers Criteria recommends to reduce the dose in older adults ≥65 years with a CrCl between 30 to 50 mL/minute (specific dosage adjustment not provided) (Beers Criteria [AGS 2015]).

CrCl <30 mL/minute: Avoid use.

ESRD requiring hemodialysis: Nondialyzable; use is not recommended (Chan 2016).

Canadian labeling:

CrCl ≥30 mL/minute: No dosage adjustment necessary.

CrCl <30 mL/minute: Avoid use.

Nonvalvular atrial fibrillation:

US labeling:

CrCl >50 mL/minute: No dosage adjustment necessary.

CrCl 15 to 50 mL/minute: 15 mg once daily with the evening meal; assess renal function as clinically indicated and adjust dose accordingly; discontinue use in patients who develop acute renal failure. According to the AHA/ACC/HRS, may consider dose reduction in patients with moderate to severe chronic kidney disease (CKD), although safety and efficacy of this approach has not been established (AHA/ACC/HRS [January 2014]). The Beers Criteria recommends to reduce the dose in older adults ≥65 years with a CrCl between 30 to 50 mL/minute (specific dosage adjustment not provided) and avoiding use if CrCl is <30 mL/minute (Beers Criteria [AGS 2015]).

CrCl <15 mL/minute: There are no dosage adjustments provided in the manufacturer’s labeling; discontinue use in patients who develop acute renal failure. Note: In patients with severe or end-stage chronic kidney disease, warfarin remains the anticoagulant of choice (AHA/ACC/HRS [January 2014]).

ESRD requiring hemodialysis: Nondialyzable; use is not recommended (Chan 2016). Note: In patients with severe or end-stage chronic kidney disease, warfarin remains the anticoagulant of choice (AHA/ACC/HRS [January 2014]).

Canadian labeling:

CrCl ≥50 mL/minute: No dosage adjustment necessary.

CrCl 30 to 49 mL/minute: 15 mg once daily

CrCl <30 mL/minute: Avoid use.

Postoperative thromboprophylaxis:

CrCl >50 mL/minute: No dosage adjustment necessary.

CrCl 30 to 50 mL/minute: There are no dosage adjustments provided in the manufacturer’s labeling; use with caution and monitor for any signs or symptoms of blood loss. Discontinue use in patients who develop acute renal failure. The Beers Criteria recommends to reduce the dose in older adults ≥65 years with a CrCl between 30 to 50 mL/minute (specific dosage adjustment not provided) (Beers Criteria [AGS 2015]).

CrCl <30 mL/minute: Avoid use.

ESRD requiring hemodialysis: Nondialyzable; use is not recommended (Chan 2016).

Dosing: Hepatic Impairment

US labeling:

Mild impairment (Child-Pugh class A): There are no dosage adjustments provided in the manufacturer’s labeling. Limited data indicates pharmacokinetics and pharmacodynamic response were similar to healthy subjects.

Moderate to severe impairment (Child-Pugh class B or C) and any hepatic disease associated with coagulopathy: Avoid use.

Canadian labeling:

Mild hepatic impairment (Child-Pugh class A): There are no dosage adjustments provided in the manufacturer’s labeling. Limited data indicate pharmacokinetics and pharmacodynamic response were similar to healthy subjects.

Moderate impairment (Child-Pugh class B): There are no dosage adjustments provided in the manufacturer’s labeling; use with caution. Limited data indicate a significant increase in pharmacodynamic response and pharmacokinetics (eg, increased AUC [~2.3-fold for total and ~2.6-fold for unbound] and Cmax [27% for total and 38% for unbound]).

Severe hepatic impairment (Child-Pugh class C): There are no dosage adjustments provided in the manufacturer’s labeling (has not been studied).

Hepatic impairment (including Child-Pugh class B and C) associated with coagulopathy, and having clinically relevant bleeding risk: Use is contraindicated.

Dosing: Obesity

Body weight >120 kg did not significantly influence rivaroxaban exposure (Kubitza 2007). Clinical outcomes in postoperative thromboprophylaxis trials were also not affected by weight (up to 190 kg) (Turpie 2011). Therefore, dosage adjustment is not required.

Administration

Administer doses ≥15 mg/day with food; dose of 10 mg/day may be administered without regard to meals. For nonvalvular atrial fibrillation, administer with the evening meal. For patients who cannot swallow whole tablets, the tablets (all strengths) may be crushed and mixed with applesauce immediately prior to use; immediately follow administration of the 15 mg and 20 mg tablets with food (10 mg tablets may be administered without regards to food).

For nasogastric/gastric feeding tube administration, the tablets (all strengths) may be crushed and mixed in 50 mL of water; administer the suspension within 4 hours of preparation and follow administration of the 15 mg and 20 mg tablets immediately with enteral feeding (10 mg tablets may be administered without regards to food). Avoid administration distal to the stomach; a decrease in the AUC and Cmax (29% and 56%, respectively) was observed when rivaroxaban was delivered to the proximal small intestine; further decreases may be seen with delivery to the distal small intestine or ascending colon.

Missed doses: Patients receiving 15 mg twice daily dosing who miss a dose should take a dose immediately to ensure 30 mg of rivaroxaban is administered per day (two 15 mg tablets may be taken together); resume therapy the following day as previously taken. Patients receiving once-daily dosing who miss a dose should take a dose as soon as possible on the same day; resume therapy the following day as previously taken.

Storage

Store at 25°C (77°F); excursions permitted to 15°C to 30°C (59°F to 86°F).

Drug Interactions

Agents with Antiplatelet Properties (e.g., P2Y12 inhibitors, NSAIDs, SSRIs, etc.): May enhance the anticoagulant effect of Rivaroxaban. Management: Carefully consider risks and benefits of this combination and monitor closely; Canadian labeling recommends avoiding prasugrel or ticagrelor. Monitor therapy

Anticoagulants: May enhance the anticoagulant effect of Rivaroxaban. Refer to separate drug interaction content and to full drug monograph content regarding use of rivaroxaban with vitamin K antagonists (eg, warfarin, acenocoumarol) during anticoagulant transition and bridging periods. Exceptions: Acenocoumarol; Warfarin. Avoid combination

Antiplatelet Agents (P2Y12 Inhibitors): May enhance the adverse/toxic effect of Rivaroxaban. Specifically, the risk of bleeding may be increased. Management: Carefully consider risks and benefits of this combination and monitor closely; Canadian labeling recommends avoiding prasugrel or ticagrelor. Consider therapy modification

Apixaban: May enhance the anticoagulant effect of Anticoagulants. Refer to separate drug interaction content and to full drug monograph content regarding use of apixaban with vitamin K antagonists (eg, warfarin, acenocoumarol) during anticoagulant transition and bridging periods. Avoid combination

Aspirin: May enhance the adverse/toxic effect of Rivaroxaban. Specifically, the risk of bleeding may be increased. Management: Carefully consider risks and benefits of this combination and monitor closely. Consider therapy modification

Bosentan: May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

Clarithromycin: May increase the serum concentration of Rivaroxaban. Management: In patients with impaired renal function, clarithromycin should not be used unless the potential benefits outweigh the potential risks. This interaction is unlikely clinically significant in patients with normal renal function. Consider therapy modification

Collagenase (Systemic): Anticoagulants may enhance the adverse/toxic effect of Collagenase (Systemic). Specifically, the risk of injection site bruising and/or bleeding may be increased. Monitor therapy

CYP3A4 Inducers (Moderate): May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

CYP3A4 Inducers (Strong): May decrease the serum concentration of Rivaroxaban. Avoid combination

Dabigatran Etexilate: May enhance the anticoagulant effect of Anticoagulants. Refer to separate drug interaction content and to full drug monograph content regarding use of dabigatran etexilate with vitamin K antagonists (eg, warfarin, acenocoumarol) during anticoagulant transition and bridging periods. Avoid combination

Dabrafenib: May decrease the serum concentration of CYP3A4 Substrates. Management: Seek alternatives to the CYP3A4 substrate when possible. If concomitant therapy cannot be avoided, monitor clinical effects of the substrate closely (particularly therapeutic effects). Consider therapy modification

Dasatinib: May enhance the anticoagulant effect of Anticoagulants. Monitor therapy

Deferasirox: May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

Deferasirox: Anticoagulants may enhance the adverse/toxic effect of Deferasirox. Specifically, the risk for GI ulceration/irritation or GI bleeding may be increased. Monitor therapy

Deoxycholic Acid: Anticoagulants may enhance the adverse/toxic effect of Deoxycholic Acid. Specifically, the risk for bleeding or bruising in the treatment area may be increased. Monitor therapy

Edoxaban: May enhance the anticoagulant effect of Anticoagulants. Refer to separate drug interaction content and to full drug monograph content regarding use of edoxaban with vitamin K antagonists (eg, warfarin, acenocoumarol) during anticoagulant transition and bridging periods. Management: Some limited combined use may be indicated during periods of transition from one anticoagulant to another. See the full edoxaban drug monograph for specific recommendations on switching anticoagulant treatment. Avoid combination

Erythromycin (Systemic): May increase the serum concentration of Rivaroxaban. Management: In patients with impaired renal function, erythromycin should not be used unless the potential benefits outweigh the potential risks. This interaction is unlikely clinically significant in patients with normal renal function. Consider therapy modification

Estrogen Derivatives: May diminish the anticoagulant effect of Anticoagulants. More specifically, the potential prothrombotic effects of some estrogens and progestin-estrogen combinations may counteract anticoagulant effects. Management: Carefully weigh the prospective benefits of estrogens against the potential increased risk of procoagulant effects and thromboembolism. Use is considered contraindicated under some circumstances. Refer to related guidelines for specific recommendations. Exceptions: Tibolone. Consider therapy modification

Factor X (Human): Anticoagulants (Inhibitors of Factor Xa) may diminish the therapeutic effect of Factor X (Human). Monitor therapy

Fusidic Acid (Systemic): May increase the serum concentration of Rivaroxaban. Management: Consider alternatives to this combination when possible. Rivaroxaban dose adjustments may be required when used with systemic fusidic acid. Patients using this combination should be monitored extra closely. Consider therapy modification

Hemin: May enhance the anticoagulant effect of Anticoagulants. Avoid combination

Herbs (Anticoagulant/Antiplatelet Properties) (eg, Alfalfa, Anise, Bilberry): May enhance the adverse/toxic effect of Anticoagulants. Bleeding may occur. Consider therapy modification

Ibritumomab: Anticoagulants may enhance the adverse/toxic effect of Ibritumomab. Both agents may contribute to an increased risk of bleeding. Monitor therapy

Ibrutinib: May enhance the adverse/toxic effect of Anticoagulants. Monitor therapy

Inhibitors of CYP3A4 (Moderate) and P-glycoprotein: May increase the serum concentration of Rivaroxaban. Management: No action is needed in patients with normal renal function. US labeling recommends avoidance in patients with estimated creatinine clearance 15 to 80 mL/min unless prospective benefits outweigh the risks. See monograph for details of Canadian labeling. Consider therapy modification

Inhibitors of CYP3A4 (Strong) and P-glycoprotein: May increase the serum concentration of Rivaroxaban. Exceptions: Clarithromycin. Avoid combination

Limaprost: May enhance the adverse/toxic effect of Anticoagulants. The risk for bleeding may be increased. Monitor therapy

Nevirapine: May decrease the serum concentration of Rivaroxaban. Monitor therapy

Nintedanib: Anticoagulants may enhance the adverse/toxic effect of Nintedanib. Specifically, the risk for bleeding may be increased. Monitor therapy

Nonsteroidal Anti-Inflammatory Agents: May enhance the anticoagulant effect of Anticoagulants. Monitor therapy

NSAID (Nonselective): May enhance the adverse/toxic effect of Rivaroxaban. Specifically, the risk of bleeding may be increased. Management: A comprehensive risk to benefit assessment should be done for all patients before any concurrent use of rivaroxaban and nonsteroidal anti-inflammatory drugs (NSAIDs). If combined, monitor patients extra closely for signs and symptoms of bleeding. Consider therapy modification

Obinutuzumab: Anticoagulants may enhance the adverse/toxic effect of Obinutuzumab. Specifically, the risk of serious bleeding-related events may be increased. Monitor therapy

Omacetaxine: Anticoagulants may enhance the adverse/toxic effect of Omacetaxine. Specifically, the risk for bleeding-related events may be increased. Management: Avoid concurrent use of anticoagulants with omacetaxine in patients with a platelet count of less than 50,000/uL. Avoid combination

Omega-3 Fatty Acids: May enhance the anticoagulant effect of Anticoagulants. Monitor therapy

Osimertinib: May increase the serum concentration of CYP3A4 Substrates. Osimertinib may decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

Pentosan Polysulfate Sodium: May enhance the anticoagulant effect of Anticoagulants. Monitor therapy

Progestins: May diminish the therapeutic effect of Anticoagulants. More specifically, the potential prothrombotic effects of some progestins and progestin-estrogen combinations may counteract anticoagulant effects. Management: Carefully weigh the prospective benefits of progestins against the potential increased risk of procoagulant effects and thromboembolism. Use is considered contraindicated under some circumstances. Refer to related guidelines for specific recommendations. Consider therapy modification

Prostacyclin Analogues: May enhance the adverse/toxic effect of Anticoagulants. Specifically, the antiplatelet effects of these agents may lead to an increased risk of bleeding with the combination. Monitor therapy

Salicylates: May enhance the anticoagulant effect of Anticoagulants. Monitor therapy

Siltuximab: May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

St John's Wort: May decrease the serum concentration of Rivaroxaban. Avoid combination

Sugammadex: May enhance the anticoagulant effect of Anticoagulants. Monitor therapy

Thrombolytic Agents: May enhance the anticoagulant effect of Anticoagulants. Management: See full drug monograph for guidelines for the use of alteplase for acute ischemic stroke during treatment with oral anticoagulants. Monitor therapy

Tibolone: May enhance the anticoagulant effect of Anticoagulants. Monitor therapy

Tipranavir: May enhance the anticoagulant effect of Anticoagulants. Monitor therapy

Tocilizumab: May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

Tositumomab and Iodine I 131 Tositumomab: Anticoagulants may enhance the adverse/toxic effect of Tositumomab and Iodine I 131 Tositumomab. Specifically, the risk of bleeding-related adverse effects may be increased. Monitor therapy

Urokinase: May enhance the anticoagulant effect of Anticoagulants. Avoid combination

Vitamin E: May enhance the anticoagulant effect of Anticoagulants. Vitamin E may also increase the overall risk for bleeding. Monitor therapy

Vitamin E (Oral): May enhance the anticoagulant effect of Anticoagulants. Monitor therapy

Vitamin K Antagonists (eg, warfarin): Anticoagulants may enhance the anticoagulant effect of Vitamin K Antagonists. Monitor therapy

Vorapaxar: May enhance the adverse/toxic effect of Anticoagulants. More specifically, this combination is expected to increase the risk of bleeding. Avoid combination

Test Interactions

Prolongs activated partial thromboplastin time (aPTT), HepTest, and Russell viper venom time

Adverse Reactions

Frequency not always defined.

Central nervous system: Fatigue (1%), syncope (1%)

Dermatologic: Wound secretion (3%), pruritus (2%), skin blister (1%)

Gastrointestinal: Nausea (1% to 3%), abdominal pain (2%), dyspepsia (1%), toothache (1%)

Genitourinary: Urinary tract infection (1%)

Hematologic & oncologic: Hemorrhage (DVT prophylaxis: 5% to 6% [major: <1%]; DVT/PE treatment: 28% [major: ≤1%]), pulmonary hemorrhage (with and without bronchiectasis)

Hepatic: Increased serum transaminases (>3 x ULN: 2% [Watkins 2011])

Neuromuscular & skeletal: Back pain (4%), limb pain (2%), osteoarthritis (2%), muscle spasm (1%)

Respiratory: Oropharyngeal pain (1%), sinusitis (1%)

<1% (Limited to important or life-threatening): Agranulocytosis, cholestasis, decreased hemoglobin (≥2 g/dL), dysuria, ecchymoses, epidural hematoma, gastrointestinal hemorrhage, hemiparesis, hemophthalmos, hepatitis, hepatic injury (Liakoni 2014), hypermenorrhea, hypersensitivity, hypotension, increased amylase, increased blood urea nitrogen, increased lactate dehydrogenase, increased serum alkaline phosphatase, increased serum creatinine, increased serum lipase, intracranial hemorrhage, jaundice, retroperitoneal hemorrhage, Stevens-Johnson syndrome, subdural hematoma, tachycardia, thrombocytopenia (<100,000/mm3 or <50% baseline)

ALERT: U.S. Boxed Warning

Premature discontinuation increases the risk of thrombotic events:

Premature discontinuation of any oral anticoagulant, including rivaroxaban, increases the risk of thrombotic events. If anticoagulation with rivaroxaban is discontinued for a reason other than pathological bleeding or completion of a course of therapy, consider coverage with another anticoagulant.

Spinal/Epidural hematomas:

Epidural or spinal hematomas have occurred in patients treated with rivaroxaban who are receiving neuraxial anesthesia or undergoing spinal puncture. These hematomas may result in long-term or permanent paralysis. Consider these risks when scheduling patients for spinal procedures. Factors that can increase the risk of developing epidural or spinal hematomas in these patients include use of indwelling epidural catheters; concomitant use of other drugs that affect hemostasis, such as nonsteroidal anti-inflammatory drugs (NSAIDs), platelet inhibitors, or other anticoagulants; a history of traumatic or repeated epidural or spinal punctures; or a history of spinal deformity or spinal surgery. The optimal timing between the administration of rivaroxaban and neuraxial procedures is not known.

Monitor patients frequently for signs and symptoms of neurological impairment. If neurological compromise is noted, urgent treatment is necessary.

Consider the benefits and risks before neuraxial intervention in patients who are anticoagulated or are to be anticoagulated for thromboprophylaxis.

Warnings/Precautions

Concerns related to adverse effects:

• Bleeding: The most common complication is bleeding; major hemorrhages (eg, intracranial, GI, retinal, epidural hematoma, adrenal bleeding) have been reported. Certain patients are at increased risk of bleeding; risk factors include bacterial endocarditis, congenital or acquired bleeding disorders, vascular retinopathy, thrombocytopenia, recent puncture of large vessels or organ biopsy, stroke, intracerebral surgery, or other neuraxial procedure, severe uncontrolled hypertension, renal impairment, recent major surgery, recent major bleeding (intracranial, GI, intraocular, or pulmonary), concomitant use of drugs that affect hemostasis, and advanced age. Monitor for signs and symptoms of bleeding (weakness, dizziness, unexplained edema). Prompt clinical evaluation is warranted with any unexplained decrease in hemoglobin or blood pressure. Note: No specific antidote exists for rivaroxaban reversal; not dialyzable due to high plasma protein binding. Protamine sulfate and vitamin K are not expected to affect the anticoagulant activity of rivaroxaban. The use of activated prothrombin complex concentrate (aPCC) or recombinant factor VIIa has not been evaluated. The use of a four-factor PCC (Cofact, not available in the US) in healthy subjects has been shown to reverse the anticoagulant effect (ie, normalize the prothrombin time) of rivaroxaban (Eerenberg 2011).

Disease-related concerns:

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

• Renal impairment: Use with caution in patients with moderate renal impairment (CrCl 30 to 50 mL/minute) when used for postoperative thromboprophylaxis, including patients receiving concomitant drug therapy that may increase rivaroxaban systemic exposure and those with deteriorating renal function. Monitor for any signs or symptoms of blood loss. Discontinue use in patients who develop acute renal failure. Use is not recommended in patients with ESRD requiring hemodialysis (Chan 2016). Avoid use in patients with CrCl <30 mL/minute in DVT/PE and postoperative thromboprophylaxis (rivaroxaban exposure expected to increase). According to the AHA/ACC/HRS, may consider dose reduction in patients with nonvalvular AF and moderate to severe chronic kidney disease (CKD), although safety and efficacy of this approach has not been established; rivaroxaban is not recommended for patients with AF and end-stage CKD or on hemodialysis (AHA/ACC/HRS [January 2014]).

• Valvular disease: Safety and efficacy have not been established in patients with prosthetic heart valves or significant rheumatic heart disease (eg, mitral stenosis); use is not recommended. Non-valvular atrial fibrillation is defined as atrial fibrillation that occurs in the absence of rheumatic mitral valve disease, mitral valve repair, or prosthetic heart valve (AHA/ACC/HRS [January 2014]).

Concurrent drug therapy issues:

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

Special populations:

• Elderly: Use with caution in the elderly. Elderly patients exhibit higher rivaroxaban concentrations compared to younger patients due primarily to reduced clearance. Overall, efficacy of rivaroxaban in the elderly (age ≥65 years) was similar to that of patients <65 years of age. Both thrombotic and bleeding events were higher in the elderly; however, the risk to benefit profile was favorable among all age groups.

Dosage form specific issues:

• Lactose intolerance: May contains lactose; use is not recommended in patients with lactose or galactose intolerance (eg, Lapp lactase deficiency, glucose-galactose malabsorption).

Other warnings/precautions:

• Acute pulmonary embolism: Rivaroxaban is not recommended as an alternative to unfractionated heparin in the treatment of acute pulmonary embolism in hemodynamically unstable patients or patients requiring thrombolysis or pulmonary embolectomy.

• Discontinuation of therapy: [US Boxed Warning]: As with any oral anticoagulant in the absence of adequate alternative anticoagulation, an increased risk of thrombotic events (including stroke) may occur with premature discontinuation of rivaroxaban. Consider the addition of alternative anticoagulant therapy when discontinuing rivaroxaban for reasons other than pathological bleeding or completion of a course of therapy. An increased rate of stroke was observed during the transition from rivaroxaban to warfarin in clinical trials in atrial fibrillation patients. In a post-hoc analysis of the ROCKET AF trial, patients who temporarily (>3 days) or permanently discontinued anticoagulation, the risk of stroke or non-CNS embolism was similar with rivaroxaban as compared to warfarin (Patel 2013).

• Spinal or epidural hematoma: [US Boxed Warning]: Spinal or epidural hematomas may occur with neuraxial anesthesia (epidural or spinal anesthesia) or spinal puncture in patients who are anticoagulated; may result in long-term or permanent paralysis. The risk of spinal/epidural hematoma is increased with the use of indwelling epidural catheters, concomitant administration of other drugs that affect hemostasis (eg, NSAIDS, platelet inhibitors, other anticoagulants), in patients with a history of traumatic or repeated epidural or spinal punctures, or a history of spinal deformity or spinal surgery. Monitor for signs of neurologic impairment (eg, midline back pain, numbness/weakness of legs, bowel/bladder dysfunction); prompt diagnosis and treatment are necessary. In patients who are anticoagulated or pharmacologic thromboprophylaxis is anticipated, assess risks versus benefits prior to neuraxial interventions. The optimal timing between the administration of rivaroxaban and neuraxial procedures is not known. Placement or removal of an epidural catheter or lumbar puncture is best performed when the anticoagulant effect of rivaroxaban is low. European guidelines recommend waiting at least 22 to 26 hours following the last rivaroxaban dose when using prophylactic dosing (eg, 10 mg once daily) before catheter placement or lumbar puncture (Gogarten 2010). When higher doses are used (eg, 20 mg once daily), some suggest avoidance of neuraxial procedures for at least 48 hours (Rosencher 2013). In patients who have received neuraxial anesthesia concurrently with rivaroxaban (usually in patients undergoing knee or hip replacement surgery), avoid removal of epidural catheter for at least 18 hours following the last rivaroxaban dose; avoid rivaroxaban administration for at least 6 hours following epidural catheter removal; if traumatic puncture occurs, avoid rivaroxaban administration for at least 24 hours. In addition to these and other clinical variables, consider renal function and the age of the patient (elderly patients exhibit a prolonged rivaroxaban half-life [11 to 13 hours]) (Kubitza 2010; Rosencher 2013). The Canadian labeling recommends avoiding doses >10 mg in patients with a postoperative indwelling epidural catheter.

• Surgery and invasive procedures: Discontinue rivaroxaban at least 24 hours prior to procedure. Some have recommended to discontinue rivaroxaban 3 days prior to a procedure in patients with a CrCl ≥50 mL/minute or 5 days prior in patients with a CrCl <50 mL/minute (Wysokinski 2012). The risk of bleeding should be weighed against the urgency of the procedure; reinitiate rivaroxaban when adequate hemostasis has been achieved unless oral therapy cannot be administered, then consider administration of a parenteral anticoagulant.

Monitoring Parameters

Routine monitoring of coagulation tests not required; in major clinical trials, monitoring of coagulation tests (eg, aPTT, PT/INR, or antifactor Xa activity) did not occur. Prothrombin time (PT) or antifactor Xa activity may be used to detect presence of rivaroxaban (neither is intended to be used for dosage adjustment). However, variability exists among PT assays and even more so when converted to INR. Therefore, antifactor Xa activity measurement is the preferred test (Asmis 2012; Barrett 2010; Kubitza 2005). A therapeutic range has not been defined, and dosage adjustment based on results has not been established.

CBC with differential; renal function prior to initiation, when clinically indicated, and at least annually (AHA/ACC/HRS [January 2014]); hepatic function

Pregnancy Risk Factor

C

Pregnancy Considerations

Use during pregnancy is contraindicated in the Canadian labeling.

Adverse events have been observed in animal reproduction studies. Based on ex-vivo data, rivaroxaban crosses the placenta (Bapat 2015). Information related to the use of rivaroxaban during pregnancy (Hoeltzenbein 2015) and postpartum (Rudd 2015) is limited. Data are insufficient to evaluate the safety of oral factor Xa inhibitors during pregnancy; use during pregnancy should be avoided (Guyatt 2012). Use may increase the risk of pregnancy related hemorrhage. Clinicians should note that the anticoagulant effect cannot be easily monitored or readily reversed. Prompt clinical evaluation is warranted with any unexplained decrease in hemoglobin, hematocrit or blood pressure, or fetal distress. Pregnancy planning should be discussed if use is needed in women of reproductive potential.

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Have patient report immediately to prescriber signs of bleeding (vomiting blood or vomit that looks like coffee grounds, coughing up blood, blood in the urine, black, red, or tarry stools, bleeding from the gums, abnormal vaginal bleeding, bruises without a reason or that get bigger, or any bleeding that is very bad or that you cannot stop), severe dizziness, syncope, paresthesia, loss of strength or energy, a fall hitting head, illogical thinking, severe headache, wound site pain, edema, or new drainage (HCAHPS).

• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for healthcare professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience and judgment in diagnosing, treating and advising patients.

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