Rivaroxaban

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.

If you take rivaroxaban once a day, take the missed dose as soon as you remember it on that day. Resume your regular dosing schedule the next day.

If you take rivaroxaban twice a day, take the missed dose as soon as you remember it on that day. You may take 2 doses at the same time to make up for the missed dose. Resume your regular dosing schedule on the next day

Xarelto

GENERIC AVAILABLE: No

Yes

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Rivaroxaban is a prescription medicine used in adults to:

• reduce the risk of stroke and blood clots in people who have a medical condition called atrial fibrillation. With atrial fibrillation, part of the heart does not beat the way it should. This can lead to the formation of blood clots, which can travel to the brain, causing a stroke, or to other parts of the body.
• reduce the risk of forming a blood clot in the legs and lungs of people who have just had hip or knee replacement surgery.
• treat and reduce the recurrence of blood clots in the legs [deep vein thrombosis (DVT)]
• treat and reduce the recurrence of blood clots in the lungs [pulmonary embolism (PE)]

This medication may be prescribed for other uses. Ask your doctor or pharmacist for more information.

Rivaroxaban may be found in some form under the following brand names:

• Xarelto

Grapefruit and grapefruit juice may interact with rivaroxaban and lead to potentially dangerous effects. Discuss the use of grapefruit products with your doctor.

If you take too much rivaroxaban, call your local Poison Control Center or seek emergency medical attention right away.

• Xarelto
• Xarelto Starter Pack

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

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)

Recurrent stroke/Transient ischemic attacks (prevention)

Based on the American Heart Association/American Stroke Association (AHA/ASA) guidelines for the prevention of stroke in patients with stroke and transient ischemic attack, rivaroxaban may be considered, as an alternative to warfarin in patients who are intolerant to warfarin because of nonhemorrhagic adverse events, in patients with an acute MI complicated by left ventricular mural thrombus formation or anterior or apical wall-motion abnormalities with a left ejection fraction <40% for the prevention of recurrent stroke or transient ischemic attacks.

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

Note: Extremes of body weight (<50 kg or >120 kg) do not significantly influence rivaroxaban exposure (Kubitza 2007). However, The International Society on Thrombosis and Haemostasis (ISTH) 2016 guideline suggests avoiding the use of rivaroxaban (and other direct oral anticoagulants) in patients with a BMI >40 kg/m2 or weight >120 kg due to the lack of clinical data in this population (ISTH [Martin 2016]).

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 (EINSTEIN Investigators 2010). In patients without a requirement for extended treatment at therapeutic doses (ie, 20 mg once daily), consider 10 mg once daily with food (EINSTEIN CHOICE [Weitz 2017]).

Note: Duration of treatment in the EINSTEIN-Extension Study and the EINSTEIN CHOICE trial was 6 to 12 months in addition to the initial anticoagulant treatment duration of 6 to 12 months (EINSTEIN Investigators 2010; EINSTEIN CHOICE [Weitz 2017]).

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 (US labeling) or ≤2.5 (Canadian labeling)

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

US 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):

US 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

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.

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 may not be required. The International Society on Thrombosis and Haemostasis (ISTH) 2016 guideline suggests avoiding the use of rivaroxaban (and other direct oral anticoagulants) in patients with a BMI >40 kg/m2 or weight >120 kg due to the lack of clinical data in this population. If used in a patient with a BMI >40 kg/m2 or weight >120 kg, ISTH suggests measuring peak and trough levels using an antifactor Xa assay or mass spectrometry. If drug level is below the expected range, ISTH suggests changing to a vitamin K antagonist rather than adjusting the dose of rivaroxaban (ISTH [Martin 2016]).

• 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.

Data not available; rivaroxaban is not expected to be dialyzable.

Animal studies have revealed evidence of reproductive toxicity (e.g., hemorrhagic complications) and embryofetal toxicity (e.g., post-implantation loss). Females of reproductive potential requiring anticoagulation should discuss pregnancy planning with their physician. There are no controlled data in human pregnancy. Thrombolytic agents may lead to placental hemorrhage and subsequent prematurity and fetal loss. Use with caution in pregnancy because of the potential for pregnancy-related hemorrhage and/or emergent delivery with an anticoagulant that is not reversible. AU TGA pregnancy category C: Drugs which, owing to their pharmacological effects, have caused or may be suspected of causing, harmful effects on the human fetus or neonate without causing malformations. These effects may be reversible. Accompanying texts should be consulted for further details. US FDA pregnancy category C: Animal reproduction studies have shown an adverse effect on the fetus and there are no adequate and well-controlled studies in humans, but potential benefits may warrant use of the drug in pregnant women despite potential risks.

AU and UK: Use is contraindicated US: This drug should be used during pregnancy only if the benefit outweighs the risk AU TGA pregnancy category: C US FDA pregnancy category: C Comments: Use is only recommended in women of childbearing potential using adequate methods of contraception.