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Xarelto
Classes
Factor Xa Inhibitors
Administration
Take with food (to increase absorption):
Adult dose of 15 mg or 20 mg once or twice daily. Administer with the evening meal for once daily dosing.
Pediatric dose for the treatment of and reduction in risk of recurrent venous thromboembolism.
Take with or without food:
Adult dose of 2.5 mg twice daily and 10 mg once daily.
Pediatric dose for thromboprophylaxis after Fontan procedure.
Once daily dosing: Administer doses approximately 24 hours apart.
Twice daily dosing: Administer doses approximately 12 hours apart.
Three times daily dosing: Administer doses approximately 8 hours apart.
For DVT prophylaxis after hip or knee replacement surgery, administer the initial dose at least 6 to 10 hours after surgery once hemostasis is established.
For thrombosis prophylaxis in patients with peripheral artery disease after a successful lower extremity revascularization procedure, initiate once hemostasis is established.
Missed doses
For adults receiving 2.5 mg twice daily: Take a single 2.5 mg dose at the next scheduled time.
For adults receiving 15 mg twice daily: Take 15 mg immediately to ensure intake of 30 mg/day. Two 15 mg tablets may be taken at once.
For adults receiving 20 mg, 15 mg, or 10 mg once daily: Take the missed dose immediately. Do not double the dose within the same day to make up for a missed dose.
For pediatric patients receiving once daily dosing: Take the missed dose as soon as possible once it is noticed, but only on the same day. If this is not possible, skip the dose and continue with the next dose as prescribed. Do not take 2 doses to make up for a missed dose.
For pediatric patients receiving twice daily dosing: Take the missed morning dose as soon as possible once it is noticed. A missed morning dose may be taken together with the evening dose. A missed evening dose can only be taken in the same evening.
For pediatric patients receiving 3 times daily dosing: Skip the missed dose and go back to the regular dosing schedule at the usual time without compensating for the missed dose.
Vomit or spit up doses
If the patient vomits or spits up the dose within 30 minutes of administration, give a new dose.
If the patient vomits or spits up more than 30 minutes after administration, do not re-administer the dose; take the next dose as scheduled.
If the patient vomits or spits up repeatedly, the caregiver should contact the patient's doctor immediately.
Do not split tablets.
For pediatric patients unable to swallow whole tablets, use rivaroxaban oral suspension.
For adult patients unable to swallow whole tablets, rivaroxaban tablets may be crushed and mixed with applesauce. Administer the mixture immediately and follow with food if necessary. Crushed tablets are stable in applesauce for up to 4 hours.
Administration via nasogastric (NG) or gastric feeding tube
Confirm gastric placement of tube. Avoid administration distal to the stomach which can reduce absorption.
Crush the tablet and suspend in 50 mL of water.
Administer the mixture and immediately follow with enteral feeding if necessary.
There is no adsorption of rivaroxaban (when suspended in water) to PVC or silicone NG tubing.
Storage: Crushed tablets are stable in water for up to 4 hours.
Preparation of 1 mg/mL oral suspension
Do not add flavor; product is already flavored (sweet and creamy).
Tap the bottle until all granules flow freely.
Add 150 mL of purified water for reconstitution.
Shake for 60 seconds. Confirm all granules are wet and suspension is uniform.
Push adaptor into bottleneck and recap bottle.
Storage: Store reconstituted suspension at room temperature (20 to 25 degrees C [68 to 77 degrees F]) in original bottle; use within 60 days.
Administration via NG or gastric feeding tube
Flush the feeding tube with water after administration. Follow with enteral feeding if necessary.
Rivaroxaban oral suspension can be used with PVC, polyurethane, or silicone NG tubing.
Adverse Reactions
spinal hematoma / Delayed / Incidence not known
ocular hemorrhage / Delayed / Incidence not known
Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) / Delayed / Incidence not known
Stevens-Johnson syndrome / Delayed / Incidence not known
anaphylactic shock / Rapid / Incidence not known
angioedema / Rapid / Incidence not known
agranulocytosis / Delayed / Incidence not known
eosinophilic pneumonia / Delayed / Incidence not known
depression / Delayed / 1.2-1.2
vaginal bleeding / Delayed / Incidence not known
hepatitis / Delayed / Incidence not known
cholestasis / Delayed / Incidence not known
jaundice / Delayed / Incidence not known
thrombocytopenia / Delayed / Incidence not known
menorrhagia / Delayed / 27.0-27.0
cough / Delayed / 15.6-15.6
vomiting / Early / 10.6-14.1
back pain / Delayed / 1.0-10.0
rash / Early / 9.4-9.4
fatigue / Early / 1.0-7.0
asthenia / Delayed / 7.0-7.0
abdominal pain / Early / 1.7-2.7
dizziness / Early / 2.2-2.2
pruritus / Rapid / 2.1-2.1
insomnia / Early / 1.6-1.6
anxiety / Delayed / 1.4-1.4
dyspepsia / Early / 1.3-1.3
syncope / Early / 1.2-1.2
muscle cramps / Delayed / 1.2-1.2
sinusitis / Delayed / 1.2-1.2
maculopapular rash / Early / Incidence not known
Boxed Warning
Rivaroxaban increases bleeding risk and can cause serious and fatal bleeding. Rivaroxaban is contraindicated for use by patients with active pathological bleeding in the acute phase. Bleeding can occur at any site during rivaroxaban therapy. Use rivaroxaban cautiously in patients with any disease state in which there is an increased risk of hemorrhage. The concomitant use of other drugs that affect hemostasis increases the risk of bleeding. Rivaroxaban should not be administered to acutely ill medical patients at high risk for bleeding, which includes the following conditions: history of bronchiectasis, pulmonary cavitation, or pulmonary hemorrhage, active cancer/neoplastic disease (i.e. undergoing acute, in-hospital cancer therapy), active gastrointestinal ulcer or history of bleeding within 3 months of starting treatment, or dual antiplatelet therapy. Weigh the risk of bleeding against the risk of thrombotic events in deciding whether to initiate rivaroxaban therapy in patients at increased risk of bleeding. Monitor patients for signs or symptoms of bleeding. Promptly evaluate any signs or symptoms of bleeding and consider the need for blood replacement. Discontinue rivaroxaban in patients with active pathological bleeding.[44854] A reversal agent, factor Xa, is available when the reversal of the anticoagulant effect of rivaroxaban is necessary due to life-threatening or uncontrolled bleeding.[63132] Due to high protein binding, rivaroxaban is not expected to be dialyzable. Protamine sulfate and vitamin K are not expected to affect the anticoagulant effect of rivaroxaban. Partial reversal of prothrombin time prolongation has been seen after administration of prothrombin complex concentrates (PCCs) in healthy volunteers. The use of other procoagulant reversal agents like activated prothrombin complex concentrate (APCC) or recombinant factor VIIa (rFVIIa) has not been evaluated. Consider the benefits and risks before neuraxial intervention in patients anticoagulated or to be anticoagulated for thromboprophylaxis. Epidural or spinal hematomas that may result in long-term or permanent paralysis may occur in patients who are anticoagulated and are receiving neuraxial anesthesia or undergoing spinal puncture. Consider these risks when scheduling patients for spinal procedures. To reduce the potential risk of bleeding, it is best to perform the placement or removal of an epidural catheter or lumbar puncture when the anticoagulant effect of rivaroxaban is low based on the pharmacokinetic profile of rivaroxaban. The exact timing to reach a sufficiently low anticoagulant effect in each patient is not known. Do not remove an epidural or intrathecal catheter before 2 half-lives have elapsed (i.e., 18 hours in patients aged 20 to 45 years and 26 hours in patients aged 60 to 76 years) after the last administration of rivaroxaban, and do not administer the next rivaroxaban dose earlier than 6 hours after the catheter removal. Delay rivaroxaban administration for 24 hours if a traumatic puncture occurs. 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, other anticoagulants; a history of traumatic or repeated epidural or spinal punctures; and a history of spinal deformity or spinal surgery. If epidural anesthesia, lumbar puncture, or spinal anesthesia is employed, monitor patients frequently for signs and symptoms of neurological impairment such as midline back pain, sensory and motor deficits (numbness, tingling, or weakness in lower limbs), bowel and/or bladder dysfunction. Instruct patients to immediately report if they experience any of the above signs or symptoms. If signs or symptoms of spinal hematoma are suspected, initiate urgent diagnosis and treatment, including consideration for spinal cord decompression even though such treatment may not prevent or reverse neurological sequelae. If anticoagulation must be discontinued to reduce the risk of bleeding with surgical or other procedures, discontinue rivaroxaban at least 24 hours before the procedure. When deciding whether a procedure should be delayed until 24 hours after the last rivaroxaban dose was administered, weigh the increased risk of bleeding against the urgency of the surgical procedure or intervention. Following the surgical procedure or intervention, restart rivaroxaban as soon as hemostasis has been established. If oral therapy is not possible, consider administration of a parenteral anticoagulant.[44854]
Avoid the abrupt discontinuation of rivaroxaban in the absence of adequate alternative anticoagulation. Discontinuing rivaroxaban puts patients at an increased risk of thrombotic events. An increased risk of stroke was seen in atrial fibrillation trials when patients were transitioned from rivaroxaban to warfarin. If rivaroxaban must be discontinued for reasons other than pathological bleeding or completion of a course of therapy, consider administering another anticoagulant.
Common Brand Names
Xarelto, Xarelto Granules, Xarelto Starter Pack
Dea Class
Rx
Description
Oral selective factor Xa inhibitor anticoagulant
Used for treatment and prophylaxis of thromboembolism in several clinical contexts in patients as young as neonates
Routine laboratory monitoring not required
Dosage And Indications
20 mg PO once daily. Unless pathological bleeding occurs, do not discontinue rivaroxaban in the absence of alternative anticoagulation. For eligible persons, novel oral anticoagulants are preferred over warfarin therapy.
15 mg PO twice daily for 21 days, then 20 mg PO once daily for at least 3 months. Consider reducing dose to 10 mg PO once daily if extended oral anticoagulation is used.[44854]
NOTE: Patients younger than 6 months must be at least 37 weeks gestation, have had at least 10 days of oral feeding, and weigh at least 2.6 kg at the time of dosing.
NOTE: Monitor pediatric patient's weight and review the dose regularly, especially for those weighing less than 12 kg, to ensure a therapeutic dose is maintained. Oral dosage (tablets or oral suspension) Children and Adolescents weighing 50 kg or more
20 mg PO once daily for 3 to 12 months. Assess the benefit of continued therapy beyond 3 months on an individual basis taking into account risk of recurrent thrombosis vs. risk of bleeding.
15 mg PO once daily for 3 to 12 months. Assess the benefit of continued therapy beyond 3 months on an individual basis taking into account risk of recurrent thrombosis vs. risk of bleeding.
5 mg PO twice daily for 1 to 3 months in patients younger than 2 years with catheter-related thrombosis and for 3 to 12 months in all other thrombosis. Assess the benefit of continued therapy beyond 1 month and 3 months, respectively, on an individual basis taking into account risk of recurrent thrombosis vs. risk of bleeding.
3 mg PO 3 times daily for 1 to 3 months in patients younger than 2 years with catheter-related thrombosis and for 3 to 12 months in all other thrombosis. Assess the benefit of continued therapy beyond 1 month and 3 months, respectively, on an individual basis taking into account risk of recurrent thrombosis vs. risk of bleeding.
2.8 mg PO 3 times daily for 1 to 3 months in patients younger than 2 years with catheter-related thrombosis and for 3 to 12 months in all other thrombosis. Assess the benefit of continued therapy beyond 1 month and 3 months, respectively, on an individual basis taking into account risk of recurrent thrombosis vs. risk of bleeding.
2.4 mg PO 3 times daily for 1 to 3 months in patients younger than 2 years with catheter-related thrombosis and for 3 to 12 months in all other thrombosis. Assess the benefit of continued therapy beyond 1 month and 3 months, respectively, on an individual basis taking into account risk of recurrent thrombosis vs. risk of bleeding.
1.8 mg PO 3 times daily for 1 to 3 months in patients younger than 2 years with catheter-related thrombosis and for 3 to 12 months in all other thrombosis. Assess the benefit of continued therapy beyond 1 month and 3 months, respectively, on an individual basis taking into account risk of recurrent thrombosis vs. risk of bleeding.
1.6 mg PO 3 times daily for 1 to 3 months in patients younger than 2 years with catheter-related thrombosis and for 3 to 12 months in all other thrombosis. Assess the benefit of continued therapy beyond 1 month and 3 months, respectively, on an individual basis taking into account risk of recurrent thrombosis vs. risk of bleeding.
1.4 mg PO 3 times daily for 1 to 3 months in patients younger than 2 years with catheter-related thrombosis and for 3 to 12 months in all other thrombosis. Assess the benefit of continued therapy beyond 1 month and 3 months, respectively, on an individual basis taking into account risk of recurrent thrombosis vs. risk of bleeding.
0.9 mg PO 3 times daily for 1 to 3 months in patients younger than 2 years with catheter-related thrombosis and for 3 to 12 months in all other thrombosis. Assess the benefit of continued therapy beyond 1 month and 3 months, respectively, on an individual basis taking into account risk of recurrent thrombosis vs. risk of bleeding.
0.8 mg PO 3 times daily for 1 to 3 months in patients younger than 2 years with catheter-related thrombosis and for 3 to 12 months in all other thrombosis. Assess the benefit of continued therapy beyond 1 month and 3 months, respectively, on an individual basis taking into account risk of recurrent thrombosis vs. risk of bleeding.
15 mg PO twice daily for 21 days, then 20 mg PO once daily for at least 3 months. Consider reducing dose after 6 months to 10 mg PO once daily if extended oral anticoagulation is used after pulmonary embolism in a person without cancer.[44854] Initiation of rivaroxaban is not recommended acutely as an alternative to unfractionated heparin in persons with pulmonary embolism who present with hemodynamic instability or who may receive thrombolysis or pulmonary embolectomy.[44854]
NOTE: Infants younger than 6 months must be at least 37 weeks gestation, have had at least 10 days of oral feeding, and weigh at least 2.6 kg at the time of dosing.
NOTE: Monitor child's weight and review the dose regularly, especially for those weighing less than 12 kg, to ensure a therapeutic dose is maintained.
Oral dosage (tablets) Adults
10 mg PO once daily after at least 6 months of standard anticoagulant therapy.
20 mg PO once daily for 3 to 12 months after at least 5 days of initial parenteral anticoagulant therapy. Assess the benefit of continued therapy beyond 3 months on an individual basis taking into account risk of recurrent thrombosis vs. bleeding.
15 mg PO once daily for 3 to 12 months after at least 5 days of initial parenteral anticoagulant therapy. Assess the benefit of continued therapy beyond 3 months on an individual basis taking into account risk of recurrent thrombosis vs. bleeding.
20 mg PO once daily for 3 to 12 months after at least 5 days of initial parenteral anticoagulant therapy. Assess the benefit of continued therapy beyond 3 months on an individual basis taking into account risk of recurrent thrombosis vs. bleeding.
15 mg PO once daily for 3 to 12 months after at least 5 days of initial parenteral anticoagulant therapy. Assess the benefit of continued therapy beyond 3 months on an individual basis taking into account risk of recurrent thrombosis vs. bleeding.
5 mg PO twice daily for 1 to 3 months in children younger than 2 years with catheter-related thrombosis and for 3 to 12 months in all other pediatric populations. Assess the benefit of continued therapy beyond 1 month and 3 months, respectively, on an individual basis taking into account risk of recurrent thrombosis vs. bleeding.
3 mg PO 3 times daily for 1 to 3 months in children younger than 2 years with catheter-related thrombosis and for 3 to 12 months in all other pediatric populations. Assess the benefit of continued therapy beyond 1 month and 3 months, respectively, on an individual basis taking into account risk of recurrent thrombosis vs. bleeding.
2.8 mg PO 3 times daily for 1 to 3 months in children younger than 2 years with catheter-related thrombosis and for 3 to 12 months in all other pediatric populations. Assess the benefit of continued therapy beyond 1 month and 3 months, respectively, on an individual basis taking into account risk of recurrent thrombosis vs. bleeding.
2.4 mg PO 3 times daily for 1 to 3 months in children younger than 2 years with catheter-related thrombosis and for 3 to 12 months in all other pediatric populations. Assess the benefit of continued therapy beyond 1 month and 3 months, respectively, on an individual basis taking into account risk of recurrent thrombosis vs. bleeding.
1.8 mg PO 3 times daily for 1 to 3 months in children younger than 2 years with catheter-related thrombosis and for 3 to 12 months in all other pediatric populations. Assess the benefit of continued therapy beyond 1 month and 3 months, respectively, on an individual basis taking into account risk of recurrent thrombosis vs. bleeding.
1.6 mg PO 3 times daily for 1 to 3 months in children younger than 2 years with catheter-related thrombosis and for 3 to 12 months in all other pediatric populations. Assess the benefit of continued therapy beyond 1 month and 3 months, respectively, on an individual basis taking into account risk of recurrent thrombosis vs. bleeding.
1.4 mg PO 3 times daily for 1 to 3 months in children younger than 2 years with catheter-related thrombosis and for 3 to 12 months in all other pediatric populations. Assess the benefit of continued therapy beyond 1 month and 3 months, respectively, on an individual basis taking into account risk of recurrent thrombosis vs. bleeding.
0.9 mg PO 3 times daily for 1 to 3 months in children younger than 2 years with catheter-related thrombosis and for 3 to 12 months in all other pediatric populations. Assess the benefit of continued therapy beyond 1 month and 3 months, respectively, on an individual basis taking into account risk of recurrent thrombosis vs. bleeding.
0.8 mg PO 3 times daily for 1 to 3 months in children younger than 2 years with catheter-related thrombosis and for 3 to 12 months in all other pediatric populations. Assess the benefit of continued therapy beyond 1 month and 3 months, respectively, on an individual basis taking into account risk of recurrent thrombosis vs. bleeding.
1.6 mg PO 3 times daily for 1 to 3 months in children younger than 2 years with catheter-related thrombosis and for 3 to 12 months in all other pediatric populations. Assess the benefit of continued therapy beyond 1 month and 3 months, respectively, on an individual basis taking into account risk of recurrent thrombosis vs. bleeding.
1.4 mg PO 3 times daily for 1 to 3 months in children younger than 2 years with catheter-related thrombosis and for 3 to 12 months in all other pediatric populations. Assess the benefit of continued therapy beyond 1 month and 3 months, respectively, on an individual basis taking into account risk of recurrent thrombosis vs. bleeding.
0.9 mg PO 3 times daily for 1 to 3 months in children younger than 2 years with catheter-related thrombosis and for 3 to 12 months in all other pediatric populations. Assess the benefit of continued therapy beyond 1 month and 3 months, respectively, on an individual basis taking into account risk of recurrent thrombosis vs. bleeding.
0.8 mg PO 3 times daily for 1 to 3 months in children younger than 2 years with catheter-related thrombosis and for 3 to 12 months in all other pediatric populations. Assess the benefit of continued therapy beyond 1 month and 3 months, respectively, on an individual basis taking into account risk of recurrent thrombosis vs. bleeding.
10 mg PO once daily starting at least 6 to 10 hours after surgery. The FDA-approved labeling recommends continuation of prophylaxis for 35 days after hip replacement surgery. Guidelines recommend continuation of prophylaxis for at least 10 to 14 days; up to 35 days is recommended. Rivaroxaban is recommended as an alternative to low molecular weight heparin as antithrombotic prophylaxis for persons undergoing major orthopedic surgery. The concomitant use of an intermittent pneumatic compression device (IPCD) during the hospital stay is also encouraged. For persons who decline or are uncooperative with injections or an IPCD, rivaroxaban is an alternative for thromboprophylaxis.
10 mg PO once daily during hospitalization and continued after hospital discharge for a total recommended duration of 31 to 39 days.
10 mg PO once daily starting at least 6 to 10 hours after surgery. The FDA-approved labeling recommends continuation of prophylaxis for 12 days. Guidelines recommend continuation of prophylaxis for at least 10 to 14 days; up to 35 days is recommended. Rivaroxaban is recommended as an alternative to low molecular weight heparin as antithrombotic prophylaxis for persons undergoing major orthopedic surgery. The concomitant use of an intermittent pneumatic compression device (IPCD) during the hospital stay is also encouraged. For persons who decline or are uncooperative with injections or an IPCD, rivaroxaban is an alternative for thromboprophylaxis.
10 mg PO once daily.
10 mg PO once daily.
7.5 mg PO once daily.
2.5 mg PO twice daily.
2 mg PO twice daily.
1.7 mg PO twice daily.
1.6 mg PO twice daily.
1.1 mg PO twice daily.
2.5 mg PO twice daily; give in combination with aspirin (75 to 100 mg) PO once daily. When starting rivaroxaban after a successful lower extremity revascularization procedure, initiate therapy once hemostasis has been established.
Dosing Considerations
Mild impairment (Child-Pugh Class A): No dose adjustment needed, but avoidance of rivaroxaban is recommended for any degree of hepatic disease associated with coagulopathy.
Moderate impairment (Child-Pugh Class B): Avoid use.
Severe impairment (Child-Pugh Class C): Avoid use.
CrCl 15 to 79 mL/minute: Do not administer rivaroxaban in patients receiving a combined P-glycoprotein and moderate CYP3A inhibitor unless the potential benefit justifies the potential risk.
Adults
Nonvalvular Atrial Fibrillation
CrCl 50 mL/minute or less: 15 mg PO once daily with the evening meal.
Treatment and Prophylaxis of Venous Thromboembolism (e.g., after hip or knee replacement surgery, during acute medical illness)
CrCl 15 to 29 mL/minute: Monitor closely and promptly evaluate signs or symptoms of blood loss.
CrCl less than 15 mL/minute: Avoid use.
Coronary Artery Disease and Peripheral Artery/Vascular Disease
No dose adjustment needed based on CrCl.
Children and Adolescents
eGFR less than 50 mL/minute/1.73 m2: Avoid use; limited clinical data available.
Calculate the eGFR using the updated Schwartz formula, eGFR (Schwartz) = (0.413 x height in cm)/SCr in mg/dL, if serum creatinine (SCr) is measured by an enzymatic creatinine method that has been calibrated to be traceable to isotope dilution mass spectrometry (IDMS).
If SCr is measured with routine methods that have not been recalibrated to be traceable to IDMS (e.g., the traditional Jaffe reaction), calculate the eGFR from the original Schwartz formula, eGFR (mL/minute/1.73 m2) = k x height in cm/SCr in mg/dL, where k is proportionality constant:
k = 0.55 in children 1 to 13 years
k = 0.55 in girls 14 to 17 years
k = 0.7 in boys 14 to 17 years
Neonates and Infants
Determine renal function using serum creatinine (SCr). Avoid use of rivaroxaban in neonates and infants with SCr above the 97.5th percentile as limited clinical data are available. Reference values of the 97.5th percentile of SCr in neonates and infants, based on age are as follows:
Week 2: 0.52 mg/dL (46 micromol/L)
Week 3: 0.46 mg/dL (41 micromol/L)
Week 4: 0.42 mg/dL (37 micromol/L)
Month 2: 0.37 mg/dL (33 micromol/L)
Month 3 to 9: 0.34 mg/dL (30 micromol/L)
Month 10 to 12: 0.36 mg/dL (32 micromol/L)
Hemodialysis
Systemic concentrations of rivaroxaban in patients with end-stage renal disease receiving intermittent dialysis were similar to those with moderate renal impairment. Hemodialysis had no significant impact on rivaroxaban exposure.[44854]
Drug Interactions
Abciximab: (Major) The use of abciximab within 7 days of use an oral anticoagulant is contraindicated unless the patient's prothrombin time is less than or equal to 1.2 times the control value. Because abciximab inhibits platelet aggregation, additive effects may be seen when abciximab is given in combination with other agents that affect hemostasis such as anticoagulants. An increase in bleeding time to 45 minutes was observed in 2 drug interaction studies where another platelet inhibitor and rivaroxaban (15 mg single dose) were coadministered in healthy subjects. In the first study, the increase in bleeding time to 45 minutes was observed in approximately 45% of patients. Approximately 30% of patients in the second study had the event. The change in bleeding time was approximately twice the maximum increase seen with either drug alone. No change in the pharmacokinetic parameters of either drug were noted.
Acetaminophen; Aspirin, ASA; Caffeine: (Major) Salicylates such as aspirin are known to increase bleeding, and bleeding risk may be increased when these drugs are used concomitantly with rivaroxaban. The safety of long-term concomitant use of these drugs has not been studied. Promptly evaluate any signs or symptoms of bleeding or blood loss if patients are treated concomitantly with salicylates. In a single-dose drug interaction study, no pharmacokinetic interactions were observed after concomitant administration of acetylsalicylic acid (aspirin, ASA) with rivaroxaban.
Acetaminophen; Aspirin: (Major) Salicylates such as aspirin are known to increase bleeding, and bleeding risk may be increased when these drugs are used concomitantly with rivaroxaban. The safety of long-term concomitant use of these drugs has not been studied. Promptly evaluate any signs or symptoms of bleeding or blood loss if patients are treated concomitantly with salicylates. In a single-dose drug interaction study, no pharmacokinetic interactions were observed after concomitant administration of acetylsalicylic acid (aspirin, ASA) with rivaroxaban.
Acetaminophen; Aspirin; Diphenhydramine: (Major) Salicylates such as aspirin are known to increase bleeding, and bleeding risk may be increased when these drugs are used concomitantly with rivaroxaban. The safety of long-term concomitant use of these drugs has not been studied. Promptly evaluate any signs or symptoms of bleeding or blood loss if patients are treated concomitantly with salicylates. In a single-dose drug interaction study, no pharmacokinetic interactions were observed after concomitant administration of acetylsalicylic acid (aspirin, ASA) with rivaroxaban.
Acetaminophen; Ibuprofen: (Major) An additive risk of bleeding may be seen in patients receiving anticoagulants in combination with other agents known to increase the risk of bleeding such as nonsteroidal antiinflammatory drugs (NSAIDs). Monitor clinical and laboratory response closely during concurrent use.
Ado-Trastuzumab emtansine: (Moderate) Use caution if coadministration of anticoagulants with ado-trastuzumab emtansine is necessary due to reports of severe and sometimes fatal hemorrhage, including intracranial bleeding, with ado-trastuzumab emtansine therapy. Consider additional monitoring when concomitant use is medically necessary. While some patients who experienced bleeding during ado-trastuzumab therapy were also receiving anticoagulation therapy, others had no known additional risk factors.
Alteplase: (Major) Due to the increased bleeding risk, avoid concurrent use of rivaroxaban with thrombolytic agents; the safety of concomitant use has not been studied.
Altretamine: (Moderate) Due to the thrombocytopenic effects of altretamine, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants.
Aminosalicylate sodium, Aminosalicylic acid: (Major) Salicylates such as aspirin are known to increase bleeding, and bleeding risk may be increased when these drugs are used concomitantly with rivaroxaban. The safety of long-term concomitant use of these drugs has not been studied. Promptly evaluate any signs or symptoms of bleeding or blood loss if patients are treated concomitantly with salicylates. In a single-dose drug interaction study, no pharmacokinetic interactions were observed after concomitant administration of acetylsalicylic acid (aspirin, ASA) with rivaroxaban.
Amiodarone: (Moderate) Avoid coadministration of rivaroxaban and amiodarone in patients with renal impairment (CrCL 15 to 79 mL/minute) unless the potential benefit justifies the potential risk. Rivaroxaban is a CYP3A4 and P-glycoprotein (P-gp) inhibitor and amiodarone is a P-gp and moderate CYP3A4 inhibitor. In a pharmacokinetic trial, coadministration with another combined moderate CYP3A4/P-gp inhibitor increased the AUC of rivaroxaban by 76% in patients with mild renal impairment (CrCL 50 to 79 mL/minute) and by 99% in patients with moderate renal impairment (CrCL 30 to 49 mL/minute) compared to patients with normal renal function (CrCL greater than 80 mL/minute); similar trends in pharmacodynamic effects were also observed.
Amlodipine; Celecoxib: (Major) An additive risk of bleeding may be seen in patients receiving anticoagulants in combination with other agents known to increase the risk of bleeding such as nonsteroidal antiinflammatory drugs (NSAIDs). Monitor clinical and laboratory response closely during concurrent use.
Amoxicillin; Clarithromycin; Omeprazole: (Moderate) Pharmacokinetic data suggests coadministration of rivaroxaban with clarithromycin is unlikely to affect bleeding risk. However, coadministration of rivaroxaban with other combined P-gp and strong CYP3A4 inhibitors has resulted in increased rivaroxaban exposure and is not recommended. Educate patients about the signs and symptoms of bleeding if concurrent use of clarithromycin with rivaroxaban is necessary; patients with renal impairment may be at greater risk with this combination.
Anagrelide: (Major) Avoid concurrent administration of platelet inhibitors such as anagrelide with rivaroxaban unless the benefit outweighs the risk of increased bleeding. An increase in bleeding time to 45 minutes was observed in 2 drug interaction studies where another platelet inhibitor and rivaroxaban (15 mg single dose) were coadministered in healthy subjects. In the first study, the increase in bleeding time to 45 minutes was observed in approximately 45% of patients. Approximately 30% of patients in the second study had the event. The change in bleeding time was approximately twice the maximum increase seen with either drug alone. No change in the pharmacokinetic parameters of either drug were noted.
Antithrombin III: (Major) Due to the increased bleeding risk, avoid concurrent use of rivaroxaban with antithrombin III; the safety of concomitant use has not been studied.
Apalutamide: (Major) Avoid coadministration of apalutamide with rivaroxaban due to decreased exposure to rivaroxaban which may reduce efficacy. Rivaroxaban is a CYP3A4 and P-glycoprotein (P-gp) substrate. Apalutamide is a strong CYP3A4 inducer and a weak P-gp inducer. Coadministration with another combined P-gp and strong CYP3A4 inducer decreased rivaroxaban exposure by up to 50%.
Apixaban: (Major) Avoid concomitant use of apixaban and rivaroxaban due to the increased risk for bleeding. Short-term overlaps in anticoagulation therapy may be necessary for patients transitioning from one anticoagulant to another. Monitor patients closely and promptly evaluate any signs or symptoms of bleeding if the use of multiple anticoagulants is necessary.
Aprepitant, Fosaprepitant: (Moderate) Use caution if rivaroxaban and aprepitant, fosaprepitant are used concurrently and monitor for an increase in rivaroxaban-related adverse effects for several days after administration of a multi-day aprepitant regimen. Rivaroxaban is a CYP3A4 substrate. Aprepitant, when administered as a 3-day oral regimen (125 mg/80 mg/80 mg), is a moderate CYP3A4 inhibitor and inducer and may increase plasma concentrations of rivaroxaban. For example, a 5-day oral aprepitant regimen increased the AUC of another CYP3A4 substrate, midazolam (single dose), by 2.3-fold on day 1 and by 3.3-fold on day 5. After a 3-day oral aprepitant regimen, the AUC of midazolam (given on days 1, 4, 8, and 15) increased by 25% on day 4, and then decreased by 19% and 4% on days 8 and 15, respectively. As a single 125 mg or 40 mg oral dose, the inhibitory effect of aprepitant on CYP3A4 is weak, with the AUC of midazolam increased by 1.5-fold and 1.2-fold, respectively. After administration, fosaprepitant is rapidly converted to aprepitant and shares many of the same drug interactions. However, as a single 150 mg intravenous dose, fosaprepitant only weakly inhibits CYP3A4 for a duration of 2 days; there is no evidence of CYP3A4 induction. Fosaprepitant 150 mg IV as a single dose increased the AUC of midazolam (given on days 1 and 4) by approximately 1.8-fold on day 1; there was no effect on day 4. Less than a 2-fold increase in the midazolam AUC is not considered clinically important.
Argatroban: (Major) Due to the increased bleeding risk, avoid concurrent use of rivaroxaban with thrombin inhibitors; the safety of concomitant use has not been studied. If a thrombin inhibitor is used during therapeutic transition periods, closely observe patients and promptly evaluate any signs or symptoms of blood loss.
Armodafinil: (Minor) Coadministration of rivaroxaban and armodafinil may result in decreased rivaroxaban exposure and may decrease the efficacy of rivaroxaban. Armodafinil is a mild inducer of CYP3A4, and rivaroxaban is a substrate of CYP3A4. If these drugs are administered concurrently, monitor the patient for signs of lack of efficacy of rivaroxaban.
Aspirin, ASA: (Major) Salicylates such as aspirin are known to increase bleeding, and bleeding risk may be increased when these drugs are used concomitantly with rivaroxaban. The safety of long-term concomitant use of these drugs has not been studied. Promptly evaluate any signs or symptoms of bleeding or blood loss if patients are treated concomitantly with salicylates. In a single-dose drug interaction study, no pharmacokinetic interactions were observed after concomitant administration of acetylsalicylic acid (aspirin, ASA) with rivaroxaban.
Aspirin, ASA; Butalbital; Caffeine: (Major) Salicylates such as aspirin are known to increase bleeding, and bleeding risk may be increased when these drugs are used concomitantly with rivaroxaban. The safety of long-term concomitant use of these drugs has not been studied. Promptly evaluate any signs or symptoms of bleeding or blood loss if patients are treated concomitantly with salicylates. In a single-dose drug interaction study, no pharmacokinetic interactions were observed after concomitant administration of acetylsalicylic acid (aspirin, ASA) with rivaroxaban.
Aspirin, ASA; Caffeine: (Major) Salicylates such as aspirin are known to increase bleeding, and bleeding risk may be increased when these drugs are used concomitantly with rivaroxaban. The safety of long-term concomitant use of these drugs has not been studied. Promptly evaluate any signs or symptoms of bleeding or blood loss if patients are treated concomitantly with salicylates. In a single-dose drug interaction study, no pharmacokinetic interactions were observed after concomitant administration of acetylsalicylic acid (aspirin, ASA) with rivaroxaban.
Aspirin, ASA; Caffeine; Orphenadrine: (Major) Salicylates such as aspirin are known to increase bleeding, and bleeding risk may be increased when these drugs are used concomitantly with rivaroxaban. The safety of long-term concomitant use of these drugs has not been studied. Promptly evaluate any signs or symptoms of bleeding or blood loss if patients are treated concomitantly with salicylates. In a single-dose drug interaction study, no pharmacokinetic interactions were observed after concomitant administration of acetylsalicylic acid (aspirin, ASA) with rivaroxaban.
Aspirin, ASA; Carisoprodol: (Major) Salicylates such as aspirin are known to increase bleeding, and bleeding risk may be increased when these drugs are used concomitantly with rivaroxaban. The safety of long-term concomitant use of these drugs has not been studied. Promptly evaluate any signs or symptoms of bleeding or blood loss if patients are treated concomitantly with salicylates. In a single-dose drug interaction study, no pharmacokinetic interactions were observed after concomitant administration of acetylsalicylic acid (aspirin, ASA) with rivaroxaban.
Aspirin, ASA; Carisoprodol; Codeine: (Major) Salicylates such as aspirin are known to increase bleeding, and bleeding risk may be increased when these drugs are used concomitantly with rivaroxaban. The safety of long-term concomitant use of these drugs has not been studied. Promptly evaluate any signs or symptoms of bleeding or blood loss if patients are treated concomitantly with salicylates. In a single-dose drug interaction study, no pharmacokinetic interactions were observed after concomitant administration of acetylsalicylic acid (aspirin, ASA) with rivaroxaban.
Aspirin, ASA; Citric Acid; Sodium Bicarbonate: (Major) Salicylates such as aspirin are known to increase bleeding, and bleeding risk may be increased when these drugs are used concomitantly with rivaroxaban. The safety of long-term concomitant use of these drugs has not been studied. Promptly evaluate any signs or symptoms of bleeding or blood loss if patients are treated concomitantly with salicylates. In a single-dose drug interaction study, no pharmacokinetic interactions were observed after concomitant administration of acetylsalicylic acid (aspirin, ASA) with rivaroxaban.
Aspirin, ASA; Dipyridamole: (Major) Avoid concurrent administration of platelet inhibitors such as dipyridamole with rivaroxaban unless the benefit outweighs the risk of increased bleeding. An increase in bleeding time to 45 minutes was observed in 2 drug interaction studies where another platelet inhibitor and rivaroxaban (15 mg single dose) were coadministered in healthy subjects. In the first study, the increase in bleeding time to 45 minutes was observed in approximately 45% of patients. Approximately 30% of patients in the second study had the event. The change in bleeding time was approximately twice the maximum increase seen with either drug alone. No change in the pharmacokinetic parameters of either drug were noted. (Major) Salicylates such as aspirin are known to increase bleeding, and bleeding risk may be increased when these drugs are used concomitantly with rivaroxaban. The safety of long-term concomitant use of these drugs has not been studied. Promptly evaluate any signs or symptoms of bleeding or blood loss if patients are treated concomitantly with salicylates. In a single-dose drug interaction study, no pharmacokinetic interactions were observed after concomitant administration of acetylsalicylic acid (aspirin, ASA) with rivaroxaban.
Aspirin, ASA; Omeprazole: (Major) Salicylates such as aspirin are known to increase bleeding, and bleeding risk may be increased when these drugs are used concomitantly with rivaroxaban. The safety of long-term concomitant use of these drugs has not been studied. Promptly evaluate any signs or symptoms of bleeding or blood loss if patients are treated concomitantly with salicylates. In a single-dose drug interaction study, no pharmacokinetic interactions were observed after concomitant administration of acetylsalicylic acid (aspirin, ASA) with rivaroxaban.
Aspirin, ASA; Oxycodone: (Major) Salicylates such as aspirin are known to increase bleeding, and bleeding risk may be increased when these drugs are used concomitantly with rivaroxaban. The safety of long-term concomitant use of these drugs has not been studied. Promptly evaluate any signs or symptoms of bleeding or blood loss if patients are treated concomitantly with salicylates. In a single-dose drug interaction study, no pharmacokinetic interactions were observed after concomitant administration of acetylsalicylic acid (aspirin, ASA) with rivaroxaban.
Atazanavir: (Moderate) Close monitoring for increased bleeding is recommended when rivaroxaban is administered with atazanavir. If atazanavir is boosted with ritonavir, concurrent use of rivaroxaban should be avoided. Taking these drugs together may significantly increase rivaroxaban concentrations. Atazanavir and ritonavir are CYP3A4 inhibitors; rivaroxaban is metabolized by this enzyme. Additionally, rivaroxaban is a P-glycoprotein (P-gp) substrate; ritonavir is a P-gp inhibitor.
Atazanavir; Cobicistat: (Major) Avoid concomitant administration of rivaroxaban and cobicistat; significant increases in rivaroxaban exposure may increase bleeding risk. Rivaroxaban is a substrate of CYP3A4/5 and the P-glycoprotein (P-gp) transporter. Cobicistat is a combined P-gp and strong CYP3A4 inhibitor. Concurrent use of a single dose of rivaroxaban and another combined P-gp and strong CYP3A4 inhibitor increased the steady-state rivaroxaban AUC and Cmax by 150% and 60%, respectively. Similar increases in pharmacodynamic effects such as factor Xa inhibition and PT prolongation were also observed. (Moderate) Close monitoring for increased bleeding is recommended when rivaroxaban is administered with atazanavir. If atazanavir is boosted with ritonavir, concurrent use of rivaroxaban should be avoided. Taking these drugs together may significantly increase rivaroxaban concentrations. Atazanavir and ritonavir are CYP3A4 inhibitors; rivaroxaban is metabolized by this enzyme. Additionally, rivaroxaban is a P-glycoprotein (P-gp) substrate; ritonavir is a P-gp inhibitor.
Atomoxetine: (Major) Coadministration of rivaroxaban with other drugs that affect hemostasis, such as selective norepinephrine reuptake inhibitors (SNRIs), increases the risk of bleeding. If these drugs are administered together, instruct patients to monitor for signs and symptoms of bleeding, and to promptly report any bleeding events to their practitioner.
Benzoic Acid; Hyoscyamine; Methenamine; Methylene Blue; Phenyl Salicylate: (Major) Salicylates such as aspirin are known to increase bleeding, and bleeding risk may be increased when these drugs are used concomitantly with rivaroxaban. The safety of long-term concomitant use of these drugs has not been studied. Promptly evaluate any signs or symptoms of bleeding or blood loss if patients are treated concomitantly with salicylates. In a single-dose drug interaction study, no pharmacokinetic interactions were observed after concomitant administration of acetylsalicylic acid (aspirin, ASA) with rivaroxaban.
Berotralstat: (Major) Avoid coadministration of rivaroxaban and berotralstat in patients with renal impairment (CrCL 15 to 79 mL/minute) unless the potential benefit justifies the potential risk. Rivaroxaban is a CYP3A4 and P-glycoprotein (P-gp) inhibitor and berotralstat is a P-gp and moderate CYP3A4 inhibitor. In a pharmacokinetic trial, coadministration with another combined moderate CYP3A4/P-gp inhibitor increased the AUC of rivaroxaban by 76% in patients with mild renal impairment (CrCL 50 to 79 mL/minute) and by 99% in patients with moderate renal impairment (CrCL 30 to 49 mL/minute) compared to patients with normal renal function (CrCL greater than 80 mL/minute); similar trends in pharmacodynamic effects were also observed.
Betrixaban: (Major) Avoid use of betrixaban with rivaroxaban due to the increased bleeding risk. Monitor patients closely and promptly evaluate any signs or symptoms of bleeding if betrixaban and other anticoagulants are used concomitantly. Coadministration of betrixaban and other anticoagulants may increase the risk of bleeding. Long-term concomitant treatment with betrixaban and other anticoagulants is not recommended; short-term use may be necessary for patients transitioning to or from betrixaban.
Bismuth Subsalicylate: (Major) Salicylates such as aspirin are known to increase bleeding, and bleeding risk may be increased when these drugs are used concomitantly with rivaroxaban. The safety of long-term concomitant use of these drugs has not been studied. Promptly evaluate any signs or symptoms of bleeding or blood loss if patients are treated concomitantly with salicylates. In a single-dose drug interaction study, no pharmacokinetic interactions were observed after concomitant administration of acetylsalicylic acid (aspirin, ASA) with rivaroxaban.
Bismuth Subsalicylate; Metronidazole; Tetracycline: (Major) Salicylates such as aspirin are known to increase bleeding, and bleeding risk may be increased when these drugs are used concomitantly with rivaroxaban. The safety of long-term concomitant use of these drugs has not been studied. Promptly evaluate any signs or symptoms of bleeding or blood loss if patients are treated concomitantly with salicylates. In a single-dose drug interaction study, no pharmacokinetic interactions were observed after concomitant administration of acetylsalicylic acid (aspirin, ASA) with rivaroxaban.
Bivalirudin: (Major) Due to the increased bleeding risk, avoid concurrent use of rivaroxaban with thrombin inhibitors; the safety of concomitant use has not been studied. If a thrombin inhibitor is used during therapeutic transition periods, closely observe patients and promptly evaluate any signs or symptoms of blood loss.
Bupivacaine; Meloxicam: (Major) An additive risk of bleeding may be seen in patients receiving anticoagulants in combination with other agents known to increase the risk of bleeding such as nonsteroidal antiinflammatory drugs (NSAIDs). Monitor clinical and laboratory response closely during concurrent use.
Butalbital; Aspirin; Caffeine; Codeine: (Major) Salicylates such as aspirin are known to increase bleeding, and bleeding risk may be increased when these drugs are used concomitantly with rivaroxaban. The safety of long-term concomitant use of these drugs has not been studied. Promptly evaluate any signs or symptoms of bleeding or blood loss if patients are treated concomitantly with salicylates. In a single-dose drug interaction study, no pharmacokinetic interactions were observed after concomitant administration of acetylsalicylic acid (aspirin, ASA) with rivaroxaban.
Caplacizumab: (Major) Avoid concomitant use of caplacizumab and anticoagulants when possible. Assess and monitor closely for bleeding if use together is necessary. Interrupt use of caplacizumab if clinically significant bleeding occurs.
Carbamazepine: (Major) Avoid the concomitant administration of rivaroxaban and drugs that are both strong inducers of CYP3A4 and P-gp, such as carbamazepine. Concomitant administration of rivaroxaban and carbamazepine results in decreased plasma concentrations of rivaroxaban that may be insufficient to achieve the intended therapeutic effect. In a drug interaction study, coadministration of rivaroxaban 20 mg single dose with food with a drug that is a combined P-glycoprotein and strong CYP3A4 inducer led to approximate decreases of 50% and 22% in rivaroxaban AUC and Cmax, respectively. Similar decreases in pharmacodynamic effects were also observed.
Celecoxib: (Major) An additive risk of bleeding may be seen in patients receiving anticoagulants in combination with other agents known to increase the risk of bleeding such as nonsteroidal antiinflammatory drugs (NSAIDs). Monitor clinical and laboratory response closely during concurrent use.
Celecoxib; Tramadol: (Major) An additive risk of bleeding may be seen in patients receiving anticoagulants in combination with other agents known to increase the risk of bleeding such as nonsteroidal antiinflammatory drugs (NSAIDs). Monitor clinical and laboratory response closely during concurrent use.
Chlorambucil: (Moderate) Due to the thrombocytopenic effects of chlorambucil, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants.
Chloramphenicol: (Minor) Coadministration of rivaroxaban and chloramphenicol may result in increases in rivaroxaban exposure and may increase bleeding risk. Chloramphenicol is an inhibitor of CYP3A4, and rivaroxaban is a substrate of CYP3A4. If these drugs are administered concurrently, monitor the patient for signs and symptoms of bleeding.
Chlorpheniramine; Ibuprofen; Pseudoephedrine: (Major) An additive risk of bleeding may be seen in patients receiving anticoagulants in combination with other agents known to increase the risk of bleeding such as nonsteroidal antiinflammatory drugs (NSAIDs). Monitor clinical and laboratory response closely during concurrent use.
Choline Salicylate; Magnesium Salicylate: (Major) Salicylates such as aspirin are known to increase bleeding, and bleeding risk may be increased when these drugs are used concomitantly with rivaroxaban. The safety of long-term concomitant use of these drugs has not been studied. Promptly evaluate any signs or symptoms of bleeding or blood loss if patients are treated concomitantly with salicylates. In a single-dose drug interaction study, no pharmacokinetic interactions were observed after concomitant administration of acetylsalicylic acid (aspirin, ASA) with rivaroxaban.
Cilostazol: (Major) Avoid concurrent administration of platelet inhibitors such as clopidogrel with rivaroxaban unless the benefit outweighs the risk of increased bleeding. An increase in bleeding time to 45 minutes was observed in two drug interaction studies where clopidogrel (300 mg loading dose followed by 75 mg daily maintenance dose) and rivaroxaban (15 mg single dose) were coadministered in healthy subjects. In the first study, the increase in bleeding time to 45 minutes was observed in approximately 45% of patients. Approximately 30% of patients in the second study had the event. The change in bleeding time was approximately twice the maximum increase seen with either drug alone. No change in the pharmacokinetic parameters of either drug were noted.
Citalopram: (Moderate) Advise patients of the increased bleeding risk associated with the concomitant use of selective serotonin reuptake inhibitors (SSRIs) and anticoagulants like rivaroxaban. Case reports and epidemiological studies have demonstrated an association between use of drugs that interfere with serotonin reuptake and gastrointestinal bleeding.
Clarithromycin: (Moderate) Pharmacokinetic data suggests coadministration of rivaroxaban with clarithromycin is unlikely to affect bleeding risk. However, coadministration of rivaroxaban with other combined P-gp and strong CYP3A4 inhibitors has resulted in increased rivaroxaban exposure and is not recommended. Educate patients about the signs and symptoms of bleeding if concurrent use of clarithromycin with rivaroxaban is necessary; patients with renal impairment may be at greater risk with this combination.
Clofarabine: (Moderate) Due to the thrombocytopenic effects of clofarabine, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants.
Clopidogrel: (Major) Avoid concurrent administration of platelet inhibitors such as clopidogrel with rivaroxaban unless the benefit outweighs the risk of increased bleeding. An increase in bleeding time to 45 minutes was observed in 2 drug interaction studies where clopidogrel (300 mg loading dose followed by 75 mg daily maintenance dose) and rivaroxaban (15 mg single dose) were coadministered in healthy subjects. In the first study, the increase in bleeding time to 45 minutes was observed in approximately 45% of patients. Approximately 30% of patients in the second study had the event. The change in bleeding time was approximately twice the maximum increase seen with either drug alone. No change in the pharmacokinetic parameters of either drug were noted.
Cobicistat: (Major) Avoid concomitant administration of rivaroxaban and cobicistat; significant increases in rivaroxaban exposure may increase bleeding risk. Rivaroxaban is a substrate of CYP3A4/5 and the P-glycoprotein (P-gp) transporter. Cobicistat is a combined P-gp and strong CYP3A4 inhibitor. Concurrent use of a single dose of rivaroxaban and another combined P-gp and strong CYP3A4 inhibitor increased the steady-state rivaroxaban AUC and Cmax by 150% and 60%, respectively. Similar increases in pharmacodynamic effects such as factor Xa inhibition and PT prolongation were also observed.
Cobimetinib: (Minor) If concurrent use of cobimetinib and rivaroxaban is necessary, use caution and monitor for a possible increase in cobimetinib-related adverse effects. Cobimetinib is a P-glycoprotein (P-gp) substrate, and rivaroxaban is a weak, in vitro, P-gp inhibitor; coadministration may result in increased cobimetinib exposure. However, coadministration of cobimetinib with another P-gp inhibitor, vemurafenib (960 mg twice daily), did not result in clinically relevant pharmacokinetic drug interactions.
Collagenase: (Moderate) Cautious use of injectable collagenase by patients taking anticoagulants is advised. The efficacy and safety of administering injectable collagenase to a patient taking an anticoagulant within 7 days before the injection are unknown. Receipt of injectable collagenase may cause an ecchymosis or bleeding at the injection site.
Conivaptan: (Major) Avoid coadministration of rivaroxaban and conivaptan in patients with renal impairment (CrCl 15 to 79 mL/minute) unless the potential benefit justifies the risk. Rivaroxaban is a CYP3A and P-gp substrate and conivaptan is a moderate CYP3A and P-gp inhibitor. In a pharmacokinetic trial, coadministration with another combined moderate CYP3A/P-gp inhibitor increased the overall exposure of rivaroxaban by 76% in patients with mild renal impairment (CrCl 50 to 79 mL/minute) and by 99% in patients with moderate renal impairment (CrCl 30 to 49 mL/minute) compared to patients with normal renal function (CrCl greater than 80 mL/minute); similar trends in pharmacodynamic effects were also observed.
Cyclosporine: (Minor) The coadministration of rivaroxaban and cyclosporine should be undertaken with caution in patients with renal impairment; it is unclear whether a clinically significant interaction occurs when these drugs are coadministered to patients with normal renal function. Cyclosporine is a combined mild CYP3A4 inhibitor and P-glycoprotein (P-gp) inhibitor. Rivaroxaban is a substrate of CYP3A4/5 and the P-gp transporter. Coadministration in patients with renal impairment may result in increased exposure to rivaroxaban compared with patients with normal renal function and no inhibitor use since both pathways of elimination are affected. While an increase in exposure to rivaroxaban may be expected, results from an analysis of the ROCKET-AF trial which allowed concomitant administration of rivaroxaban and a combined P-gp inhibitor and weak or moderate CYP3A4 inhibitor did not show an increased risk of bleeding in patients with CrCl 30 to < 50 mL/minute [HR (95% CI): 1.05 (0.77, 1.42)].
Cytarabine, ARA-C: (Moderate) Due to the thrombocytopenic effects of pyrimidine analogs, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants.
Dabigatran: (Major) Avoid use of dabigatran with rivaroxaban due to the increased bleeding risk. Monitor patients closely and promptly evaluate any signs or symptoms of bleeding if dabigatran and other anticoagulants are used concomitantly. Coadministration of dabigatran and other anticoagulants may increase the risk of bleeding. Long-term concomitant treatment with dabigatran and other anticoagulants is not recommended; short-term use may be necessary for patients transitioning to or from dabigatran.
Daclatasvir: (Minor) Systemic exposure of rivaroxaban, a P-glycoprotein (P-gp) substrate, may be increased when administered concurrently with daclatasvir, a P-gp inhibitor. Taking these drugs together could increase or prolong the therapeutic effects of rivaroxaban; monitor patients for potential adverse effects.
Dalteparin: (Major) Due to the increased bleeding risk, avoid concurrent use of rivaroxaban with dalteparin; the safety of concomitant use has not been studied. If dalteparin is used during therapeutic transition periods, closely observe patients and promptly evaluate any signs or symptoms of blood loss.
Danazol: (Major) Danazol can decrease hepatic synthesis of procoagulant factors, increasing the possibility of bleeding when used concurrently with anticoagulants. Coadministration of rivaroxaban and danazol may result in increases in rivaroxaban exposure and may also increase bleeding risk. Danazol is an inhibitor of CYP3A4, and rivaroxaban is a substrate of CYP3A4. If these drugs are administered concurrently, monitor the patient for signs and symptoms of bleeding.
Darunavir; Cobicistat: (Major) Avoid concomitant administration of rivaroxaban and cobicistat; significant increases in rivaroxaban exposure may increase bleeding risk. Rivaroxaban is a substrate of CYP3A4/5 and the P-glycoprotein (P-gp) transporter. Cobicistat is a combined P-gp and strong CYP3A4 inhibitor. Concurrent use of a single dose of rivaroxaban and another combined P-gp and strong CYP3A4 inhibitor increased the steady-state rivaroxaban AUC and Cmax by 150% and 60%, respectively. Similar increases in pharmacodynamic effects such as factor Xa inhibition and PT prolongation were also observed.
Darunavir; Cobicistat; Emtricitabine; Tenofovir alafenamide: (Major) Avoid concomitant administration of rivaroxaban and cobicistat; significant increases in rivaroxaban exposure may increase bleeding risk. Rivaroxaban is a substrate of CYP3A4/5 and the P-glycoprotein (P-gp) transporter. Cobicistat is a combined P-gp and strong CYP3A4 inhibitor. Concurrent use of a single dose of rivaroxaban and another combined P-gp and strong CYP3A4 inhibitor increased the steady-state rivaroxaban AUC and Cmax by 150% and 60%, respectively. Similar increases in pharmacodynamic effects such as factor Xa inhibition and PT prolongation were also observed.
Dasatinib: (Moderate) Monitor for evidence of bleeding if coadministration of dasatinib and anticoagulants is necessary. Dasatinib can cause serious and fatal bleeding. Concomitant anticoagulants may increase the risk of hemorrhage.
Deferasirox: (Moderate) Because gastric ulceration and GI bleeding have been reported in patients taking deferasirox, use caution when coadministering with other drugs known to increase the risk of peptic ulcers or gastric hemorrhage including anticoagulants.
Defibrotide: (Contraindicated) Coadministration of defibrotide with antithrombotic agents like anticoagulants is contraindicated. The pharmacodynamic activity and risk of hemorrhage with antithrombotic agents are increased if coadministered with defibrotide. If therapy with defibrotide is necessary, discontinue systemic antithrombotic agents (not including use for routine maintenance or reopening of central venous catheters) prior to initiation of defibrotide therapy. Consider delaying the onset of defibrotide treatment until the effects of the antithrombotic agent have abated.
Delavirdine: (Minor) Coadministration of rivaroxaban and delavirdine may result in increases in rivaroxaban exposure and may increase bleeding risk. Delavirdine is a potent inhibitor of CYP3A4, and rivaroxaban is a substrate of CYP3A4. If these drugs are administered concurrently, monitor the patient for signs and symptoms of bleeding.
Desirudin: (Major) Due to the increased bleeding risk, avoid concurrent use of rivaroxaban with thrombin inhibitors; the safety of concomitant use has not been studied. If a thrombin inhibitor is used during therapeutic transition periods, closely observe patients and promptly evaluate any signs or symptoms of blood loss.
Dextran: (Moderate) Because of the potential effects of certain dextran formulations on bleeding time, use with caution in patients on anticoagulants concurrently.
Dextromethorphan; Quinidine: (Minor) Coadministration of rivaroxaban and quinidine may result in increases in rivaroxaban exposure and may increase bleeding risk. Quinidine is an inhibitor of P-glycoprotein (P-gp), and rivaroxaban is a substrate of P-gp. If these drugs are administered concurrently, monitor the patient for signs and symptoms of bleeding.
Diclofenac: (Major) An additive risk of bleeding may be seen in patients receiving anticoagulants in combination with other agents known to increase the risk of bleeding such as nonsteroidal antiinflammatory drugs (NSAIDs). Monitor clinical and laboratory response closely during concurrent use.
Diclofenac; Misoprostol: (Major) An additive risk of bleeding may be seen in patients receiving anticoagulants in combination with other agents known to increase the risk of bleeding such as nonsteroidal antiinflammatory drugs (NSAIDs). Monitor clinical and laboratory response closely during concurrent use.
Diflunisal: (Major) An additive risk of bleeding may be seen in patients receiving anticoagulants in combination with other agents known to increase the risk of bleeding such as nonsteroidal antiinflammatory drugs (NSAIDs). Monitor clinical and laboratory response closely during concurrent use.
Diphenhydramine; Ibuprofen: (Major) An additive risk of bleeding may be seen in patients receiving anticoagulants in combination with other agents known to increase the risk of bleeding such as nonsteroidal antiinflammatory drugs (NSAIDs). Monitor clinical and laboratory response closely during concurrent use.
Diphenhydramine; Naproxen: (Major) An additive risk of bleeding may be seen in patients receiving anticoagulants in combination with other agents known to increase the risk of bleeding such as nonsteroidal antiinflammatory drugs (NSAIDs). Monitor clinical and laboratory response closely during concurrent use.
Dipyridamole: (Major) Avoid concurrent administration of platelet inhibitors such as dipyridamole with rivaroxaban unless the benefit outweighs the risk of increased bleeding. An increase in bleeding time to 45 minutes was observed in 2 drug interaction studies where another platelet inhibitor and rivaroxaban (15 mg single dose) were coadministered in healthy subjects. In the first study, the increase in bleeding time to 45 minutes was observed in approximately 45% of patients. Approximately 30% of patients in the second study had the event. The change in bleeding time was approximately twice the maximum increase seen with either drug alone. No change in the pharmacokinetic parameters of either drug were noted.
Dronedarone: (Moderate) Avoid concomitant administration of rivaroxaban and dronedarone in patients with CrCl 15 to 80 ml/min unless the potential benefit justifies the potential risk. Dronedarone is a moderate CYP3A4 inhibitor and P-glycoprotein (P-gp) inhibitor. Rivaroxaban is a substrate of CYP3A4/5 and the P-gp transporter. Pharmacokinetic data from a trial with erythromycin indicate that concurrent use of rivaroxaban and drugs that are combined P-gp inhibitors and moderate CYP3A4 inhibitors in patients with renal impairment results in increased exposure to rivaroxaban compared to patients with normal renal function and no inhibitor use. Significant increases in rivaroxaban exposure may increase bleeding risk. However, while an increase in exposure to rivaroxaban may be expected, results from an analysis of the ROCKET-AF trial which allowed concomitant administration of rivaroxaban and a combined P-gp inhibitor and weak or moderate CYP3A4 inhibitor did not show an increased risk of bleeding in patients with CrCl 30 to < 50 ml/min [HR (95% CI): 1.05 (0.77, 1.42)].
Edoxaban: (Major) Avoid concurrent use of edoxaban with rivaroxaban due to the increased bleeding risk. Monitor patients closely and promptly evaluate any signs or symptoms of bleeding if edoxaban and other anticoagulants are used concomitantly. Coadministration of edoxaban and other anticoagulants may increase the risk of bleeding. Long-term concomitant treatment with edoxaban and other anticoagulants is not recommended; short-term use may be necessary for patients transitioning to or from edoxaban.
Efavirenz: (Minor) Coadministration of rivaroxaban and efavirenz may result in decreased rivaroxaban exposure and may decrease the efficacy of rivaroxaban. Efavirenz is an inducer of CYP3A4, and rivaroxaban is a substrate of CYP3A4. If these drugs are administered concurrently, monitor the patient for signs of lack of efficacy of rivaroxaban.
Efavirenz; Emtricitabine; Tenofovir Disoproxil Fumarate: (Minor) Coadministration of rivaroxaban and efavirenz may result in decreased rivaroxaban exposure and may decrease the efficacy of rivaroxaban. Efavirenz is an inducer of CYP3A4, and rivaroxaban is a substrate of CYP3A4. If these drugs are administered concurrently, monitor the patient for signs of lack of efficacy of rivaroxaban.
Efavirenz; Lamivudine; Tenofovir Disoproxil Fumarate: (Minor) Coadministration of rivaroxaban and efavirenz may result in decreased rivaroxaban exposure and may decrease the efficacy of rivaroxaban. Efavirenz is an inducer of CYP3A4, and rivaroxaban is a substrate of CYP3A4. If these drugs are administered concurrently, monitor the patient for signs of lack of efficacy of rivaroxaban.
Elagolix: (Minor) Coadministration of rivaroxaban and elagolix may result in increases in rivaroxaban exposure and may increase bleeding risk. Elagolix is an inhibitor of P-gp, and rivaroxaban is a substrate of P-gp. If these drugs are administered concurrently, monitor the patient for signs and symptoms of bleeding.
Elagolix; Estradiol; Norethindrone acetate: (Minor) Coadministration of rivaroxaban and elagolix may result in increases in rivaroxaban exposure and may increase bleeding risk. Elagolix is an inhibitor of P-gp, and rivaroxaban is a substrate of P-gp. If these drugs are administered concurrently, monitor the patient for signs and symptoms of bleeding.
Elbasvir; Grazoprevir: (Minor) Administering rivaroxaban with grazoprevir may result in elevated rivaroxaban plasma concentrations. Rivaroxaban is a substrate of CYP3A; grazoprevir is a weak CYP3A inhibitor. If these drugs are used together, closely monitor for signs of adverse events.
Elexacaftor; tezacaftor; ivacaftor: (Minor) The coadministration of rivaroxaban and ivacaftor should be undertaken with caution in patients with renal impairment; it is unclear whether a clinically significant interaction occurs when these two drugs are coadministered to patients with normal renal function. Ivacaftor is a combined mild CYP3A4 inhibitor and mild P-glycoprotein (P-gp) inhibitor. Rivaroxaban is a substrate of CYP3A4/5 and the P-gp transporter. Coadministration in patients with renal impairment may result in increased exposure to rivaroxaban compared with patients with normal renal function and no inhibitor use since both pathways of elimination are affected. While an increase in exposure to rivaroxaban may be expected, results from an analysis of the ROCKET-AF trial which allowed concomitant administration of rivaroxaban and a combined P-gp inhibitor and weak or moderate CYP3A4 inhibitor did not show an increased risk of bleeding in patients with CrCl 30 to < 50 ml/min [HR (95% CI): 1.05 (0.77, 1.42)].
Eliglustat: (Moderate) Coadministration of rivaroxaban and eliglustat may increase exposure to rivaroxaban and increase the risk of bleeding; monitor patients closely. Rivaroxaban is a P-glycoprotein (P-gp) substrate; eliglustat is a P-gp inhibitor.
Eltrombopag: (Moderate) Use caution when discontinuing eltrombopag in patients receiving anticoagulants (e.g., warfarin, enoxaparin, dabigatran, rivaroxaban). The risk of bleeding and recurrent thrombocytopenia is increased in patients receiving these drugs when eltrombopag is discontinued.
Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Alafenamide: (Major) Avoid concomitant administration of rivaroxaban and cobicistat; significant increases in rivaroxaban exposure may increase bleeding risk. Rivaroxaban is a substrate of CYP3A4/5 and the P-glycoprotein (P-gp) transporter. Cobicistat is a combined P-gp and strong CYP3A4 inhibitor. Concurrent use of a single dose of rivaroxaban and another combined P-gp and strong CYP3A4 inhibitor increased the steady-state rivaroxaban AUC and Cmax by 150% and 60%, respectively. Similar increases in pharmacodynamic effects such as factor Xa inhibition and PT prolongation were also observed.
Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Disoproxil Fumarate: (Major) Avoid concomitant administration of rivaroxaban and cobicistat; significant increases in rivaroxaban exposure may increase bleeding risk. Rivaroxaban is a substrate of CYP3A4/5 and the P-glycoprotein (P-gp) transporter. Cobicistat is a combined P-gp and strong CYP3A4 inhibitor. Concurrent use of a single dose of rivaroxaban and another combined P-gp and strong CYP3A4 inhibitor increased the steady-state rivaroxaban AUC and Cmax by 150% and 60%, respectively. Similar increases in pharmacodynamic effects such as factor Xa inhibition and PT prolongation were also observed.
Enoxaparin: (Major) Avoid concurrent administration of rivaroxaban and enoxaparin due to increased bleeding risk unless the benefits outweigh the risks. In a drug interaction study, single doses of enoxaparin (40 mg subcutaneous) and rivaroxaban (10 mg) given concomitantly resulted in an additive effect on anti-factor Xa activity. Enoxaparin did not affect the pharmacokinetic parameters of rivaroxaban.
Epoprostenol: (Moderate) When used concurrently with anticoagulants, epoprostenol may increase the risk of bleeding.
Eptifibatide: (Major) Avoid concurrent administration of platelet inhibitors such as eptifibatide with rivaroxaban unless the benefit outweighs the risk of increased bleeding. An increase in bleeding time to 45 minutes was observed in 2 drug interaction studies where another platelet inhibitor and rivaroxaban (15 mg single dose) were coadministered in healthy subjects. In the first study, the increase in bleeding time to 45 minutes was observed in approximately 45% of patients. Approximately 30% of patients in the second study had the event. The change in bleeding time was approximately twice the maximum increase seen with either drug alone. No change in the pharmacokinetic parameters of either drug were noted.
Erythromycin: (Moderate) Avoid coadministration of rivaroxaban and erythromycin in patients with renal impairment (CrCL 15 to 79 mL/minute) unless the potential benefit justifies the potential risk. Rivaroxaban is a CYP3A4 and P-glycoprotein (P-gp) inhibitor and erythromycin is a P-gp and moderate CYP3A4 inhibitor. In a pharmacokinetic trial, coadministration with erythromycin increased the AUC of rivaroxaban by 76% in patients with mild renal impairment (CrCL 50 to 79 mL/minute) and by 99% in patients with moderate renal impairment (CrCL 30 to 49 mL/minute) compared to patients with normal renal function (CrCL greater than 80 mL/minute); similar trends in pharmacodynamic effects were also observed.
Escitalopram: (Moderate) Advise patients of the increased bleeding risk associated with the concomitant use of selective serotonin reuptake inhibitors (SSRIs) and anticoagulants like rivaroxaban. Case reports and epidemiological studies have demonstrated an association between use of drugs that interfere with serotonin reuptake and gastrointestinal bleeding.
Eslicarbazepine: (Minor) Coadministration of rivaroxaban and eslicarbazepine may result in decreased rivaroxaban exposure and may decrease the efficacy of rivaroxaban. Eslicarbazepine is an inducer of CYP3A4, and rivaroxaban is a substrate of CYP3A4. If these drugs are administered concurrently, monitor the patient for signs of lack of efficacy of rivaroxaban.
Esterified Estrogens; Methyltestosterone: (Moderate) Methyltestosterone can increase the effects of anticoagulants through reduction of procoagulant factor. Patients receiving oral anticoagulant therapy should be closely monitored, especially when methyltestosterone treatment is initiated or discontinued.
Etodolac: (Major) An additive risk of bleeding may be seen in patients receiving anticoagulants in combination with other agents known to increase the risk of bleeding such as nonsteroidal antiinflammatory drugs (NSAIDs). Monitor clinical and laboratory response closely during concurrent use.
Etravirine: (Minor) Coadministration of rivaroxaban and etravirine may result in increases or decreases in rivaroxaban exposure and may increase bleeding risk or decrease efficacy of rivaroxaban. Etravirine is an inducer of CYP3A4 and inhibitor of P-gp, and rivaroxaban is a substrate of CYP3A4 and P-gp. If these drugs are administered concurrently, monitor the patient for signs and symptoms of bleeding and lack of efficacy.
Factor X: (Major) The actions of factor X are likely to be counteracted by factor Xa inhibitors such as rivaroxaban.
Felbamate: (Minor) Coadministration of rivaroxaban and felbamate may result in decreased rivaroxaban exposure and may decrease the efficacy of rivaroxaban. Felbamate is a mild inducer of CYP3A4, and rivaroxaban is a substrate of CYP3A4. If these drugs are administered concurrently, monitor the patient for signs of lack of efficacy of rivaroxaban.
Felodipine: (Minor) The coadministration of rivaroxaban and felodipine should be undertaken with caution in patients with renal impairment; it is unlikely that a clinically significant interaction occurs when these two drugs are coadministered to patients with normal renal function. Felodipine is a combined mild CYP3A4 inhibitor and P-glycoprotein (P-gp) inhibitor. Rivaroxaban is a substrate of CYP3A4/5 and the P-gp transporter. Coadministration in patients with renal impairment may result in increased exposure to rivaroxaban compared with patients with normal renal function and no inhibitor use since both pathways of elimination are affected. While an increase in exposure to rivaroxaban may be expected, results from an analysis of the ROCKET-AF trial which allowed concomitant administration of rivaroxaban and a combined P-gp inhibitor and weak or moderate CYP3A4 inhibitor did not show an increased risk of bleeding in patients with CrCl 30 to < 50 ml/min [HR (95% CI): 1.05 (0.77, 1.42)].
Fenoprofen: (Major) An additive risk of bleeding may be seen in patients receiving anticoagulants in combination with other agents known to increase the risk of bleeding such as nonsteroidal antiinflammatory drugs (NSAIDs). Monitor clinical and laboratory response closely during concurrent use.
Fish Oil, Omega-3 Fatty Acids (Dietary Supplements): (Moderate) Drug interactions with fish oil, omega-3 fatty acids (Dietary Supplements) or fish oil, omega-3 fatty acids (FDA-approved) are unclear at this time. However, because fish oil, omega-3 fatty acids inhibit platelet aggregation, caution is advised when fish oils are used concurrently with anticoagulants, platelet inhibitors, or thrombolytic agents. Theoretically, the risk of bleeding may be increased, but some studies that combined these agents did not produce clinically significant bleeding events. In one placebo-controlled, randomized, double-blinded, parallel study, patients receiving stable, chronic warfarin therapy were administered various doses of fish oil supplements to determine the effect on INR determinations. Patients were randomized to receive a 4-week treatment period of either placebo or 3 or 6 grams of fish oil daily. Patients were followed on a twice-weekly basis for INR determinations and adverse reactions. There was no statistically significant difference in INRs between the placebo or treatment period within each group. There was also no difference in INRs found between groups. One episode of ecchymosis was reported, but no major bleeding episodes occurred. The authors concluded that fish oil supplementation in doses of 3-6 grams per day does not have a statistically significant effect on the INR of patients receiving chronic warfarin therapy. However, an increase in INR from 2.8 to 4.3 in a patient stable on warfarin therapy has been reported when increasing the dose of fish oil, omega-3 fatty acids from 1 gram/day to 2 grams/day. The INR decreased once the patient decreased her dose of fish oil to 1 gram/day. This implies that a dose-related effect of fish oil on warfarin may be possible. Patients receiving warfarin that initiate concomitant fish oil therapy should have their INR monitored more closely and the dose of warfarin adjusted accordingly.
Fluoxetine: (Moderate) Advise patients of the increased bleeding risk associated with the concomitant use of selective serotonin reuptake inhibitors (SSRIs) and anticoagulants like rivaroxaban. Case reports and epidemiological studies have demonstrated an association between use of drugs that interfere with serotonin reuptake and gastrointestinal bleeding.
Flurbiprofen: (Major) An additive risk of bleeding may be seen in patients receiving anticoagulants in combination with other agents known to increase the risk of bleeding such as nonsteroidal antiinflammatory drugs (NSAIDs). Monitor clinical and laboratory response closely during concurrent use.
Flutamide: (Minor) Coadministration of rivaroxaban and flutamide may result in decreased rivaroxaban exposure and may decrease the efficacy of rivaroxaban. Flutamide is an inducer of CYP3A4, and rivaroxaban is a substrate of CYP3A4. If these drugs are administered concurrently, monitor the patient for signs of lack of efficacy of rivaroxaban.
Fluvoxamine: (Moderate) Advise patients of the increased bleeding risk associated with the concomitant use of selective serotonin reuptake inhibitors (SSRIs) and anticoagulants like rivaroxaban. Case reports and epidemiological studies have demonstrated an association between use of drugs that interfere with serotonin reuptake and gastrointestinal bleeding.
Fondaparinux: (Major) Discontinue rivaroxaban before starting fondaparinux due to the increased bleeding risk, unless these agents are essential. If coadministration is necessary, monitor patients closely and promptly evaluate any signs or symptoms of bleeding.
Fosamprenavir: (Minor) Coadministration of rivaroxaban and fosamprenavir may result in elevated fosamprenavir and altered rivaroxaban exposures, which may increase bleeding risk or decrease efficacy of rivaroxaban. Fosamprenavir is an inhibitor and inducer of CYP3A4 and a substrate/inducer of P-glycoprotein (P-gp). Rivaroxaban is a substrate of CYP3A4 and a substrate/inhibitor of P-gp. If these drugs are administered concurrently, monitor the patient for signs and symptoms of bleeding and lack of efficacy.
Fosphenytoin: (Major) Avoid concomitant use of rivaroxaban with fosphenytoin. Consider increasing the rivaroxaban dose if fosphenytoin must be coadministered. Rivaroxaban exposure and efficacy may be reduced. Rivaroxaban is a P-gp and CYP3A4 substrate. Fosphenytoin is a P-gp and strong CYP3A4 Inducer. In a drug interaction study, coadministration of a drug that is a combined P-glycoprotein and strong CYP3A4 inducer led to an approximate decrease of 50% and 22% in AUC and Cmax, respectively. Similar decreases in pharmacodynamic effects were also observed.
Garlic, Allium sativum: (Moderate) Garlic produces clinically significant antiplatelet effects so additive risk of bleeding may occur if anticoagulants are given in combination. Avoid concurrent use of herbs which interact with anticoagulants when possible. If garlic dietary supplements are taken, monitor the INR or other appropriate parameters to attain clinical and anticoagulant endpoints. In regard to warfarin, published data are limited to a random case report; however, the product labeling for warfarin includes garlic as having potential for interaction due to additive pharmacologic activity. A case of spontaneous spinal epidural hematoma, attributed to dysfunctional platelets from excessive garlic use in a patient not receiving concomitant anticoagulation, has been reported.
Ginger, Zingiber officinale: (Moderate) Additive bleeding may occur if anticoagulants are given in combination with ginger, zingiber officinale. Ginger inhibits thromboxane synthetase (platelet aggregation inducer) and is a prostacyclin agonist. Patients taking ginger and an anticoagulant should be monitored closely for bleeding.
Ginkgo, Ginkgo biloba: (Moderate) Monitor for signs or symptoms of bleeding with coadministration of ginkgo biloba and Direct Oral Anticoagulants (DOACs) as an increased bleeding risk may occur. Although data are mixed, ginkgo biloba is reported to inhibit platelet aggregation and several case reports describe bleeding complications with ginkgo biloba, with or without concomitant drug therapy.
Grapefruit juice: (Major) Avoid concomitant administration of rivaroxaban and grapefruit juice; significant increases in rivaroxaban exposure may increase bleeding risk. Rivaroxaban is a substrate of CYP3A4/5 and the P-glycoprotein (P-gp) transporter. Grapefruit juice is a combined P-gp inhibitor and strong CYP3A4 inhibitor. Concurrent use of a single dose of rivaroxaban and ritonavir, a combined P-gp and strong CYP3A4 inhibitor, led to an increase in the steady-state rivaroxaban AUC by 150% and to an increase in Cmax by 60%. Similar increases in pharmacodynamic effects such as factor Xa inhibition and PT prolongation were also observed.
Green Tea: (Moderate) Green tea has demonstrated antiplatelet and fibrinolytic actions in animals. It is possible that the use of green tea may increase the risk of bleeding if co-administered with anticoagulants (e.g., enoxaparin, heparin, warfarin, and others), thrombolytic agents, or platelet inhibitors (e.g., aspirin, clopidogrel, cilostazol and others). Caution and careful monitoring of clinical and/or laboratory parameters are warranted if green tea is coadministered with any of these agents. Exogenous administration or occult sources of vitamin K may decrease or reverse the activity of warfarin; stability of the diet can be an important factor in maintaining anticoagulation goals. Occult sources of vitamin K include green tea and green tea dietary supplements. Published data are limited in regard to this interaction. A patient with previous INRs of 3.2 and 3.79 on a dose of 7.5mg daily of warfarin (goal INR 2.5 to 3.5) had an INR of 1.37. One month later, the patient's INR was 1.14. The patient admitted that he had started consuming 0.51 gallon of green tea daily approximately one week prior to the INR of 1.37. The patient denied noncompliance and other changes in diet, medications, or health. The patient discontinued green tea and one week later his INR was 2.55. While the amount of vitamin K in a single cup of brewed green tea may not be high (0.03 mcg/100 g), the actual amount may vary from cup to cup depending on the amount of tea leaves used, the length of time the tea bags are allowed to brew, and the volume of tea consumed. Additionally, if a patient drinks multiple cups of tea per day, the amount of vitamin K could reach significance. It is recommended that patients on warfarin maintain a stable intake of green tea.
Griseofulvin: (Minor) Coadministration of rivaroxaban and griseofulvin may result in decreased rivaroxaban exposure and may decrease the efficacy of rivaroxaban. Griseofulvin is an inducer of CYP3A4, and rivaroxaban is a substrate of CYP3A4. If these drugs are administered concurrently, monitor the patient for signs of lack of efficacy of rivaroxaban.
Hemin: (Major) Because hemin has exhibited transient, mild anticoagulant effects during clinical studies, concurrent use of anticoagulants should be avoided. The extent and duration of the hypocoagulable state induced by hemin has not been established.
Heparin: (Major) Due to the increased bleeding risk, avoid concurrent use of rivaroxaban with heparin; the safety of concomitant use has not been studied. If heparin is used during therapeutic transition periods, closely observe patients and promptly evaluate any signs or symptoms of blood loss.
Hydrocodone; Ibuprofen: (Major) An additive risk of bleeding may be seen in patients receiving anticoagulants in combination with other agents known to increase the risk of bleeding such as nonsteroidal antiinflammatory drugs (NSAIDs). Monitor clinical and laboratory response closely during concurrent use.
Hyoscyamine; Methenamine; Methylene Blue; Phenyl Salicylate; Sodium Biphosphate: (Major) Salicylates such as aspirin are known to increase bleeding, and bleeding risk may be increased when these drugs are used concomitantly with rivaroxaban. The safety of long-term concomitant use of these drugs has not been studied. Promptly evaluate any signs or symptoms of bleeding or blood loss if patients are treated concomitantly with salicylates. In a single-dose drug interaction study, no pharmacokinetic interactions were observed after concomitant administration of acetylsalicylic acid (aspirin, ASA) with rivaroxaban.
Ibritumomab Tiuxetan: (Major) During and after therapy, avoid the concomitant use of Yttrium (Y)-90 ibrutumomab tiuxetan with drugs that interfere with coagulation such as anticoagulants; the risk of bleeding may be increased. If coadministration with anticoagulants is necessary, monitor platelet counts more frequently for evidence of thrombocytopenia.
Ibrutinib: (Moderate) The concomitant use of ibrutinib and anticoagulant agents such as rivaroxaban may increase the risk of bleeding; monitor patients for signs of bleeding. Severe bleeding events have occurred with ibrutinib therapy including intracranial hemorrhage, GI bleeding, hematuria, and post procedural hemorrhage; some events were fatal. The mechanism for bleeding with ibrutinib therapy is not well understood.
Ibuprofen: (Major) An additive risk of bleeding may be seen in patients receiving anticoagulants in combination with other agents known to increase the risk of bleeding such as nonsteroidal antiinflammatory drugs (NSAIDs). Monitor clinical and
Ibuprofen; Famotidine: (Major) An additive risk of bleeding may be seen in patients receiving anticoagulants in combination with other agents known to increase the risk of bleeding such as nonsteroidal antiinflammatory drugs (NSAIDs). Monitor clinical and laboratory response closely during concurrent use.
Ibuprofen; Oxycodone: (Major) An additive risk of bleeding may be seen in patients receiving anticoagulants in combination with other agents known to increase the risk of bleeding such as nonsteroidal antiinflammatory drugs (NSAIDs). Monitor clinical and laboratory response closely during concurrent use.
Ibuprofen; Pseudoephedrine: (Major) An additive risk of bleeding may be seen in patients receiving anticoagulants in combination with other agents known to increase the risk of bleeding such as nonsteroidal antiinflammatory drugs (NSAIDs). Monitor clinical and laboratory response closely during concurrent use.
Icosapent ethyl: (Moderate) Icosapent ethyl is an ethyl ester of the omega-3 fatty acid eicosapentaenoic acid (EPA). Because omega-3 fatty acids inhibit platelet aggregation, caution is advised when icosapent ethyl is used concurrently with anticoagulants, platelet inhibitors, or thrombolytic agents. Theoretically, the risk of bleeding may be increased, but some studies that combined these agents did not produce clinically significant bleeding events. In one placebo-controlled, randomized, double-blinded, parallel study, patients receiving stable, chronic warfarin therapy were administered various doses of fish oil supplements to determine the effect on INR determinations. Patients were randomized to receive a 4-week treatment period of either placebo or 3 or 6 grams of fish oil daily. Patients were followed on a twice-weekly basis for INR determinations and adverse reactions. There was no statistically significant difference in INRs between the placebo or treatment period within each group. There was also no difference in INRs found between groups. One episode of ecchymosis was reported, but no major bleeding episodes occurred. The authors concluded that fish oil supplementation in doses of 36 grams per day does not have a statistically significant effect on the INR of patients receiving chronic warfarin therapy. However, an increase in INR from 2.8 to 4.3 in a patient stable on warfarin therapy has been reported when increasing the dose of fish oil, omega-3 fatty acids from 1 gram/day to 2 grams/day. The INR decreased once the patient decreased her dose of fish oil to 1 gram/day. This implies that a dose-related effect of fish oil on warfarin may be possible. Patients receiving warfarin that initiate concomitant icosapent ethyl therapy should have their INR monitored more closely and the dose of warfarin adjusted accordingly.
Idelalisib: (Major) Avoid concomitant use of idelalisib, a strong CYP3A inhibitor, with rivaroxaban, a CYP3A substrate, as rivaroxaban toxicities may be significantly increased. The AUC of a sensitive CYP3A substrate was increased 5.4-fold when coadministered with idelalisib.
Iloprost: (Moderate) When used concurrently with anticoagulants, inhaled iloprost may increase the risk of bleeding.
Imatinib: (Major) Due to the thrombocytopenic effects of imatinib an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants. Coadministration of rivaroxaban and imatinib, STI-571 may also result in increases in rivaroxaban exposure, which may increase bleeding risk. Imatinib is an inhibitor of CYP3A4, and rivaroxaban is a substrate of CYP3A4. If these drugs are administered concurrently, monitor the patient for signs and symptoms of bleeding.
Indinavir: (Major) Avoid concomitant administration of rivaroxaban and indinavir; significant increases in rivaroxaban exposure may increase bleeding risk. Rivaroxaban is a substrate of CYP3A4/5 and the P-glycoprotein (P-gp) transporter. Indinavir, a strong CYP3A4 inhibitor, is typically given in combination with ritonavir, a combined P-gp and strong CYP3A4 inhibitor. Concurrent use of a single dose of rivaroxaban and ritonavir, a combined P-gp and strong CYP3A4 inhibitor, led to an increase in the steady-state rivaroxaban AUC by 150% and to an increase in Cmax by 60%. Similar increases in pharmacodynamic effects such as factor Xa inhibition and PT prolongation were also observed.
Indomethacin: (Major) An additive risk of bleeding may be seen in patients receiving anticoagulants in combination with other agents known to increase the risk of bleeding such as nonsteroidal antiinflammatory drugs (NSAIDs). Monitor clinical and laboratory response closely during concurrent use.
Inotersen: (Moderate) Use caution with concomitant use of inotersen and anticoagulants due to the potential risk of bleeding from thrombocytopenia. Consider discontinuation of anticoagulants in a patient taking inotersen with a platelet count of less than 50,000 per microliter.
Intravenous Lipid Emulsions: (Moderate) Drug interactions with fish oil, omega-3 fatty acids (Dietary Supplements) or fish oil, omega-3 fatty acids (FDA-approved) are unclear at this time. However, because fish oil, omega-3 fatty acids inhibit platelet aggregation, caution is advised when fish oils are used concurrently with anticoagulants, platelet inhibitors, or thrombolytic agents. Theoretically, the risk of bleeding may be increased, but some studies that combined these agents did not produce clinically significant bleeding events. In one placebo-controlled, randomized, double-blinded, parallel study, patients receiving stable, chronic warfarin therapy were administered various doses of fish oil supplements to determine the effect on INR determinations. Patients were randomized to receive a 4-week treatment period of either placebo or 3 or 6 grams of fish oil daily. Patients were followed on a twice-weekly basis for INR determinations and adverse reactions. There was no statistically significant difference in INRs between the placebo or treatment period within each group. There was also no difference in INRs found between groups. One episode of ecchymosis was reported, but no major bleeding episodes occurred. The authors concluded that fish oil supplementation in doses of 3-6 grams per day does not have a statistically significant effect on the INR of patients receiving chronic warfarin therapy. However, an increase in INR from 2.8 to 4.3 in a patient stable on warfarin therapy has been reported when increasing the dose of fish oil, omega-3 fatty acids from 1 gram/day to 2 grams/day. The INR decreased once the patient decreased her dose of fish oil to 1 gram/day. This implies that a dose-related effect of fish oil on warfarin may be possible. Patients receiving warfarin that initiate concomitant fish oil therapy should have their INR monitored more closely and the dose of warfarin adjusted accordingly.
Isavuconazonium: (Moderate) Concomitant use of isavuconazonium with rivaroxaban may result in increased serum concentrations of rivaroxaban which may increase the bleeding risk. Rivaroxaban is a substrate of the hepatic isoenzyme CYP3A4 and drug transporter P-glycoprotein (P-gp); isavuconazole, the active moiety of isavuconazonium, is an inhibitor of CYP3A4 and P-gp. Caution and close monitoring are advised if these drugs are used together.
Isoniazid, INH; Pyrazinamide, PZA; Rifampin: (Major) Avoid concomitant use of rivaroxaban with drugs that are combined P-glycoprotein and strong CYP3A4 inducers such as rifampin. Consider increasing the rivaroxaban dose if rifampin must be coadministered. In a drug interaction study, coadministration of rivaroxaban 20 mg single dose with food with a drug that is a combined P-glycoprotein and strong CYP3A4 inducer (rifampicin titrated up to 600 mg once daily) led to an approximate decrease of 50% in AUC and an approximate decrease of 22% in Cmax. Similar decreases in pharmacodynamic effects were also observed. These decreases in exposure to rivaroxaban may decrease efficacy.
Isoniazid, INH; Rifampin: (Major) Avoid concomitant use of rivaroxaban with drugs that are combined P-glycoprotein and strong CYP3A4 inducers such as rifampin. Consider increasing the rivaroxaban dose if rifampin must be coadministered. In a drug interaction study, coadministration of rivaroxaban 20 mg single dose with food with a drug that is a combined P-glycoprotein and strong CYP3A4 inducer (rifampicin titrated up to 600 mg once daily) led to an approximate decrease of 50% in AUC and an approximate decrease of 22% in Cmax. Similar decreases in pharmacodynamic effects were also observed. These decreases in exposure to rivaroxaban may decrease efficacy.
Itraconazole: (Major) Avoid use of rivaroxaban during and for 2 weeks after discontinuation of itraconazole treatment. Itraconazole is a combined P-glycoprotein (P-gp) and strong CYP3A4 inhibitor while rivaroxaban is a substrate of CYP3A4/5 and the P-gp transporter. Concurrent use of rivaroxaban and ketoconazole, another combined P-gp and strong CYP3A4 inhibitor, led to an increase in the steady-state rivaroxaban AUC by 160% and Cmax by 70%. Increases in pharmacodynamic effects such as factor Xa inhibition and PT prolongation were also observed. Significant increases in rivaroxaban exposure may increase bleeding risk. Similar effects may be expected with concurrent itraconazole use.
Ivacaftor: (Minor) The coadministration of rivaroxaban and ivacaftor should be undertaken with caution in patients with renal impairment; it is unclear whether a clinically significant interaction occurs when these two drugs are coadministered to patients with normal renal function. Ivacaftor is a combined mild CYP3A4 inhibitor and mild P-glycoprotein (P-gp) inhibitor. Rivaroxaban is a substrate of CYP3A4/5 and the P-gp transporter. Coadministration in patients with renal impairment may result in increased exposure to rivaroxaban compared with patients with normal renal function and no inhibitor use since both pathways of elimination are affected. While an increase in exposure to rivaroxaban may be expected, results from an analysis of the ROCKET-AF trial which allowed concomitant administration of rivaroxaban and a combined P-gp inhibitor and weak or moderate CYP3A4 inhibitor did not show an increased risk of bleeding in patients with CrCl 30 to < 50 ml/min [HR (95% CI): 1.05 (0.77, 1.42)].
Ketoconazole: (Major) Avoid concomitant administration of rivaroxaban and ketoconazole; significant increases in rivaroxaban exposure may increase bleeding risk. Rivaroxaban is a substrate of CYP3A4/5 and the P-glycoprotein transporter. Concurrent use of rivaroxaban and ketoconazole, a combined P-glycoprotein and strong CYP3A4 inhibitor, led to an increase in the steady-state rivaroxaban AUC by 160% and Cmax by 70%. Similar increases in pharmacodynamic effects such as factor Xa inhibition and PT prolongation were also observed.
Ketoprofen: (Major) An additive risk of bleeding may be seen in patients receiving anticoagulants in combination with other agents known to increase the risk of bleeding such as nonsteroidal antiinflammatory drugs (NSAIDs). Monitor clinical and laboratory response closely during concurrent use.
Ketorolac: (Major) An additive risk of bleeding may be seen in patients receiving anticoagulants in combination with other agents known to increase the risk of bleeding such as nonsteroidal antiinflammatory drugs (NSAIDs). Monitor clinical and laboratory response closely during concurrent use.
Lansoprazole; Amoxicillin; Clarithromycin: (Moderate) Pharmacokinetic data suggests coadministration of rivaroxaban with clarithromycin is unlikely to affect bleeding risk. However, coadministration of rivaroxaban with other combined P-gp and strong CYP3A4 inhibitors has resulted in increased rivaroxaban exposure and is not recommended. Educate patients about the signs and symptoms of bleeding if concurrent use of clarithromycin with rivaroxaban is necessary; patients with renal impairment may be at greater risk with this combination.
Ledipasvir; Sofosbuvir: (Moderate) Coadministration of rivaroxaban and ledipasvir may result in increases in rivaroxaban exposure and may increase bleeding risk. Ledipasviris an inhibitor of P-glycoprotein (P-gp) and rivaroxaban is a substrate of P-gp. If these drugs are administered concurrently, monitor the patient for signs and symptoms of bleeding.
Lenacapavir: (Major) Avoid concomitant use of rivaroxaban and lenacapavir in patients with renal impairment (CrCl 15 to 79 mL/minute) unless the potential benefit justifies the risk. Rivaroxaban is a CYP3A and P-gp substrate and lenacapavir is a P-gp and moderate CYP3A inhibitor. In a pharmacokinetic trial, coadministration with another combined moderate CYP3A/P-gp inhibitor increased the AUC of rivaroxaban by 76% in patients with mild renal impairment (CrCl 50 to 79 mL/min) and by 99% in patients with moderate renal impairment (CrCl 30 to 49 mL/min) compared to patients with normal renal function (CrCl greater than 80 mL/min); similar trends in pharmacodynamic effects were also observed.
Levoketoconazole: (Major) Avoid concomitant administration of rivaroxaban and ketoconazole; significant increases in rivaroxaban exposure may increase bleeding risk. Rivaroxaban is a substrate of CYP3A4/5 and the P-glycoprotein transporter. Concurrent use of rivaroxaban and ketoconazole, a combined P-glycoprotein and strong CYP3A4 inhibitor, led to an increase in the steady-state rivaroxaban AUC by 160% and Cmax by 70%. Similar increases in pharmacodynamic effects such as factor Xa inhibition and PT prolongation were also observed.
Lomustine, CCNU: (Moderate) Due to the bone marrow suppressive and thrombocytopenic effects of lomustine, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants.
Lonafarnib: (Major) Avoid coadministration of rivaroxaban and lonafarnib; significant increases in rivaroxaban exposure may occur which may increase the bleeding risk. Rivaroxaban is a substrate of CYP3A4/5 and the P-glycoprotein (P-gp) transporter; lonafarnib is a combined P-gp and strong CYP3A4 inhibitor. Concurrent use of a single dose of rivaroxaban and another combined P-gp and strong CYP3A4 inhibitor increased the steady-state rivaroxaban AUC and Cmax by 150% and 60%, respectively. Similar increases in pharmacodynamic effects such as factor Xa inhibition and PT prolongation were also observed.
Lopinavir; Ritonavir: (Major) Avoid concomitant administration of rivaroxaban and ritonavir; significant increases in rivaroxaban exposure may increase bleeding risk. Rivaroxaban is a substrate of CYP3A4/5 and the P-glycoprotein (P-gp) transporter. Concurrent use of a single dose of rivaroxaban and ritonavir, a combined P-gp and strong CYP3A4 inhibitor, led to an increase in the rivaroxaban AUC by 150% and Cmax by 60%. Similar increases in pharmacodynamic effects such as factor Xa inhibition and PT prolongation were also observed.
Lumacaftor; Ivacaftor: (Major) Lumacaftor; ivacaftor is expected to alter the systemic exposure of rivaroxaban; if possible, avoid concomitant use. Because rivaroxaban is a substrate of CYP3A and the P-glycoprotein (P-gp) efflux transporter, its FDA-approved labeling recommends avoiding concomitant use with combined P-gp and strong CYP3A inducers. Lumacaftor is a strong CYP3A inducer, but its net effect on P-gp is less clear. In vitro data suggest lumacaftor; ivacaftor may induce and/or inhibit P-gp. Although induction of rivaroxaban clearance through the CYP3A pathway is expected to reduce rivaroxaban exposure, the net effect of lumacaftor; ivacaftor on P-gp transport is undefined. If these drugs must be used together, monitor the patient closely for decreased anticoagulant efficacy or increased or prolonged therapeutic effects and adverse events (e.g., bleeding).
Lumacaftor; Ivacaftor: (Minor) The coadministration of rivaroxaban and ivacaftor should be undertaken with caution in patients with renal impairment; it is unclear whether a clinically significant interaction occurs when these two drugs are coadministered to patients with normal renal function. Ivacaftor is a combined mild CYP3A4 inhibitor and mild P-glycoprotein (P-gp) inhibitor. Rivaroxaban is a substrate of CYP3A4/5 and the P-gp transporter. Coadministration in patients with renal impairment may result in increased exposure to rivaroxaban compared with patients with normal renal function and no inhibitor use since both pathways of elimination are affected. While an increase in exposure to rivaroxaban may be expected, results from an analysis of the ROCKET-AF trial which allowed concomitant administration of rivaroxaban and a combined P-gp inhibitor and weak or moderate CYP3A4 inhibitor did not show an increased risk of bleeding in patients with CrCl 30 to < 50 ml/min [HR (95% CI): 1.05 (0.77, 1.42)].
Magnesium Salicylate: (Major) Salicylates such as aspirin are known to increase bleeding, and bleeding risk may be increased when these drugs are used concomitantly with rivaroxaban. The safety of long-term concomitant use of these drugs has not been studied. Promptly evaluate any signs or symptoms of bleeding or blood loss if patients are treated concomitantly with salicylates. In a single-dose drug interaction study, no pharmacokinetic interactions were observed after concomitant administration of acetylsalicylic acid (aspirin, ASA) with rivaroxaban.
Meclofenamate Sodium: (Major) An additive risk of bleeding may be seen in patients receiving anticoagulants in combination with other agents known to increase the risk of bleeding such as nonsteroidal antiinflammatory drugs (NSAIDs). Monitor clinical and laboratory response closely during concurrent use.
Mefenamic Acid: (Major) An additive risk of bleeding may be seen in patients receiving anticoagulants in combination with other agents known to increase the risk of bleeding such as nonsteroidal antiinflammatory drugs (NSAIDs). Monitor clinical and laboratory response closely during concurrent use.
Mefloquine: (Minor) Coadministration of rivaroxaban and mefloquine may result in increases in rivaroxaban exposure and may increase bleeding risk. Mefloquine is an inhibitor of P-gp, and rivaroxaban is a substrate of P-gp. If these drugs are administered concurrently, monitor the patient for signs and symptoms of bleeding.
Meloxicam: (Major) An additive risk of bleeding may be seen in patients receiving anticoagulants in combination with other agents known to increase the risk of bleeding such as nonsteroidal antiinflammatory drugs (NSAIDs). Monitor clinical and laboratory response closely during concurrent use.
Methenamine; Sodium Salicylate: (Major) Salicylates such as aspirin are known to increase bleeding, and bleeding risk may be increased when these drugs are used concomitantly with rivaroxaban. The safety of long-term concomitant use of these drugs has not been studied. Promptly evaluate any signs or symptoms of bleeding or blood loss if patients are treated concomitantly with salicylates. In a single-dose drug interaction study, no pharmacokinetic interactions were observed after concomitant administration of acetylsalicylic acid (aspirin, ASA) with rivaroxaban.
Methotrexate: (Major) Avoid concomitant use of methotrexate and direct oral anticoagulants due to the risk of severe methotrexate-related adverse reactions. If concomitant use is unavoidable, closely monitor for adverse reactions. Methotrexate is approximately 50% protein bound; direct oral anticoagulants are highly protein-bound. Coadministration may displace methotrexate from its protein binding sites, increasing methotrexate plasma concentrations.
Methoxsalen: (Minor) Agents, such as anticoagulants, that decrease clotting could decrease the efficacy of photosensitizing agents used in photodynamic therapy.
Methylsulfonylmethane, MSM: (Moderate) Increased effects from concomitant anticoagulant drugs such as increased bruising or blood in the stool have been reported in patients taking methylsulfonylmethane, MSM. Although these effects have not been confirmed in published medical literature or during clinical studies, clinicians should consider using methylsulfonylmethane, MSM with caution in patients who are taking anticoagulants such as warfarin until data confirming the safety of MSM in patients taking these drugs are available. During one of the available, published clinical trials in patients with osteoarthritis, those patients with bleeding disorders or using anticoagulants or antiplatelets were excluded from enrollment. Patients who choose to consume methylsulfonylmethane, MSM while receiving warfarin should be observed for increased bleeding.
Methyltestosterone: (Moderate) Methyltestosterone can increase the effects of anticoagulants through reduction of procoagulant factor. Patients receiving oral anticoagulant therapy should be closely monitored, especially when methyltestosterone treatment is initiated or discontinued.
Mifepristone: (Contraindicated) When mifepristone is used for the termination of pregnancy, concurrent use of anticoagulants is contraindicated due to the risk of serious bleeding.
Miltefosine: (Moderate) Caution is advised when administering miltefosine with anticoagulants, as use of these drugs together may increase risk for bleeding. Miltefosine, when administered for the treatment of visceral leishmaniasis, has been associated with thrombocytopenia; monitor platelet counts in patients receiving treatment for this indication. In addition, monitor closely for increased bleeding if use in combination with an anticoagulant.
Mitotane: (Major) Use caution if mitotane and rivaroxaban are used concomitantly, and monitor for decreased efficacy of rivaroxaban and a possible change in dosage requirements. Mitotane is a strong CYP3A4 inducer and rivaroxaban is a CYP3A4 substrate; coadministration may result in decreased plasma concentrations of rivaroxaban.
Modafinil: (Minor) Coadministration of rivaroxaban and modafinil may result in decreased rivaroxaban exposure and may decrease the efficacy of rivaroxaban. Modafinil is an inducer of CYP3A4, and rivaroxaban is a substrate of CYP3A4. If these drugs are administered concurrently, monitor the patient for signs of lack of efficacy of rivaroxaban.
Mycophenolate: (Moderate) Mycophenolate may causes thrombocytopenia and increase the risk for bleeding. Agents which may lead to an increased incidence of bleeding in patients with thrombocytopenia include anticoagulants.
Nabumetone: (Major) An additive risk of bleeding may be seen in patients receiving anticoagulants in combination with other agents known to increase the risk of bleeding such as nonsteroidal antiinflammatory drugs (NSAIDs). Monitor clinical and laboratory response closely during concurrent use.
Nafcillin: (Minor) Coadministration of rivaroxaban and nafcillin may result in decreased rivaroxaban exposure and may decrease the efficacy of rivaroxaban. Nafcillin is an inducer of CYP3A4, and rivaroxaban is a substrate of CYP3A4. If these drugs are administered concurrently, monitor the patient for signs of lack of efficacy of rivaroxaban.
Naproxen: (Major) An additive risk of bleeding may be seen in patients receiving anticoagulants in combination with other agents known to increase the risk of bleeding such as nonsteroidal antiinflammatory drugs (NSAIDs). Monitor clinical and laboratory response closely during concurrent use.
Naproxen; Esomeprazole: (Major) An additive risk of bleeding may be seen in patients receiving anticoagulants in combination with other agents known to increase the risk of bleeding such as nonsteroidal antiinflammatory drugs (NSAIDs). Monitor clinical and laboratory response closely during concurrent use.
Naproxen; Pseudoephedrine: (Major) An additive risk of bleeding may be seen in patients receiving anticoagulants in combination with other agents known to increase the risk of bleeding such as nonsteroidal antiinflammatory drugs (NSAIDs). Monitor clinical and laboratory response closely during concurrent use.
Nefazodone: (Minor) Coadministration of rivaroxaban and nefazodone may result in increases in rivaroxaban exposure and may increase bleeding risk. Nefazodone is a potent inhibitor of CYP3A4, and rivaroxaban is a substrate of CYP3A4. If these drugs are administered concurrently, monitor the patient for signs and symptoms of bleeding.
Nelarabine: (Moderate) Due to the thrombocytopenic effects of nelarabine, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants.
Nelfinavir: (Major) Avoid concomitant administration of rivaroxaban and nelfinavir; significant increases in rivaroxaban exposure may increase bleeding risk. Rivaroxaban is a substrate of CYP3A4/5 and the P-glycoprotein (P-gp) transporter. Nelfinavir is a combined P-gp inhibitor and strong CYP3A4 inhibitor. Concurrent use of a single dose of rivaroxaban and ritonavir, a combined P-gp and strong CYP3A4 inhibitor, led to an increase in the steady-state rivaroxaban AUC by 150% and to an increase in Cmax by 60%. Similar increases in pharmacodynamic effects such as factor Xa inhibition and PT prolongation were also observed.
Nevirapine: (Major) Coadministration of rivaroxaban and nevirapine may result in decreased rivaroxaban exposure and reduced efficacy of rivaroxaban. Alternative anticoagulant therapy should be considered. Rivaroxaban is a CYP3A substrate and nevirapine is a weak CYP3A inducer.
Nilotinib: (Moderate) Patients with renal impairment (CrCl 15 to 79 mL/min) may be at an increased risk for rivaroxaban-related adverse effects such as bleeding and bruising if rivaroxaban and nilotinib are used together. The manufacturer of rivaroxaban recommends avoiding use of dual moderate CYP3A and P-gp inhibitors in patients with renal impairment. Nilotinib is a moderate CYP3A inhibitor however the extent to which it inhibits P-gp has not been fully elucidated. In a pharmacokinetic trial, coadministration with a combined moderate CYP3A4/P-gp inhibitor increased the AUC of rivaroxaban by 76% in patients with mild renal impairment (CrCl 50 to 79 mL/min) and by 99% in patients with moderate renal impairment (CrCl 30 to 49 mL/min) compared to patients with normal renal function (CrCl greater than 80 mL/min); similar trends in pharmacodynamic effects were also observed.
Nintedanib: (Moderate) Nintedanib is a VEGFR inhibitor and may increase the risk of bleeding. Monitor patients who are taking anticoagulants closely and adjust anticoagulation therapy as necessary. Use nintedanib in patients with known risk of bleeding only if the anticipated benefit outweighs the potential risk.
Nirmatrelvir; Ritonavir: (Major) Avoid concomitant administration of rivaroxaban and ritonavir; significant increases in rivaroxaban exposure may increase bleeding risk. Rivaroxaban is a substrate of CYP3A4/5 and the P-glycoprotein (P-gp) transporter. Concurrent use of a single dose of rivaroxaban and ritonavir, a combined P-gp and strong CYP3A4 inhibitor, led to an increase in the rivaroxaban AUC by 150% and Cmax by 60%. Similar increases in pharmacodynamic effects such as factor Xa inhibition and PT prolongation were also observed. (Major) Consider temporary discontinuation of rivaroxaban during treatment with ritonavir-boosted nirmatrelvir and for at least 2 to 3 days after treatment completion. For patients at high risk of arterial or venous thrombosis, consult the primary or specialty provider and consider using an alternative anticoagulant or COVID-19 therapy. Coadministration may increase rivaroxaban exposure resulting in increased risk of bleeding. Rivaroxaban is a CYP3A substrate and nirmatrelvir is a CYP3A inhibitor.
Nonsteroidal antiinflammatory drugs: (Major) An additive risk of bleeding may be seen in patients receiving anticoagulants in combination with other agents known to increase the risk of bleeding such as nonsteroidal antiinflammatory drugs (NSAIDs). Monitor clinical and laboratory response closely during concurrent use.
Obinutuzumab: (Moderate) Fatal hemorrhagic events have been reported in patients treated with obinutuzumab; all events occured during cycle 1. Monitor all patients for thrombocytopenia and bleeding, and consider withholding concomitant medications which may increase bleeding risk (i.e., anticoagulants, platelet inhibitors), especially during the first cycle.
Olanzapine; Fluoxetine: (Moderate) Advise patients of the increased bleeding risk associated with the concomitant use of selective serotonin reuptake inhibitors (SSRIs) and anticoagulants like rivaroxaban. Case reports and epidemiological studies have demonstrated an association between use of drugs that interfere with serotonin reuptake and gastrointestinal bleeding.
Omacetaxine: (Major) Avoid the concomitant use of omacetaxine and anticoagulants when the platelet count is less than 50,000 cells/microliter due to an increased risk of bleeding.
Omeprazole; Amoxicillin; Rifabutin: (Minor) Coadministration of rivaroxaban and rifabutin may result in decreased rivaroxaban exposure and may decrease the efficacy of rivaroxaban. Rifabutin is an inducer of CYP3A4, and rivaroxaban is a substrate of CYP3A4. If these drugs are administered concurrently, monitor the patient for signs lack of efficacy of rivaroxaban.
Omidubicel: (Moderate) Because of the potential effects of certain dextran formulations on bleeding time, use with caution in patients on anticoagulants concurrently.
Oritavancin: (Moderate) Rivaroxaban is metabolized by CYP3A4; oritavancin is a weak CYP3A4 inducer. Plasma concentrations and efficacy of rivaroxaban may be reduced if these drugs are administered concurrently.
Orlistat: (Moderate) Patients on chronic stable doses of anticoagulants like rivaroxaban should be monitored closely for changes in coagulation parameters when orlistat is prescribed. Reports of decreased prothrombin, increased INR, and unbalanced anticoagulant treatment resulting in change of hemostatic parameters have been reported in patients treated concomitantly with orlistat and anticoagulants.
Oxaliplatin: (Major) Increase the frequency of monitoring in patients who are receiving concomitant therapy with oxaliplatin and rivaroxaban. Prolonged PT/INR occasionally associated with hemorrhage have been reported in patients who received oxaliplatin in combination with fluorouracil/leucovorin while on anticoagulants.
Oxandrolone: (Moderate) An increased effect of anticoagulants may occur with oxandrolone; the anticoagulant dosage may need adjustment downward with oxandrolone initiation or adjustment upward with oxandrolone discontinuation to maintain the desired clinical effect. Oxandrolone suppresses clotting factors II, V, VII, and X, which results in an increased prothrombin time. An increase in plasminogen-activator activity, and serum concentrations of plasminogen, protein C, and antithrombin III have occurred with several 17-alpha-alkylated androgens. For example, concurrent use of oxandrolone and warfarin may result in unexpectedly large increases in the INR or prothrombin time (PT). A multidose study of oxandrolone (5 or 10 mg PO twice daily) in 15 healthy individuals concurrently treated with warfarin resulted in significant increases in warfarin half-life and AUC; a 5.5-fold decrease in the mean warfarin dosage from 6.13 mg/day to 1.13 mg/day (approximately 80 to 85% dose reduction) was necessary to maintain a target INR of 1.5. According to the manufacturer, if oxandrolone therapy is initiated in a patient already receiving warfarin, the dose of warfarin may need to be decreased significantly to reduce the potential for excessive INR elevations and associated risk of serious bleeding events. The patient should be closely monitored with frequent evaluation of the INR and clinical parameter, and the dosage of warfarin should be adjusted as necessary until a stable target INR is achieved. Careful monitoring of the INR and necessary adjustment of the warfarin dosage are also recommended when the androgen therapy is changed or discontinued.
Oxaprozin: (Major) An additive risk of bleeding may be seen in patients receiving anticoagulants in combination with other agents known to increase the risk of bleeding such as nonsteroidal antiinflammatory drugs (NSAIDs). Monitor clinical and laboratory response closely during concurrent use.
Paroxetine: (Moderate) Advise patients of the increased bleeding risk associated with the concomitant use of selective serotonin reuptake inhibitors (SSRIs) and anticoagulants like rivaroxaban. Case reports and epidemiological studies have demonstrated an association between use of drugs that interfere with serotonin reuptake and gastrointestinal bleeding.
Pentosan: (Major) Due to the increased bleeding risk, avoid concurrent use of rivaroxaban with pentosan. Pentosan is a weak anticoagulant. Pentosan has one-fifteenth the anticoagulant activity of heparin.
Perampanel: (Minor) Coadministration of rivaroxaban and perampanel may result in decreased rivaroxaban exposure and may decrease the efficacy of rivaroxaban. Perampanel is an inducer of CYP3A4, and rivaroxaban is a substrate of CYP3A4. If these drugs are administered concurrently, monitor the patient for signs of lack of efficacy of rivaroxaban.
Phenobarbital: (Major) Avoid concomitant use of rivaroxaban with drugs that are combined P-glycoprotein (P-gp) and strong CYP3A4 inducers, such as phenobarbital. In a drug interaction study, coadministration of rivaroxaban 20 mg single dose with food with a drug that is a combined P-gp and strong CYP3A4 inducer (rifampicin titrated up to 600 mg once daily) led to an approximate decrease of 50% in AUC and an approximate decrease of 22% in Cmax. Similar decreases in pharmacodynamic effects were also observed. These decreases in exposure to rivaroxaban may decrease efficacy.
Phenobarbital; Hyoscyamine; Atropine; Scopolamine: (Major) Avoid concomitant use of rivaroxaban with drugs that are combined P-glycoprotein (P-gp) and strong CYP3A4 inducers, such as phenobarbital. In a drug interaction study, coadministration of rivaroxaban 20 mg single dose with food with a drug that is a combined P-gp and strong CYP3A4 inducer (rifampicin titrated up to 600 mg once daily) led to an approximate decrease of 50% in AUC and an approximate decrease of 22% in Cmax. Similar decreases in pharmacodynamic effects were also observed. These decreases in exposure to rivaroxaban may decrease efficacy.
Phenytoin: (Major) Avoid concomitant use of rivaroxaban with drugs that are combined P-glycoprotein and strong CYP3A4 inducers such as phenytoin. Consider increasing the rivaroxaban dose if phenytoin must be coadministered. In a drug interaction study, coadministration of rivaroxaban 20 mg single dose with food with a drug that is a combined P-glycoprotein and strong CYP3A4 inducer (rifampicin titrated up to 600 mg once daily) led to an approximate decrease of 50% in AUC and an approximate decrease of 22% in Cmax. Similar decreases in pharmacodynamic effects were also observed. These decreases in exposure to rivaroxaban may decrease efficacy.
Piperacillin; Tazobactam: (Moderate) Some penicillins (e.g., piperacillin) can inhibit platelet aggregation, which may increase the risk of bleeding with any anticoagulants. Clinically important bleeding of this type, however, is relatively rare. The concomitant use of warfarin with many classes of antibiotics, including penicillins, may result in an increased INR thereby potentiating the risk for bleeding. Inhibition of vitamin K synthesis due to alterations in the intestinal flora may be a mechanism; however, concurrent infection is also a potential risk factor for elevated INR. Monitor patients for signs and symptoms of bleeding. Additionally, increased monitoring of the INR, especially during initiation and upon discontinuation of the antibiotic, may be necessary in patients receiving warfarin.
Piroxicam: (Major) An additive risk of bleeding may be seen in patients receiving anticoagulants in combination with other agents known to increase the risk of bleeding such as nonsteroidal antiinflammatory drugs (NSAIDs). Monitor clinical and laboratory response closely during concurrent use.
Posaconazole: (Major) Avoid concomitant administration of rivaroxaban and posaconazole; significant increases in rivaroxaban exposure may increase bleeding risk. Rivaroxaban is a substrate of CYP3A4/5 and the P-glycoprotein (P-gp) transporter. Posaconazole is a combined P-gp inhibitor and strong CYP3A4 inhibitor. Concurrent use of rivaroxaban and ketoconazole, a combined P-gp and strong CYP3A4 inhibitor, led to an increase in the steady-state rivaroxaban AUC by 160% and Cmax by 70%. Similar increases in pharmacodynamic effects such as factor Xa inhibition and PT prolongation were also observed.
Prasterone, Dehydroepiandrosterone, DHEA (Dietary Supplements): (Major) Prasterone (DHEA) is contraindicated for use in patients with active deep vein thrombosis, pulmonary embolism or history of these conditions. Prasterone is also contraindicated in patients with active arterial thromboembolic disease (for example, stroke and myocardial infarction), or a history of these conditions. Thus, patients receiving anticoagulation due to a history of these conditions are not candidates for prasterone treatment. DHEA is converted to androgens and estrogens within the human body and thus may affect hemostasis via androgenic or estrogenic effects. Estrogens increase the production of clotting factors VII, VIII, IX, and X. Androgens, such as testosterone, increase the synthesis of several anticoagulant and fibrinolytic proteins. Because of the potential effects on coagulation, patients receiving prasterone or DHEA concurrently with preventative anticoagulants (e.g., warfarin or heparin) or other platelet inhibitors, including aspirin, ASA should be monitored for side effects or the need for dosage adjustments.
Prasterone, Dehydroepiandrosterone, DHEA (FDA-approved): (Major) Prasterone (DHEA) is contraindicated for use in patients with active deep vein thrombosis, pulmonary embolism or history of these conditions. Prasterone is also contraindicated in patients with active arterial thromboembolic disease (for example, stroke and myocardial infarction), or a history of these conditions. Thus, patients receiving anticoagulation due to a history of these conditions are not candidates for prasterone treatment. DHEA is converted to androgens and estrogens within the human body and thus may affect hemostasis via androgenic or estrogenic effects. Estrogens increase the production of clotting factors VII, VIII, IX, and X. Androgens, such as testosterone, increase the synthesis of several anticoagulant and fibrinolytic proteins. Because of the potential effects on coagulation, patients receiving prasterone or DHEA concurrently with preventative anticoagulants (e.g., warfarin or heparin) or other platelet inhibitors, including aspirin, ASA should be monitored for side effects or the need for dosage adjustments.
Prasugrel: (Major) Avoid concurrent administration of platelet inhibitors such as prasugrel with rivaroxaban unless the benefit outweighs the risk of increased bleeding. An increase in bleeding time to 45 minutes was observed in 2 drug interaction studies where another platelet inhibitor and rivaroxaban (15 mg single dose) were coadministered in healthy subjects. In the first study, the increase in bleeding time to 45 minutes was observed in approximately 45% of patients. Approximately 30% of patients in the second study had the event. The change in bleeding time was approximately twice the maximum increase seen with either drug alone. No change in the pharmacokinetic parameters of either drug were noted.
Primidone: (Major) Avoid concomitant use of rivaroxaban with drugs that are combined P-glycoprotein (P-gp) and strong CYP3A4 inducers, such as primidone. Phenobarbital is a strong inducer of both CYP3A4 and P-gp. Because primidone is metabolized to phenobarbital, drug interactions occurring with phenobarbital must be considered when primidone is administered. In a drug interaction study, coadministration of a single dose of rivaroxaban 20 mg with food with a drug that is a combined P-gp and strong CYP3A4 inducer (rifampicin titrated up to 600 mg once daily) led to an approximate decrease of 50% in AUC and an approximate decrease of 22% in Cmax of rivaroxaban. Similar decreases in pharmacodynamic effects were also observed. These decreases in exposure to rivaroxaban may decrease efficacy.
Prothrombin Complex Concentrate, Human: (Major) The actions of factor X are likely to be counteracted by factor Xa inhibitors such as rivaroxaban.
Quinidine: (Minor) Coadministration of rivaroxaban and quinidine may result in increases in rivaroxaban exposure and may increase bleeding risk. Quinidine is an inhibitor of P-glycoprotein (P-gp), and rivaroxaban is a substrate of P-gp. If these drugs are administered concurrently, monitor the patient for signs and symptoms of bleeding.
Quinine: (Minor) Coadministration of rivaroxaban and quinine may result in increases or decreases in rivaroxaban exposure and may increase bleeding risk or decrease efficacy of rivaroxaban. Quinine is an inhibitor and inducer of CYP3A4, and rivaroxaban is a substrate of CYP3A4. If these drugs are administered concurrently, monitor the patient for signs and symptoms of bleeding and lack of efficacy.
Ranolazine: (Minor) The coadministration of rivaroxaban and ranolazine should be undertaken with caution in patients with renal impairment; it is unclear whether a clinically significant interaction occurs when these two drugs are coadministered to patients with normal renal function. Ranolazine is a combined mild CYP3A4 inhibitor and P-glycoprotein (P-gp) inhibitor. Rivaroxaban is a substrate of CYP3A4/5 and the P-gp transporter. Coadministration in patients with renal impairment may result in increased exposure to rivaroxaban compared with patients with normal renal function and no inhibitor use since both pathways of elimination are affected. While an increase in exposure to rivaroxaban may be expected, results from an analysis of the ROCKET-AF trial which allowed concomitant administration of rivaroxaban and a combined P-gp inhibitor and weak or moderate CYP3A4 inhibitor did not show an increased risk of bleeding in patients with CrCl 30 to < 50 ml/min [HR (95% CI): 1.05 (0.77, 1.42)].
Reteplase, r-PA: (Major) Due to the increased bleeding risk, avoid concurrent use of rivaroxaban with thrombolytic agents; the safety of concomitant use has not been studied.
Rifabutin: (Minor) Coadministration of rivaroxaban and rifabutin may result in decreased rivaroxaban exposure and may decrease the efficacy of rivaroxaban. Rifabutin is an inducer of CYP3A4, and rivaroxaban is a substrate of CYP3A4. If these drugs are administered concurrently, monitor the patient for signs lack of efficacy of rivaroxaban.
Rifampin: (Major) Avoid concomitant use of rivaroxaban with drugs that are combined P-glycoprotein and strong CYP3A4 inducers such as rifampin. Consider increasing the rivaroxaban dose if rifampin must be coadministered. In a drug interaction study, coadministration of rivaroxaban 20 mg single dose with food with a drug that is a combined P-glycoprotein and strong CYP3A4 inducer (rifampicin titrated up to 600 mg once daily) led to an approximate decrease of 50% in AUC and an approximate decrease of 22% in Cmax. Similar decreases in pharmacodynamic effects were also observed. These decreases in exposure to rivaroxaban may decrease efficacy.
Ritonavir: (Major) Avoid concomitant administration of rivaroxaban and ritonavir; significant increases in rivaroxaban exposure may increase bleeding risk. Rivaroxaban is a substrate of CYP3A4/5 and the P-glycoprotein (P-gp) transporter. Concurrent use of a single dose of rivaroxaban and ritonavir, a combined P-gp and strong CYP3A4 inhibitor, led to an increase in the rivaroxaban AUC by 150% and Cmax by 60%. Similar increases in pharmacodynamic effects such as factor Xa inhibition and PT prolongation were also observed.
Salicylates: (Major) Salicylates such as aspirin are known to increase bleeding, and bleeding risk may be increased when these drugs are used concomitantly with rivaroxaban. The safety of long-term concomitant use of these drugs has not been studied. Promptly evaluate any signs or symptoms of bleeding or blood loss if patients are treated concomitantly with salicylates. In a single-dose drug interaction study, no pharmacokinetic interactions were observed after concomitant administration of acetylsalicylic acid (aspirin, ASA) with rivaroxaban.
Salsalate: (Major) Salicylates such as aspirin are known to increase bleeding, and bleeding risk may be increased when these drugs are used concomitantly with rivaroxaban. The safety of long-term concomitant use of these drugs has not been studied. Promptly evaluate any signs or symptoms of bleeding or blood loss if patients are treated concomitantly with salicylates. In a single-dose drug interaction study, no pharmacokinetic interactions were observed after concomitant administration of acetylsalicylic acid (aspirin, ASA) with rivaroxaban.
Saquinavir: (Major) Avoid concomitant administration of rivaroxaban and saquinavir; significant increases in rivaroxaban exposure may increase bleeding risk. Rivaroxaban is a substrate of CYP3A4/5 and the P-glycoprotein (P-gp) transporter. Saquinavir, a combined P-gp inhibitor and strong CYP3A4 inhibitor, is given with ritonavir, a combined P-gp and strong CYP3A4 inhibitor. Concurrent use of a single dose of rivaroxaban and ritonavir, a combined P-gp and strong CYP3A4 inhibitor, led to an increase in the steady-state rivaroxaban AUC by 150% and to an increase in Cmax by 60%. Similar increases in pharmacodynamic effects such as factor Xa inhibition and PT prolongation were also observed.
Sarilumab: (Moderate) Monitor for a decrease in efficacy of rivaroxaban if used with sarilumab. Until more data are available, consider using an anticoagulant without dependence on CYP450 enzymes for metabolism (e.g., heparins, edoxaban). The formation of CYP450 enzymes may be suppressed by increased concentrations of cytokines such as IL-6 during chronic inflammation. It is expected that the activity of CYP450 enzymes could increase to normal concentrations during treatment with an IL-6 antagonist such as sarilumab; these effects on CYP450 enzyme activity may persist for several weeks after stopping sarilumab. In vitro, sarilumab has the potential to affect expression of multiple CYP enzymes [including CYP1A2, CYP2B6, CYP2C9, CYP2C19, CYP2D6, and CYP3A4]. Rivaroxaban is a substrate for CYP3A4/5.
Selective norepinephrine reuptake inhibitors: (Major) Coadministration of rivaroxaban with other drugs that affect hemostasis, such as selective norepinephrine reuptake inhibitors (SNRIs), increases the risk of bleeding. If these drugs are administered together, instruct patients to monitor for signs and symptoms of bleeding, and to promptly report any bleeding events to their practitioner.
Serotonin norepinephrine reuptake inhibitors: (Moderate) Advise patients of the increased bleeding risk associated with the concomitant use of serotonin norepinephrine reuptake inhibitors (SNRIs) and anticoagulants like rivaroxaban. Case reports and epidemiological studies have demonstrated an association between use of drugs that interfere with serotonin reuptake and gastrointestinal bleeding.
Sertraline: (Moderate) Advise patients of the increased bleeding risk associated with the concomitant use of selective serotonin reuptake inhibitors (SSRIs) and anticoagulants like rivaroxaban. Case reports and epidemiological studies have demonstrated an association between use of drugs that interfere with serotonin reuptake and gastrointestinal bleeding.
Siltuximab: (Moderate) Monitor for a decrease in efficacy of rivaroxaban if used with siltuximab. Until more data are available, consider using an anticoagulant without dependence on CYP450 enzymes for metabolism (e.g., heparins, edoxaban). The formation of CYP450 enzymes may be suppressed by increased concentrations of cytokines such as IL-6 during chronic inflammation. It is expected that the activity of CYP450 enzymes could increase to normal concentrations during treatment with an IL-6 antagonist such as siltuximab; these effects on CYP450 enzyme activity may persist for several weeks after stopping siltuximab. In vitro, siltuximab has the potential to affect expression of multiple CYP enzymes [including CYP1A2, CYP2B6, CYP2C9, CYP2C19, CYP2D6, and CYP3A4]. Rivaroxaban is a substrate for CYP3A4/5.
Sodium Iodide: (Moderate) Anticoagulants may alter sodium iodide I-131 pharmacokinetics and dynamics for up to 1 week after administrations.
Sofosbuvir; Velpatasvir; Voxilaprevir: (Moderate) Plasma concentrations of rivaroxaban, a P-glycoprotein (P-gp) substrate, may be increased when administered concurrently with voxilaprevir, a P-gp inhibitor. Monitor patients for increased side effects if these drugs are administered concurrently.
St. John's Wort, Hypericum perforatum: (Major) Avoid concomitant use of rivaroxaban with combined P-glycoprotein and strong CYP3A4 inducers such as St. John's Wort, due to decreased efficacy and an increased risk for thrombotic events. Consider increasing the rivaroxaban dose if St. John's Wort must be used. In a drug interaction study, coadministration of rivaroxaban (20 mg single dose) with a combined P-glycoprotein and strong CYP3A4 inducer led to an approximate 50% decrease in rivaroxaban AUC and 22% decrease in Cmax.
Sulindac: (Major) An additive risk of bleeding may be seen in patients receiving anticoagulants in combination with other agents known to increase the risk of bleeding such as nonsteroidal antiinflammatory drugs (NSAIDs). Monitor clinical and laboratory response closely during concurrent use.
Sumatriptan; Naproxen: (Major) An additive risk of bleeding may be seen in patients receiving anticoagulants in combination with other agents known to increase the risk of bleeding such as nonsteroidal antiinflammatory drugs (NSAIDs). Monitor clinical and laboratory response closely during concurrent use.
Telavancin: (Moderate) Telavancin has no effect on coagulation or platelet aggregation; however, caution is advised when administering telavancin concurrently with anticoagulants as telavancin may interfere with laboratory tests used in monitoring these medications. The coagulation tests affected by telavancin include prothrombin time (PT), international normalized ratio (INR), activated partial thromboplastin time (aPTT), activated clotting time, and coagulation based factor Xa tests. When measured shortly after completion of a telavancin infusion, the results of these tests are increased; however, the effects of telavancin on these tests dissipate over time as plasma concentrations of telavancin decrease. Therefore, when administering telavancin in conjunction with anticoagulants ensure that blood samples for these coagulation tests are collected as close as possible to the patient's next telavancin dose.
Tenecteplase: (Major) Due to the increased bleeding risk, avoid concurrent use of rivaroxaban with thrombolytic agents; the safety of concomitant use has not been studied.
Tenofovir Alafenamide: (Minor) Caution is advised when administering tenofovir alafenamide concurrently with rivaroxaban, as coadministration may result in elevated tenofovir alafenamide plasma concentrations. Inhibitors of the drug transporter P-glycoprotein (P-gp), such as rivaroxaban, may increase absorption of tenofovir alafenamide, a P-gp substrate. If these medications are administered together, monitor for tenofovir-associated adverse reactions. Of note, when tenofovir alafenamide is administered as part of a cobicistat-containing product, its availability is increased by cobicistat and a further increase of tenofovir alafenamide concentrations is not expected upon coadministration of an additional P-gp inhibitor.
Tezacaftor; Ivacaftor: (Minor) The coadministration of rivaroxaban and ivacaftor should be undertaken with caution in patients with renal impairment; it is unclear whether a clinically significant interaction occurs when these two drugs are coadministered to patients with normal renal function. Ivacaftor is a combined mild CYP3A4 inhibitor and mild P-glycoprotein (P-gp) inhibitor. Rivaroxaban is a substrate of CYP3A4/5 and the P-gp transporter. Coadministration in patients with renal impairment may result in increased exposure to rivaroxaban compared with patients with normal renal function and no inhibitor use since both pathways of elimination are affected. While an increase in exposure to rivaroxaban may be expected, results from an analysis of the ROCKET-AF trial which allowed concomitant administration of rivaroxaban and a combined P-gp inhibitor and weak or moderate CYP3A4 inhibitor did not show an increased risk of bleeding in patients with CrCl 30 to < 50 ml/min [HR (95% CI): 1.05 (0.77, 1.42)].
Thrombin Inhibitors: (Major) Due to the increased bleeding risk, avoid concurrent use of rivaroxaban with thrombin inhibitors; the safety of concomitant use has not been studied. If a thrombin inhibitor is used during therapeutic transition periods, closely observe patients and promptly evaluate any signs or symptoms of blood loss.
Thrombolytic Agents: (Major) Due to the increased bleeding risk, avoid concurrent use of rivaroxaban with thrombolytic agents; the safety of concomitant use has not been studied.
Ticagrelor: (Major) Avoid concurrent administration of platelet inhibitors with rivaroxaban unless the benefit outweighs the risk of increased bleeding. An increase in bleeding time to 45 minutes was observed in 2 drug interaction studies where another platelet inhibitor and rivaroxaban (15 mg single dose) were coadministered in healthy subjects. In the first study, the increase in bleeding time to 45 minutes was observed in approximately 45% of patients. Approximately 30% of patients in the second study had the event. The change in bleeding time was approximately twice the maximum increase seen with either drug alone. No change in the pharmacokinetic parameters of either drug were noted. The coadministration of rivaroxaban and ticagrelor should be undertaken with caution in patients with renal impairment; it is unclear whether a clinically significant interaction occurs when these 2 drugs are coadministered to patients with normal renal function. Ticagrelor is a combined mild CYP3A4 inhibitor and mild P-glycoprotein (P-gp) inhibitor. Rivaroxaban is a substrate of CYP3A4/5 and the P-gp transporter. Coadministration in patients with renal impairment may result in increased exposure to rivaroxaban compared with patients with normal renal function and no inhibitor use since both pathways of elimination are affected. While an increase in exposure to rivaroxaban may be expected, results from an analysis of the ROCKET-AF trial which allowed concomitant administration of rivaroxaban and a combined P-gp inhibitor and weak or moderate CYP3A4 inhibitor did not show an increased risk of bleeding in patients with CrCl 30 to less than 50 mL/minute.
Ticlopidine: (Major) Avoid concurrent administration of platelet inhibitors such as clopidogrel with rivaroxaban unless the benefit outweighs the risk of increased bleeding. An increase in bleeding time to 45 minutes was observed in two drug interaction studies where clopidogrel (300 mg loading dose followed by 75 mg daily maintenance dose) and rivaroxaban (15 mg single dose) were coadministered in healthy subjects. In the first study, the increase in bleeding time to 45 minutes was observed in approximately 45% of patients. Approximately 30% of patients in the second study had the event. The change in bleeding time was approximately twice the maximum increase seen with either drug alone. No change in the pharmacokinetic parameters of either drug were noted.
Tipranavir: (Minor) Coadministration of rivaroxaban and tipranavir may result in increases or decreases in rivaroxaban exposure and may increase bleeding risk or decrease efficacy of rivaroxaban. Tipranavir is a potent inhibitor CYP3A4 and mild inducer of P-gp, and rivaroxaban is a substrate of CYP3A4 and P-gp. If these drugs are administered concurrently, monitor the patient for signs and symptoms of bleeding and lack of efficacy.
Tirofiban: (Major) Avoid concurrent administration of platelet inhibitors such as clopidogrel with rivaroxaban unless the benefit outweighs the risk of increased bleeding. An increase in bleeding time to 45 minutes was observed in two drug interaction studies where clopidogrel (300 mg loading dose followed by 75 mg daily maintenance dose) and rivaroxaban (15 mg single dose) were coadministered in healthy subjects. In the first study, the increase in bleeding time to 45 minutes was observed in approximately 45% of patients. Approximately 30% of patients in the second study had the event. The change in bleeding time was approximately twice the maximum increase seen with either drug alone. No change in the pharmacokinetic parameters of either drug were noted.
Tocilizumab: (Moderate) Monitor for a decrease in efficacy of rivaroxaban if used with tocilizumab. Until more data are available, consider using an anticoagulant without dependence on CYP450 enzymes for metabolism (e.g., heparins, edoxaban). The formation of CYP450 enzymes may be suppressed by increased concentrations of cytokines such as IL-6 during chronic inflammation. It is expected that the activity of CYP450 enzymes could increase to normal concentrations during treatment with an IL-6 antagonist such as tocilizumab; these effects on CYP450 enzyme activity may persist for several weeks after stopping tocilizumab. In vitro, tocilizumab has the potential to affect expression of multiple CYP enzymes [including CYP1A2, CYP2B6, CYP2C9, CYP2C19, CYP2D6, and CYP3A4]. Rivaroxaban is a substrate for CYP3A4/5.
Tolmetin: (Major) An additive risk of bleeding may be seen in patients receiving anticoagulants in combination with other agents known to increase the risk of bleeding such as nonsteroidal antiinflammatory drugs (NSAIDs). Monitor clinical and laboratory response closely during concurrent use.
Trandolapril; Verapamil: (Moderate) Avoid coadministration of rivaroxaban and verapamil in patients with renal impairment (CrCL 15 to 79 mL/minute) unless the potential benefit justifies the potential risk. Rivaroxaban is a CYP3A4 and P-glycoprotein (P-gp) inhibitor and verapamil is a P-gp and moderate CYP3A4 inhibitor. In a pharmacokinetic trial, coadministration with another combined moderate CYP3A4/P-gp inhibitor increased the AUC of rivaroxaban by 76% in patients with mild renal impairment (CrCL 50 to 79 mL/minute) and by 99% in patients with moderate renal impairment (CrCL 30 to 49 mL/minute) compared to patients with normal renal function (CrCL greater than 80 mL/minute); similar trends in pharmacodynamic effects were also observed.
Trazodone: (Moderate) Patients should be instructed to monitor for signs and symptoms of bleeding while taking trazodone concurrently with anticoagulants and to promptly report any bleeding events to the practitioner. Serotonergic agents may increase the risk of bleeding when combined with anticoagulants via inhibition of serotonin uptake by platelets; however, the absolute risk is not known. It would be prudent for clinicians to monitor the INR and patient's clinical status closely if trazodone is added to or removed from the regimen of a patient stabilized on anticoagulant therapy.
Treprostinil: (Moderate) When used concurrently with anticoagulants, treprostinil may increase the risk of bleeding.
Tucatinib: (Major) Avoid coadministration of rivaroxaban and tucatinib; significant increases in rivaroxaban exposure may occur which may increase the bleeding risk. Rivaroxaban is a substrate of CYP3A4/5 and the P-glycoprotein (P-gp) transporter. Tucatinib is a combined P-gp and strong CYP3A4 inhibitor. Concurrent use of a single dose of rivaroxaban and another combined P-gp and strong CYP3A4 inhibitor increased the steady-state rivaroxaban AUC and Cmax by 150% and 60%, respectively. Similar increases in pharmacodynamic effects such as factor Xa inhibition and PT prolongation were also observed.
Valdecoxib: (Major) An additive risk of bleeding may be seen in patients receiving anticoagulants in combination with other agents known to increase the risk of bleeding such as nonsteroidal antiinflammatory drugs (NSAIDs). Monitor clinical and laboratory response closely during concurrent use.
Vemurafenib: (Minor) Coadministration of rivaroxaban and vemurafenib may result in increases or decreases in rivaroxaban exposure and may increase bleeding risk or decrease efficacy of rivaroxaban. Vemurafenib is an inducer of CYP3A4 and a mild inhibitor of P-gp. Rivaroxaban is a substrate of CYP3A4 and P-gp. If these drugs are administered concurrently, monitor the patient for signs and symptoms of bleeding and lack of efficacy.
Verapamil: (Moderate) Avoid coadministration of rivaroxaban and verapamil in patients with renal impairment (CrCL 15 to 79 mL/minute) unless the potential benefit justifies the potential risk. Rivaroxaban is a CYP3A4 and P-glycoprotein (P-gp) inhibitor and verapamil is a P-gp and moderate CYP3A4 inhibitor. In a pharmacokinetic trial, coadministration with another combined moderate CYP3A4/P-gp inhibitor increased the AUC of rivaroxaban by 76% in patients with mild renal impairment (CrCL 50 to 79 mL/minute) and by 99% in patients with moderate renal impairment (CrCL 30 to 49 mL/minute) compared to patients with normal renal function (CrCL greater than 80 mL/minute); similar trends in pharmacodynamic effects were also observed.
Verteporfin: (Moderate) Use caution if coadministration of verteporfin with anticoagulants is necessary due to the risk of d ecreased verteporfin efficacy. Verteporfin is a light-activated drug. Once activated, local damage to neovascular endothelium results in a release of procoagulant and vasoactive factors resulting in platelet aggregation, fibrin clot formation, and vasoconstriction. Concomitant use of drugs that decrease clotting could decrease the efficacy of verteporfin therapy.
Vilazodone: (Moderate) Patients should be instructed to monitor for signs and symptoms of bleeding while taking vilazodone concurrently with anticoagulants and to promptly report any bleeding events to the practitioner. Serotonergic agents may increase the risk of bleeding when combined with anticoagulants via inhibition of serotonin uptake by platelets; however, the absolute risk is not known. In addition, both vilazodone and warfarin are highly protein bound, which may result in displacement of warfarin from protein binding sites and an increased anticoagulant effect. It would be prudent for clinicians to monitor the INR and clinical status of the patient closely if vilazodone is added to or removed from the regimen of a patient stabilized on warfarin.
Viloxazine: (Major) Coadministration of rivaroxaban with other drugs that affect hemostasis, such as selective norepinephrine reuptake inhibitors (SNRIs), increases the risk of bleeding. If these drugs are administered together, instruct patients to monitor for signs and symptoms of bleeding, and to promptly report any bleeding events to their practitioner.
Vonoprazan; Amoxicillin; Clarithromycin: (Moderate) Pharmacokinetic data suggests coadministration of rivaroxaban with clarithromycin is unlikely to affect bleeding risk. However, coadministration of rivaroxaban with other combined P-gp and strong CYP3A4 inhibitors has resulted in increased rivaroxaban exposure and is not recommended. Educate patients about the signs and symptoms of bleeding if concurrent use of clarithromycin with rivaroxaban is necessary; patients with renal impairment may be at greater risk with this combination.
Vorapaxar: (Major) Avoid concomitant use of vorapaxar and warfarin or other anticoagulants. Because vorapaxar inhibits platelet aggregation, a potential additive risk for bleeding exists if vorapaxar is given in combination with other agents that affect hemostasis such as anticoagulants.
Vortioxetine: (Moderate) Platelet aggregation may be impaired by vortioxetine due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication (e.g., gastrointestinal bleeding, ecchymoses, epistaxis, hematomas, petechiae, hemorrhage) in patients receiving anticoagulants. Bleeding events related to drugs that inhibit serotonin reuptake have ranged from ecchymosis to life-threatening hemorrhages. Patients should be instructed to monitor for signs and symptoms of bleeding while taking vortioxetine concurrently with anticoagulants and to promptly report any bleeding events to the practitioner. Co-administration of vortioxetine and warfarin has not been shown to significantly affect the pharmacokinetics of either agent.
Warfarin: (Major) Avoid use of rivaroxaban with warfarin due to the increased bleeding risk. Monitor patients closely and promptly evaluate any signs or symptoms of bleeding if rivaroxaban and other anticoagulants are used concomitantly. Coadministration of rivaroxaban and other anticoagulants may increase the risk of bleeding. Long-term concomitant treatment with rivaroxaban and other anticoagulants is not recommended; short-term use may be necessary for patients transitioning to or from rivaroxaban.
Zafirlukast: (Minor) Coadministration of rivaroxaban and zafirlukast may result in increases in rivaroxaban exposure and may increase bleeding risk. Zafirlukast is an inhibitor of CYP3A4, and rivaroxaban is a substrate of CYP3A4. If these drugs are administered concurrently, monitor the patient for signs and symptoms of bleeding.
Zonisamide: (Minor) Zonisamide is a weak inhibitor of P-glycoprotein (P-gp), and rivaroxaban is a substrate of P-gp. There is theoretical potential for zonisamide to affect the pharmacokinetics of drugs that are P-gp substrates. Use caution when starting or stopping zonisamide or changing the zonisamide dosage in patients also receiving drugs which are P-gp substrates.
How Supplied
Xarelto Granules Oral Gran F/Recon: 1mg, 1mL
Xarelto/Xarelto Starter Pack Oral Tab: 2.5mg, 10mg, 15mg, 20mg, 15-20mg
Maximum Dosage
30 mg/day PO.
Geriatric30 mg/day PO.
Adolescentsweighing 50 kg or more: 20 mg/day PO.
weighing 30 to 49.9 kg: 15 mg/day PO.
weighing 50 kg or more: 20 mg/day PO.
weighing 30 to 49.9 kg: 15 mg/day PO.
weighing 12 to 29.9 kg: 10 mg/day PO.
weighing 10 to 11.9 kg: 9 mg/day PO.
weighing 9 to 9.9 kg: 8.4 mg/day PO.
weighing 8 to 8.9 kg: 7.2 mg/day PO.
weighing 7 to 7.9 kg: 5.4 mg/day PO.
weighing 12 to 29.9 kg: 10 mg/day PO.
weighing 10 to 11.9 kg: 9 mg/day PO.
weighing 9 to 9.9 kg: 8.4 mg/day PO.
weighing 8 to 8.9 kg: 7.2 mg/day PO.
weighing 7 to 7.9 kg: 5.4 mg/day PO.
weighing 5 to 6.9 kg: 4.8 mg/day PO.
weighing 4 to 4.9 kg: 4.2 mg/day PO.
weighing 3 to 3.9 kg: 2.7 mg/day PO.
weighing 2.6 to 2.9 kg: 2.4 mg/day PO.
weighing 5 to 6.9 kg: 4.8 mg/day PO.
weighing 4 to 4.9 kg: 4.2 mg/day PO.
weighing 3 to 3.9 kg: 2.7 mg/day PO.
weighing 2.6 to 2.9 kg: 2.4 mg/day PO.
Mechanism Of Action
Rivaroxaban is an oral factor Xa inhibitor that selectively blocks the active site of factor Xa and does not require a cofactor such as Anti-thrombin III for activity. Rivaroxaban inhibits free factor Xa and prothrombinase activity; inhibition of factor Xa decreases the generation of thrombin. Rivaroxaban has no direct effect on platelet aggregation, but indirectly inhibits platelet aggregation induced by thrombin.]
Pharmacokinetics
Rivaroxaban is administered orally. Plasma protein binding is approximately 92% to 95%, primarily to albumin. Vd at steady state is approximately 50 L in healthy adult subjects. Oxidative degradation catalyzed by CYP3A4/5 and CYP2J2 and hydrolysis are the major sites of biotransformation. Unchanged rivaroxaban is the predominant moiety in plasma with no major or active circulating metabolites. Unchanged drug is excreted into urine, mainly via active tubular secretion and to a lesser extent via glomerular filtration (approximate 5:1 ratio); 36% and 7% is recovered in the urine and feces, respectively, as unchanged drug. Rivaroxaban is a low-clearance drug, with a systemic clearance of approximately 10 L/hour. The terminal elimination half-life of rivaroxaban is 5 to 9 hours in healthy patients aged 20 to 45 years.[44854]
Rivaroxaban produces dose-dependent inhibition of factor Xa activity. Clotting tests such as prothrombin time (PT), activated partial thromboplastin time (aPTT), and HepTest are also prolonged dose-dependently. Monitoring for safety and efficacy with these parameters or the international normalized ratio (INR) is not recommended.[44854]
Affected cytochrome P450 isoenzymes and drug transporters: CYP3A4, CYP3A5, CYP2J2, P-gp, ABCG2
Rivaroxaban is a substrate of CYP3A4/5, CYP2J2, and the P-glycoprotein (P-gp) and ATP-binding cassette G2 (ABCG2) transporters. Rivaroxaban's affinity for influx transporter proteins is unknown. Inhibitors and inducers of these CYP450 enzymes or transporters may result in changes in rivaroxaban exposure. Concomitant use of combined P-gp and strong CYP3A inhibitors can increase rivaroxaban exposure while concomitant use of combined P-gp and strong CYP3A inducers can decrease exposure. In vitro studies indicate that rivaroxaban neither inhibits the major cytochrome P450 enzymes CYP1A2, 2C8, 2C9, 2C19, 2D6, 2J2, and 3A nor induces CYP1A2, 2B6, 2C19, or 3A. In vitro data also indicates a low rivaroxaban inhibitory potential for P-gp and ABCG2 transporters. However, no significant pharmacokinetic interactions were observed in studies comparing concomitant use of rivaroxaban with midazolam (substrate of CYP3A4), digoxin (substrate of P-gp), or atorvastatin (substrate of CYP3A4 and P-gp) in healthy volunteers.[44854]
Rate and extent of absorption are similar between the tablet and oral suspension. Absolute bioavailability is dose-dependent. Bioavailability of the 2.5 mg and 10 mg tablets is estimated to be 80% and 100%, respectively, and is not affected by food. Rivaroxaban 20 mg, administered in the fasted state, has a bioavailability of approximately 66%; coadministration with food increases the bioavailability (the mean AUC and Cmax increased by 39% and 76%, respectively). Maximum concentrations (Cmax) of rivaroxaban occur 2 to 4 hours after oral administration. Absorption is dependent on the site of drug release in the gastrointestinal tract. A 29% and 56% decrease in AUC and Cmax was reported when rivaroxaban granulate was released in the proximal small intestine compared to values obtained with tablet administration. Exposure is further reduced when drug is released in the distal small intestine or ascending colon. Mean AUC and Cmax of a crushed 20 mg tablet mixed in applesauce was comparable to that of a whole tablet. When the crushed tablet was suspended in water and given via nasogastric tube followed by a liquid meal, AUC was comparable but Cmax was 18% lower.[44854]
Pregnancy And Lactation
Data are limited with rivaroxaban use in pregnant women and insufficient to inform a drug-associated risk. Use rivaroxaban with caution during pregnancy because of the potential for pregnancy-related hemorrhage and/or emergent delivery. Further, the anticoagulant effect of rivaroxaban cannot be monitored with standard laboratory testing. Consider the benefits and risks of rivaroxaban for the mother and possible risks to the fetus when prescribing rivaroxaban to a pregnant woman. Rivaroxaban has been shown to cross the placenta in animals and a human model. Based on the 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. Animal reproduction studies showed increased fetal toxicity (i.e., increased resorptions, decreased number of live fetuses, and decreased fetal body weight) in rabbits when exposed to oral doses approximately 4 times the human exposure of unbound drug, based on AUC comparisons at the highest recommended human dose of 20 mg/day. In rats, fetal body weights decreased when pregnant rats were given oral doses of rivaroxaban 120 mg/kg during organogenesis; additionally, peripartal maternal bleeding and maternal and fetal death occurred at a rivaroxaban dose equivalent to about 6 times the maximum human exposure of unbound drug. Instruct patients to immediately report if they become pregnant or intend to become pregnant during treatment. Also, instruct pregnant women to immediately report any bleeding or symptoms of blood loss. Promptly evaluate any signs or symptoms suggesting blood loss such as a drop in hemoglobin and/or hematocrit, hypotension, or fetal distress. Balance the risk of bleeding with the risk of thrombotic events when considering the use of rivaroxaban during labor or obstetric delivery.[44854]