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    Factor Xa Inhibitors

    BOXED WARNING

    Bleeding, epidural anesthesia, lumbar puncture, spinal anesthesia, surgery

    Rivaroxaban increases the bleeding risk and can cause serious and fatal bleeding. Rivaroxaban is contraindicated for use by patients with active major 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. The risk of bleeding should be weighed against the risk of thrombotic events in deciding whether to initiate rivaroxaban therapy in patients at increased risk of bleeding. Patients should be monitored 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. The terminal half-life of rivaroxaban is 5 to 9 hours in heathy patients aged 20 to 45 years. There is no specific antidote for rivaroxaban. 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 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. Restart rivaroxaban as soon as hemostasis has been established. If oral therapy is not possible, consider administration of a parenteral anticoagulant.

    Abrupt discontinuation

    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.

    DEA CLASS

    Rx

    DESCRIPTION

    Oral inhibitor of coagulation factor Xa
    Used for DVT prophylaxis after knee or hip replacement, treatment of DVT and PE, reduction of risk of DVT and PE, and stroke prophylaxis in nonvalvular atrial fibrillation
    Can not monitor anticoagulant effect with standard lab testing; effect not readily reversed

    COMMON BRAND NAMES

    Xarelto, Xarelto Starter Pack

    HOW SUPPLIED

    Xarelto/Xarelto Starter Pack Oral Tab: 10mg, 15mg, 20mg, 15-20mg

    DOSAGE & INDICATIONS

    For stroke prophylaxis and systemic embolism prophylaxis in patients with nonvalvular atrial fibrillation.
    Oral dosage
    Adults

    20 mg PO once daily with the evening meal. Unless pathological bleeding occurs, do not discontinue rivaroxaban in the absence of alternative anticoagulation. Data are limited on the relative effectiveness of rivaroxaban and well-controlled warfarin therapy in reducing the risk of systemic embolism and stroke. In the ROCKET AF study, rivaroxaban was compared to dose-adjusted warfarin in >14,000 patients with nonvalvular AF at increased risk for stroke. In the intention-to-treat analysis, rivaroxaban was proven noninferior to warfarin for the prevention of stroke or systemic embolism (2.1% per year vs. 2.4% per year; HR 0.88; 95% CI 0.74—1.03). No significant difference was seen in the risk of major bleeding between treatment groups; intracranial and fatal bleeding occurred less frequently in the rivaroxaban group.

    For the treatment of deep venous thrombosis (DVT) or pulmonary embolism.
    NOTE: Initiation of rivaroxaban is not recommended acutely as an alternative to unfractionated heparin in patients with pulmonary embolism who present with hemodynamic instability or who may receive thrombolysis or pulmonary embolectomy.
    Oral dosage
    Adults

    15 mg PO twice daily with food for the first 21 days then 20 mg PO once daily with food for a total of 6 months. Administer doses at approximately the same time each day. The efficacy and safety of rivaroxaban was compared to standard therapy consisting of enoxaparin followed by a vitamin K antagonist for the treatment of DVT (n = 3449) and pulmonary embolism (n = 4832) in the EINSTEIN program. Rivaroxaban was found to be noninferior to standard therapy for the primary composite endpoint of time to first occurrence of recurrent DVT or non-fatal or fatal PE. Major or clinically relevant nonmajor bleeding rates were similar between groups. In the pulmonary embolism trial, major bleeding was reported in 1.1% of patients in the rivaroxaban group compared to 2.2% in the standard therapy group (HR 0.49; 95% CI 0.31—0.79, p = 0.003).

    For deep venous thrombosis (DVT) prophylaxis and pulmonary embolism prophylaxis.
    For reduction in risk of recurrence of deep venous thrombosis (DVT) and/or pulmonary embolism (PE) in patients at continued risk for DVT and/or PE after completion of initial treatment.
    Oral dosage
    Adults

    10 mg PO once daily after at least 6 months of standard anticoagulant therapy.

    For deep venous thrombosis (DVT) prophylaxis, which may lead to pulmonary embolism PE, in patients undergoing knee or hip replacement surgery.
    Oral dosage
    Adults

    10 mg PO once daily for 12 days after knee replacement surgery or for 35 days after hip replacement surgery. Administer the initial dose at least 6 to 10 hours after surgery, once hemostasis has been established.

    MAXIMUM DOSAGE

    Adults

    30 mg/day PO.

    Geriatric

    30 mg/day PO.

    Adolescents

    Safety and efficacy have not been established.

    Children

    Safety and efficacy have not been established.

    Infants

    Safety and efficacy have not been established.

    Neonates

    Safety and efficacy have not been established.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    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.

    Renal Impairment

    CrCl 15 to 80 mL/minute: Do not administer rivaroxaban in patients receiving a combined P-glycoprotein and moderate CYP3A4 inhibitor unless the potential benefit justifies the potential risk.
     
    Nonvalvular Atrial Fibrillation
    CrCl 15 to 50 mL/minute: 15 mg PO once daily with evening meal.
    CrCl less than 15 mL/minute: Periodically assess renal function and adjust dose accordingly. Adjust dose or discontinue use in patients who develop acute renal failure while on rivaroxaban.
     
    Treatment of Deep Vein Thrombosis (DVT) and/or Pulmonary Embolism (PE) and Reduction in the Risk of Recurrence of DVT and of PE
    CrCl less than 30 mL/minute: Avoid use due to an expected increase in rivaroxaban exposure and pharmacodynamic effects. Discontinue use in patients who develop acute renal failure while on rivaroxaban.
     
    Prophylaxis of DVT Following Hip or Knee Replacement Surgery
    CrCl 30 to 50 mL/minute: Observe closely and promptly evaluate any signs or symptoms of blood loss.
    CrCl less than 30 mL/minute: Avoid use due to an expected increase in rivaroxaban exposure and pharmacodynamic effects. Discontinue use in patients who develop acute renal failure while on rivaroxaban.
     
    Hemodialysis
    Rivaroxaban is not expected to be removed by dialysis due to high protein binding.

    ADMINISTRATION

    Oral Administration
    Oral Solid Formulations

    The 15 mg and 20 mg tablets should be taken with food. For patients unable to swallow whole tablets, the 10 mg, 15 mg, or 20 mg tablets may be crushed, mixed with applesauce, and administered orally. Immediately following administration of a crushed 15 mg or 20 mg tablet, the patient should be instructed to eat a meal. Crushed tablets are stable in applesauce for up to 4 hours. 
    The 10 mg tablet can be taken with or without food.
    For DVT prophylaxis after hip/knee replacement surgery, administer the initial dose at least 6—10 hours after surgery once hemostasis has been established.
    For stroke prophylaxis in patients with nonvalvular atrial fibrillation, administer once daily with the evening meal.
     
    Nasogastric (NG) tube or gastric feeding tube:
    Confirm gastric placement of tube.
    Crush 10 mg, 15 mg, or 20 mg tablet, suspend in 50 ml of water, and administer via NG or gastric feeding tube.
    To minimize reduced absorption, avoid administration distal to the stomach.
    Enteral feeding should immediately follow administration of a crushed 15 mg or 20 mg dose.
    Crushed tablets are stable in water for up to 4 hours.
    There is no adsorption of rivaroxaban (when suspended in water) to PVC or silicone NG tubing.
     
    Missed doses
    Patients receiving 15 mg twice daily should take their missed dose immediately to ensure intake of 30 mg per day. Two 15-mg tablets may be taken at once followed by the regular 15 mg twice daily dose the next day.
    For patients receiving once daily dosing, take the missed dose as soon as it is remembered.

    STORAGE

    Xarelto:
    - Store at 77 degrees F; excursions permitted to 59-86 degrees F
    Xarelto Starter Pack:
    - Store at 77 degrees F; excursions permitted to 59-86 degrees F

    CONTRAINDICATIONS / PRECAUTIONS

    General Information

    Rivaroxaban is contraindicated for use by patients with severe hypersensitivity to the drug.

    Bleeding, epidural anesthesia, lumbar puncture, spinal anesthesia, surgery

    Rivaroxaban increases the bleeding risk and can cause serious and fatal bleeding. Rivaroxaban is contraindicated for use by patients with active major 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. The risk of bleeding should be weighed against the risk of thrombotic events in deciding whether to initiate rivaroxaban therapy in patients at increased risk of bleeding. Patients should be monitored 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. The terminal half-life of rivaroxaban is 5 to 9 hours in heathy patients aged 20 to 45 years. There is no specific antidote for rivaroxaban. 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 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. Restart rivaroxaban as soon as hemostasis has been established. If oral therapy is not possible, consider administration of a parenteral anticoagulant.

    Anticoagulant therapy

    Rivaroxaban should be used with caution in patients receiving other anticoagulant therapy (e.g., warfarin), platelet inhibitors (e.g., aspirin, ticlopidine), fibrolytics, or NSAIDs due to the potential increased risk of bleeding (see Drug Interactions). If coadministration of these agents with rivaroxaban continues, closely monitor patients.

    Coagulopathy, hepatic disease

    Avoid use of rivaroxaban in patients with moderate or severe hepatic disease (Child-Pugh Class B or C) or in any patient with hepatic disease associated with coagulopathy; rivaroxaban exposure and bleeding risk may be increased in these patients. Clinical data in patients with moderate hepatic impairment indicate a significant increase in rivaroxaban exposure and pharmacodynamic effects. No clinical data are available for patients with severe hepatic impairment.

    Renal failure, renal impairment

    Avoid the use of rivaroxaban in patients with renal failure or severe renal impairment, defined as a creatinine clearance < 30 ml/min for use as DVT prophylaxis and treatment and < 15 ml/min for stroke and systemic embolism prophylaxis in nonvalvular atrial fibrillation, due to an expected increase in rivaroxaban exposure and pharmacodynamic effects. Discontinue rivaroxaban if a patient develops acute renal failure. For patients being treated for DVT prophylaxis with moderate renal impairment defined as CrCl 30 to < 50 ml/min, closely observe them and promptly evaluate any signs or symptoms of blood loss. Dose reduction is recommended for patients with atrial fibrillation and CrCl 15—50 ml/min; periodically assess renal function as clinically indicated and adjust therapy when necessary. Do not administer rivaroxaban to patients with CrCl 15—80 ml/min who are receiving concomitant combined P-glycoprotein and moderate CYP3A4 inhibitors unless the potential benefit justifies the potential risk.

    Abrupt discontinuation

    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.

    Geriatric

    In clinical studies, geriatric patients exhibited higher rivaroxaban plasma concentrations than younger patients (see Pharmacokinetics). Age related changes in renal function may play a role in this age effect. Rivaroxaban should be used with caution in patients with renal impairment; elderly patients are at risk for renal impairment. In clinical trials, rivaroxaban efficacy was similar in geriatric patients to that seen in younger patients. Thrombotic and bleeding event rates were higher in older patients, but the risk-benefit profile was favorable in all age groups. According to the Beers Criteria, the dose of rivaroxaban should be reduced in geriatric patients with a creatinine clearance in the range of 30 mL/min to 50 mL/min and avoided in those with a creatinine clearance less than 30 mL/min due to an increased risk of bleeding. The creatinine clearance threshold for which the Beers expert panel recommends avoiding use of rivaroxaban is based on clinical trial exclusion criteria and may not be the same as that in the product labeling.

    Prosthetic heart valves

    The use of rivaroxaban in patients with prosthetic heart valves has not been studied; use in this population is not recommended.

    Labor, obstetric delivery, pregnancy

    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 with an anticoagulant that is not readily reversible. 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.

    Breast-feeding

    Rivaroxaban has been detected in human milk. There are insufficient data to determine the effects of rivaroxaban on the breast-fed child or on milk production. Consider the developmental and health benefits of breast-feeding along with the mother's clinical need for rivaroxaban and any potential adverse effects on the breast-fed infant from rivaroxaban or the underlying maternal condition. If pharmacotherapy is necessary in the nursing mother, previous American Academy of Pediatrics (AAP) recommendations considered warfarin to be usually compatible with breast-feeding. Low-molecular weight heparins and heparin have relatively high molecular weights ; therefore, these drugs are not expected to be excreted into human milk to a clinically significant degree.

    Reproductive risk

    Rivaroxaban may be associated with reproductive risk. Discuss pregnancy planning with females of reproductive potential requiring anticoagulation.

    ADVERSE REACTIONS

    Severe

    Stevens-Johnson syndrome / Delayed / Incidence not known
    angioedema / Rapid / Incidence not known
    anaphylactic shock / Rapid / Incidence not known
    agranulocytosis / Delayed / Incidence not known

    Moderate

    jaundice / Delayed / Incidence not known
    hepatitis / Delayed / Incidence not known
    cholestasis / Delayed / Incidence not known
    thrombocytopenia / Delayed / Incidence not known

    Mild

    back pain / Delayed / 1.0-10.0
    pruritus / Rapid / 2.1-2.1
    abdominal pain / Early / 1.7-1.7
    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
    fatigue / Early / 1.0-1.0

    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 blood loss if patients are treated concomitantly with salicylates. In a single-dose drug interaction study, no pharmacokinetic or pharmacodynamic interactions were observed after concomitant administration of naproxen or acetylsalicylic acid with rivaroxaban.
    Acetaminophen; Caffeine; Magnesium Salicylate; Phenyltoloxamine: (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 blood loss if patients are treated concomitantly with salicylates. In a single-dose drug interaction study, no pharmacokinetic or pharmacodynamic interactions were observed after concomitant administration of naproxen or acetylsalicylic acid with rivaroxaban.
    Acetaminophen; Caffeine; Phenyltoloxamine; Salicylamide: (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 blood loss if patients are treated concomitantly with salicylates. In a single-dose drug interaction study, no pharmacokinetic or pharmacodynamic interactions were observed after concomitant administration of naproxen or acetylsalicylic acid with rivaroxaban.
    Ado-Trastuzumab emtansine: (Major) Use caution if coadministration of anticoagulants such as antithrombin III, apixaban, argatroban, bivalirudin, dabigatran, dalteparin, danaparoid, desirudin, enoxaparin, fondaparinux, heparin, lepirudin, rivaroxaban, and warfarin with ado-trastuzumab emtansine is necessary due to reports of severe and sometimes fatal hemorrhage, including intracranial bleeding with ado-trastuzumab emtansine therapy. According to the manufacturer of ado-trastuzumab emtansine, if anticoagulant therapy cannot be avoided, additional monitoring of platelets and bleeding risk may be necessary. In a randomized, multicenter, open-label clinical trial of patients with HER2-positive metastatic breast cancer, hemorrhage occurred in 32.2% (>= grade 3, 1.8%) of patients treated with ado-trastuzumab emtansine (n = 490) compared with 16.4% (>= grade 3, 0.8%) of those who received lapatinib plus capecitabine (n = 488); some patients who experienced bleeding were also receiving anticoagulation therapy, antiplatelet therapy, or had thrombocytopenia, while others had no known additional risk factors.
    Afatinib: (Moderate) If the concomitant use of rivaroxaban and afatinib is necessary, consider reducing the afatinib dose by 10 mg per day if the original dose is not tolerated; resume the previous dose of afatinib as tolerated after discontinuation of rivaroxaban. Afatinib is a P-glycoprotein (P-gp) substrate and inhibitor in vitro, and rivaroxaban is a weak P-gp inhibitor in vitro; coadministration may increase plasma concentrations of afatinib. Administration of another P-gp inhibitor, ritonavir (200 mg twice daily for 3 days), 1 hour before afatinib (single dose) increased the afatinib AUC and Cmax by 48% and 39%, respectively; there was no change in the afatinib AUC when ritonavir was administered at the same time as afatinib or 6 hours later. In healthy subjects, the relative bioavailability for AUC and Cmax of afatinib was 119% and 104%, respectively, when coadministered with ritonavir, and 111% and 105% when ritonavir was administered 6 hours after afatinib. The manufacturer of afatinib recommends permanent discontinuation of therapy for severe or intolerant adverse drug reactions at a dose of 20 mg per day, but does not address a minimum dose otherwise.
    Alogliptin; Pioglitazone: (Minor) Coadministration of rivaroxaban and pioglitazone may result in decreased rivaroxaban exposure and may decrease the efficacy of rivaroxaban. Pioglitazone 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.
    Alteplase, tPA: (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 blood loss if patients are treated concomitantly with salicylates. In a single-dose drug interaction study, no pharmacokinetic or pharmacodynamic interactions were observed after concomitant administration of naproxen or acetylsalicylic acid with rivaroxaban.
    Amiodarone: (Moderate) The coadministration of rivaroxaban and amiodarone 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. Amiodarone is a combined CYP3A4 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)].
    Amlodipine; Atorvastatin: (Minor) Coadministration of rivaroxaban and atorvastatin may result in increases in rivaroxaban exposure and may increase bleeding risk. Atorvastatin 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.
    Amoxicillin; Clarithromycin; Lansoprazole: (Moderate) Coadministration of rivaroxaban and clarithromycin may result in increases in rivaroxaban exposure. Rivaroxaban is a substrate of CYP3A4/5 and the P-glycoprotein (P-gp) transporter. Concurrent use of single-dose rivaroxaban and clarithromycin, a combined P-gp and strong CYP3A4 inhibitor, led to an increase in the rivaroxaban AUC by 50% and to an increase in Cmax by 40%. These increases were smaller than the increases seen with other CYP3A4 and P-gp inhibitors such as ketoconazole and ritonavir, which may be due to the relative difference in P-gp inhibition. According to the manufacturer of rivaroxaban, when clinical data suggest the change in exposure is unlikely to affect bleeding risk (e.g., clarithromycin), no precautions are necessary during coadministration. More generally, coadministration of rivaroxaban with other combined CYP3A4 and strong P-gp inhibitors is to be avoided. (Minor) Coadministration of rivaroxaban and lansoprazole may result in increases in rivaroxaban exposure and may increase bleeding risk. Lansoprazole 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.
    Amoxicillin; Clarithromycin; Omeprazole: (Moderate) Coadministration of rivaroxaban and clarithromycin may result in increases in rivaroxaban exposure. Rivaroxaban is a substrate of CYP3A4/5 and the P-glycoprotein (P-gp) transporter. Concurrent use of single-dose rivaroxaban and clarithromycin, a combined P-gp and strong CYP3A4 inhibitor, led to an increase in the rivaroxaban AUC by 50% and to an increase in Cmax by 40%. These increases were smaller than the increases seen with other CYP3A4 and P-gp inhibitors such as ketoconazole and ritonavir, which may be due to the relative difference in P-gp inhibition. According to the manufacturer of rivaroxaban, when clinical data suggest the change in exposure is unlikely to affect bleeding risk (e.g., clarithromycin), no precautions are necessary during coadministration. More generally, coadministration of rivaroxaban with other combined CYP3A4 and strong P-gp inhibitors is to be avoided. (Minor) Coadministration of rivaroxaban and omeprazole may result in increases in rivaroxaban exposure and may increase bleeding risk. Omeprazole 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.
    Amprenavir: (Moderate) Coadministration of rivaroxaban and amprenavir may result in increases in rivaroxaban exposure and may increase bleeding risk. Amprenavir 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.
    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.
    Anthracyclines: (Moderate) Due to the thrombocytopenic effects of anthracyclines, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants. In addition, rivaroxaban is a mild P-glycoprotein (P-gp) inhibitor and doxorubicin is a major substrate of P-gp. Clinically significant interactions have been reported when doxorubicin was coadministered with inhibitors of P-gp, resulting in increased concentration and clinical effect of doxorubicin. Avoid coadministration of rivaroxaban and doxorubicin if possible. If not possible, closely monitor for increased side effects of doxorubicin including myelosuppression and cardiotoxicity.
    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.
    Antithymocyte Globulin: (Moderate) Drugs that can cause thrombocytopenia, such as antithymocyte globulin, may lead to an increased risk of bleeding when given concurrently with anticoagulants.
    Apixaban: (Major) Avoid concurrent use of rivaroxaban with apixaban 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. If switching from apixaban to another anticoagulant, discontinue apixaban and start the other anticoagulant at the usual time of the next dose of apixaban. If switching from another anticoagulant to apixaban, discontinue the other anticoagulant and start apixaban at the usual time of the next dose of the other anticoagulant. Coadministration of rivaroxaban and other anticoagulants may increase the risk of bleeding.
    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.
    Arsenic Trioxide: (Moderate) An additive risk of bleeding may be seen in thrombocytopenic patients receiving antineoplastic agents and anticoagulants concomitantly.
    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 blood loss if patients are treated concomitantly with salicylates. In a single-dose drug interaction study, no pharmacokinetic or pharmacodynamic interactions were observed after concomitant administration of naproxen or acetylsalicylic acid 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 blood loss if patients are treated concomitantly with salicylates. In a single-dose drug interaction study, no pharmacokinetic or pharmacodynamic interactions were observed after concomitant administration of naproxen or acetylsalicylic acid with rivaroxaban.
    Aspirin, ASA; Butalbital; 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 blood loss if patients are treated concomitantly with salicylates. In a single-dose drug interaction study, no pharmacokinetic or pharmacodynamic interactions were observed after concomitant administration of naproxen or acetylsalicylic acid with rivaroxaban.
    Aspirin, ASA; Caffeine; Dihydrocodeine: (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 blood loss if patients are treated concomitantly with salicylates. In a single-dose drug interaction study, no pharmacokinetic or pharmacodynamic interactions were observed after concomitant administration of naproxen or acetylsalicylic acid 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 blood loss if patients are treated concomitantly with salicylates. In a single-dose drug interaction study, no pharmacokinetic or pharmacodynamic interactions were observed after concomitant administration of naproxen or acetylsalicylic acid 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 blood loss if patients are treated concomitantly with salicylates. In a single-dose drug interaction study, no pharmacokinetic or pharmacodynamic interactions were observed after concomitant administration of naproxen or acetylsalicylic acid 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 blood loss if patients are treated concomitantly with salicylates. In a single-dose drug interaction study, no pharmacokinetic or pharmacodynamic interactions were observed after concomitant administration of naproxen or acetylsalicylic acid 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 blood loss if patients are treated concomitantly with salicylates. In a single-dose drug interaction study, no pharmacokinetic or pharmacodynamic interactions were observed after concomitant administration of naproxen or acetylsalicylic acid with rivaroxaban. (Minor) Coadministration of rivaroxaban and omeprazole may result in increases in rivaroxaban exposure and may increase bleeding risk. Omeprazole 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.
    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 blood loss if patients are treated concomitantly with salicylates. In a single-dose drug interaction study, no pharmacokinetic or pharmacodynamic interactions were observed after concomitant administration of naproxen or acetylsalicylic acid with rivaroxaban.
    Aspirin, ASA; Pravastatin: (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 blood loss if patients are treated concomitantly with salicylates. In a single-dose drug interaction study, no pharmacokinetic or pharmacodynamic interactions were observed after concomitant administration of naproxen or acetylsalicylic acid with rivaroxaban.
    Atazanavir: (Minor) Coadministration of rivaroxaban and atazanavir may result in increases in rivaroxaban exposure and may increase bleeding risk. Atazanavir 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.
    Atazanavir; Cobicistat: (Minor) Coadministration of rivaroxaban and atazanavir may result in increases in rivaroxaban exposure and may increase bleeding risk. Atazanavir 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. (Minor) The coadministration of rivaroxaban and cobicistat 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. Cobicistat is a combined CYP3A4 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)].
    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.
    Atorvastatin: (Minor) Coadministration of rivaroxaban and atorvastatin may result in increases in rivaroxaban exposure and may increase bleeding risk. Atorvastatin 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.
    Atorvastatin; Ezetimibe: (Minor) Coadministration of rivaroxaban and atorvastatin may result in increases in rivaroxaban exposure and may increase bleeding risk. Atorvastatin 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.
    Atropine; 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 blood loss if patients are treated concomitantly with salicylates. In a single-dose drug interaction study, no pharmacokinetic or pharmacodynamic interactions were observed after concomitant administration of naproxen or acetylsalicylic acid with rivaroxaban.
    Atropine; Hyoscyamine; Phenobarbital; 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.
    Azithromycin: (Minor) The coadministration of rivaroxaban and azithromycin 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. Azithromycin 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)].
    Basiliximab: (Minor) Coadministration of rivaroxaban and basiliximab may result in increases in rivaroxaban exposure and may increase bleeding risk. Basiliximab is a mild 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.
    Belladonna Alkaloids; Ergotamine; 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.
    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 blood loss if patients are treated concomitantly with salicylates. In a single-dose drug interaction study, no pharmacokinetic or pharmacodynamic interactions were observed after concomitant administration of naproxen or acetylsalicylic acid with rivaroxaban.
    Betrixaban: (Major) Avoid concurrent 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.
    Bevacizumab: (Moderate) An additive risk of bleeding may be seen in thrombocytopenic patients receiving antineoplastic agents and anticoagulants concomitantly.
    Bexarotene: (Minor) Coadministration of rivaroxaban and bexarotene may result in decreased rivaroxaban exposure and may decrease the efficacy of rivaroxaban. Bexarotene 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.
    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 blood loss if patients are treated concomitantly with salicylates. In a single-dose drug interaction study, no pharmacokinetic or pharmacodynamic interactions were observed after concomitant administration of naproxen or acetylsalicylic acid 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 blood loss if patients are treated concomitantly with salicylates. In a single-dose drug interaction study, no pharmacokinetic or pharmacodynamic interactions were observed after concomitant administration of naproxen or acetylsalicylic acid 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.
    Boceprevir: (Major) Avoid concomitant administration of rivaroxaban and boceprevir; significant increases in rivaroxaban exposure may increase bleeding risk. Rivaroxaban is a substrate of CYP3A4/5 and the P-glycoprotein (P-gp) transporter. Boceprevir is a combined mild 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.
    Bosentan: (Minor) Coadministration of rivaroxaban and bosentan may result in decreased rivaroxaban exposure and may decrease the efficacy of rivaroxaban. Bosentan 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.
    Bosutinib: (Minor) Coadministration of rivaroxaban and bosutinib may result in increases in rivaroxaban exposure and may increase bleeding risk. Bosutinib is an inhibitor of P-glycoprotein (P-gp), in vitro, and rivaroxaban is a substrate of P-gp. If these drugs are administered concurrently, monitor the patient for signs and symptoms of bleeding.
    Bupropion; Naltrexone: (Moderate) Give the extended-release injectable suspension of naltrexone cautiously to patients taking anticoagulants. Steps should be taken to avoid the risk of bleeding and hematoma formation following intramuscular injection.
    Cabozantinib: (Moderate) Monitor for an increase in rivaroxaban-related adverse events if concomitant use with cabozantinib is necessary, as plasma concentrations of rivaroxaban may be increased. Cabozantinib is a P-glycoprotein (P-gp) inhibitor and rivaroxaban is a substrate of P-gp; the clinical relevance of this finding is unknown.
    Carbamazepine: (Major) Avoid concomitant use of rivaroxaban with drugs that are combined P-glycoprotein and strong CYP3A4 inducers such as carbamazepine. Consider increasing the rivaroxaban dose if carbamazepine 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.
    Carbenicillin: (Moderate) Some penicillins (e.g., carbenicillin) can inhibit platelet aggregation, which may increase the risk of bleeding with any anticoagulants. Clinically important bleeding of this type 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.
    Carvedilol: (Moderate) Altered concentrations of rivaroxaban and/or carvedilol may occur during coadministration. Carvedilol and rivaroxaban are both substrates and inhibitors of P-glycoprotein (P-gp). Use caution if concomitant use is necessary and monitor for increased side effects.
    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.
    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.
    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 blood loss if patients are treated concomitantly with salicylates. In a single-dose drug interaction study, no pharmacokinetic or pharmacodynamic interactions were observed after concomitant administration of naproxen or acetylsalicylic acid with rivaroxaban.
    Chondroitin; Glucosamine: (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.
    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.
    Cimetidine: (Minor) Coadministration of rivaroxaban and cimetidine may result in increases in rivaroxaban exposure and may increase bleeding risk. Cimetidine is a mild 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.
    Citalopram: (Major) Selective serotonin reuptake inhibitors (SSRIs) can inhibit serotonin uptake by platelets, thus causing platelet dysfunction and increasing the risk for bleeding with rivaroxaban; however, the absolute risk is not known. 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.
    Clarithromycin: (Moderate) Coadministration of rivaroxaban and clarithromycin may result in increases in rivaroxaban exposure. Rivaroxaban is a substrate of CYP3A4/5 and the P-glycoprotein (P-gp) transporter. Concurrent use of single-dose rivaroxaban and clarithromycin, a combined P-gp and strong CYP3A4 inhibitor, led to an increase in the rivaroxaban AUC by 50% and to an increase in Cmax by 40%. These increases were smaller than the increases seen with other CYP3A4 and P-gp inhibitors such as ketoconazole and ritonavir, which may be due to the relative difference in P-gp inhibition. According to the manufacturer of rivaroxaban, when clinical data suggest the change in exposure is unlikely to affect bleeding risk (e.g., clarithromycin), no precautions are necessary during coadministration. More generally, coadministration of rivaroxaban with other combined CYP3A4 and strong P-gp inhibitors is to be avoided.
    Clobazam: (Minor) Coadministration of rivaroxaban and clobazam may result in decreased rivaroxaban exposure and may decrease the efficacy of rivaroxaban. Clobazam 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.
    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: (Minor) The coadministration of rivaroxaban and cobicistat 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. Cobicistat is a combined CYP3A4 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)].
    Cobicistat; Elvitegravir; Emtricitabine; Tenofovir Alafenamide: (Minor) The coadministration of rivaroxaban and cobicistat 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. Cobicistat is a combined CYP3A4 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)].
    Cobicistat; Elvitegravir; Emtricitabine; Tenofovir Disoproxil Fumarate: (Minor) The coadministration of rivaroxaban and cobicistat 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. Cobicistat is a combined CYP3A4 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)].
    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.
    Cod Liver Oil: (Major) Cod liver oil should be used only with caution and with frequent monitoring in patients on concurrent anticoagulants. In a limited number of patients, the hypoprothrombinemic response to warfarin was increased following large doses of vitamin A. Additionally, omega-3 fatty acids contained in cod liver oil may inhibit platelet aggregation. Theoretically, the risk of bleeding may be increased, but some studies that combined omega-3 fatty acids and anticoagulant 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 to 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 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 cod liver oil therapy should have their INR monitored more closely and the dose of warfarin adjusted accordingly. (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.
    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 concomitant administration of rivaroxaban and conivaptan, a combined P-glycoprotein (P-gp) and strong CYP3A4 inhibitor; significant increases in rivaroxaban exposure may increase bleeding risk. Subsequent treatment with rivaroxaban may be initiated no sooner than 1 week after completion of conivaptan therapy. 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. Similar effects may be expected with concurrent conivaptan use.
    Crizotinib: (Major) Avoid coadministration of rivaroxaban and crizotinib in patients with renal impairment (CrCL 15 to 79 mL/min) unless the potential benefit justifies the potential risk. Rivaroxaban is a CYP3A4 and P-glycoprotein (P-gp) inhibitor. Crizotinib is a moderate CYP3A4 inhibitor, and also inhibits P-gp at clinically relevant concentrations. 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/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.
    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) Due to the increased bleeding risk, avoid concurrent use of rivaroxaban with 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.
    Dalfopristin; Quinupristin: (Minor) Coadministration of rivaroxaban and dalfopristin; quinupristin may result in increases in rivaroxaban exposure and may increase bleeding risk. Quinupristin 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.
    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.
    Danaparoid: (Major) Due to the increased bleeding risk, avoid concurrent use of rivaroxaban with danaparoid; the safety of concomitant use has not been studied. If danaparoid 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: (Major) Avoid concomitant administration of rivaroxaban and darunavir; significant increases in rivaroxaban exposure may increase bleeding risk. Rivaroxaban is a substrate of CYP3A4/5 and the P-glycoprotein (P-gp) transporter. Darunavir, 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.
    Darunavir; Cobicistat: (Major) Avoid concomitant administration of rivaroxaban and darunavir; significant increases in rivaroxaban exposure may increase bleeding risk. Rivaroxaban is a substrate of CYP3A4/5 and the P-glycoprotein (P-gp) transporter. Darunavir, 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. (Minor) The coadministration of rivaroxaban and cobicistat 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. Cobicistat is a combined CYP3A4 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)].
    Dasabuvir; Ombitasvir; Paritaprevir; 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.
    Dasatinib: (Moderate) Due to the thrombocytopenic and possible platelet inhibiting effects of dasatinib, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants. In addition, dasatinib is an inhibitor of CYP3A4, and rivaroxaban is a substrate of CYP3A4. Coadministration may result in increases in rivaroxaban exposure and may increase bleeding risk. Caution should be exercised if patients are required to take anticoagulants concomitantly with dasatinib.
    Decitabine: (Moderate) Due to the thrombocytopenic effects of antineoplastic agents, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants.
    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: (Severe) 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.
    Denileukin Diftitox: (Moderate) An additive risk of bleeding may be seen in thrombocytopenic patients receiving antineoplastic agents in combination with anticoagulants.
    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.
    Desvenlafaxine: (Major) Platelet aggregation may be impaired by desvenlafaxine due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication in patients receiving anticoagulants. Elevations in prothrombin time, activated partial thromboplastin and INR values have been reported post-marketing when venlafaxine was added to established warfarin therapy. The causality and mechanism of this potential interaction have not been established. Patients should be instructed to monitor for signs and symptoms of bleeding while taking an SNRI with an anticoagulant medication and to promptly report any bleeding events to the practitioner.
    Dexamethasone: (Minor) Coadministration of rivaroxaban and dexamethasone may result in decreased rivaroxaban exposure and may decrease the efficacy of rivaroxaban. Dexamethasone 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.
    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.
    Diltiazem: (Moderate) Avoid concomitant administration of rivaroxaban and diltiazem in patients with CrCl 15 to 80 ml/min unless the potential benefit justifies the potential risk. Diltiazem 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)].
    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)].
    Drospirenone; Ethinyl Estradiol: (Minor) Coadministration of rivaroxaban and ethinyl estradiol may result in increases in rivaroxaban exposure and may increase bleeding risk. Ethinyl estradiol is a mild inhibitor of CYP3A4, in vitro, and rivaroxaban is a substrate of CYP3A4. If these drugs are administered concurrently, monitor the patient for signs and symptoms of bleeding.
    Drospirenone; Ethinyl Estradiol; Levomefolate: (Minor) Coadministration of rivaroxaban and ethinyl estradiol may result in increases in rivaroxaban exposure and may increase bleeding risk. Ethinyl estradiol is a mild inhibitor of CYP3A4, in vitro, and rivaroxaban is a substrate of CYP3A4. If these drugs are administered concurrently, monitor the patient for signs and symptoms of bleeding.
    Drotrecogin Alfa: (Major) Treatment with drotrecogin alfa should be carefully considered in patients who are receiving or have received any anticoagulants. There is an additive risk of beeding.
    Duloxetine: (Major) Platelet aggregation may be impaired by duloxetine 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. Elevations in prothrombin time, activated partial thromboplastin and INR values have been reported post-marketing when venlafaxine was added to established warfarin therapy. The causality and mechanism of this potential interaction have not been established. Patients should be instructed to monitor for signs and symptoms of bleeding while taking an SNRI with an anticoagulant medication and to promptly report any bleeding events to the practitioner.
    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: (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.
    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.
    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.
    Enalapril; 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)].
    Enoxaparin: (Major) Due to the increased bleeding risk, avoid concurrent use of rivaroxaban with enoxaparin; the safety of concomitant use has not been studied. If enoxaparin is used during therapeutic transition periods, closely observe patients, and promptly evaluate any signs or symptoms of blood loss. 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) Coadministration of rivaroxaban and erythromycin may result in increases in rivaroxaban exposure. Rivaroxaban is a substrate of CYP3A4/5 and the P-glycoprotein (P-gp) transporter. Concurrent use of single-dose rivaroxaban and erythromycin, a combined P-gp and moderate CYP3A4 inhibitor, led to increases in the rivaroxaban AUC and Cmax by 30% in adult patients with normal renal function. A single dose of rivaroxaban was administered to patients wtih mild (CrCl 50 to 79 ml/min) or moderate (CrCl 30 to 49 ml/min) renal dysfunction receiving multiple doses of erythromycin. Compared to rivaroxaban administered alone to patients with normal renal function, patients with mild and moderate renal dysfunction reported a 76% and 99% increase in rivaroxaban AUC and a 56% and 64% increase in rivaroxaban Cmax, respectively. 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)]. According to the manufacturer of rivaroxaban, when clinical data suggest the change in exposure is unlikely to affect bleeding risk (e.g., erythromycin), no precautions are necessary during coadministration. More generally, coadministration of rivaroxaban with other combined CYP3A4 and moderate P-gp inhibitors is to be avoided in patients with CrCl 15 to 80 ml/min unless the potential benefit justifies the potential risk.
    Erythromycin; Sulfisoxazole: (Moderate) Coadministration of rivaroxaban and erythromycin may result in increases in rivaroxaban exposure. Rivaroxaban is a substrate of CYP3A4/5 and the P-glycoprotein (P-gp) transporter. Concurrent use of single-dose rivaroxaban and erythromycin, a combined P-gp and moderate CYP3A4 inhibitor, led to increases in the rivaroxaban AUC and Cmax by 30% in adult patients with normal renal function. A single dose of rivaroxaban was administered to patients wtih mild (CrCl 50 to 79 ml/min) or moderate (CrCl 30 to 49 ml/min) renal dysfunction receiving multiple doses of erythromycin. Compared to rivaroxaban administered alone to patients with normal renal function, patients with mild and moderate renal dysfunction reported a 76% and 99% increase in rivaroxaban AUC and a 56% and 64% increase in rivaroxaban Cmax, respectively. 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)]. According to the manufacturer of rivaroxaban, when clinical data suggest the change in exposure is unlikely to affect bleeding risk (e.g., erythromycin), no precautions are necessary during coadministration. More generally, coadministration of rivaroxaban with other combined CYP3A4 and moderate P-gp inhibitors is to be avoided in patients with CrCl 15 to 80 ml/min unless the potential benefit justifies the potential risk.
    Escitalopram: (Major) Selective serotonin reuptake inhibitors (SSRIs) can inhibit serotonin uptake by platelets, thus causing platelet dysfunction and increasing the risk for bleeding with rivaroxaban; however, the absolute risk is not known. 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.
    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.
    Esomeprazole; 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.
    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.
    Estramustine: (Moderate) An additive risk of bleeding may be seen in thrombocytopenic patients receiving antineoplastic agents in combination with anticoagulants.
    Ethanol: (Minor) Use rivaroxaban cautiously in patients who consume alcohol. Coadministration of rivaroxaban and ethanol may result in decreased rivaroxaban exposure and may decrease the efficacy of rivaroxaban. Ethanol is an inducer of CYP3A4, and rivaroxaban is a substrate of CYP3A4. If a patient taking rivaroxaban also consumes alcohol, monitor the patient for signs of lack of efficacy of rivaroxaban.
    Ethinyl Estradiol: (Minor) Coadministration of rivaroxaban and ethinyl estradiol may result in increases in rivaroxaban exposure and may increase bleeding risk. Ethinyl estradiol is a mild inhibitor of CYP3A4, in vitro, and rivaroxaban is a substrate of CYP3A4. If these drugs are administered concurrently, monitor the patient for signs and symptoms of bleeding.
    Ethinyl Estradiol; Desogestrel: (Minor) Coadministration of rivaroxaban and ethinyl estradiol may result in increases in rivaroxaban exposure and may increase bleeding risk. Ethinyl estradiol is a mild inhibitor of CYP3A4, in vitro, and rivaroxaban is a substrate of CYP3A4. If these drugs are administered concurrently, monitor the patient for signs and symptoms of bleeding.
    Ethinyl Estradiol; Ethynodiol Diacetate: (Minor) Coadministration of rivaroxaban and ethinyl estradiol may result in increases in rivaroxaban exposure and may increase bleeding risk. Ethinyl estradiol is a mild inhibitor of CYP3A4, in vitro, and rivaroxaban is a substrate of CYP3A4. If these drugs are administered concurrently, monitor the patient for signs and symptoms of bleeding.
    Ethinyl Estradiol; Etonogestrel: (Minor) Coadministration of rivaroxaban and ethinyl estradiol may result in increases in rivaroxaban exposure and may increase bleeding risk. Ethinyl estradiol is a mild inhibitor of CYP3A4, in vitro, and rivaroxaban is a substrate of CYP3A4. If these drugs are administered concurrently, monitor the patient for signs and symptoms of bleeding.
    Ethinyl Estradiol; Levonorgestrel: (Minor) Coadministration of rivaroxaban and ethinyl estradiol may result in increases in rivaroxaban exposure and may increase bleeding risk. Ethinyl estradiol is a mild inhibitor of CYP3A4, in vitro, and rivaroxaban is a substrate of CYP3A4. If these drugs are administered concurrently, monitor the patient for signs and symptoms of bleeding.
    Ethinyl Estradiol; Levonorgestrel; Folic Acid; Levomefolate: (Minor) Coadministration of rivaroxaban and ethinyl estradiol may result in increases in rivaroxaban exposure and may increase bleeding risk. Ethinyl estradiol is a mild inhibitor of CYP3A4, in vitro, and rivaroxaban is a substrate of CYP3A4. If these drugs are administered concurrently, monitor the patient for signs and symptoms of bleeding.
    Ethinyl Estradiol; Norelgestromin: (Minor) Coadministration of rivaroxaban and ethinyl estradiol may result in increases in rivaroxaban exposure and may increase bleeding risk. Ethinyl estradiol is a mild inhibitor of CYP3A4, in vitro, and rivaroxaban is a substrate of CYP3A4. If these drugs are administered concurrently, monitor the patient for signs and symptoms of bleeding.
    Ethinyl Estradiol; Norethindrone Acetate: (Minor) Coadministration of rivaroxaban and ethinyl estradiol may result in increases in rivaroxaban exposure and may increase bleeding risk. Ethinyl estradiol is a mild inhibitor of CYP3A4, in vitro, and rivaroxaban is a substrate of CYP3A4. If these drugs are administered concurrently, monitor the patient for signs and symptoms of bleeding.
    Ethinyl Estradiol; Norethindrone Acetate; Ferrous fumarate: (Minor) Coadministration of rivaroxaban and ethinyl estradiol may result in increases in rivaroxaban exposure and may increase bleeding risk. Ethinyl estradiol is a mild inhibitor of CYP3A4, in vitro, and rivaroxaban is a substrate of CYP3A4. If these drugs are administered concurrently, monitor the patient for signs and symptoms of bleeding.
    Ethinyl Estradiol; Norethindrone: (Minor) Coadministration of rivaroxaban and ethinyl estradiol may result in increases in rivaroxaban exposure and may increase bleeding risk. Ethinyl estradiol is a mild inhibitor of CYP3A4, in vitro, and rivaroxaban is a substrate of CYP3A4. If these drugs are administered concurrently, monitor the patient for signs and symptoms of bleeding.
    Ethinyl Estradiol; Norethindrone; Ferrous fumarate: (Minor) Coadministration of rivaroxaban and ethinyl estradiol may result in increases in rivaroxaban exposure and may increase bleeding risk. Ethinyl estradiol is a mild inhibitor of CYP3A4, in vitro, and rivaroxaban is a substrate of CYP3A4. If these drugs are administered concurrently, monitor the patient for signs and symptoms of bleeding.
    Ethinyl Estradiol; Norgestimate: (Minor) Coadministration of rivaroxaban and ethinyl estradiol may result in increases in rivaroxaban exposure and may increase bleeding risk. Ethinyl estradiol is a mild inhibitor of CYP3A4, in vitro, and rivaroxaban is a substrate of CYP3A4. If these drugs are administered concurrently, monitor the patient for signs and symptoms of bleeding.
    Ethinyl Estradiol; Norgestrel: (Minor) Coadministration of rivaroxaban and ethinyl estradiol may result in increases in rivaroxaban exposure and may increase bleeding risk. Ethinyl estradiol is a mild inhibitor of CYP3A4, in vitro, and rivaroxaban is a substrate of CYP3A4. If these drugs are administered concurrently, monitor the patient for signs and symptoms of bleeding.
    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.
    Etoposide, VP-16: (Minor) Monitor for an increased incidence of etoposide-related adverse effects if used concomitantly with rivaroxaban. In vitro, rivaroxaban is a weak inhibitor of P-glycoprotein (P-gp); etoposide, VP-16 is a P-gp substrate. Coadministration may increase etoposide concentrations.
    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.
    Ezetimibe; Simvastatin: (Minor) Coadministration of rivaroxaban and simvastatin may result in increases in rivaroxaban exposure and may increase bleeding risk. Simvastatin 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.
    Factor X: (Major) The actions of factor X are likely to be counteracted by factor Xa inhibitors such as rivaroxaban.
    Famotidine; 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.
    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.
    Floxuridine: (Moderate) An additive risk of bleeding may be seen in thrombocytopenic patients receiving antineoplastic agents in combination with anticoagulants.
    Fluconazole: (Minor) Coadminister rivaroxaban and fluconazole with caution. Rivaroxaban is a substrate of P-glycoprotein (P-gp) and CYP3A4/5; fluconazole is a moderate CYP3A4 inhibitor. Concurrent use of rivaroxaban and fluconazole led to an increase in the steady-state rivaroxaban AUC by 40% and Cmax by 30%. These increases were smaller than the increases seen with ketoconazole and itraconazole; however, both ketoconazole and itraconazole inhibit P-gp and are strong CYP3A4 inhibitors. Significant increases in rivaroxaban exposure may increase bleeding risk.
    Fluorouracil, 5-FU: (Major) An additive risk of bleeding may be seen in thrombocytopenic patients receiving antineoplastic agents and anticoagulants concomitantly.
    Fluoxetine: (Major) Selective serotonin reuptake inhibitors (SSRIs) can inhibit serotonin uptake by platelets, thus causing platelet dysfunction and increasing the risk for bleeding with rivaroxaban; however, the absolute risk is not known. In addition, coadministration of rivaroxaban and fluoxetine may result in increases in rivaroxaban exposure and may increase bleeding risk. Fluoxetine is a mild inhibitor of CYP3A4, and rivaroxaban is a substrate of CYP3A4. 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.
    Fluoxetine; Olanzapine: (Major) Selective serotonin reuptake inhibitors (SSRIs) can inhibit serotonin uptake by platelets, thus causing platelet dysfunction and increasing the risk for bleeding with rivaroxaban; however, the absolute risk is not known. In addition, coadministration of rivaroxaban and fluoxetine may result in increases in rivaroxaban exposure and may increase bleeding risk. Fluoxetine is a mild inhibitor of CYP3A4, and rivaroxaban is a substrate of CYP3A4. 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.
    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: (Major) Selective serotonin reuptake inhibitors (SSRIs) can inhibit serotonin uptake by platelets, thus causing platelet dysfunction and increasing the risk for bleeding with rivaroxaban; however, the absolute risk is not known.In addition, coadministration of rivaroxaban and fluovoxamine may result in increases in rivaroxaban exposure and may increase bleeding risk. Fluvoxamine is an inhibitor of CYP3A4, and rivaroxaban is a substrate of CYP3A4. 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.
    Folate analogs: (Moderate) Due to the thrombocytopenic effects of folate analogs, when used as antineoplastic agents, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants.
    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 drugs that are combined P-glycoprotein (P-gp) and strong CYP3A4 inducers such as phenytoin or fosphenytoin. 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.
    Fulvestrant: (Moderate) Because fulvestrant is given intramuscularly, it should not be used or given with caution in patients receiving anticoagulants. Fulvestrant IM injections may cause bleeding, bruising, or hematomas in these patients.
    Garlic, Allium sativum: (Moderate) Garlic produces clinically significant antiplatelet effects so additive bleeding may occur if anticoagulants are given in combination with garlic, allium sativum. In regard to warfarin, no substantial clinical data are available to support or deny a potential for interaction; the data are limited to a random case report. 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. Avoid concurrent use of herbs which interact with warfarin when possible. If these herbal products are taken concurrently with warfarin, monitor INR and adjust warfarin dosage to attain clinical and anticoagulant endpoints.
    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: (Major) Ginkgo, Ginkgo biloba is reported to inhibit platelet aggregation and several case reports describe bleeding complications with Ginkgo biloba, with or without concomitant drug therapy. Since ginkgo produces clinically-significant antiplatelet effects, it should be used cautiously in patients drugs that inhibit platelet aggregation or pose a risk for bleeding, such as anticoagulants. Ginkgo, Ginkgo biloba is reported to inhibit platelet aggregation and several case reports describe bleeding complications with Ginkgo biloba, with or without concomitant drug therapy. Since ginkgo produces clinically-significant antiplatelet effects, it should be used cautiously in patients drugs that inhibit platelet aggregation or pose a risk for bleeding, such as anticoagulants (e.g., warfarin), aspirin, ASA or other platelet inhibitors, or thrombolytic agents. A patient who had been taking aspirin 325 mg/day PO for 3 years following coronary-artery bypass surgery, developed spontaneous bleeding into his eye after taking a standardized extract of Ginkgo biloba (Ginkoba commercial product) 40 mg PO twice daily for one week. The patient stopped taking the ginkgo but continued taking the aspirin with no recurrence of bleeding over a 3-month period. Other clinical data exist that describe spontaneous subdural hematomas associated with chronic ginkgo biloba ingestion.
    Glimepiride; Pioglitazone: (Minor) Coadministration of rivaroxaban and pioglitazone may result in decreased rivaroxaban exposure and may decrease the efficacy of rivaroxaban. Pioglitazone 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.
    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.
    Guarana: (Major) Guarana has been shown to possess minor antiplatelet activity and, therefore, concurrent use of guarana and anticoagulants or platelet inhibitors should be avoided.
    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.
    Hydroxyurea: (Moderate) An additive risk of bleeding may be seen in thrombocytopenic patients receiving antineoplastic agents and anticoagulants concomitantly.
    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 blood loss if patients are treated concomitantly with salicylates. In a single-dose drug interaction study, no pharmacokinetic or pharmacodynamic interactions were observed after concomitant administration of naproxen or acetylsalicylic acid with rivaroxaban.
    Ibritumomab Tiuxetan: (Moderate) Due to the thrombocytopenic effects of the ibritumomab tiuxetan therapeutic regimen, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants.
    Ibrutinib: (Minor) Use caution with concomitant use of ibrutinib and anticoagulants such as rivaroxaban. Bleeding or bruising events occurred in 48% to 63% (grade 3 or 4, 5% to 6%) of patients treated with ibrutinib in clinical trials. The mechanism for bleeding is not well understood, and the risk of hemorrhage may be increased in patients receiving anticoagulant therapy. Closely monitor patients for signs and symptoms of bleeding.
    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.
    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.
    Ifosfamide: (Moderate) Due to the thrombocytopenic effects of ifosfamide, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants.
    Iloperidone: (Minor) Coadministration of rivaroxaban and iloperidone may result in increases in rivaroxaban exposure and may increase bleeding risk. Iloperidone is a mild 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.
    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.
    Interferon Alfa-2a: (Moderate) An additive risk of bleeding may be seen in thrombocytopenic patients receiving antineoplastic agents in combination with anticoagulants.
    Interferon Alfa-2b: (Moderate) An additive risk of bleeding may be seen in thrombocytopenic patients receiving antineoplastic agents in combination with anticoagulants.
    Interferon Alfa-2b; Ribavirin: (Moderate) An additive risk of bleeding may be seen in thrombocytopenic patients receiving antineoplastic agents in combination with anticoagulants.
    Interferon Alfacon-1: (Moderate) An additive risk of bleeding may be seen in thrombocytopenic patients receiving antineoplastic agents in combination with anticoagulants.
    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: (Minor) Coadministration of rivaroxaban and isoniazid, INH may result in increases in rivaroxaban exposure and may increase bleeding risk. Isoniazid 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.
    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. (Minor) Coadministration of rivaroxaban and isoniazid, INH may result in increases in rivaroxaban exposure and may increase bleeding risk. Isoniazid 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.
    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. (Minor) Coadministration of rivaroxaban and isoniazid, INH may result in increases in rivaroxaban exposure and may increase bleeding risk. Isoniazid 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.
    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)].
    Kava Kava, Piper methysticum: (Moderate) Kava kava, Piper methysticum does appear to have some anti-thrombotic activity. Persons who are receiving anticoagulants should not take kava kava without first discussing use with their health care professional. Kava kava, Piper methysticum exhibits antithrombotic activity and also inhibits CYP isozymes important in warfarin clearance such as CYP2C9, 2C19, 1A2 and 3A4. Avoid concurrent use of herbs which interact with warfarin when possible. If these herbal products are taken concurrently with warfarin, monitor INR and adjust warfarin dosage to attain clinical and anticoagulant endpoints.
    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: (Minor) Coadministration of rivaroxaban and lansoprazole may result in increases in rivaroxaban exposure and may increase bleeding risk. Lansoprazole 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.
    Lansoprazole; 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. (Minor) Coadministration of rivaroxaban and lansoprazole may result in increases in rivaroxaban exposure and may increase bleeding risk. Lansoprazole 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.
    Lapatinib: (Minor) The coadministration of rivaroxaban and lapatinib 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. Lapatinib is a combined CYP3A4 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)].
    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.
    Lepirudin: (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.
    Levomilnacipran: (Major) Platelet aggregation may be impaired by serotonin norepinephrine reuptake inhibitors (SNRIs) 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. The causality and mechanism of this potential interaction have not been established. Patients should be instructed to monitor for signs and symptoms of bleeding while taking an SNRI with an anticoagulant medication and to promptly report any bleeding events to the practitioner.
    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.
    Loperamide: (Moderate) The plasma concentration of loperamide, a P-glycoprotein (P-gp) substrate, may be increased when administered concurrently with rivaroxaban, a mild P-gp inhibitor. If these drugs are used together, monitor for loperamide-associated adverse reactions, such as CNS effects and cardiac toxicities (i.e., syncope, ventricular tachycardia, QT prolongation, torsade de pointes, cardiac arrest).
    Loperamide; Simethicone: (Moderate) The plasma concentration of loperamide, a P-glycoprotein (P-gp) substrate, may be increased when administered concurrently with rivaroxaban, a mild P-gp inhibitor. If these drugs are used together, monitor for loperamide-associated adverse reactions, such as CNS effects and cardiac toxicities (i.e., syncope, ventricular tachycardia, QT prolongation, torsade de pointes, cardiac arrest).
    Lopinavir; Ritonavir: (Major) Avoid concomitant administration of rivaroxaban and lopinavir; ritonavir; 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 ritonavir, a combined P-glycoprotein 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. (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.
    Lovastatin: (Minor) Coadministration of rivaroxaban and lovastatin may result in increases in rivaroxaban exposure and may increase bleeding risk. Lovastatin 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.
    Lovastatin; Niacin: (Minor) Coadministration of rivaroxaban and lovastatin may result in increases in rivaroxaban exposure and may increase bleeding risk. Lovastatin 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.
    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 blood loss if patients are treated concomitantly with salicylates. In a single-dose drug interaction study, no pharmacokinetic or pharmacodynamic interactions were observed after concomitant administration of naproxen or acetylsalicylic acid 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.
    Mestranol; Norethindrone: (Minor) Coadministration of rivaroxaban and oral contraceptives containing ethinyl estradiol, including mestranol; norethindrone and ethinyl estradiol; etonogestrel vaginal ring, may result in increases in rivaroxaban exposure and may increase bleeding risk. Mestranol is rapidly metabolized by demethylation to ethinyl estradiol, the biologically active form, up on absorption. Ethinyl estradiol is a mild inhibitor of CYP3A4, in vitro, and rivaroxaban is a substrate of CYP3A4. If these drugs are administered concurrently, monitor the patient for signs and symptoms of bleeding
    Metformin; Pioglitazone: (Minor) Coadministration of rivaroxaban and pioglitazone may result in decreased rivaroxaban exposure and may decrease the efficacy of rivaroxaban. Pioglitazone 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.
    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.
    Metyrapone: (Minor) Coadministration of rivaroxaban and metyrapone may result in decreased rivaroxaban exposure and may decrease the efficacy of rivaroxaban. Metyrapone 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.
    Mifepristone, RU-486: (Major) When mifepristone, RU-486 (Mifeprex) is used for the termination of pregnancy, concurrent use of anticoagulants is contraindicated due to the increased risk of serious bleeding. When mifepristone (Korlym) is used, concurrent use of some anticoagulants should be approached with caution. The coadministration of rivaroxaban and mifepristone, RU-486 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. Mifepristone is a combined CYP3A4 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)].
    Milnacipran: (Major) Platelet aggregation may be impaired by serotonin norepinephrine reuptake inhibitors (SNRIs) 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. The causality and mechanism of this potential interaction have not been established. Patients should be instructed to monitor for signs and symptoms of bleeding while taking an SNRI with an anticoagulant medication and to promptly report any bleeding events to the practitioner.
    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.
    Mirabegron: (Minor) Coadministration of rivaroxaban and mirabegron may result in increases in rivaroxaban exposure and may increase bleeding risk. Mirabegron is a mild 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.
    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.
    Naltrexone: (Moderate) Give the extended-release injectable suspension of naltrexone cautiously to patients taking anticoagulants. Steps should be taken to avoid the risk of bleeding and hematoma formation following intramuscular injection.
    Nandrolone Decanoate: (Moderate) Androgens can enhance the effects of anticoagulants. Dosage of the anticoagulant may have to be decreased in order to maintain prothrombin time at the desired therapeutic level. When anabolic steroid or androgen therapy is started or stopped in patients on anticoagulant therapy, close monitoring is required. Additionally, nandrolone decanoate may generate a pharmacodynamic interaction with warfarin by independently affecting the activity of circulating coagulation proteins. Androgens reduce the amount or activity of circulating coagulant proteins thereby enhancing the anticoagulant effect of warfarin.
    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; 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.
    Naproxen; Sumatriptan: (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.
    Natural Antineoplastics: (Moderate) Due to the risk of bleeding with natural antineoplastics, patients should receive other agents that may increase the risk of bleeding, such as anticoagulants.
    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: (Minor) Coadministration of rivaroxaban and nevirapine may result in decreased rivaroxaban exposure and may decrease the efficacy of rivaroxaban. Nevirapine 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.
    Niacin; Simvastatin: (Minor) Coadministration of rivaroxaban and simvastatin may result in increases in rivaroxaban exposure and may increase bleeding risk. Simvastatin 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.
    Nicardipine: (Minor) The coadministration of rivaroxaban and nicardipine 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. In vitro, nicardipine is a combined CYP3A4 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)].
    Nifedipine: (Minor) Coadministration of rivaroxaban and nifedipine may result in increases in rivaroxaban exposure and may increase bleeding risk. Nifedipine is a mild 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.
    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.
    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.
    Octreotide: (Minor) Coadministration of rivaroxaban and octreotide may result in increases in rivaroxaban exposure and may increase bleeding risk. Octreotide 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.
    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.
    Ombitasvir; Paritaprevir; 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.
    Omeprazole: (Minor) Coadministration of rivaroxaban and omeprazole may result in increases in rivaroxaban exposure and may increase bleeding risk. Omeprazole 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.
    Omeprazole; Sodium Bicarbonate: (Minor) Coadministration of rivaroxaban and omeprazole may result in increases in rivaroxaban exposure and may increase bleeding risk. Omeprazole 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.
    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.
    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.
    Oxcarbazepine: (Minor) Coadministration of rivaroxaban and oxcarbazepine may result in decreased rivaroxaban exposure and may decrease the efficacy of rivaroxaban. Oxcarbazepine 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.
    Paliperidone: (Minor) Coadministration of rivaroxaban and paliperidone may result in increases in rivaroxaban exposure and may increase bleeding risk. Paliperidone 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.
    Pantoprazole: (Minor) The coadministration of rivaroxaban and pantoprazole 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. Pantoprazole is a combined CYP3A4 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)].
    Paroxetine: (Major) Selective serotonin reuptake inhibitors (SSRIs) can inhibit serotonin uptake by platelets, thus causing platelet dysfunction and increasing the risk for bleeding with rivaroxaban; however, the absolute risk is not known. 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.
    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.
    Phentermine; Topiramate: (Moderate) Concurrent use of topiramate and anticoagulants may increase the risk of bleeding. In a pooled analysis of placebo-controlled trials, bleeding was more frequently reported in patients receiving topiramate (4.5%) compared to placebo (2-3%). In those with severe bleeding events, patients were often taking drugs that cause thrombocytopenia or affect platelet function or coagulation. However, coadministration of rivaroxaban and topiramate may result in decreased rivaroxaban exposure and may decrease the efficacy of rivaroxaban. Topiramate 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 bleeding or lack of efficacy of rivaroxaban.
    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.
    Photosensitizing agents: (Minor) Drugs that decrease clotting, such as anticoagulants, could decrease the efficacy of photodynamic therapy.
    Pioglitazone: (Minor) Coadministration of rivaroxaban and pioglitazone may result in decreased rivaroxaban exposure and may decrease the efficacy of rivaroxaban. Pioglitazone 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.
    Piperacillin: (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.
    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.
    Porfimer: (Minor) Drugs that decrease clotting, such as anticoagulants, could decrease the efficacy of photodynamic therapy.
    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.
    Propafenone: (Minor) Coadministration of rivaroxaban and propafenone may result in increases in rivaroxaban exposure and may increase bleeding risk. Propafenone 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.
    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.
    Rabies Immune Globulin, human RIG: (Minor) The intramuscular rabies immune globulin, human RIG should be administered cautiously to persons receiving anticoagulants. If used concurrently, monitor patients closely for bleeding at the IM injection site. All steps to avoid hematoma formation are recommended.
    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)].
    Regorafenib: (Minor) The coadministration of rivaroxaban and regorafenib 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. Regorafenib 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/minute [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.
    Rifaximin: (Moderate) Rifaximin is a combined mild P-glycoprotein inhibitor and CYP3A4 inhibitor. The coadministration of rivaroxaban and rifaximin 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. Based on simulated pharmacokinetic data, patients with renal impairment receiving rivaroxaban with drugs that are combined P-glycoprotein and weak or moderate CYP3A4 inhibitors such as rifaximin may have significant increases in exposure compared with patients with normal renal function and no inhibitor use, since both pathways of rivaroxaban elimination are affected. Because these increases may increase bleeding risk, only use rivaroxaban in this situation if the potential benefit justifies the potential risk. In addition, although rifaximin is an inhibitor of both CYP3A4 and P-glycoprotein, which may increase rivaroxaban exposure, the manufacturer of rivaroxaban states that clinical data suggest that the change in rivaroxaban exposure when coadministered with another CYP3A4/P-gp inhibitor, erythromycin, is unlikely to affect bleeding risk in patients with normal renal function.
    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.
    Rofecoxib: (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.
    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 blood loss if patients are treated concomitantly with salicylates. In a single-dose drug interaction study, no pharmacokinetic or pharmacodynamic interactions were observed after concomitant administration of naproxen or acetylsalicylic acid 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 blood loss if patients are treated concomitantly with salicylates. In a single-dose drug interaction study, no pharmacokinetic or pharmacodynamic interactions were observed after concomitant administration of naproxen or acetylsalicylic acid with rivaroxaban.
    Sapropterin: (Minor) Caution is advised with the concomitant use of sapropterin and rivaroxaban as coadministration may result in increased systemic exposure of rivaroxaban. Rivaroxaban is a substrate for the drug transporter P-glycoprotein (P-gp); in vitro data show that sapropterin may inhibit P-gp. If these drugs are used together, closely monitor for increased side effects of 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.
    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.
    Sertraline: (Major) Selective serotonin reuptake inhibitors (SSRIs) can inhibit serotonin uptake by platelets, thus causing platelet dysfunction and increasing the risk for bleeding with rivaroxaban; however, the absolute risk is not known. 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.
    Simeprevir: (Minor) Coadministration of rivaroxaban and simeprevir may result in increases in rivaroxaban exposure and may increase bleeding risk. Simeprevir is a mild 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.
    Simvastatin: (Minor) Coadministration of rivaroxaban and simvastatin may result in increases in rivaroxaban exposure and may increase bleeding risk. Simvastatin 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.
    Simvastatin; Sitagliptin: (Minor) Coadministration of rivaroxaban and simvastatin may result in increases in rivaroxaban exposure and may increase bleeding risk. Simvastatin 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.
    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 drugs that are combined P-glycoprotein and strong CYP3A4 inducers such as St. John's wort. Consider increasing the rivaroxaban dose if St. John's wort 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.
    Streptogramins: (Minor) Coadministration of rivaroxaban and dalfopristin; quinupristin may result in increases in rivaroxaban exposure and may increase bleeding risk. Quinupristin 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.
    Streptokinase: (Major) Due to the increased bleeding risk, avoid concurrent use of rivaroxaban with thrombolytic agents; the safety of concomitant use has not been studied.
    Sulfinpyrazone: (Major) Sulfinpyrazone should be avoided when possible with concurrent anticoagulants, thrombin inhibitors, and thrombolytic agents due to potential for increased bleeding risk. Alternative uricosuric agents may be considered. Sulfinpyrazone is a platelet inhibitor and exhibits antithrombotic actions in addition to its uricosuric effects. Additive hematological effects are possible as a result of the platelet inhibitory effects of sulfinpyrazone; the sulfide metabolite of sulfinpyrazone appears responsible for this effect. Sulfinpyrazone is also known to markedly potentiate the effect of warfarin. Sulfinpyrazone may inhibit CYP2C9, leading to a decrease in the clearance of S-warfarin. If concurrent therapy is warranted, significant initial dosage reductions (e.g., 50%) of warfarin may be necessary, with further dosage adjusted based on INR values. The INR should be closely monitored during concurrent therapy with warfarin, particularly during the initiation or termination phases of sulfinpyrazone treatment.
    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.
    Taxanes: (Moderate) Due to the thrombocytopenic effects of taxanes, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants.
    Telaprevir: (Major) Avoid concomitant administration of rivaroxaban and telaprevir; significant increases in rivaroxaban exposure may increase bleeding risk. Rivaroxaban is a substrate of CYP3A4/5 and the P-glycoprotein (P-gp) transporter. Telaprevir 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.
    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.
    Telithromycin: (Major) Avoid concomitant administration of rivaroxaban and telithromycin; significant increases in rivaroxaban exposure may increase bleeding risk. Rivaroxaban is a substrate of CYP3A4/5 and the P-glycoprotein (P-gp) transporter. Telithromycin 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.
    Telotristat Ethyl: (Moderate) Use caution if coadministration of telotristat ethyl and rivaroxaban is necessary, as the systemic exposure of rivaroxaban may be decreased resulting in reduced efficacy. If these drugs are used together, monitor patients for suboptimal efficacy of rivaroxaban; consider increasing the dose of rivaroxaban if necessary. Rivaroxaban is a CYP3A4 substrate. The mean Cmax and AUC of another sensitive CYP3A4 substrate was decreased by 25% and 48%, respectively, when coadministered with telotristat ethyl; the mechanism of this interaction appears to be that telotristat ethyl increases the glucuronidation of the CYP3A4 substrate.
    Temsirolimus: (Moderate) Use caution if coadministration of temsirolimus with rivaroxaban is necessary, and monitor for an increase in temsirolimus- and rivaroxaban-related adverse reactions. Avoid use of this combination with an additional drug that strongly inhibits CYP3A4. Temsirolimus is a P-glycoprotein (P-gp) substrate / inhibitor in vitro. Rivaroxaban is also a P-gp substrate and weak inhibitor, as well as a CYP3A4 substrate. Pharmacokinetic data are not available for concomitant use of temsirolimus with P-gp inhibitors or substrates, but exposure to both rivaroxaban and temsirolimus (and active metabolite, sirolimus) is likely to increase. Data are also not available for rivaroxaban with P-gp inhibitors or substrates. However, in drug interaction studies evaluating the use of rivaroxaban with drugs that are combined P-gp and strong CYP3A4 inhibitors (ketoconazole, ritonavir, clarithromycin), increases in rivaroxaban exposure (from 40% to 160%) and pharmacodynamic effects (i.e., factor Xa inhibition and PT prolongation) were observed; the effects of P-gp inhibition and moderate CYP3A4 inhibition were less (AUC increased by 30% to 50%).
    Tenecteplase, TNK-tPA: (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.
    Testosterone: (Minor) Coadministration of rivaroxaban and testosterone may result in increases in rivaroxaban exposure and may increase bleeding risk. Testosterone 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.
    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.
    Ticarcillin: (Moderate) Some penicillins (e.g., ticarcillin) 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.
    Ticarcillin; Clavulanic Acid: (Moderate) Some penicillins (e.g., ticarcillin) 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.
    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.
    Tinzaparin: (Major) Due to the increased bleeding risk, avoid concurrent use of rivaroxaban with other anticoagulants; the safety of long-term concomitant use of these drugs has not been studied. If another anticoagulant is used during therapeutic transition periods, closely observe patients, and promptly evaluate any signs or symptoms of blood loss.
    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.
    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.
    Tolvaptan: (Minor) Coadministration of rivaroxaban and tolvaptan may result in increases in rivaroxaban exposure and may increase bleeding risk. Tolvaptan is an inhibitor of P-gp (potency unknown), and rivaroxaban is a substrate of P-gp. If these drugs are administered concurrently, monitor the patient for signs and symptoms of bleeding.
    Topiramate: (Moderate) Concurrent use of topiramate and anticoagulants may increase the risk of bleeding. In a pooled analysis of placebo-controlled trials, bleeding was more frequently reported in patients receiving topiramate (4.5%) compared to placebo (2-3%). In those with severe bleeding events, patients were often taking drugs that cause thrombocytopenia or affect platelet function or coagulation. However, coadministration of rivaroxaban and topiramate may result in decreased rivaroxaban exposure and may decrease the efficacy of rivaroxaban. Topiramate 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 bleeding or lack of efficacy of rivaroxaban.
    Topotecan: (Major) Avoid the concomitant use of rivaroxaban, a weak in vitro P-glycoprotein (P-gp) inhibitor, with oral topotecan, a P-gp substrate; P-gp inhibitors have less of an effect on intravenous topotecan and these may be coadministered with caution. If coadministration of rivaroxaban and oral topotecan is necessary, carefully monitor for increased toxicity of topotecan, including severe myelosuppression and diarrhea. In a pharmacokinetic cohort study, coadministration of oral topotecan with a potent P-gp inhibitor (n = 8) increased the Cmax and AUC of topotecan by 2 to 3 fold (p = 0.008); coadministration with intravenous topotecan (n = 8) increased total topotecan exposure by 1.2-fold (p = 0.02) and topotecan lactone by 1.1-fold (not significant).
    Trandolapril; Verapamil: (Moderate) Avoid concomitant administration of rivaroxaban and verapamil in patients with CrCl 15 to 80 ml/min unless the potential benefit justifies the potential risk. Verapamil 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)].
    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.
    Tretinoin, ATRA: (Moderate) An additive risk of bleeding may be seen in thrombocytopenic patients receiving antineoplastic agents in combination with anticoagulants.
    Ulipristal: (Minor) Coadministration of rivaroxaban and ulipristal may result in increases in rivaroxaban exposure and may increase bleeding risk. Ulipristal is a mild 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.
    Urokinase: (Major) Due to the increased bleeding risk, avoid concurrent use of rivaroxaban with thrombolytic agents; the safety of concomitant use has not been studied.
    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.
    Vandetanib: (Moderate) Use caution if coadministration of vandetanib with rivaroxaban is necessary, due to a possible increase in rivaroxaban-related adverse reactions including bleeding; this risk may be increased in patients with renal impairment or those taking a concomitant CYP3A4 inhibitor. Rivaroxaban is a substrate of CYP3A4 and P-glycoprotein (P-gp). Coadministration with vandetanib increased the Cmax and AUC of digoxin, another P-gp substrate, by 29% and 23%, respectively.
    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.
    Venlafaxine: (Major) Platelet aggregation may be impaired by venlafaxine 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. Elevations in prothrombin time, activated partial thromboplastin and INR values have been reported post-marketing when venlafaxine was added to established warfarin therapy. Monitor INR levels when venlafaxine is added to or discontinued from warfarin therapy. Patients should be instructed to monitor for signs and symptoms of bleeding while taking venlafaxine concurrently with an anticoagulant medication and to promptly report any bleeding events to the practitioner.
    Verapamil: (Moderate) Avoid concomitant administration of rivaroxaban and verapamil in patients with CrCl 15 to 80 ml/min unless the potential benefit justifies the potential risk. Verapamil 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)].
    Verteporfin: (Minor) Drugs that decrease clotting, such as anticoagulants, could decrease the efficacy of photodynamic 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.
    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.
    Voriconazole: (Minor) Coadministration of rivaroxaban and voriconazole may result in increases in rivaroxaban exposure and may increase bleeding risk. Voriconazole 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.
    Vorinostat: (Moderate) Concomitant use of vorinostat with anticoagulants may result in an additive risk of bleeding due to vorinostat-induced thrombocytopenia; monitor patients closely.
    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) Due to the increased bleeding risk, avoid concurrent use of rivaroxaban with other anticoagulants; the safety of concomitant use of these drugs has not been studied. In a drug interaction study, single doses of warfarin (15 mg) and rivaroxaban (5 mg) resulted in an additive effect on factor Xa inhibition and PT. Warfarin did not affect the pharmacokinetic parameters of 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.

    PREGNANCY AND LACTATION

    Pregnancy

    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 with an anticoagulant that is not readily reversible. 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.

    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 of rivaroxaban in human plasma is approximately 92% to 95%; albumin is the main binding component. The volume of distribution at steady state is approximately 50 L in heathy subjects. Oxidative degradation catalyzed by CYP3A4/5 and CYP2J2 and hydrolysis are the major sites of biotransformation. Unchanged rivaroxaban was the predominant moiety in plasma with no major or active circulating metabolites. After oral administration, 66% of the dose was recovered in urine (36% as unchanged drug and 30% as metabolites) and 28% was recovered in feces (7% as unchanged drug and 21% as metabolites). Unchanged drug is excreted into urine, mainly via active tubular secretion and to a lesser extent via glomerular filtration (approximate 5:1 ratio). Rivaroxaban is a substrate of the efflux transporter proteins P-glycoprotein and ABCG2 (also abbreviated BCRP). Rivaroxaban’s affinity for influx transporter proteins is unknown. 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.
     
    The anticoagulant effect of rivaroxaban cannot be monitored with standard laboratory testing or be readily reversed. Dose-dependent inhibition of factor Xa activity was observed in humans and the Neoplastin prothrombin time (PT), activated partial thromboplastin time (aPTT), and HepTest are prolonged dose-dependently. Anti-factor Xa activity is also influenced by rivaroxaban. No data exist on the use of the International Normalized Ratio (INR). The predictive value of these coagulation parameters for bleeding risk or efficacy has not been established.
     
    Affected cytochrome P450 isoenzymes and drug transporters: CYP3A4, CYP3A5, CYP2J2, P-glycoprotein (P-gp), ABCG2
    Rivaroxaban is a substrate of CYP3A4/5, CYP2J2, and the P-gp and ATP-binding cassette G2 (ABCG2) transporters. Inhibitors and inducers of these CYP450 enzymes or transporters may result in changes in rivaroxaban exposure. Avoid use of rivaroxaban with combined P-gp and strong CYP3A4 inhibitors, which cause significant increases in rivaroxaban exposure that may increase bleeding risk. In vitro studies indicate that rivaroxaban neither inhibits the major cytochrome P450 enzymes CYP1A2, 2C8, 2C9, 2C19, 2D6, 2J2, and 3A4 nor induces CYP1A2, 2B6, 2C19, or 3A4. In vitro data also indicates a low rivaroxaban inhibitory potential for P-glycoprotein and ABCG2 transporters. However, no significant pharmacokinetic interactions were observed in studies comparing concomitant rivaroxaban 20 mg and 7.5 mg single dose of midazolam (substrate of CYP3A4), 0.375 mg once-daily dose of digoxin (substrate of P-gp), or 20 mg once daily dose of atorvastatin (substrate of CYP3A4 and P-gp) in healthy volunteers.

    Oral Route

    The absolute bioavailability of rivaroxaban is estimated to be 80% to 100% for the 10 mg dose and is not affected by food. The absolute bioavailability of the 20 mg dose, in the fasted state, is approximately 66%; coadministration with food increases the bioavailability (the mean AUC and Cmax increases by 39% and 76%, respectively). The 10 mg tablet can be taken with or without food while the 15 mg and 20 mg tablets should be taken with food. Rivaroxaban is rapidly absorbed with maximum concentrations (Cmax) appearing 2 to 4 hours after oral administration. Rivaroxaban pharmacokinetics are linear with no relevant accumulation beyond steady-state after multiple doses. Intake with food does not affect rivaroxaban AUC or Cmax at the 10 mg dose. The pharmacokinetic parameters of rivaroxaban were not affected by drugs altering gastric pH. Absorption of rivaroxaban is dependent on the site of drug release in the GI tract. A 29% decrease in AUC and a 56% decrease in Cmax was reported when rivaroxaban granulate is 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. Avoid administration of rivaroxaban via a method that could deposit the drug directly into the proximal small intestine (e.g., feeding tube positioned in the proximal small intestine), which can result in reduced absorption and related drug exposure.