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This information is intended for US healthcare professionals to access current scientific information about J&J Innovative Medicine products. It is prepared by Medical Information and is not intended for promotional purposes, nor to provide medical advice.

XARELTO® (rivaroxaban)

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Drug-Drug Interaction Profile of XARELTO

Last Updated: 02/14/2025

SUMMARY

AVOID concomitant use of XARELTO with known¹:
- Combined P-glycoprotein (P-gp) and strong cytochrome P450 3A (CYP3A) inducers due to increased risk of thromboembolic events
- Combined P-gp and strong CYP3A inhibitors due to increased bleeding risk
- Anticoagulants due to increased bleeding risk unless benefit outweighs risk
Combined P-gp and moderate CYP3A inhibitors should not be used with XARELTO in patients with creatinine clearance (CrCl) 15 to <80 mL/min, unless the potential benefit justifies the potential risk.¹
Combined P-gp and weak CYP3A inhibitors do not have specific recommendations.¹
Nonsteroidal anti-inflammatory drugs (NSAIDs) and aspirin are known to increase bleeding, and bleeding risk may be increased when NSAIDs or aspirin are used concomitantly with XARELTO.¹
Selective serotonin reuptake inhibitors and serotonin norepinephrine reuptake inhibitors can impair hemostasis and increase the risk of bleeding when used concomitantly with XARELTO.¹
P2Y₁₂ platelet inhibitors, dual antiplatelet therapy, other antithrombotic agents, and fibrinolytic therapy can impair hemostasis and may further increase bleeding when used concomitantly with XARELTO.¹
Additional drug-drug interactions that are organized by drug class are discussed in the table Drug-Drug Interactions.²^-²²
Additional studies pertaining to drug-drug interactions associated with XARELTO have been included in the REFERENCES section for your review.²³^-⁶²

PRODUCT LABELING

Please refer to the following sections of the enclosed Full Prescribing Information that are relevant to your inquiry: BOXED WARNING, DOSAGE AND ADMINISTRATION, DRUG INTERACTIONS, CLINICAL PHARMACOLOGY, and WARNINGS AND PRECAUTIONS.

Drug Interactions

Rivaroxaban is a substrate of CYP3A4/5, CYP2J2, and the P-gp and ATP-binding cassette G2 (ABCG2) transporters. Combined P-gp and strong CYP3A inhibitors increase exposure to rivaroxaban and may increase the risk of bleeding. Combined P-gp and strong CYP3A inducers decrease exposure to rivaroxaban and may increase the risk of thromboembolic events.¹

CLINICAL DATA

Drug-Drug Interactions

XARELTO has been evaluated alone and in combination with a variety of drugs to assess changes in pharmacokinetics and pharmacodynamics and impact on outcomes. The following studies were all designed to evaluate the respective drug's effect on the efficacy, safety, tolerability, and pharmacokinetic/pharmacodynamic parameters of XARELTO (see Table: Drug-Drug Interactions).²^-²²

The following medication are in the table organized by drug class. Click the link to take you to the specific medication within the table.

Amiodarone Anastrozole Aspirin Atorvastatin Carbamazepine Clarithromycin Clopidogrel	Cyclosporine Digoxin Diltiazem Enoxaparin Erythromycin Exemestane Fluconazole	Itraconazole Ketoconazole Letrozole Levetiracetam Midazolam Naproxen Omeprazole	Phenytoin Ranitidine Rifampin Ritonavir Simvastatin SNRIs SSRIs	St. John’s Wort Tacrolimus Tamoxifen Verapamil Warfarin

Drug-Drug Interactions²^-²²

Drug	Category	Clinical Studies	Prescribing Information Recommendation¹
Acid Reducing Medications
Ranitidine, antacids	Drugs that affect gastric pH	No significant pharmacokinetic interactions.²¹	No specific recommendations provided in prescribing information
Omeprazole	Proton pump inhibitor	No effect on bioavailability and exposure of XARELTO.²²	No specific recommendations provided in prescribing information
Antiarrhythmics
Amiodarone	Combined P-gp and weak CYP3A inhibitor	Concomitant use in the ROCKET-AF trial did not show an increase in bleeding in patients with mild (CrCl 30 to <50 mL/min) renal function.¹⁷ No significant differences in efficacy (stroke or non-CNS embolism, interaction P=0.063) or safety (major or nonmajor bleeding, interaction P=0.33) endpoints when compared to warfarin.¹⁷ No significant differences in mortality (P=0.9) when compared to other antiarrhythmic drugs or XARELTO alone.¹⁷ A prospective, observational study compared patients taking XARELTO to those taking XARELTO + amiodarone (combination group). After propensity matching to adjust for between-group differences, the primary outcome (first occurrence of a composite of major, clinically relevant nonmajor and minor bleeding) was observed in 10.4% and 26.0% of the patients in the XARELTO group and combination group, respectively (P<0.001).⁶³ In an observational study in patients who were receiving a DOAC (XARELTO, apixaban, dabigatran, edoxaban), use with amiodarone was associated with above-range peak and trough DOAC concentrations compared to amiodarone non-users (P=0.01). Major bleeding was observed in 2 patients in the amiodarone group and 16 patients in the amiodarone non-user group (P=0.44).⁶⁴ For patients taking XARELTO, estimated AUCs were higher in those taking amiodarone compared to amiodarone non-users (3396.6±1886.5 ng/mLh vs 2777.3±1414 ng/mLh, respectively; P=0.05).⁶⁴	No specific recommendations provided in the prescribing information
Digoxin	Substrate of CYP3A, P-gp	In a study of healthy volunteers, no significant pharmacokinetic interactions.¹⁸^,¹⁹	No specific recommendations provided in the prescribing information
Anticoagulants/antiplatelets
Aspirin	Platelet aggregation inhibitor	Concomitant aspirin identified as an independent risk factor for major bleeding in efficacy trials.⁵ No pharmacokinetic or pharmacodynamic interactions observed.⁵ In a subanalysis of the XAMOS study, platelet aggregation inhibitor users (86% taking aspirin) had increased incidences of total and symptomatic arterial thromboembolic events and treatment-emergent bleeding vs non-users in both the XARELTO and standard of care groups.⁶^,⁷	Promptly evaluate signs or symptoms of blood loss if given concomitantly
Clopidogrel	Platelet aggregation inhibitor	Coadministration resulted in an increase in bleeding time for some subjects.¹¹^,¹² No change in pharmacokinetics of either drug was observed.¹¹^,¹² In a subanalysis of the XAMOS study, platelet aggregation inhibitor users (7% taking clopidogrel) had increased incidences of total and symptomatic arterial thromboembolic events and treatment-emergent bleeding vs non-users in both the XARELTO and standard of care groups.⁶^,⁷	Promptly evaluate signs or symptoms of blood loss if given concomitantly
Enoxaparin	Anticoagulant	Additive effect on antifactor Xa activity did not affect the pharmacokinetics of XARELTO.⁴	Avoid concomitant administration unless benefit outweighs risk
Warfarin	Anticoagulant	Additive effect on factor Xa inhibition and prothrombin time did not affect the pharmacokinetics of XARELTO.¹	Avoid concomitant administration unless benefit outweighs risk
Antihyperlipidemics
Atorvastatin	Substrate of CYP3A	In a study of healthy volunteers, no significant pharmacokinetic interactions.¹⁹^,²⁰	No specific recommendations provided in the prescribing information
Simvastatin	Substrate of CYP3A	In an observational cohort study of patients with non-valvular atrial fibrillation, median peak XARELTO concentration in patients taking simvastatin was significantly higher compared to patients who were not on simvastatin (median 241.25 ng/mL vs 180.42 ng/mL, respectively; P=0.047).⁶⁵ In the XARELTO cohort, factors that significantly affected bleeding were CrCl (P=0.047) and concomitant simvastatin use (P=0.024).⁶⁵	No specific recommendations provided in the prescribing information
Antihypertensives
Diltiazem and Verapamil	Combined P-gp and moderate CYP3A inhibitor	In a post hoc analysis of the ROCKET-AF trial, non-DHP CCB use was not associated with an increased risk of stroke or non-CNS embolism (P=0.11) or the composite outcome of nonmajor clinically relevant or major bleeding (P=0.087), however, there was an increased risk of major bleeding (P=0.0091) and intracranial hemorrhage (P=0.001).¹⁴ No significant interactions with concomitant use of non-DHP CCB with XARELTO vs warfarin in the primary efficacy (stroke or non-CNS embolism, interaction P=0.38) or safety outcomes (nonmajor clinically relevant bleeding or major bleeding, interaction P=0.14).¹⁴ No differences in efficacy or safety of XARELTO vs warfarin and concomitant use across renal function subgroups (interaction P=0.76).¹⁴ In a case-cohort analysis, coadministration of XARELTO with diltiazem did not result in an increased rate of bleeding.¹⁵ In a pharmacokinetic study, verapamil independently increased XARELTO AUC to a similar degree in both mild renal impairment and normal renal function groups.¹⁶ Concentration-effect profiles for prothrombin time and Factor Xa inhibition were not affected by renal function or concomitant verapamil.¹⁶ A retrospective, cohort study of patients≥65 years with atrial fibrillation taking either apixaban or XARELTO compared those who subsequently began diltiazem vs. metoprolol. After adjusting for baseline between-group differences with overlap weight estimated from the propensity score, diltiazem use was associated with an increased risk of bleeding-related hospitalization (HR 1.22 [95% CI, 1.13-1.31]) and death with recent bleeding evidence (HR 1.19 [95% CI, 1.05-1.34]) compared to those on metoprolol.⁶⁶	No specific recommendations provided in the prescribing information
Anti-Infectives
Antibiotics
Clarithromycin³	Combined P-gp and strong CYP3A inhibitor	Coadministration of XARELTO and clarithromycin increased XARELTO AUC by 94% and Cmax by 92% in a study of healthy Caucasian males.¹³	No precautions are necessary based on pharmacokinetic data
Erythromycin	Combined P-gp and moderate CYP3A inhibitor	In a pharmacokinetic trial, concomitant use of erythromycin in patients with mild (CrCl 50-79 mL/min) or moderate (CrCl 30-49 mL/min) renal impairment reported a 76% and 99% increase in AUC, respectively, and a 56% and 64% increase in Cmax, respectively.³ Similar trends in pharmacodynamic effects were observed.³	Should not be used in patients with CrCl 15 to <80 mL/min unless the potential benefit justifies the potential risk
Rifampin	Combined P-gp and strong CYP3A inducer	Combined P-gp and strong CYP3A4 inducers, such as rifampin, decrease exposure to XARELTO and may increase risk of thromboembolic events.¹ Systematic review of 29 studies to evaluate the effects of using rifamycins (rifampin, rifabutin or rifapentine) concomitantly with AC/AP therapies. XARELTO had 1 PK study and 2 case reports.⁶⁷ The PK study was a report from the U.S. Food & Drug Administration (FDA) clinical pharmacology review of 20 healthy Caucasian males, administered XARELTO 20 mg once daily, found that after 7 days of pretreatment with increasing doses of rifampin (150-300-450-600 mg daily), XARELTO’s AUC and C_max were reduced by 49% and 22%, respectively. There was no change in t_max, and the t_1/2 decreased by approximately 50%.⁶⁷	Avoid concomitant administration
Antifungals
Fluconazole	Moderate CYP3A inhibitor	Moderate effects on XARELTO exposure [42% increase in AUC; 28% increase in Cmax] were not considered clinically relevant.³	No specific recommendations are provided in the prescribing information
Itraconazole	Combined P-gp and strong CYP3A inhibitor	In an analysis of the FDA adverse event reporting system (FAERS) database, the crude RORs of hemorrhages were significant for coadministration of itraconazole and XARELTO (ROR 2.92, 95% CI 1.36–6.29). After using multiple logistic regression to adjust for possible confounders, itraconazole plus XARELTO still indicated hemorrhagic signals (ROR 3.58, 95% CI 1.30–9.85).⁶⁸	No specific recommendations are provided in the prescribing information
Ketoconazole	Combined P-gp and strong CYP3A/2J2 inhibitor	Increase in XARELTO exposure and pharmacodynamic effects.³	Avoid concomitant administration
Antivirals
Ritonavir	Combined P-gp and strong CYP3A inhibitor	Increase in XARELTO exposure and pharmacodynamic effects.³ In a single centre, open label, fixed sequence clinical trial of healthy volunteers, coadministration of ritonavir with XARELTO for 5 days resulted in an increased AUC_0-24of XARELTO from baseline (3574 pg/mL/hr vs 6700 pg/mL/hr; P<0.05).⁶⁹	Avoid concomitant administration
Antiseizure Medications
Carbamazepine	Combined P-gp and strong CYP3A inducer	Combined P-gp and strong CYP3A4 inducers, such as carbamazepine, decrease exposure to XARELTO and may increase risk of thromboembolic events.¹	Avoid concomitant administration
Levetiracetam	Anticonvulsant	A retrospective review of patients who had plasma concentrations of apixaban or XARELTO during hospitalization compared those who were taking levetiracetam to patients taking an enzyme-inducing antiseizure medications (EI-ASM) or not taking any antiseizure medication. EI-ASM use was associated with an increased odds below-range apixaban or XARELTO plasma concentrations, but levetiracetam use was not.⁷⁰ A retrospective analysis of an epilepsy's center database compared plasma DOAC concentrations in patients taking EI-ASM, non-enzyme inducing antiseizure medications, and levetiracetam. In an ordered proportional odds logit model, the combination of XARELTO with EI-ASM was associated with lower DOAC dosages than XARELTO with levetiracetam.⁷¹ A retrospective analysis of the FAERS database evaluated patients with atrial fibrillation taking a DOAC and levetiracetam and ischemic event reports. In a logistic regression model, there was a significant signal of ischemic stroke and DOAC-levetiracetam drug interaction. The association was strongest with edoxaban (adj ROR 5.59; 95% CI, 4.23-7.39) and weakest with XARELTO (adj ROR 3.69; 95% CI 2.92-4.67).⁷² Patients who were taking a DOAC and levetiracetam were identified through an anticoagulation clinical database and had their DOAC trough concentration compared to patients not taking levetiracetam from a previous study. There were no significant differences in trough concentrations for patients taking rivaroxaban and levetiracetam compared to the previous data of patients not taking levetiracetam.⁷³	No specific recommendations provided in the prescribing information
Phenytoin	Combined P-gp and strong CYP3A inducer	Combined P-gp and strong CYP3A4 inducers, such as phenytoin, decrease exposure to XARELTO and may increase risk of thromboembolic events.¹	Avoid concomitant administration
Benzodiazepines
Midazolam	Substrate of CYP3A	In a study of healthy volunteers, no significant pharmacokinetic interactions.³	No specific recommendations provided in the prescribing information
Herbal Medications
St. John's Wort	Combined P-gp and strong CYP3A inducer	Decreases in XARELTO exposure with similar decreases in pharmacodynamic effect.²	Avoid concomitant administration
Hormone Therapy
Aromatase Inhibitors and Tamoxifen		Population based retrospective cohort study evaluated the risk of hemorrhage requiring hospitalization or emergency department visits in patients with breast cancer taking a DOAC with tamoxifen versus aromatase inhibitors.⁷⁴ The risk of major hemorrhage while receiving a DOAC was not higher with concurrent tamoxifen (29 of 1179 patients [2.5%]; 23.4 [95% CI, 16.3-33.7] per 1000 person-years) compared with a concurrent AI (119 of 3574 patients [3.3%]; 31.1 [95% CI, 26-37.2] per 1000 person-years). This was consistent in weighted models (absolute risk difference, -0.8%; HR, 0.68 [95% CI, 0.44-1.06]).⁷⁴	No specific recommendations provided in the prescribing information
Immunosuppressants
Calcineurin Inhibitors		Retrospective study in 39 patients who were taking XARELTO or apixaban with tacrolimus or cyclosporine.⁷⁵ Group average dose-corrected CNI trough concentration (C0/D) before and during NOAC treatment was not significantly different for any CNI-NOAC combination. C0/D changed significantly (>20%) in 19/39 individual patients for all CNI-NOAC combinations, including 13/22 patients in the tacrolimus-XARELTO group and 2/7 patients in the cyclosporine-XARELTO group; however, the average dose of tacrolimus or cyclosporine was not significantly altered after NOAC initiation. In a multivariable analysis, independent predictors of C0/D in tacrolimus patients were methylprednisolone dose (P=0.039) and concomitant use of a CYP3A inhibitor (P=0.007), while predictors in the cyclosporine group were age (P=0.018) and NOAC use (P=0.020). Pharmacokinetic study in 12 healthy volunteers to evaluate effects of cyclosporine on XARELTO PK alone and in combination with fluconazole.⁷⁶ Cyclosporine and cyclosporine + fluconazole increased XARELTO exposure with a geometric mean AUC ratio of 1.47 (90% CI 1.28-1.68) and C_max ratio of 2.04 (1.70-2.46) and an AUC ratio of 1.86 (1.58-2.19) and C_max ratio of 2.15 (1.83-2.53) compared to baseline, respectively.	No specific recommendations provided in the prescribing information
Pain medications
Naproxen and other NSAIDs	NSAIDs	Coadministration of chronic NSAIDs use may increase the risk of bleeding.¹ No pharmacokinetic or pharmacodynamic interactions were observed with naproxen⁸^,⁹ In a subanalysis of the XAMOS study, NSAID use had no impact on thromboembolic events in both the XARELTO and standard of care groups but was associated with a higher incidence of treatment-emergent bleeding and major bleeding events in both groups vs no NSAID use.⁶	Promptly evaluate signs or symptoms of blood loss if given concomitantly
SSRI/SNRI
SSRIs or SNRIs	SSRIs or SNRIs	Concomitant use of other drugs that impair hemostasis, such as selective serotonin reuptake inhibitors and serotonin norepinephrine reuptake inhibitors, increases the risk of bleeding.¹ A post hoc analysis of the ROCKET-AF trial did not find that SSRIs raised the risk of major plus nonmajor clinically relevant bleeding events when combined with anticoagulants overall, and with either XARELTO or warfarin, alone.¹⁰ No significant differences in efficacy (stroke or non-CNS embolism, interaction P=0.44) or safety (major or nonmajor bleeding, interaction P=0.69) endpoints when compared to warfarin¹⁰	No specific recommendations provided in the prescribing information
Abbreviations: AC, anticoagulant; AP, antiplatelet; AUC, area under the curve; CCB, calcium channel blocker; C_max, maximum serum concentration; CNS, central nervous system; CrCl, creatinine clearance; CYP, cytochrome P450; HR, hazard ratio; NOAC, novel oral anticoagulant; NSAIDS, nonsteroidal anti-inflammatory drugs; Non-DHP, non-dihydropyridine; P-gp, P-glycoprotein; PK/PD, pharmacokinetic/pharmacodynamic; PY, person-years; RD, rate difference; SNRIs, serotonin norepinephrine reuptake inhibitors; SSRIs, selective serotonin reuptake inhibitors

Literature Search

A literature search of MEDLINE^®, Embase^®, BIOSIS Previews^®, Derwent Drug File (and/or other resources, including internal/external databases) pertaining to this topic was conducted on 07 February 2025.

References

Show

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