SUMMARY

• The respective product labels do not specifically indicate a drug interaction between XARELTO and azithromycin; however, drug interactions have been observed between XARELTO and other macrolide products (clarithromycin and erythromycin).^1,2
• Hill et al (2020)³ conducted a population-based, retrospective cohort study to assess the 30-day risk of hospitalization due to hemorrhagic events in older patients (aged ≥66 years) receiving concomitant direct oral anticoagulant (DOAC), including XARELTO, and azithromycin.
  • Major hemorrhage occurred in 79 of 18,351 patients (0.43%) taking azithromycin, with a crude incidence rate of 53.1/1000 patient-years (95% confidence interval [CI], 50.2-56.2).
• Li et al (2023)^4,5 conducted an analysis of pooled data from the Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS) database to identify hemorrhagic signals caused by coadministration of DOACs (including XARELTO) and different cytochrome P450 3A4 (CYP3A4) inhibitors (including azithromycin).
  • The hemorrhagic signal was not significant for XARELTO + azithromycin (crude reporting odds ratio [ROR], 0.28; 95% CI, 0.24-0.33) compared with XARELTO monotherapy.
• A review of potential interaction risk between drugs used for cardiovascular conditions, including XARELTO, and drugs used in COVID-19 treatment, including azithromycin, across 6 drug interaction databases has been cited for your reference.⁶

PRODUCT LABELING

Please refer to the following sections of the enclosed Full Prescribing Information that are relevant to your inquiry: DRUG INTERACTIONS and CLINICAL PHARMACOLOGY.

Drug Interactions

Rivaroxaban is a substrate of CYP3A4/5, CYP2J2, and the Pglycoprotein (P-gp) and ATP-binding cassette G2 (ABCG2) transporters.¹ Combined P-gp and strong CYP3A inhibitors increase exposure to rivaroxaban and may increase the risk of bleeding. Thus, it is recommended to avoid concomitant administration of XARELTO with known combined P-gp and strong CYP3A inhibitors. Combined P-gp and strong CYP3A inducers decrease exposure to rivaroxaban and may increase the risk of thromboembolic events. Thus, it is recommended to avoid concomitant use of XARELTO with drugs that are combined P-gp and strong CYP3A inducers.

The respective XARELTO and azithromycin product labels do not specifically indicate a drug interaction between XARELTO and azithromycin (a macrolide antibacterial drug); however, drug interactions have been observed between XARELTO and other macrolide products (clarithromycin and erythromycin).^1,2 Per the XARELTO Prescribing Information, although clarithromycin is a combined P-gp and strong CYP3A inhibitor, pharmacokinetic data suggests that no precautions are necessary with concomitant administration with XARELTO as the change in exposure is unlikely to affect the bleeding risk.¹ XARELTO should not be used in patients with creatinine clearance (CrCl) 15 to <80 mL/min who are receiving concomitant combined P-gp and moderate CYP3A inhibitors, such as erythromycin, unless the potential benefit justifies the potential risk.

CLINICAL DATA

Hill et al (2020)³ conducted a population-based, retrospective cohort study to assess the 30-day risk of hospitalization due to hemorrhagic events in older patients (aged ≥66 years) receiving concomitant DOAC, including XARELTO, and azithromycin.

Study Design/Methods

• This cohort study based on information from databases housed at the Institute for Clinical Sciences (ICES) was conducted between June 23, 2009 and December 31, 2016.
• The main outcome was an event of major hemorrhage up to 30 days after initiating the antibiotic that led to hospitalization or an emergency department visit.

Results

Select Baseline Characteristics

• Overall, 24,943 patients were included in the study and 18,351 received azithromycin.
• Among the patients who received azithromycin, majority of the patients were 
  76‍-85 years of age (42.8%), were female (50.4%), and received treatment with XARELTO (39.3%).
  • The most common comorbidities (occurring in >30% of patients) included hypertension (87.2%) and diabetes (35.2%).
  • The mean (standard deviation [SD]) daily dose of XARELTO was 17.9 (6.7) mg and the mean (SD) duration of DOAC treatment prior to azithromycin exposure was 380.5 (360.1) days.

Safety Outcomes: Occurrence of Hemorrhagic Events

• Major hemorrhage occurred in 79 (0.43%) patients taking azithromycin, with a crude incidence rate of 53.1/1000 patientyears (95% CI, 50.2-56.2). See Table: 30-Day Hemorrhagic Events With Concomitant DOAC and Azithromycin.

Li et al (2023)^4,5 conducted an analysis of pooled data from the FAERS database to identify hemorrhagic signals caused by coadministration of DOACs (including XARELTO) and different CYP3A4 inhibitors (including azithromycin).

Methods

• Adverse events (AEs) associated with DOACs were retrieved from the database from the third quarter of 2010 (3Q 2010) to the first quarter of 2021 (1Q 2021).
• Hemorrhagic signals were expressed using RORs and 95% CIs based on interaction/noninteraction methodology as (a/c) / (b/d).
  • A hemorrhagic signal was considered significant when the lower limit of the 95% CI was >1 and the case number of the interaction group was ≥3.

Results

• A total of 382,853 distinct cases of AEs associated with DOACs (including 165,365 cases with XARELTO) were retrieved.
• Among the 136,764 distinct cases of hemorrhagic events, 78,911 were associated with XARELTO.
• The hemorrhagic signal was not significant for XARELTO + azithromycin (crude ROR, 0.28; 95% CI, 0.24-0.33) compared with XARELTO monotherapy.⁵
• Hemorrhagic signals were further refined using multiple logistic regression by adjusting possible confounders, including sex, reporter type, age group, and the role of drugs in an event.
  • The hemorrhagic signal was not significant for XARELTO + azithromycin (ROR, 0.70; 95% CI, 0.56-0.89) compared with XARELTO monotherapy.

Literature Search

A literature search of MEDLINE^®, EMBASE^®, BIOSIS Previews^®, and DERWENT^® (and/or other resources, including internal/external databases) pertaining to this topic was conducted on 13 January 2025.