SUMMARY  

• AVOID concomitant use of XARELTO with known combined P-glycoprotein (P-gp) and strong cytochrome P450 3A (CYP3A) inhibitors (eg ketoconazole and ritonavir) due to increased bleeding risk.¹
• Mueck et al (2013)² reported the results of a series of mechanism-guided, clinical drug-drug interaction (DDI) studies conducted in healthy patients, including a nonrandomized, open-label study assessing the potential interaction between a single dose of XARELTO and steady-state ritonavir. A significant increase in XARELTO exposure was demonstrated with the strong CYP3A4, P-gp/breast cancer resistance protein (BCRP; ATP-binding cassette G2 [ABCG2]) inhibitor ritonavir.
• Wang et al (2022)^3,4 a physiologically-based pharmacokinetic modeling study reporting the effects of ritonavir on XARELTO concentrations.
• Additional citations are included in the REFERENCES section for your review.^5-7

PRODUCT LABELING

Please refer to the following section of the enclosed Full Prescribing Information that is relevant to your inquiry: DRUG INTERACTIONS.

Drug Interactions

Rivaroxaban is a substrate of CYP3A4/5, CYP2J2, and the P-gp and ABCG2 transporters. Combined P-gp and strong CYP3A inhibitors increase exposure to rivaroxaban and may increase the risk of bleeding.¹

CLINICAL DATA

Pharmacokinetic Study

Mueck et al (2013)² assessed the pharmacokinetic effects of CYP3A4, P-gp, and BCRP substrates and inhibitors on XARELTO in healthy volunteers.

• Seven single-center studies were assessed to determine the extent of potential interactions with single doses of XARELTO (10 mg or 20 mg) and steady-state ketoconazole, ritonavir, clarithromycin, erythromycin, fluconazole, and midazolam.
• Healthy male subjects between 18-55 years of age with a body mass index of 18-32 kg/m² were enrolled in these studies. Patients were eligible for inclusion if they had a resting heart rate of 45-90 beats/min, systolic blood pressure of 100-145 mmHg, diastolic blood pressure of <95 mmHg, and no relevant pathological changes on their electrocardiogram. Exclusion criteria included any clinically relevant condition that may have interfered with the study and any known coagulation disorders, or disorders associated with an increased risk of bleeding.
• Interaction between a single dose of XARELTO and steady-state ritonavir was evaluated in a nonrandomized, open-label study in which patients received a single dose of XARELTO 10 mg on day 1, ritonavir 600 mg twice daily on days 3-7, and ritonavir 600 mg twice daily plus a single dose of XARELTO on day 8. All study drugs were administered with food.
• Eighteen patients were enrolled, with a mean age of 33.2 years (range, 18-44 years) and mean weight of 84.3 ± 11.1 kg.
• A total of 16 patients were included in the safety analysis. All patients received a single dose of XARELTO 10 mg on day 1 and at least 1 dose of ritonavir (600 mg). Twelve patients received the combination of XARELTO and ritonavir on day 8; however, none of the patients received the second dose of ritonavir on day 8 due to tolerability issues, which were likely related to ritonavir.
• Four patients withdrew from the study secondary to ritonavir-related adverse events, leaving 12 patients eligible for the pharmacokinetic analyses.
• Steady-state ritonavir significantly increased the area under the plasma concentration-time curve (AUC) and maximum drug concentration in plasma (C_max) of XARELTO. Mean AUC increased by 153% (90% confidence interval [CI]: 134-174%) and mean C_max increased by 55% (90% CI: 41-69%) compared with XARELTO alone. Mean plasma concentrations of XARELTO were shown to increase with concomitant use.
• Ritonavir significantly decreased the clearance of blood from plasma (CL/F) of XARELTO (60% reduction; 90% CI: -63 to -57%) without affecting the fraction of free (unbound) drug in plasma (f_u) of XARELTO; clearance by active renal secretion (CL_RS) was also significantly reduced (82% reduction; 90% CI: -86% to -76%).

Wang et al (2022)^3,4applied physiologically-based pharmacokinetic and pharmacodynamic modeling and simulations to investigate disease-drug-drug interactions (DDDIs) between ritonavir-boosted nirmatrelvir and XARELTO and recommend dosage adjustment.

• Models and simulations were implemented within the population based Simcyp Simulator (version 19, Sheffield, UK).
• The ritonavir model was utilized based on previous studies while XARELTO models were constructed for the simulation. Nirmatrelvir was not incorporated into the simulation due to low DDI potential.
• The populations utilized in this simulation were healthy population, general white population, geriatric population (65 to 85 years), and moderate renal impairment (creatinine clearance [CrCl] 30 to 49 mL/min) population.
• The ritonavir dose was set at 100 mg BID for 5 days. In patients with moderate renal impairment, the XARELTO dose was decreased from 20 mg to 15 mg daily. A lower dose of XARELTO 10 mg daily was prospectively simulated as a dose adjustment strategy.
• The DDI potential with XARELTO was based on simulated plasma concentrations of XARELTO and the fold-change of AUC on the fifth day of ritonavir treatment and was further calculated for risk of major bleeding.
• An AUC fold-change range of 0.7 to 1.43 was pre-defined to be appropriate as equivalent to the in vivo exposure of XARELTO.
• In the presence of ritonavir 100 mg and normal XARELTO doses (20 mg or 15 mg), the fold change in AUC was 1.91 in the general population with normal renal function, 2 in the general population with moderate renal impairment, 2.08 in the geriatric population with normal renal function, and 2.12 in the geriatric population with moderate renal impairment. The overexposure of XARELTO normalized on day 4 post discontinuation of ritonavir.
• In the presence of ritonavir 100 mg and adjusted XARELTO dose (10 mg), the fold change in AUC was 1.03, 1.21, 1.26, and 1.44 in the respective populations.

Literature Search

A literature search of MEDLINE^®, EMBASE^®, BIOSIS Previews^®, DERWENT^® (and/or other resources, including internal/external databases) was conducted on 07 February 2024.