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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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Effect of Food on XARELTO

Last Updated: 01/28/2025

Summary

In adults for the XARELTO 2.5 mg and 10 mg dose, the absolute bioavailability is estimated to be 80% to 100% and is not affected by food. XARELTO 2.5 mg and 10 mg tablets can be taken with or without food. Co-administration of XARELTO with food increases the bioavailability of the 20 mg dose. XARELTO 15 mg and 20 mg tablets should be taken with food. In the nonvalvular atrial fibrillation (AF) efficacy study XARELTO was taken with the evening meal.¹ No recommendations were made in the COMPASS or VOYAGER PAD studies as to co-administration with food.²^,³
In pediatric patients, for the treatment of venous thromboembolism (VTE) and reduction in the risk of recurrent VTE all doses should be taken with feeding or with food since exposures match that of 20 mg daily dose in adults. For thromboprophylaxis in pediatric patients with congenital heart disease after the Fontan procedure all doses can be taken with or without food since exposures match that of 10 mg daily dose in adults.¹
Based on a study to evaluate the pharmacokinetics (PK) and pharmacodynamics (PD) of XARELTO 10 mg and 20 mg under fasting and fed conditions in healthy adult subjects, fed conditions increased time to maximum plasma concentration (T_max; from 2.75 hrs to 4 hrs) and area-under-the-curve (AUC) after receiving XARELTO 10 mg or 20 mg. The half-life (T_1/2) remained unaffected in the XARELTO 10 mg group. Prothrombin time (PT) prolongation and time to maximum PT prolongation (PT_max) increased under fed conditions after receiving XARELTO 10 mg or 20 mg. In subjects who received XARELTO 10 mg, inhibition of factor Xa activity was similar during fasting and fed conditions. However, factor Xa inhibition was greater during the fed state (51%) compared to fasted state (34%) in those who received XARELTO 20 mg tablets. PK/PD changes did not differ based on type of meal (high-fat, high-calorie, or high-carbohydrate).⁴
Based on a study to evaluate the effect of food on the PK and absorption of XARELTO in healthy adult subjects, the PK of doses up to 10 mg were dose proportional and had high bioavailability, independent of food and formulation.⁵
A model compared the predicted XARELTO PK parameters and steady-state exposures with those observed from the 20 mg once-daily dose regimen in the DVT and AF studies in adults and found that the PK of XARELTO at this dose is not influenced by the timing or the content of the meal intake, i.e. morning meal versus evening meal.⁶
The physiologically based pharmacokinetic (PBPK) and in vitro-in vivo correlation (IVIVC) models evaluating the PK parameters of XARELTO immediate release (IR) 20 mg tablet predicted that maximum plasma concentration (C_max) and AUC increased and T_max decreased in the fed versus fasted state. Overall, C_max and AUC were comparable between the models. A virtual bioequivalence trial predicted that the in vivo PK study of XARELTO IR 20 mg tablet was comparable in all populations in the fed state but not in the fasted state.⁷
Additional literature pertaining to drug-food interaction associated with XARELTO identified is included in the REFERENCES section for your review.⁸^-¹¹

PRODUCT LABELING

Please refer to the following sections of the enclosed Full Prescribing Information that are relevant to your inquiry: DOSAGE AND ADMINISTRATION (Recommended Dosage in Adults, Recommended Dosage in Pediatric Patients, Administration Options), CLINICAL PHARMACOLOGY (Pharmacokinetics).

CLINICAL STUDIES

Drug-Food Effects

XARELTO has been evaluated under fed and fasting conditions for changes in PK and PD (see Table: Drug-Food Effects).⁴

Drug - Food Effects

Study	Design	Interventions	Endpoints	Results
Zhang et al (2017)⁶	Model-based, cross study comparison to evaluate the impact of food on the PK of XARELTO in adults using data collected from the Phase 2 EINSTEIN-DVT dose-ranging study and the Phase 3 ROCKET AF study	EINSTEIN-DVT Study: XARELTO 20 mg administered once daily with a morning meal for a duration of 12 weeks. Neither the amount nor the type of food that would accompany the XARELTO dose was prespecified. ROCKET AF Study: XARELTO 20 mg (15 mg in patients with CrCl of 30–‍49 mL/min) once daily taken with the evening meal	PK parameters including: plasma clearance after oral administration (CL/F), volume of distribution after oral administration (V/F), area under the plasma concentration–time curve (AUC), and maximum plasma concentration (C_max).	PK parameter estimates from the joint model (combined DVT and AF models) were similar to those reported for the DVT and AF models individually The relative bioavailability of the AF data compared to the DVT data was estimated to be 112%, which was within the bioequivalence limits of 80% - 125 %, suggesting equivalent PK of XARELTO under evening meal and morning meal conditions. The model compared the predicted XARELTO PK parameters and steady state exposure with those observed from the 20-‍mg once daily dose regimen in the DVT and AF studies. The differences between the simulated and estimated values were less than 20%, suggesting that any differences between the PK of XARELTO administered with a morning meal or an evening meal are not likely to be clinically significant. Results suggested that, for a 20-mg once-daily regimen, the PK of XARELTO are consistent regardless of meal intake timing and content (ie, morning meal versus evening meal).
Kubitza et al (2006)⁴	Randomized, open-label, crossover study in healthy adult subjects	XARELTO 10 – 20 mg along with; Fasting or fed conditions (high-fat, high-calorie, or high-carbohydrate meals were provided)	PK and PD of XARELTO under fasting and fed conditions	Fed conditions increased T_max (from 2.75 hrs to 4 hrs) and AUC after receiving XARELTO 10 mg or 20 mg T½ unaffected for XARELTO 10 mg XARELTO 10 mg: no difference in factor Xa inhibition during fed or fasted states XARELTO 20 mg: greater factor Xa inhibition during fed state (51%) versus fasted state (34%) PT prolongation and time to PT_max, increased under fed conditions for XARELTO 10 mg or 20 mg PK/PD changes did not differ based on type of meal (high-fat, high-calorie, or high-carbohydrate) No serious adverse events were reported
Stampfuss et al (2013)⁵	6 independent, single-dose, crossover, Phase 1 studies	Study 1: absolute bioavailability study compared 5 mg and 20 mg XARELTO tablet doses with 1 mg IV dose Study 2: confirmatory food-effect study evaluated 10 mg XARELTO tablet Study 3: confirmatory food-effect study evaluated 20 mg XARELTO tablet Study 4: formulation study evaluated 10 mg XARELTO oral suspension (fasting) and 20 mg XARELTO oral suspension (fasting and fed) versus 10 mg XARELTO tablet (fasted) Study 5: dose-proportionality study that assessed 2.5 mg, 5 mg, and 10 mg	Effect of food on absorption, PK, safety, and tolerability at different XARELTO doses and formulations	PK of doses up to 10 mg were dose proportional and had high bioavailability, independent of food and formulation When taken with food, 15 mg and 20 mg XARELTO achieved high bioavailability (≥80%) XARELTO was well-tolerated and showed an acceptable safety profile in healthy individuals.
Kushwah et al (2021)⁷	PBPK model- and IVIVC model-based study to evaluate the bioavailability of XARELTO. A virtual in vivo PK study evaluating a single-dose, 3treatment crossover trial in 50 healthy subjects to predict the PK profile of XARELTO in the fed state.	PBPK model: once model was established, the PK profile of XARELTO IR 20 mg tablet was predicted in the fed and fasted states. IVIVC model: XARELTO IR 20 mg tablet was used to determine results in the fed and fasted states. Virtual bioequivalence trial: XARELTO IR 20 mg tablet was administered in subjects in the fed state, including populations A, B, and C, with 50 subjects in each.	Correlation of predicted results from the IVIVC model with the PBPK model, and assessment of PK parameters of the formulation in the fed state considering population variability.	According to the PBPK model, the predicted C_max and AUC increased and the predicted T_max decreased in the fed versus fasted state. Similar results were predicted by the IVIVC model. The C_max and AUC values predicted by both models were comparable. The predicted population in the in vivo PK study of XARELTO IR 20 mg tablet was comparable in all populations in the fed state but not in the fasted state (population geometric means, 80% to 125% and >80% to 125%, respectively).
Abbreviations: AUC, area-under-the-curve; C_max, maximum plasma concentration; IR, immediate-release; IVIVC, in vitro-in vivo correlation; PBPK, physiologically based pharmacokinetic; PD, pharmacodynamic; PK, pharmacokinetic; PT, prothrombin time; PT_max, maximum prothrombin time; T_1/2, half-life; T_max, time to maximum plasma concentration.

Administration with Evening Meal

The pharmacokinetic data for 20 mg shows that this dose has increased bioavailability with food. The recommendation for the evening administration is based¹² on the ROCKET protocol where XARELTO doses were administered with the evening meal. No specific recommendations can be made for calorie or fat requirements for the evening meal.

LITERATURE SEARCH

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

References

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1	XARELTO (rivaroxaban) [Prescribing Information]. Titusville, NJ: Janssen Pharmaceuticals, Inc;https://www.janssenlabels.com/package-insert/product-monograph/prescribing-information/XARELTO-pi.pdf
2	Eikelboom JW, Connolly SJ, Bosch J, et al. Rivaroxaban with or without aspirin in stable cardiovascular disease [Protocol]. N Engl J Med. 2017;377(14):1319-1330.
3	Bonaca MP, Bauersachs RM, Anand SS, et al. Rivaroxaban in peripheral artery disease after revascularization. N Engl J Med. 2020;382(21):1994-2004.
4	Kubitza D, Becka M, Zuehlsdorf M, et al. Effect of food, an antacid, and the H2 antagonist ranitidine on the absorption of BAY 59-7939 (rivaroxaban), an oral, direct factor Xa inhibitor, in healthy subjects. J Clin Pharmacol. 2006;46(5):549-558.
5	Stampfuss J, Kubitza D, Becka M, et al. The effect of food on the absorption and pharmacokinetics of rivaroxaban. Int J Clin Pharmacol Ther. 2013;51(7):549-561.
6	Zhang L, Peters G, Haskell L, et al. A cross‐study analysis evaluating the effects of food on the pharmacokinetics of rivaroxaban in clinical studies. J Clin Pharmacol. 2017;57(12):1607-1615.
7	Kushwah V, Arora S, Katona M, et al. On absorption modeling and food effect prediction of rivaroxaban, a BCS II drug orally administered as an immediate-release tablet. Pharmaceutics. 2021;13(2):283.
8	Patel M, Mahaffey K, Garg J, et al. Supplement to: Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med. 2011;365(10):883-891.
9	Roberti R, Iannone LF, Palleria C, et al. Direct oral anticoagulants: from randomized clinical trials to real-world clinical practice. Front Pharmacol. 2021;12:684638.
10	Tao Y, Jiang X, Shi P, et al. Bioequivalence and food effect assessment of 2 rivaroxaban formulations in healthy Chinese volunteers: an open, randomized, single‐dose, and 4‐period crossover study. Clin Pharmacol Drug Dev. 2022;11(3):358-363.
11	Patel RP, Cristofoletti R, Wu F, et al. In vitro lipolysis model to predict food effect of poorly water-soluble drugs itraconazole, rivaroxaban, and ritonavir. J Pharm Sci. 2024;113(8):2361-2373.
12	Fox K, Becker R, Berkowitz S, et al. Rationale and design of the ROCKET AF study: rivaroxaban once daily, oral, direct factor Xa inhibition compared with vitamin K antagonism for prevention of stroke and embolism trial in atrial fibrillation. Poster presented at: European Society of Cardiology (ESC) Congress 2009; August 29-September 2, 2009; Barcelona, Spain.