Summary

• Absorption of rivaroxaban is dependent on the site of drug release in the gastrointestinal (GI) tract. A 29% and 56% decrease in area under the curve (AUC) and maximum plasma concentration (C_max), respectively, compared to tablet, was reported when rivaroxaban granulate was released in the proximal small intestine. Exposure is further reduced when drug is released in the distal small intestine, or ascending colon. Avoid administration of rivaroxaban distal to the stomach which can result in reduced absorption and related drug exposure.¹
• The C_max of rivaroxaban appears 2-4 hours after tablet intake. The pharmacokinetics of rivaroxaban were not affected by drugs altering gastric pH. Coadministration of XARELTO (30-mg single dose) with the H2-receptor antagonist ranitidine (150 mg twice daily) or the antacid aluminum hydroxide/magnesium hydroxide (10 mL), or XARELTO (20-mg single dose) with the proton pump inhibitor omeprazole (40 mg once daily) did not show an effect on the bioavailability and exposure of rivaroxaban.¹
• The relative bioavailability of XARELTO depends on the site of absorption along the GI tract. It is markedly reduced in the ascending colon.²

PRODUCT LABELING

Pharmacokinetics

Absorption

The absolute bioavailability of rivaroxaban is dose-dependent. For the 2.5 mg and 10-mg dose, it is estimated to be 80%-100% and is not affected by food. XARELTO 2.5 mg and 10 mg tablets can be taken with or without food. For the 20-mg dose in the fasted state, the absolute bioavailability is approximately 66%. Coadministration of XARELTO with food increases the bioavailability of the 20-mg dose (mean AUC and C_max increasing by 39% and 76%, respectively, with food). XARELTO 15 mg and 20 mg tablets should be taken with food.¹

In a study with 44 healthy subjects, both mean AUC and C_max values for 20 mg rivaroxaban administered orally as a crushed tablet mixed in applesauce were comparable to that after the whole tablet. However, for the crushed tablet suspended in water and administered via a nasogastric tube followed by a liquid meal, only mean AUC was comparable to that after the whole tablet, and C_max was 18% lower.¹

CLINICAL STUDIES

Phase 1 Studies

A single-center, nonrandomized, nonplacebo-controlled, nonblinded, crossover study was conducted to evaluate the pharmacokinetics of XARELTO after the topical release of granules corresponding to the 10-mg dose (crushed 10 mg tablet) or the topical release of 5 mg XARELTO solution (via Enterion™ capsule) in the proximal and distal small bowel and ascending colon.² This was compared to the oral administration of 10 mg XARELTO. Nine healthy male subjects (18-50 years) were enrolled in the study, which utilized 5 regimens:

• Regimen A: 2 x 5 mg XARELTO administered orally
• Regimen B: 10 mg XARELTO granules from crushed tablets administered to proximal small bowel via Enterion™ capsule
• Regimen C: 10 mg XARELTO granulate from crushed tablets administered to distal small bowel via Enterion™ capsule
• Regimen D: 10 mg XARELTO granulate from crushed tablets administered to the ascending colon via Enterion™ capsule
• Regimen E: 5 mg XARELTO solution administered to the ascending colon via Enterion™ capsule (2 capsules were used)

Single doses were administered with at least a 7-day interval between dosing regimens.

When compared with the administration of Regimen A:

• Regimen B resulted in lower AUC normalized to dose and body weight (AUC_norm; 71%) and C_max normalized to dose and body weight (C_max,_norm; 45%)
• Regimen C resulted in lower AUC_norm (56%) and C_max,_norm (29%)
• Regimen D resulted in lower AUC_norm (25%) and C_max,_norm (9%)
• Regimen E resulted in lower AUC_norm (60%) and C_max,_norm (42%)
• The relative bioavailability of XARELTO depends on the site of absorption along the GI tract. It is markedly reduced in the ascending colon. In this study, the relative bioavailability of the granulate was reduced in comparison to the topically administered solution. Administration of a single dose into the distal small bowel and ascending colon was safe and well tolerated.

LITERATURE SEARCH

A literature search of MEDLINE^®, EMBASE^®, BIOSIS Previews^®, DERWENT^® (and/or other resources, including internal/external databases) was conducted on 18 April 2024.