General Information

• XARELTO tablets are film-coated tablets for oral administration. The tablets are not scored and therefore are not designed to be split. XARELTO tablets are not delayedrelease, extended-release, or controlled-release.¹

PRODUCT LABELING

Dosage and Administration/Administration Options

Administration via Nasogastric (NG) Tube or Gastric Feeding Tube: After confirming gastric placement of the tube, XARELTO tablets may be crushed and suspended in 50 mL of water and administered via an NG tube or gastric feeding tube. Since XARELTO absorption is dependent on the site of drug release, avoid administration of rivaroxaban distal to the stomach which can result in reduced absorption and thereby, reduced drug exposure. After the administration of a crushed XARELTO 15 mg or 20 mg tablet, the dose should then be immediately followed by enteral feeding.¹

Crushed XARELTO tablets are stable in water and in applesauce for up to 4 hours. An in vitro compatibility study indicated that there is no adsorption of rivaroxaban from a water suspension of a crushed XARELTO tablet to polyvinyl chloride or silicone NG tubing.¹

For children unable to swallow 10, 15, or 20 mg whole tablets, XARELTO oral suspension should be used. XARELTO 2.5 mg tablets are not recommended for use in pediatric patients.¹

Clinical Pharmacology

The absolute bioavailability of rivaroxaban is dose dependent. For the 10 mg dose, it is estimated to be 80% to 100% and is not affected by food. XARELTO 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 area under the plasma concentration-time curve [AUC] and maximum plasma concentration [C_max] increasing by 39% and 76%, respectively, with food). XARELTO 15 mg and 20 mg tablets should be taken with food.¹

C_max of rivaroxaban appear 2 to 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), 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

Absorption of rivaroxaban is dependent on the site of drug release in the gastrointestinal tract. A 29% and 56% decrease in AUC and C_max compared to tablet was reported when rivaroxaban granulate is 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

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 an NG tube followed by a liquid meal, only mean AUC was comparable to that after the whole tablet, and C_max was 18% lower.¹

FDA guidance

• In March 2013, the Food and Drug Administration (FDA) issued a guidance document regarding the scientific basis for functional scoring on solid oral dosage form products to ensure the quality of split tablet products. Scored tablets that meet certain criteria for splitability described in the FDA guidance can be labeled as having functional scoring.³
• XARELTO tablets are not scored and have not been evaluated against these FDA splitability criteria.³

CLinical studies

Wada et al (2019)⁵ investigated the anticoagulation intensity of rivaroxaban between tablets, crushed tablets, and fine granules in a single-center, prospective, observational study in Japan.

• Blood samples were collected from 114 patients with acute ischemic stroke or transient ischemic attack or acute intracerebral hemorrhage (age, ≥75 years) before and after 4 hours of receiving rivaroxaban. Of them, 38 and 76 patients received a dose of 15 mg and 10 mg, respectively.
• The primary outcome was concentration in the fine granules group vs that in the whole tablets and crushed tablets group.
• Among the patients who received rivaroxaban 15 mg, the trough concentration (C_0h) was higher in the fine granules vs crushed tablets group (27.6±6.8 vs 4.0±4.1 ng/mL; P=0.01) and was comparable between the fine granules vs whole tablets group (27.6±6.8 vs 33.3±25.2 ng/mL; P=0.51).
• Among the patients who received rivaroxaban 15 mg, the peak concentration (C4h) was higher in the fine granules vs crushed tablets group (223.0±66.6 vs 103.0±79.5 ng/mL; P=0.02) and was comparable between the fine granules vs whole tablets group (223.0±66.6 vs 229.5±121.6 ng/mL; P=0.88).
• Among the patients who received rivaroxaban 10 mg, the C_0h was higher in the fine granules vs crushed tablets group (23.2±7.9 vs 7.5±6.2 ng/mL; P<0.01) and was comparable between the fine granules vs whole tablets group (23.2±7.9 vs 19.0±15.8 ng/mL; P=0.35).
• Among the patients who received rivaroxaban 10 mg, C_4h was higher in the fine granules vs crushed tablets group (150.7±85.4 vs 85.1±46.8 ng/mL; P<0.01) and was lower in the fine granules vs whole tablets group (150.7±85.4 vs 189.8±92.7 ng/mL; P=0.18).

Moore et al (2014)² investigated stability and NG-tube adsorption characteristics and relative bioavailability of rivaroxaban in a phase 1, single-center, open-label, randomized, 3period, 3-treatment crossover study.

• In 55 healthy adults, the relative bioavailability of rivaroxaban 20 mg administered orally as a whole tablet (Whole-Oral), crushed tablet in 70 mL applesauce suspension (Crushed-Oral), or crushed tablet in 50 mL water suspension via NG tube (Crushed-NG) were determined.
• There were no significant changes in mean percentages of nondegraded rivaroxaban recovered over 4 hours for crushed tablet suspensions in water, applesauce, and juice (50 mL orange or cranberry juice) (≥98.5% recovery across all suspensions and time points) or after NG tube exposure (recovery: 99.1% for silicone and 98.9% for polyvinyl chloride NG tubes).
• 98% of subjects who received the Crushed-NG displayed a double concentration-time peak.
  • The first peak occurred ~45 minutes after dosing. The second peak occurred 4-6 hours after dosing and was consistent with the time of peak plasma concentrations seen with Whole-oral and Crushed-Oral dose administrations.
• Relative bioavailability was similar between Crushed-Oral and Whole-oral (C_max and AUC values were within 80%-125% bioequivalence limits).
• Relative bioavailability was also similar between the Crushed-NG and Whole-oral (AUC values were within bioequivalence limits; C_max [90% CI: 78.5%-85.8%] was slightly below the 80% lower bioequivalence limit).

LITERATURE SEARCH

A literature search of MEDLINE^®, EMBASE^®, BIOSIS Previews^®, and DERWENT^® (and/or other resources, including internal/external databases) was conducted on 09 December 2023.