Summary

• XARELTO tablets are available as film-coated tablets.¹
• The safety and efficacy of XARELTO in patients with bariatric surgical procedures have not been specifically investigated in well-controlled clinical trials. Limited data from pharmacokinetic (PK)/pharmacodynamic (PD) studies and case reports are available.
• 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 concentration (C_max) compared to tablet was reported when rivaroxaban granulate is released in the proximal small intestine. Exposure is further reduced when the 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 relative bioavailability of XARELTO depends on the site of absorption along the GI tract. It is markedly reduced in the ascending colon.²
• A phase 1, single-center study compared the PK of XARELTO in patients who had undergone a Roux-en-Y gastric bypass (RYGB) or sleeve gastrectomy (SG) with the PK observed in individuals with a body mass index (BMI) of ≥40 kg/m² (class III obesity group) and a group of healthy volunteers (control group). The mean area under the concentration-time curve under 24 hours (AUC_0-24) and C_max were lower in the surgical groups than in the control group after the first dose. None of the surgical groups met the steady-state bioequivalence criteria for either AUC or C_max; however, the group with class III obesity met the bioequivalence criteria compared with the controls at steady state. No unexpected adverse events or deaths occurred during the study.³
• In a phase 1 study, single, oral doses of XARELTO resulted in similar systemic drug exposures prior to and following bariatric surgery, regardless of the type of bariatric procedure that was performed. XARELTO was well tolerated.⁴
• It has been suggested that low caloric intake (~500 calories per day), which is typical after bariatric surgery, may affect the absorption of XARELTO.⁵ Clinicians should assess the risks and benefits of XARELTO therapy in each patient.
• A retrospective chart review of 102 patients prescribed apixaban or XARELTO after bariatric surgery found no recurrent venous thromboembolism (VTE) in the apixaban group and 1 (1.7%) in the XARELTO group.⁶
• In a retrospective cohort study of 191 patients with a history of bariatric surgery who had received a direct acting oral anticoagulant (DOAC; apixaban, dabigatran, or XARELTO), clotting and bleeding events occurred in 11 (5.8%) and 42 (22%) patients, respectively. The use of XARELTO vs apixaban was associated with a statistically significant increased risk of bleeding (hazard ratio [HR], 3.16; 95% confidence interval [CI], 1.04-9.63; P=0.043).⁷
• In a retrospective cohort study of 272 patients, XARELTO was randomized to two groups: short prophylaxis (7 days) and long prophylaxis (28 days) post bariatric surgery. One incidence of asymptomatic deep vein thrombosis (DVT) occurred in a patient undergoing SG in the long prophylaxis group (0.4%; 95% CI, 0.02-2.2).⁸
• There are 3 case reports that described the use of XARELTO following gastric bypass surgery. One report described the incidence of recurrent thrombi despite multiple anticoagulation therapies in an obese patient with a history of bariatric surgery.⁹ Another report described the use of XARELTO following gastric bypass surgery in a patient with atrial fibrillation (AF) at high risk for stroke.¹⁰ XARELTO absorption was found to be immediate and not reduced following the surgery. The other report described a patient with a history of recurrent VTE and started on XARELTO after laparoscopic bariatric surgery.¹¹ The highest plasma concentration of XARELTO occurred 3 hours after dosing and declined to a trough level at 24 hours after dosing. Achievement of therapeutic anti Xa levels did not appear to be affected by bariatric surgery.
• Additional citations identified during a literature search are included in the REFERENCES section for your review.^12-22

PRODUCT LABELING

Please refer to the following section of the enclosed Full Prescribing Information that is relevant to your inquiry: PHARMACOKINETICS (Section 12.3).

CLINICAL STUDIES

Phase 1 Studies

ABSORB³ (Rivaroxaban Pharmacokinetics and Pharmacodynamics After Bariatric Surgery and in Morbid Obesity) was a phase 1, single-center, bioequivalence, nonrandomized, open-label, multiple-dose, parallel design study that compared the PK of XARELTO 20 mg daily for 8 days in patients who had undergone RYGB or SG with the PK observed in individuals with a BMI of ≥40 kg/m² (class III obesity group) and a group of healthy volunteers (control group).

• The primary endpoint was the XARELTO plasma concentration profile on day 1 and at steady state on day 8; this was measured to determine C_max, time required to reach C_max (T_max), and AUC.
• A total of 64 individuals were included in the PK analysis:
  • Class III obesity group: n=16; mean age, 38.7 years; 75.0% were female.
  • RYGB group: n=16; mean age, 48.1 years; 87.5% were female.
  • SG group: n=16; mean age, 44.4 years; 68.8% were female.
  • Control group (individuals without a history of bariatric surgery but with a similar age and BMI as those of the patients in the surgical groups): n=16; mean age, 45.7 years; 75.0% were female.
• After the first dose:
  • The mean AUC_0-24 was lower in the surgical groups (RYGB, 1806.8 ng.h/mL; SG, 1648.9 ng.h/mL) than in the control group (1893.5 ng.h/mL).
  • The mean C_max was lower in the RYGB group (214.9 ng/mL) than in the other groups (class III obesity, 260.5 ng/mL; SG, 252.5 ng/mL; and control group, 264.1 ng/mL). However, this difference was less pronounced once steady state was reached (RYGB, 256.9 ng/mL; class III obesity, 292.7 ng/mL; SG, 265.8 ng/mL; and control group, 288.8 ng/mL).
• At steady state, the AUC values remained lower in the surgical groups (RYGB, 2129.9 ng.h/mL; SG, 1946.4 ng.h/mL) than in the control group (2224.8 ng.h/mL).
• On day 8, compared with the control group, none of the surgical groups met the steady-state bioequivalence criteria for AUC (RYGB: ratio of the geometric mean [GMR], 93.6% [90% CI, 78.0-122.2]; SG: GMR, 86.3% [90% CI, 71.4-104.2]) or C_max (RYGB: GMR, 87.3% [90% CI, 72.6-104.9]; SG: GMR, 93.2% [90% CI, 77.6-112.1]). However, compared with the control group, the class III obesity group met the steady-state bioequivalence criteria for AUC (GMR, 102.4% [90% CI, 85.4-122.7]) and C_max (GMR, 96.8% [90% CI, 80.6-116.4]).
• No unexpected adverse events or deaths occurred during the study. One patient experienced a major bleeding event (menorrhagia resulting in a hemoglobin fall of 30 g/L) in the RYGB group which resolved with discontinuation of treatment. Minor bleeding was observed in 4 patients in the class III obesity group and 2 patients in the SG group.

Kroll et al (2017)⁴ conducted a phase 1, single-center, open-label, nonrandomized study to assess effect of weight loss and type of bariatric surgery on PK/PD parameters of XARELTO (N=12).

• Six RYGB patients and 6 SG patients with a mean age of 39 years in each group were evaluated. The initial mean BMI was 44.6 kg/m² and 38.5 kg/m², in the SG and RYGB groups, respectively.
• Patients received single, oral doses of XARELTO 10 mg a day prior to and 3 days following bariatric surgery, under non-fasting conditions.
• Primary endpoints included single-dose PK parameters following XARELTO administration before and after RYGB and SG. Safety endpoints included mortality, proximal or distal DVT, pulmonary embolism (PE), and all bleeding events.
• Single doses of XARELTO 10 mg resulted in similar systemic drug exposures prior to and following bariatric surgery, regardless of the type of bariatric procedure that was performed. See Table: Pharmacokinetic Parameters for RYGB and SG Patients.
• XARELTO was well tolerated. There were 2 events (hematoma of abdominal wall near incision and low hemoglobin) reported as being possibly related to XARELTO use; both events were mild or moderate in intensity.

Kroll et al (2018)²³ conducted a monocentric, extension trial in patients (n=12), who participated in the study described above, to assess PK and PD parameters 6 to 8 months after bariatric surgery and compare with prebariatric surgery results.

• A single oral dose of XARELTO 10 mg was given under non-fasting conditions 6 to 8 months after SG (n=6) or RYGB (n=6).
• Both surgical procedures showed no relevant difference in the PK/PD of XARELTO.
• The SG group had excess weight loss of 71.4% (interquartile range [IQR], 56.4-87.9) and an excess weight loss of 76.6% (IQR, 64.5-85.7) in the RYGB group.
• The mean AUC of XARELTO 6-8 months after the bariatric surgery was comparable to measurements preoperatively, 922.4 ug x h/L, coefficient of variation 43.2 and 952.6 ug x h/L, coefficient of variation 16.8, respectively. For the 2 surgical treatment groups, see Table: Pharmacokinetic Parameters for SG and RYGB Patients, Before Surgery and after (Midterm Follow up).
• No adverse events occurred during this extension trial.

Pharmacokinetic Study² was a single-center, non-randomized, non-placebo-controlled, non-blinded cross-over study that evaluated the PK 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™ capsule²⁴) in the proximal and distal small bowel and ascending colon. This was compared to the oral administration of XARELTO 10 mg. Nine healthy male subjects (18-50 years) were enrolled in the study, which utilized 5 regimens:

• Regimen A: XARELTO 5 mg administered orally x 2
• 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 dose-normalized AUC (AUC_norm) (71%) and normalized Cmax (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 solution. Administration of a single dose into the distal small bowel and ascending colon was safe and well tolerated.

Phase 2 Studies

Kroll et al (2023)⁸ conducted an assessor-blinded, phase 2, multicenter randomized clinical trial to determine the efficacy and safety of a prophylactic oral dose of XARELTO 10 mg in patients with severe obesity after bariatric surgery. A total of 272 adult patients (≥18 years) were randomly assigned to short prophylaxis (7 days; n=134) or long prophylaxis (28 days; n=135) on post-operative day 1. Patients were stratified based on the surgical procedure (RYGB, SG, or revisional surgery), sex, and study center. Overall, patients had a mean age of 40.0 years, 80.3% were female, and had a mean BMI of 42.2. Both study groups were well-balanced except for diabetes and smoking, which were more present in patients assigned to the short prophylaxis group. The primary outcome was confirmation of any DVT (proximal or distal and asymptomatic or symptomatic). The primary safety outcome was the incidence of major bleeding (MB) defined by the International Society on Thrombosis and Haemostasis (ISTH; bleeding leading to transfusion or a decrease in the hemoglobin level of ≥2 g/dL) during the intervention and observation periods.

Asymptomatic DVT occurred in 1 patient undergoing SG in the long prophylaxis group (0.4%; 95% CI, 0.02%-2.2%). No patient experienced an overt DVT or PE. MB or clinically relevant nonmajor bleeding (CRNMB) events were observed in 5 patients (1.9%): 2 in the short prophylaxis group and 3 in the long prophylaxis group. The difference was not statistically significant between the two groups. See table: Secondary Outcomes: Major Bleeding and Clinically Relevant Nonmajor Bleeding.

Clinically nonsignificant bleeding events were observed in 10 patients (3.7%): 3 in the short prophylaxis group and 7 in the long prophylaxis group. Postoperative complication events observed in the short prophylaxis and long prophylaxis groups were 7 and 17, respectively. However, the difference was not statistically significant. In total, 72 adverse events occurred in 58 patients (21.6%) of which 19 were classified as serious adverse events. A total of 12 patients discontinued XARELTO because of an adverse event.

REAL-WORLD EVIDENCE

Langworthy et al (2022)⁷ conducted a retrospective cohort study to characterize clotting and bleeding outcomes in 191 adult patients with a history of bariatric surgery who had received a DOAC (apixaban, dabigatran, or XARELTO) for the prophylaxis or treatment of VTE or for the prevention of stroke and systemic embolism in AF between January 2011 and December 2018. The primary outcomes were characterization of clotting and bleeding events, and secondary outcomes included characterization of bleeding rates based on bariatric surgery type, time since surgery, and DOAC agent. Overall, the mean age of DOAC initiation was 60.4 years, and 73.8% of patients were females. Majority of patients had a history of RYGB (72.8%), and most patients received XARELTO (68.6%) as the index (defined as the patient’s first prescription for a DOAC that occurred after bariatric surgery during the study window and was considered an active course until the medication was stopped for >30 days) DOAC agent. The median follow-up time was 207 days (IQR, 37-903).

Clotting events occurred in 11 (5.8%) patients receiving a DOAC, with a calculated clotting rate of 3.9 clots per 100 person-years (PY). Bleeding events occurred in 42 (22%) patients receiving a DOAC, with a calculated bleeding rate of 17.1 bleeds per 100 PY. In the unadjusted analysis, overall effect of index DOAC agents on bleeding events was found to be nonsignificant (P=0.113); however, after adjustment, the use of XARELTO vs apixaban was associated with a statistically significant increased risk of bleeding (HR, 3.16; 95% CI, 1.04-9.63; P=0.043). See Table: Overall Cohort Hazard of Clotting and Bleeding Events Based on Index DOACs.

The results for clotting and bleeding events were also found to be consistent with the initial multivariate analysis on the therapeutic intensity doses of DOACs in a subgroup analysis of patients.

Kushnir et al (2019)⁶ conducted a retrospective chart review of 102 patients (≥ 18 years) prescribed DOACs (apixaban or XARELTO) to determine safety and efficacy in prevention of recurrent VTE in patients who have undergone gastric bypass (51%), SG (37.3%), or gastric banding (11.8%). Patient demographics, BMI, and type of bariatric surgery were reviewed between July 2013 and June 2018 and clinical outcomes of recurrent VTE and bleeding events, MB and CRNMB, were documented. Characteristics identified included mean age of 48.5 years, median BMI of 35.7 kg/m², and 82.4% female at initiation of apixaban (n=42) or XARELTO (n=60).

In the XARELTO group, recurrent VTE occurred in 1 (1.7%) patient, MB in 4 patients (6.7%, p=0.3), and no CRNMB. No recurrent VTE events or MB, and 1 CRNMB (2.4%) was recorded in the apixaban group. Patients from a prior study with a BMI >40 kg/m² were compared to the current study in post-bariatric patients. In that comparison, there was no significant difference in VTE recurrence rates between the 2 studies.

CASE REPORTS

Briggler et al (2022)⁹ described the case of a 58-year-old female patient with class 3 obesity (BMI, 53 kg/m²) who developed VTE within 4 weeks of an elective gastric bypass surgery 15 years ago. The patient was started on warfarin therapy and was stable on a dose of 5 mg daily with the therapeutic international normalized ratios (INRs) between 2 and 3. The patient switched to apixaban 2.5 mg twice daily (BID) after 7 years of treatment with warfarin. At this time, patient BMI had returned to >50 kg/m² and remained consistent for the duration of the case. Although the patient developed PE 5 years after the switch, no central PE was identified, and the regimen was continued with no changes. After 6 years, the patient had knee arthroplasty, and apixaban was stopped 4 days prior to surgery during which a questionable PE was found in the right pulmonary artery. Post surgery, the patient was restarted on apixaban 10 mg BID for 7 days, followed by 5 mg BID thereafter. A PE of the left pulmonary artery was found 1 month after the surgery, and the patient was administered enoxaparin 1 mg/kg every 12 hours in the hospital; apixaban was discontinued and XARELTO was started at 15 mg BID for the first 21 days, followed by 20 mg daily thereafter. However, the patient developed DVT within the next month and was administered 1 dose of enoxaparin 150 mg (1 mg/kg) and was discharged on the previous XARELTO regimen (20 mg daily) for unknown reasons. After 2 years, the patient developed right lower PE and warfarin was added to the current XARELTO regimen. XARELTO was discontinued when the patient’s INR decreased from 1.8 to 1.4, and enoxaparin 150 mg (1 mg/kg) was added to warfarin. However, the INR continued to decrease, despite warfarin dose up-titration. Patient was then hospitalized with gross hematuria, INR of 1.3, and a new PE was located. The patient underwent cystoscopy with ureteral stent placement and was treated with enoxaparin 150 mg (1 mg/kg) BID and warfarin 5 mg daily. Warfarin was discontinued and the patient was discharged on enoxaparin 120 mg (0.8 mg/kg) BID (anti-Xa level of 1.05 IU/mL). Eleven days after discharge, the patient was hospitalized for stomach pain and bleeding; thereafter, patient was discharged on a dose of enoxaparin 90 mg (0.6 mg/kg) BID. Two weeks after discharge, this regimen was changed to enoxaparin 100 mg (0.7 mg/kg) BID (anti-Xa level 1.41 IU/mL) with warfarin 15 mg daily and an inferior vena cava filter. Currently, this regimen has been efficacious for 18 months, as shown by anti-Xa and INR levels that are in the range of 2-3 with no evidence of new VTE. The consolidated timeline of anticoagulation therapies and thrombotic events are presented in the Table: Timeline of Anticoagulation Therapies and Thrombotic Events.

Cintineo et al (2015)¹⁰ reported on the use of XARELTO in a 60-year-old woman with AF and a history of proximal RYGB surgery. The patient had received vitamin K antagonist (VKA) therapy prior to bariatric surgery but was not receiving anticoagulant therapy immediately before or following the gastric bypass procedure. Three years postoperatively, a diagnosis of transient ischemic attack resulted in initiation of XARELTO 20 mg once daily. A chromogenic, anti-Xa assay assessed the potential effects of gastric bypass on XARELTO levels. Trough plasma concentration, which was collected 23 hours after administration of XARELTO 20 mg, was <30 mcg/mL. Peak plasma concentration, which was collected 2 hours after administration, was 275 mcg/mL. INR and prothrombin values were consistent with an anticoagulant effect. XARELTO absorption was found to be immediate and not reduced in this patient following gastric bypass.

Mahlmann et al (2013)¹¹ described a 27-year-old woman who was initiated on XARELTO therapy for prevention of VTE after undergoing gastric bypass without gastrectomy and Y-gastro-jejunostomy. The patient had previously received a VKA for long-term anticoagulant therapy due to recurrent VTE but had unstable INR and coagulation values. She was at a high risk for VTE due to prior VTE episodes and required continued anticoagulation. After switching to XARELTO 20 mg once daily, plasma drug concentrations, INR, and activated partial thromboplastin time were measured. Following the first XARELTO dose, plasma drug concentrations increased rapidly, reaching peak values that were within the expected range. See Table: Plasma Concentrations After Administration of XARELTO 20 mg Once Daily in a Patient Who Underwent Bariatric Surgery.

The peak plasma concentrations that were achieved suggest that standard-dose XARELTO resulted in therapeutic anti-Xa levels and was not significantly impaired by bariatric surgery in this patient.¹¹

Higher XARELTO doses, which are used for prevention of stroke in AF and for treatment of VTE, have poor bioavailability (~66% for a 20-mg dose). PK studies have shown that the bioavailability of these higher doses is significantly improved (≥80%) when taken with food. It has been suggested that low caloric intake (~500 calories per day), which is typical after bariatric surgery, may affect the absorption of XARELTO.⁵

LITERATURE SEARCH

A literature search of MEDLINE^®, EMBASE^®, BIOSIS Previews^®, DERWENT^® (and/or other resources, including internal/external databases) was conducted on 15 November 2024.