SUMMARY

• XARELTO is indicated for the treatment of venous thromboembolism (VTE) and the reduction in the risk of recurrent VTE in pediatric patients from birth to less than 18 years after at least 5 days of initial parenteral anticoagulant treatment.¹
• XARELTO is indicated for thromboprophylaxis in pediatric patients aged 2 years and older with congenital heart disease who have undergone the Fontan procedure.¹
• McCrindle et al (2021)^2,3 reported the efficacy and safety results of oral XARELTO compared with aspirin from the phase 3, randomized, multicenter, 2-part, open-label UNIVERSE study in pediatric patients aged 2-8 years with single-ventricle physiology who had undergone the Fontan procedure within 4 months prior to study enrollment.
  • In part A, single- and multiple-dose pharmacokinetic (PK) and pharmacodynamic (PD) characteristics of weight-based XARELTO dosing were evaluated (n=12).
  • In part B, the safety and efficacy of weight-based XARELTO dosing (n=66) for thromboprophylaxis was evaluated compared to aspirin (n=34).
  • In both part A and B, the exposure of weight-based XARELTO dosing in children after the Fontan procedure was similar to the exposure in adults receiving a 10 mg total daily dose for thromboprophylaxis.
  • One patient in the XARELTO part B group had a major bleeding event (2%; epistaxis). No major bleeding events were reported in the aspirin part B or XARELTO part A groups. In the XARELTO vs aspirin part B groups, clinically relevant nonmajor bleeding occurred in 4 (6%) vs 3 (9%) patients and trivial bleeding occurred in 21 (33%) vs 12 (35%) patients.
• Male et al (2020)⁴ reported results from the phase 3, randomized, open-label, activecontrolled EINSTEIN Junior study evaluating the efficacy and safety of XARELTO in a body weight-adjusted 20 mg-equivalent dose compared with standard of care for the treatment of pediatric patients aged ≤17 years with acute VTE. XARELTO was administered as either immediate-release film-coated tablets (strengths of 5, 10, 15, or 20 mg) or an oral suspension (1 mg/mL). Symptomatic recurrent VTE occurred in 4 (1%) of the 335 patients in the XARELTO group and in 5 (3%) of the 165 patients in the comparator group (hazard ratio [HR] 0.40, 95% confidence interval [CI] 0.11-1.41). Major or clinically relevant nonmajor bleeding occurred in 10 (3%) and 3 (2%) patients in the XARELTO and comparator groups, respectively.
• Monagle et al (2019)⁵ assessed the efficacy and safety outcomes of the phase 2, multicenter, single-arm, open-label, nonrandomized EINSTEIN Junior study evaluating XARELTO in pediatric patients aged ≤17 years with objectively confirmed VTE. XARELTO was dosed according to an age- and body weight-adjusted 20 mg-equivalent dosing schedule for a total of 30 days (7 days for patients younger than 6 months). No patient had a major bleeding event, and 4 (4%) patients had a clinically relevant nonmajor bleeding event. No symptomatic recurrent VTE was found in any patients (0%; 95% CI 0-3.9). Adverse events (AEs) were reported in 61 (66%) patients.
• A literature search identified additional citations for your review.^6-8

PRODUCT LABELING

Please refer to the full Prescribing Information, Medication Guide, and Instructions for Use for complete information on Dosage and Administration.

Pediatric Use

The safety and effectiveness of XARELTO have been established in pediatric patients from birth to less than 18 years for the treatment of VTE and the reduction in risk of recurrent VTE. Use of XARELTO is supported in these age groups by evidence from adequate and wellcontrolled studies of XARELTO in adults with additional PK, safety, and efficacy data from a multicenter, prospective, open-label, active-controlled randomized study in 500 pediatric patients from birth to less than 18 years of age. XARELTO was not studied and therefore dosing cannot be reliably determined or recommended in children less than 6 months who were less than 37 weeks of gestation at birth, had less than 10 days of oral feeding, or had a body weight of less than 2.6 kg.¹

The safety and effectiveness of XARELTO have been established for use in pediatric patients aged 2 years and older with congenital heart disease who have undergone the Fontan procedure. Use of XARELTO is supported in these age groups by evidence from adequate and well-controlled studies of XARELTO in adults with additional data from a multicenter, prospective, open-label, active-controlled study in 112 pediatric patients to evaluate the single- and multiple-dose PK properties of XARELTO and the safety and efficacy of XARELTO when used for thromboprophylaxis for 12 months in children with single-ventricle physiology who had the Fontan procedure.¹

Clinical studies that evaluated safety, efficacy, PK and pharmacodynamic data support the use of XARELTO 10 mg, 15 mg, and 20 mg tablets in pediatric patients. For the XARELTO 2.5 mg tablets, there are no safety, efficacy, PK and PD data to support the use in pediatric patients. Therefore, XARELTO 2.5 mg tablets are not recommended for use in pediatric patients.¹

Recommended Dosage in Pediatric Patients

Treatment of VTE and Reduction in Risk of Recurrent VTE in Pediatric Patients

See Table: Recommended Dosage in Pediatric Patients Birth to Less than 18 Years for Treatment of and Reduction in Risk of Recurrent VTE.

Dosing of XARELTO was not studied and therefore dosing cannot be reliably determined in the following patient populations. Its use is therefore not recommended in children less than 6 months of age with any of the following:¹

• Less than 37 weeks of gestation at birth
• Less than 10 days of oral feeding
• Body weight of less than 2.6 kg

To increase absorption, all doses should be taken with feeding or with food.¹

Monitor the child’s weight and review the dose regularly, especially for children below 12 kg. This is to ensure a therapeutic dose is maintained.¹

All Pediatric Patients (Except <2 Years Old With Catheter-Related Thrombosis)

Therapy with XARELTO should be continued for at least 3 months in children with thrombosis. Treatment can be extended up to 12 months when clinically necessary. The benefit of continued therapy beyond 3 months should be assessed on an individual basis taking into account the risk for recurrent thrombosis versus the potential risk of bleeding.¹

Pediatric Patients <2 Years Old With Catheter-Related Thrombosis

Therapy with XARELTO should be continued for at least 1 month in children less than 2 years old with catheter-related thrombosis. Treatment can be extended up to 3 months when clinically necessary. The benefit of continued therapy beyond 1 month should be assessed on an individual basis taking into account the risk for recurrent thrombosis versus the potential risk of bleeding.¹

Thromboprophylaxis in Pediatric Patients With Congenital Heart Disease After the Fontan Procedure

See Table: Recommended Dosage for Thromboprophylaxis in Pediatric Patients with Congenital Heart Disease.

Administration in Pediatric Patients

Food Effect

For the treatment of VTE in children, the dose should be taken with food to increase absorption. For thromboprophylaxis after Fontan procedure, the dose can be taken with or without food.¹

Vomit or Spit Up

If the patient vomits or spits up the dose within 30 minutes after receiving the dose, a new dose should be given. However, if the patient vomits more than 30 minutes after the dose is taken, the dose should not be re-administered and the next dose should be taken as scheduled. If the patient vomits or spits up the dose repeatedly, the caregiver should contact the child’s doctor right away.¹

Tablets

XARELTO tablet must not be split in an attempt to provide a fraction of a tablet dose. 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

Use in Renal Impairment in Pediatric Patients

Patients 1 Year of Age or Older

• Mild renal impairment (estimated glomerular filtration rate [eGFR]: 50 to ≤80 mL/min/1.73 m²): No dose adjustment is required.¹
• Moderate or severe renal impairment (eGFR: <50 mL/min/1.73 m²): avoid use, as limited clinical data are available.¹

eGFR can be done using the updated Schwartz formula, eGFR (Schwartz) = (0.413 × height in cm)/serum creatinine (SCr) in mg/dL, if SCr is measured by an enzymatic creatinine method that has been calibrated to be traceable to isotope dilution mass spectrometry (IDMS).¹

If SCr is measured with routine methods that have not been recalibrated to be traceable to IDMS (eg, the traditional Jaffé reaction), the eGFR should be obtained from the original Schwartz formula: eGFR (mL/min/1.73 m²) = k × height (cm)/SCr (mg/dL), where k is proportionality constant¹:

• k=0.55 in children 1 year to 13 years
• k=0.55 in girls > 13 and < 18 years
• k=0.70 in boys > 13 and < 18 years

Patients Less Than 1 Year of Age

• Determine renal function using SCr. Avoid use of XARELTO in pediatric patients younger than 1 year with SCr results above 97.5th percentile, as no clinical data are available.¹ See Table: Reference Values of Serum Creatinine in Pediatric Patients <1 Year of Age.

Administration of XARELTO Suspension via Nasogastric (NG) Tube or Gastric Feeding Tube

• XARELTO oral suspension may be given through NG or gastric feeding tube. After the administration, flush the feeding tube with water.¹
• For the treatment or reduction in risk of recurrent VTE in pediatric patients, the dose should then be immediately followed by enteral feeding to increase absorption. For the thromboprophylaxis in pediatric patients with congenital heart disease who have undergone the Fontan procedure, the dose does not require to be followed by enteral feeding.¹
• An in vitro compatibility study indicated that XARELTO suspension can be used with PVC, polyurethane, or silicone NG tubing.¹

Clinical Data

UNIVERSE Study

Phase 3 Study

McCrindle et al (2021)^2,3 reported the efficacy and safety results of oral XARELTO compared with aspirin from the phase 3, randomized, multicenter, 2-part, open-label UNIVERSE study in pediatric patients aged 2 - 8 years with single-ventricle physiology who had undergone the Fontan procedure within 4 months prior to study enrollment.

Study Design/Methods

• Part A was designed to characterize the single- and multiple-dose PK and PD profiles following oral administration of XARELTO, while part B evaluated the safety and efficacy of XARELTO compared to aspirin for thromboprophylaxis. Dosing interventions included:
  • XARELTO 0.1% (1 mg/mL) oral suspension twice daily by body weight in parts A and B for 12 months. See Table: XARELTO Dosing.
  • Aspirin ~5 mg/kg once daily for 12 months in part B.
• Patients were required to be clinically stable and able to tolerate oral or nasogastric feedings. An initial post-Fontan transthoracic echocardiographic screening without any evidence of thrombosis was required.
• Key exclusion criteria included thrombosis, a history of gastrointestinal disease or surgery associated with impaired absorption, active bleeding or high risk of bleeding including history of intracranial hemorrhage or contraindications to aspirin or XARELTO.
• In part A, there was a 12-day initial PK, PD, and safety assessment period, followed by a 12-month open-label treatment period, and a 30-day follow up.
• Patients in part B were randomized 2:1 on day 1 to receive XARELTO oral suspension or aspirin for 12 months.
• The primary safety outcome was major bleeding events, as defined by the International Society on Thrombosis and Haemostasis; secondary safety outcome was clinically relevant nonmajor bleeding and trivial (minimal) bleeding events.
• The primary efficacy outcome included any thrombotic event (venous or arterial) defined as the appearance of a new thrombotic burden within the cardiovascular system noted on routine surveillance or clinically indicated imaging; or the occurrence of a clinical event known to be strongly associated with thrombus, such as stroke or pulmonary embolism.
• The study was not powered to formally test for efficacy, due to the limited number of study patients and low rate of events.

Results

• A total of 112 patients were included (12 in the XARELTO part A group, 66 in the XARELTO part B group, and 34 in the aspirin part B group).
• In the XARELTO part A group, the mean age at screening was 2.5 (±0.7) years, 58% patients were male, mean weight was 13.8 (±2.4) kg, mean duration between the Fontan procedure and first study drug dose was 12 (±17) days.
• In the XARELTO vs aspirin part B groups, the mean age at screening was 4.1 (±1.7) years vs 4.2 (±1.8) years, 55% vs 68% patients were male, mean weight was 15.8 (±3.7) kg vs 15.7 (±3.1) kg, mean duration between the Fontan procedure and first study drug dose was 45 (±41) days vs 37 (±35) days.
• In both part A and B, the exposure of XARELTO in children after the Fontan procedure was similar to the exposure in adults receiving a 10 mg total daily dose for thromboprophylaxis.
• One patient in the XARELTO part B group had a major bleeding event (2%; epistaxis). The epistaxis was in a noncritical site and was considered a major bleeding event because the patient required a blood transfusion. Bleeding events are presented in Table: Summary of Bleeding Events.
• Thrombotic events in part B (efficacy) occurred in 1 (2%) patient in the XARELTO group (pulmonary embolism) and 3 (9%) patients in the aspirin group (2 patients with venous thrombosis and 1 patient with ischemic stroke). One patient (8%) in the XARELTO part A group had a venous thrombotic event. The study was not powered to evaluate efficacy.
• In the XARELTO vs aspirin part B groups, 86% (n=55) vs 85% (n=29) of patients reported ≥1 adverse event, and 28% (n=18) vs 24% (n=8) of patients reported ≥1 serious adverse event, respectively.
• The rates of adverse events and serious adverse events were generally balanced between both treatment groups, except for pleural effusions (19% in the XARELTO group vs 6% in the aspirin group), which were considered not related to the study drug by the investigators.
• Infections (63% in the XARELTO group vs 65% in the aspirin group) were the most common adverse event reported in both treatment groups.

EINSTEIN Junior Program

Phase 3 Study

Male et al (2020)⁴ evaluated the efficacy and safety of a bodyweight-adjusted 20 mgequivalent dose of XARELTO compared with standard of care for treatment in pediatric patients aged ≤17 years with acute VTE in the randomized, active-controlled, open-label, phase 3 EINSTEIN Junior study.

Study Design/Methods

• Pediatric patients aged 0-17 years with objectively confirmed VTE who had completed at least 5 days of initial heparin therapy were eligible. Key exclusion criteria included active bleeding or high risk for bleeding, contraindicating anticoagulant therapy, a platelet count of <50 × 10⁹ cells/L, hepatic disease associated with a coagulopathy, severe renal impairment, or a life expectancy of <3 months.
• Patients were randomized 2:1 to XARELTO or standard anticoagulation (heparin/vitamin K antagonist [VKA]) for a treatment duration of 3 months (patients aged <2 years with catheter-related thrombosis had a main treatment period of 1 month).
• XARELTO was administered as a body weight-adjusted 20 mg-equivalent dose once daily in patients with a body weight of ≥30 kg, twice daily in patients with a body weight of 12 to <30 kg, or thrice daily in patients with a body weight of <12 kg as either immediate-release film-coated tablets (strengths of 5, 10, 15, or 20 mg) or an oral suspension (1 mg/mL).
• The primary efficacy outcome was symptomatic recurrent VTE. The primary safety outcome was the composite of overt major and clinically relevant nonmajor bleeding.

Results

• A total of 500 patients (0-23 months, n=54; 2-5 years, n=69; 6-11 years, n=101; 1217 years, n=276) were randomized (XARELTO, n=335; comparator, n=165). Nine patients did not receive any study medication.
• In the XARELTO vs comparator groups, 52% vs 48% of patients were male, index VTE was caused by cerebral vein or sinus thrombosis in 22% vs 26% of patients, by catheterrelated VTE in 27% vs 22% of patients, and by noncatheter-related VTE in 51% vs 52% of patients.
• After a median follow-up of 91 days (interquartile range [IQR] 87-95) in patients who had a study treatment of 3 months (n=463) and 31 days (IQR 29-35) in patients who had a study treatment period of 1 month (n=37), symptomatic recurrent VTE occurred in 4 (1%) of the 335 patients in the XARELTO group and in 5 (3%) of the 165 patients in the comparator group (HR 0.40, 95% CI 0.11-1.41).
• Clinically relevant bleeding was observed in 10 (3%) of the 329 patients in the XARELTO group (all were non-major) and in 3 (2%) of the 162 patients in the comparator group (2 major and 1 non-major) (HR 1.58, 95% CI 0.51-6.27).

Phase 2 Study

Monagle et al (2019)⁵ reported the efficacy and safety results from the EINSTEIN Junior phase 2 program, which consisted of three multicenter, single-arm studies that evaluated age and body weight-adjusted XARELTO dosage regimens in pediatric patients aged ≤17 years.

Study Design/Methods

• Pediatric patients with objectively confirmed VTE treated with low-molecular-weight heparin (LMWH), fondaparinux, and/or VKA for at least 2 months (≥6 weeks in the case of catheter-related thrombosis) were eligible. Key exclusion criteria included active bleeding or high risk of bleeding contraindicating anticoagulant therapy and eGFR <30 mL/min/1.73 m².
• XARELTO was dosed according to an age- and body weight-adjusted dosing schedule to achieve a similar exposure as observed in adults treated with XARELTO 20 mg once daily for VTE. Patients received XARELTO for a total of 30 days (7 days for those younger than 6 months). See Table: Body Weight-Adjusted Dosage Schedule.

• Predefined efficacy endpoints were symptomatic recurrent VTE, asymptomatic deterioration on repeat imaging, and PK and PD findings at the end of the study treatment period. The predefined safety outcomes were major and clinically relevant nonmajor bleeding.

Results

• A total of 93 pediatric patients (<6 months, n=10; 6 months to 1 year, n=15; 25 years, n=25; 6-11 years, n=32; and 12-17 years, n=11) were enrolled.
• No patient had a major bleeding event, and 4 (4%) patients had a clinically relevant nonmajor bleeding event (3 with menorrhagia and 1 with gingival bleeding in the 617 year age group).
• No symptomatic recurrent VTE was found in any patients (0%; 95% CI 0-3.9).
• Study confirmed therapeutic XARELTO exposures with once-daily dosing in patients with body weight of at least 30 kg and with twice-daily dosing in patients with body weight of at least 20 kg and less than 30 kg. In patients with low body weight (<20 kg, particularly <12 kg), therapeutic XARELTO exposures were lower than the median or less than the adult reference range.

Literature search

A literature search of MEDLINE^®, EMBASE^®, BIOSIS Previews^®, and DERWENT^® (and/or other resources, including internal/external databases) was conducted on 11 November 2024.