VTE - PEDIATRIC

XARELTO®, studied in the EINSTEIN-Jr clinical trial, is the Only DOAC FDA APPROVED to treat VTE and reduce risk of recurrence in children from birth to <18 years of age1-3

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XARELTO® is indicated for the treatment of VTE and the reduction in the risk of recurrent VTE in pediatric patients from birth to <18 years, after ≥5 days of initial parenteral anticoagulant treatment

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DOAC = direct oral anticoagulant.

CLINICAL TRIAL

In the EINSTEIN-Jr clinical trial The largest pediatric DOAC trial conducted for the treatment of VTE and the first to evaluate a liquid formulation in this population1-6

Objective

A randomized, multicenter, active-controlled, open-label, phase 3 trial to evaluate XARELTO® vs comparator* for treatment of acute VTE in a pediatric population3,7

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Not powered for noninferiority due to the low incidence of VTE in children and the lack of well-documented information on recurrence and treatment effect with standard anticoagulants in children; hence, there was no formal a priori sample size calculation.3

aBodyweight-adjusted rivaroxaban dose equivalent to 20 mg once daily adult dose.

bChildren aged <2 years with CVC-VTE: extension with maximum 2 blocks of 1 month, maximum duration of 3 months; decision to stop or continue treatment made after each 3- or 1-month block.

*Comparator treatment = UFH, LMWH, fondaparinux, or VKA.

CVC-VTE = central venous catheter-related VTE; DOAC = direct oral anticoagulant; FPFV = first patient first visit; LMWH = low-molecular-weight heparin; LPLV = last patient last visit; UFH = unfractionated heparin; VKA = vitamin K antagonist.

EINSTEIN-Jr clinical trial study design3,7

STUDY POPULATION

Children aged 0 to 17 years of age with acute VTE initially started on UFH, LMWH, or fondaparinux for ≥5 days before randomization

TREATMENT GROUPS

  • Randomized in a 2:1 ratio to XARELTO® (n=335) or comparator (n=165), stratified by age and VTE site
    • XARELTO® administered as tablets or oral suspension and weight adjusted to achieve drug exposure comparable to 20 mg/day in adults
    • Standard anticoagulation*: continued heparin treatment or switched to a vitamin K antagonist
  • Main treatment duration: 3 months, or 1 month in children <2 years with catheter-related VTE
    • With the option to continue treatment in 3-month increments up to a maximum of 12 months, with the exception of children <2 years of age with CVC-VTE who were treated with XARELTO® in 1-month increments up to a maximum of 3 months

OUTCOMES

  • Primary efficacy outcome: symptomatic recurrent VTE in ITT population
  • Secondary efficacy outcomes:
    • Composite of recurrent VTE and deterioration on repeated vascular (clot) imaging
  • Principal safety outcome: composite of overt major bleeding and clinically relevant nonmajor bleeding†

Not powered for noninferiority due to the low incidence of VTE in children and the lack of well-documented information on recurrence and treatment effect with standard anticoagulants in children; hence, there was no formal a priori sample size calculation.3‡

*Comparators were given at therapeutic doses, according to international guidelines, and included UFH, LMWH, or fondaparinux. Following completion of 5 to 9 days of standard anticoagulation, participants continued with heparin treatment or were switched to a VKA at the discretion of the treating physician for a main study treatment period of 3 months (or 1 month for children <2 years with CVC-VTE). A diagnostic imaging test was obtained at baseline and at the end of the main study treatment. When clinically necessary, treatment was extended up to 12 months in total (or up to 3 months in total for children <2 years with CVC-VTE.)1,3,7

†Clinically relevant nonmajor bleeding is clinically overt bleeding, which did not meet the criteria for major bleeding, but was associated with medical intervention, unscheduled contact with a physician, temporary cessation of treatment, discomfort for the patient, or impairment of activities of daily life. Major bleeding is clinically overt bleeding associated with a decrease in hemoglobin of ≥2 g/dL, a transfusion of ≥2 units of packed red blood cells or whole blood, bleeding at a critical site, or with a fatal outcome.

‡The study could not be powered to independently show noninferiority for efficacy of rivaroxaban in comparison to standard therapy in children; therefore, interpretation of the results relies in part on extrapolation of data obtained with rivaroxaban in adults; hence, there was no formal a priori sample size calculation.

CVC-VTE = central venous catheter-related VTE; ITT = intent-to-treat; LMWH = low-molecular-weight heparin; UFH = unfractionated heparin; VKA = vitamin K antagonist.

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SAFETY PROFILE

In the EINSTEIN-Jr clinical trial XARELTO® demonstrated similar rates of major and clinically relevant nonmajor bleeding vs standard anticoagulation1*†‡

Safety outcome

Not powered for noninferiority due to the low incidence of VTE in children and the lack of well-documented information on recurrence and treatment effect with standard anticoagulants in children; hence, there was no formal a priori sample size calculation.3

*Major bleeding is clinically overt bleeding associated with a decrease in hemoglobin of ≥2 g/dL, a transfusion of ≥2 units of packed red blood cells or whole blood, bleeding at a critical site, or with a fatal outcome.

†Comparators were given at therapeutic doses, according to international guidelines, and included UFH, LMWH, or fondaparinux. Following completion of 5 to 9 days of standard anticoagulation, participants continued with heparin treatment or were switched to a VKA at the discretion of the treating physician for a main study treatment period of 3 months (or 1 month for children <2 years with CVC-VTE). A diagnostic imaging test was obtained at baseline and at the end of the main study treatment. When clinically necessary, treatment was extended up to 12 months in total (or up to 3 months in total for children <2 years with CVC-VTE).1,3,7

‡Clinically relevant nonmajor bleeding is clinically overt bleeding, which did not meet the criteria for major bleeding, but was associated with medical intervention, unscheduled contact with a physician, temporary cessation of treatment, discomfort for the patient, or impairment of activities of daily life.

CVC-VTE = central venous catheter-related VTE; LMWH = low-molecular-weight heparin; UFH = unfractionated heparin; VKA = vitamin K antagonist.

Additional Adverse Events Summary

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A clinically relevant adverse reaction in XARELTO®-treated patients was vomiting (10.6% in the XARELTO® group vs 8% in the comparator group).

EFFICACY PROFILE

The EINSTEIN-Jr clinical trial was not powered for efficacy 60% RRR in recurrent VTE with XARELTO® vs standard anticoagulation3*

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After a median follow-up of 91 days (IQR 87-95) in children who had a study treatment period of 3 months (n=463), and 31 days (IQR 29-35) in children who had a study treatment period of 1 month (n=37).

Observed clot resolution over time:
Complete resolution of index thrombus on repeat imaging

XARELTO®: 38% (128/335; 95% CI 33.0%, 43.5%) vs comparator: 26% (43/165; 95% CI 19.8%, 33.0%)1,3

Symptomatic recurrent VTE or asymptomatic deterioration on repeat imaging

XARELTO®: 1.5% (5/335) vs comparator: 3.6% (6/165), (HR: 0.41; 95% CI 0.12 to 1.36)1,3

Symptomatic recurrent VTE or major bleeding events

XARELTO®: 1.2% (4/335; 95% CI 0.4%, 3.0%) and comparator: 4.2% (7/165; 95% CI 2.0%, 8.4%)1,3

Not powered for noninferiority due to the low incidence of VTE in children and the lack of well-documented information on recurrence and treatment effect with standard anticoagulants in children; hence, there was no formal a priori sample size calculation.3

*Comparators were given at therapeutic doses, according to international guidelines, and included UFH, LMWH, or fondaparinux. Following completion of 5 to 9 days of standard anticoagulation, participants continued with heparin treatment or were switched to a VKA at the discretion of the treating physician for a main study treatment period of 3 months (or 1 month for children <2 years with CVC-VTE). A diagnostic imaging test was obtained at baseline and at the end of the main study treatment. When clinically necessary, treatment was extended up to 12 months in total (or up to 3 months in total for children <2 years with CVC-VTE).1,3,7

†ARR = 3.0-1.2 = 1.8.

ARR = absolute risk reduction; CI = confidence interval; CVC-VTE = central venous catheter-related VTE; HR = hazard ratio; IQR = interquartile range; LMWH = low-molecular-weight heparin; OR = overall response; RRR = relative risk reduction; UFH = unfractionated heparin; VKA = vitamin K antagonist.

DOSING

XARELTO® is the only FDA-approved antithrombotic treatment to offer pediatric patients both an oral suspension and tablets1,2

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NO injections*
NO INR monitoring required
NO special diet required†

The oral-suspension formulation is administered through a color-coded device to help with dosing and administration

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*After ≥5 days of parenteral treatment.

†All doses should be taken with feeding or with food since exposures match that of 20-mg daily dose in adults.

Pediatric dosing of XARELTO® is based on the child’s weight1

Recommended dosage in pediatric patients from birth to <18 years of age for treatment of VTE and reduction in risk of recurrent VTE*†

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*Initiate XARELTO treatment following ≥5 days of initial parenteral anticoagulation therapy.

†Patients <6 months of age should meet the following criteria: at birth were ≥37 weeks of gestation, have had ≥10 days of oral feeding, and weigh ≥2.6 kg at the time of dosing.

‡All doses should be taken with feeding or with food since exposures match that of 20-mg daily dose in adults.

§Once a day: approximately 24 hours apart; 2 times a day: approximately 12 hours apart; 3 times a day: approximately 8 hours apart.

Administration in pediatric patients1

  • Food Effect:

For the treatment of VTE in children, the dose should be taken with food to increase absorption.

  • 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 >30 minutes after the dose is taken, the dose should not be readministered 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.

  • Tablets:
    • XARELTO® tablet must not be split in an attempt to provide a fraction of a tablet dose
    • For children unable to swallow 10-mg, 15-mg, or 20-mg tablets whole, XARELTO® oral suspension should be used
    • XARELTO® 2.5-mg tablets are not recommended for use in pediatric patients
  • In Children <6 Months of Age:

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:

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

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.

Please see the “Instructions for Use” in Prescribing Information for directions on using the oral-suspension formulation.

Additional Administration Considerations

Use in renal impairment in pediatric patients:

PATIENTS 1 YEAR OF AGE OR OLDER:

  • Mild renal impairment (eGFR: 50 to ≤80 mL/min/1.73 m2 ): no dose adjustment is required.
  • Moderate or severe renal impairment (eGFR: <50 mL/min/1.73 m2 ): avoid use, as limited clinical data are available.
  • eGFR can be done using the updated Schwartz formula, eGFR (Schwartz) = (0.413 x height in cm)/SCr in mg/dL, if SCr is measured by an enzymatic creatinine method that has been calibrated to be traceable to IDMS.
  • 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 constant:
    • 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 <1 YEAR OF AGE:

Determine renal function using serum creatinine. Avoid use of XARELTO® in pediatric patients younger than 1 year with serum creatinine results above 97.5th percentile, as no clinical data are available.

Reference values of serum creatinine in pediatric patients <1 year of age

serum-creatitine

Pharmacokinetic Considerations:

  • The half-life of rivaroxaban in plasma of pediatric patients treated for VTE decreased with decreasing age
  • Mean half-life values were 4.2 hours in adolescents, 3 hours in children 2 to 12 years of age, 1.9 hours in children 0.5 to <2 years of age, and 1.6 hours in children <0.5 years of age
  • An exploratory analysis in pediatric patients treated for VTE did not reveal relevant differences in rivaroxaban exposure based on gender

Switching to and from XARELTO®

From warfarin to XARELTO® - When switching patients from warfarin to XARELTO®, discontinue warfarin and start XARELTO® as soon as the INR is below 2.5 in pediatric patients to avoid periods of inadequate anticoagulation.

From XARELTO® to warfarin - To ensure adequate anticoagulation during the transition from XARELTO® to warfarin, continue XARELTO® for ≥2 days after the first dose of warfarin. After 2 days of coadministration, an INR should be obtained prior to the next scheduled dose of XARELTO®. Coadministration of XARELTO® and warfarin is advised to continue until the INR is ≥2.0.

Once XARELTO® is discontinued, INR testing may be done reliably 24 hours after the last dose.

From XARELTO® to anticoagulants other than warfarin - For pediatric patients currently taking XARELTO® and transitioning to an anticoagulant with rapid onset, discontinue XARELTO® and give the first dose of the other anticoagulant (oral or parenteral) at the time that the next XARELTO® dose would have been taken.

From anticoagulants other than warfarin to XARELTO® - For pediatric patients currently receiving an anticoagulant other than warfarin, start XARELTO® 0 to 2 hours prior to the next scheduled administration of the drug (eg, LMWH or non-warfarin oral anticoagulant) and omit administration of the other anticoagulant. For UFH being administered by continuous infusion, stop the infusion and start XARELTO® at the same time.

Missed dose

  • If XARELTO® is taken once a day, the patient should take the missed dose as soon as possible once it is noticed, but only on the same day. If this is not possible, the patient should skip the dose and continue with the next dose as prescribed. The patient should not take two doses to make up for a missed dose
  • If XARELTO® is taken 2 times a day, the patient should take the missed morning dose as soon as possible once it is noticed. A missed morning dose may be taken together with the evening dose. A missed evening dose can only be taken in the same evening
  • If XARELTO® is taken 3 times a day, if a dose is missed, the patient should skip the missed dose and go back to the regular dosing schedule at the usual time without compensating for the missed dose

On the following day, the patient should continue with their regular regimen.

Administration options

Administration of XARELTO® suspension via 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.

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.

An in vitro compatibility study indicated that XARELTO® oral suspension can be used with PVC, polyurethane or silicone NG tubing.

CHD = congenital heart disease; dL = deciliter; eGFR = estimated glomerular filtration rate; IDMS = isotope dilution mass spectrometry; INR = international normalized ratio; LMWH = low-molecular-weight heparin; μmol/L = micromole per liter; NG = nasogastric; PVC = polyvinyl chloride; UFH = unfractionated heparin.

SUMMARY

Pediatric VTE is complex.8

Helping protect against thrombosis doesn’t have to be.

In EINSTEIN-Jr, the largest clinical trial in pediatric VTE treatment and first to evaluate a liquid formulation, XARELTO®, compared with standard anticoagulation:3-6*

The EINSTEIN-Jr clinical trial was not powered for efficacy

  • 60% RRR, 1.8% ARR in percentage of recurrent DVT/PE
    vs comparator
  • Similar rates of major and clinically relevant nonmajor bleeding vs comparator

XARELTO® is the only FDA-APPROVED antithrombotic treatment to offer pediatric patients1,2:

dosing img1oral suspension

tabtablet

Not powered for noninferiority due to the low incidence of VTE in children and the lack of well-documented information on recurrence and treatment effect with standard anticoagulants in children; hence, there was no formal a priori sample size calculation.3

*Comparators were given at therapeutic doses, according to international guidelines, and included UFH, LMWH, or fondaparinux. Following completion of 5 to 9 days of standard anticoagulation, participants continued with heparin treatment or were switched to a VKA at the discretion of the treating physician for a main study treatment period of 3 months (or 1 month for children <2 years with CVC-VTE). A diagnostic imaging test was obtained at baseline and at the end of the main study treatment. When clinically necessary, treatment was extended up to 12 months in total (or up to 3 months in total for children <2 years with CVC-VTE).1,3,7

CVC-VTE = central venous catheter-related VTE; LMWH = low-molecular-weight heparin; UFH = unfractionated heparin; VKA = vitamin K antagonist.

References: 1. XARELTO® [prescribing information]. Titusville, NJ: Janssen Pharmaceuticals, Inc. 2. Pradaxa® [prescribing information]. Ridgefield, CT: Boehringer lngelheim Pharmaceuticals, Inc.; 2021. 3. Male C, Lensing AWA, Palumbo JS, et al; EINSTEIN-Jr Phase 3 Investigators. Rivaroxaban compared with standard anticoagulants for the treatment of acute venous thromboembolism in children: a randomised, controlled, phase 3 trial. Lancet Haematol. 2019;7(1):e18-e27. 4. ClinicalTrials.gov. NCT01895777. Open label study comparing efficacy and safety of dabigatran etexilate to standard of care in paediatric patients with venous thromboembolism (VTE). Accessed April 29, 2022. 5. ClinicalTrials.gov. NCT02464969. Apixaban for the acute treatment of venous thromboembolism in children. Accessed April 29, 2022. 6. ClinicalTrials.gov. NCT02798471. Hokusai study in pediatric patients with confirmed venous thromboembolism (VTE). Accessed April 29, 2022. 7. Lensing AWA, Male C, Young G, et al. Rivaroxaban versus standard anticoagulation for acute venous thromboembolism in childhood. Design of the EINSTEIN-Jr phase III study. Thromb J. 2018;16:34. doi:10.1186/s12959-018-0188-y 8. Monagle P, Cuello CA, Augustine C, et al. American Society of Hematology 2018 Guidelines for Management of Venous Thromboembolism: treatment of pediatric venous thromboembolism. Blood Adv. 2018;2(22):3292-3316. doi:10.1182/bloodadvances.2018024828