PEDIATRIC – POST FONTAN

Evaluated in the UNIVERSE clinical trial XARELTO® is the only anticoagulant FDA approved for use in children with congenital heart disease as thromboprophylaxis post-Fontan procedure1,2

Postfontan hero

XARELTO® is indicated for thromboprophylaxis in pediatric patients aged 2 years and older with congenital heart disease who have undergone the Fontan procedure.

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CLINICAL TRIAL

In the UNIVERSE clinical trial The first and only randomized study of a direct oral anticoagulant (DOAC) conducted to evaluate thromboprophylaxis in children post Fontan3

Objective

Randomized, multicenter, open-label, active-controlled, 2-part, phase 3 study to examine the use of a novel, oral suspension formulation of XARELTO® in children 2-8 years old with single ventricle physiology who had the Fontan procedure within 4 months before enrollment 2,3

Clinicaldoac  img

The UNIVERSE clinical trial comprised 2 parts2:

  • Part A assessed the PK and PD of XARELTO® in young children to determine a dose that would approximate the drug exposure achieved in adults with XARELTO® 10 mg QD
  • Part B evaluated the safety and efficacy of XARELTO® vs aspirin for thromboprophylaxis post-Fontan procedure for 12 months

Not powered to test formal hypotheses for efficacy and safety due to the limited availability of the study population and the expected low event rates.2,3

BID = twice daily; DRC = Data Review Committee; EOT = end of treatment; IDMC = independent data monitoring committee; PD = pharmacodynamics; PK = pharmacokinetics; QD = every day; R = randomization.

UNIVERSE clinical trial study design2,3

STUDY POPULATION

  • Children aged 2-8 years with single ventricle physiology, post-Fontan procedure (within 4 months prior to study enrollment)
  • This was a VTE-prevention study; patients with thrombosis requiring treatment were excluded
  • Main exclusion criteria:
    • Evidence of thrombosis
    • History of GI disease or surgery associated with impaired absorption
    • Active bleeding or high risk of bleeding contraindicating antiplatelet or anticoagulation therapy, including history of intracranial hemorrhage, or contraindication to aspirin or rivaroxaban
    • Chronic use of NSAIDs
    • Platelet count <50 x 109/L at screening
    • Estimated eGFR <30 mL/min/1.73m2

TREATMENT GROUPS

  • Subjects were randomized (2:1) to XARELTO® or antiplatelet therapy with aspirin (N=112)
  • XARELTO® was administered BID as a suspension; weight-adjusted to achieve drug exposure comparable to the thromboprophylactic 10 mg/day dose in adults
  • Aspirin dose: 5 mg/kg/day, up to a maximum of 81 to 100 mg/day (per local practice)

OUTCOMES

  • Primary efficacy outcome: Any thrombotic event, venous or arterial
  • Safety outcomes: Major bleeding events (primary); nonmajor and trivial/minimal bleeding (secondary)

Not powered to test formal hypotheses for efficacy and safety due to the limited availability of the study population and the expected low event rates.2,3

BID = twice a day; eGFR = glomerular filtration rate; NSAIDs = nonsteroidal anti-inflammatory drugs.

SAFETY PROFILE

In the UNIVERSE clinical trial A comparable prevalence of overall bleeding events was observed with XARELTO® versus aspirin1

vs table

Bleeding events were comparable across treatment groups1,2*

Major Bleed: single case of epistaxis (nosebleed) occurred in the rivaroxaban part B group.

Trivial bleeds: most frequent site of trivial bleeding was the skin in both groups.

Clinically relevant nonmajor bleeds: with rivaroxaban, bleeding events occurred in the lower GI tract, gingival tissue, and skin; with ASA, these events occurred in the lower GI tract, skin, hematoma, and subconjunctival tissue.

Not powered to test formal hypotheses for efficacy and safety due to the limited availability of the study population and the expected low event rates.2,3

*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.

ASA = aspirin; GI = gastrointestinal.

Additional Adverse Events Summary

adverse-events

EFFICACY PROFILE

The UNIVERSE clinical trial was not powered for statistical significance XARELTO® was evaluated for the prevention of thrombotic events in pediatric patients post-Fontan2

Efficacy thrombotic

Not powered to test formal hypotheses for efficacy and safety due to the limited availability of the study population and the expected low event rates.2,3

*Efficacy outcomes based on full analysis set: all participants in part A who received 1 dose of study drug and all participants in part B who were randomized and received 1 dose of study drug. In the rivaroxaban part A group, 1 participant (8%) had a venous thrombotic event on day 362 of treatment (364 days post-Fontan procedure). This study was not powered for efficacy hypothesis testing (post hoc log-rank test P=0.095).2

Part B: randomized 2:1 (XARELTO®: aspirin).

Treatment schedule: body weight-adjusted doses of XARELTO® (exposures to match that of 10 mg QD in adults) or aspirin (approximately 5 mg/kg).

QD = every day.

DOSING

XARELTO® is the only FDA-approved antithrombotic treatment to offer pediatric patients both an oral suspension and tablets1,4

dosing img1 oral suspension

tab tablet

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

dosingmb

*All doses can be taken with or without food since exposures match that of 10-mg daily dose in adults.

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

Recommended dosage for thromboprophylaxis in pediatric patients with CHD after the Fontan procedure.

Dosing weight

*All doses can be taken with or without food.

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

CHD = congenital heart disease.

Administration in pediatric patients1

  • Food Effect:

For thromboprophylaxis after Fontan procedure, the dose can be taken with or without food.

  • 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 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
  • 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 creatinine

Pharmacokinetic Considerations:

  • The half-life of rivaroxaban in plasma of pediatric patients treated for VTE decreased with decreasing
  • 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 thromboprophylaxis in pediatric patients with CHD who have undergone the Fontan procedure, the dose is not required to be followed by enteral feeding.

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; mol/L = micromole per liter; NG = nasogastric; PVC = polyvinyl chloride; UFH = unfractionated heparin.

SUMMARY

Pediatric post-Fontan care is complex.5

Helping protect against thrombosis doesn’t have to be.

In the UNIVERSE study,2 the first and only randomized study of a DOAC to prevent thromboembolism in children post-Fontan procedure, XARELTO® versus aspirin:

The UNIVERSE clinical trial was not powered for statistical significance

  • Numerically fewer thrombotic events vs aspirin
  • Similar safety profile vs aspirin was observed

XARELTO® is the only FDA-APPROVED antithrombotic treatment to offer pediatric pediatric patients1,4:

dosing img1 oral suspension

tab tablet

Not powered to test formal hypotheses for efficacy and safety due to the limited availability of the study population and the expected low event rates.2,3

DOAC = direct oral anticoagulant.