Purpose
To provide details about rivaroxaban use, the only orally available FDA-approved factor Xa inhibitor, at IHTC during hospital admission or as outpatient
Indication
VTE treatment and thromboprophylaxis in pediatric patients from birth to less than 18 years after at least 5 days of initial parenteral anticoagulant treatment, as well for thromboprophylaxis in pediatric patients 2 years and older with congenital heart disease after the Fontan procedure. Do NOT use in patients with mechanical prosthetic heart valves. Rivaroxaban isn’t recommended in patients with antiphospholipid syndrome. Rivaroxaban is indicated for pediatric VTE treatment after 5-10 days of parenteral anticoagulation.
USE
Dosage Forms
- Rivaroxaban is available as tablets or oral suspension. Rivaroxaban 2.5 mg tablets are not recommended for use in pediatric patients. For pediatric patients who cannot swallow the 10 mg, 15 mg, or 20 mg tablet whole, transition to oral suspension
| Tablets | Bottles containing either 20 mg, 15 mg, 10 mg, or 2.5 mg. There is also starter packet containing 51 tablets: 42 tablets of 15 mg and 9 tablets of 20 mg. |
| Oral Suspension | 1 mg/mL oral suspension |
- Patient assistance program for drug: Johnson & Johnson
Initiating Therapy
- Minimum Monitoring Requirements: Prior to initiation of therapy, but no longer than 48 hours before, the following labs should be checked: CBC, coagulation profile (PT, PTT, fibrinogen activity), hepatic function panel, creatinine, urine pregnancy if applicable
- Administration: Begin treatment only if tolerating full feeds.
| Administration | Rivaroxaban can be administered via mouth with food, G-tube or NG tube. |
| Splitting/crushing | Tablet can be crushed and mixed with applesauce immediately prior to use. Crushed tablets are stable in applesauce for up to 4 hours. After the administration of a crushed rivaroxaban 15 mg or 20 mg tablet, the dose should be immediately followed by food. Administration with food is not required for the 2.5 mg (rivaroxaban 2.5 mg tablets are not recommended for use in pediatric patients) or 10 mg tablets |
| Nasogastric/gastric feeding tube | Crushed tablets may be mixed in 50 mL of water and administered; administer the suspension within 4 hours of preparation. Avoid administration distal to the stomach. After the administration of a crushed rivaroxaban 15 mg or 20 mg tablet, the dose should be immediately followed by food/enteral feeding. Administration with food is not required for the 2.5 mg (rivaroxaban 2.5 mg tablets are not recommended for use in pediatric patients) or 10 mg tablets. |
Pharmacokinetics
| Half-life | 5 to 9 h (adult) 4.2 h (12 to < 18 years) 3 h (2 to 11 years) 1.9 h (6 months to 1 year) 1.6 h (< 6 months) |
| Time to peak | 2 to 4 h |
| Absorption | Primarily proximal small intestine and some gastric absorption |
| Oral availability | ~66% (fasting); ~80-100% (with food) |
| Excretion | ~2/3 primarily cleared via Hepatic degradation via the cytochrome P450 pathway~1/3 (35%) Renal elimination as unchanged drug (~1/3 also eliminated as inactive metabolites) |
| Protein binding | ~90% |
Safety Precautions
- Renal impairment: For infants >2.6 kg and < 1 year of age, avoid use when serum creatinine is > 97.5th percentile. For children and adolescents, avoid use when eGFR < 50 mL/min/1.73m2, and no dose adjustment in patients with mild renal impairment (eGFR 50 to ≤ 80 mL/min/1.73m2).
- Hepatic impairment: Avoid use in moderate to severe impairment (Child-Pugh B and C). Avoid use in patients with hepatic disease associated with either coagulopathy leading to a clinically relevant bleeding risk. In Einstein-Jr. trial, exclusion criteria included ALT >5 xULN or total bilirubin > 2xULN with direct bilirubin >20% of the total.
- Drug-Drug interactions:
- Substrate of p-glycoprotein
- For the following medications, concomitant use of rivaroxaban should be avoided: dual P-glycoprotein and CYP3A4 Inducers (ex. rifampin, phenytoin, phenobarbital or carbamazepine) and Inhibitors (ex. ketoconazole, itraconazole, posaconazole, ritonavir, erythromycin, all HIV protease inhibitors).
- Agents with Antiplatelet Properties (e.g., P2Y12 inhibitors, NSAIDs, SSRIs, etc.): May enhance the anticoagulant effect of Anticoagulant
- Substrate of p-glycoprotein
Pediatrics Dosing
**Thromboprophylaxis after Fontan procedure (children >2 years and adolescents):
| Oral Suspension | |
| 7 to 7.9 kg | 1.1 mg PO q12h |
| 8 to 9.9 kg | 1.6 mg PO q12h |
| 10 to 11.9 kg | 1.7 mg PO q12h |
| 12 to 19.9 kg | 2 mg PO q12h |
| 20 to 29.9 kg | 2.5 mg PO q12h |
| 30 to 49.9 kg | 7.5 mg PO q24h |
| Oral Tablet | |
| >50 kg | 10 mg PO q24h |
VTE treatment and prophylaxis (after ≥5 days of initial parenteral treatment*):
| Oral Suspension | |
| 2.6 to 2.9 kg | 0.8 mg PO q8h |
| 3 to 3.9 kg | 0.9 mg PO q8h |
| 4 to 4.9 kg | 1.4 mg PO q8h |
| 5 to 6.9 kg | 1.6 mg PO q8h |
| 7 to 7.9 kg | 1.8 mg PO q8h |
| 8 to 8.9 kg | 2.4 mg PO q8h |
| 9 to 9.9 kg | 2.8 mg PO q8h |
| 10 to 11.9 kg | 3 mg PO q8h |
| 12 to 29.9 kg | 5 mg PO q12h |
| 30 to 49.9 kg | 15 mg PO q24h |
| Oral Tablet | |
| 30 to 49.9 kg | 15 mg PO q24h |
| >50 kg | 20 mg daily |
**It is important to note that the pediatric clinical trials for rivaroxaban continued treatment dosing for secondary prevention of VTE in children beyond the 3-month acute treatment phase, but the dosing regimen was NOT changed. There is no data to support using dosing for thromboprophylaxis after Fontan procedure for patients whom are non-Fontan needing secondary VTE prevention management. If needed, one could consider lowering the dose in a similar ratio to maintain quality of life, although there is no data to support this. One could also consider continuing treatment dosing, given the low bleeding rate in clinical trials and the available data on efficacy.
Adult Dosing/Information
| VTE and/or PE Treatment | CrCl >30 mL/min: 15 mg PO BID with food for 21 days, followed by 20 mg qDaily with food CrCl < 30 mL/min: avoid use |
| VTE and/or PE Prophylaxis after 6 months of initial Treatment VTE Prophylaxis in acutely ill medical patients | CrCl >30 mL/min: 10 mg PO qDaily CrCl < 30 mL/min: avoid use |
| Total hip or total knee arthroplasty | CrCl >30 mL/min: 10 mg PO qDaily initiated >6-10 hours after surgery or when hemostasis achieved (usually given minimum 10-14 days and can be extended for up to 35 days) CrCl < 30 mL/min: avoid use |
| Nonvalvular atrial fibrillation (to prevent stroke and systemic embolism) | CrCl > 50 mL/min: 20 mg PO qDaily CrCl 15-50 mL/min: 15 mg PO qDaily CrCl < 15 mL/min: avoid use |
Rivaroxaban should be discontinued in acute renal failure and avoided in patients with moderate to severe hepatic impairment (Child-Pugh B and C) or in patients with any hepatic disease associated with coagulopathy. If mild hepatic impairment (Child-Pugh A), no adjustment necessary.
Anticoagulation Monitoring Parameter and Reference Range Routine coagulation testing is not required for monitoring of rivaroxaban. If monitoring is indicated, rivaroxaban anti-Xa activity assay is the preferred test to extrapolate rivaroxaban concentrations in ng/ml. Therapeutic range not defined. Dose adjustment based on results not yet established. Observed peak and trough concentrations in patients exposed to therapeutic dosing have been reported (if rivaroxaban calibrated assay is available, the expected observed peak levels for rivaroxaban are 90–195 ng/mL for 10 mg and 189–360 ng/mL for 20 mg dose. The expected trough is < 30 ng/mL).
Perioperative Management
- Decision making regarding whether rivaroxaban needs to be held depends on type of surgery and balance of bleeding versus thrombosis risk. The duration for withholding is based upon the estimated rivaroxaban half-life times 2 to 3 half-lives for low procedural bleeding risk and 4 to 5 drug half-lives for high procedural bleeding risk. If it is indicated rivaroxaban, should be discontinued at least 48 hours prior to elective surgery or invasive procedures with a moderate or high risk of unacceptable or clinically significant bleeding, and should be discontinued for at least 24 hours prior to elective surgery or invasive procedures with low bleeding risk or where the bleeding would be non-critical in location easily controlled.
- Rivaroxaban should be discontinued at least 24-72 hours prior to neuraxial intervention (including lumbar puncture). Epidural or spinal hematomas have occurred in patients treated with DOACs who are receiving neuraxial anesthesia or undergoing spinal puncture. Optimal timing between the administration of rivaroxaban and neuraxial procedures is not known.
- In CrCl < 30 mL/minute, for low bleeding risk procedure, discontinue rivaroxaban therapy >36 hours prior. If Cr < 15 mL/min for low bleeding risk procedure consider measuring rivaroxaban anti-Xa level and/or withholding >48 hours.
- In CrCl < 30 mL/minute, for moderate or high risk procedure, discontinue rivaroxaban therapy >48 hours prior. If Cr < 15 mL/min for moderate or high risk procedure., consider measuring rivaroxaban anti-Xa level and/or withholding >72 hours.
- In rare cases, in patients with very high risk of thrombosis, bridging with unfractionated heparin may be required to limit the time off anticoagulation.
- Restart rivaroxaban after the procedure as soon as adequate hemostasis has been established and once cleared by the surgeon or interventionalist. If oral medication cannot be taken after the procedure, consider switching to a parenteral anticoagulant.
Bleeding Precautions & Warnings
- While on anticoagulation avoid aspirin, ibuprofen, or other anti-platelet drugs unless specifically indicated as anti-platelet therapy.
- Try to avoid IM injections and arterial punctures. Apply pressure after venipuncture until bleeding has ceased.
Reversal Information
- Andexanet alpha is not FDA approved for non-bleeding patients. If patient requires urgent surgical or invasive procedure discussion with the surgical provider and Hematology is recommended. Determine if procedure can be delayed until 24 hours after rivaroxaban ingestion in patient with normal renal function or 48 hours after ingestion in patient with CrCl < 30 mL/min/1.73 m2, then andexanet may be considered in conjunction with Hematology consultation.
- Andexanet alfa is FDA indicated for reversal of rivaroxaban, but is NOT currently on formulary at St. Vincent. It is recommended for life-threatening bleeding, bleeding into a critical organ. It is a modified human factor Xa decoy protein that binds and sequesters factor Xa inhibitors, but also TFPI. Anti FXa assay results rapidly decrease within 2 minutes after bolus and this is maintained throughout the duration of the continuous infusion. Anti Xa levels returned to placebo levels approximately 2 hours after completion of bolus or infusion. Andexanet alfa is associated with pro-thrombotic risks.
- Recommended Adult dose:
Rivaroxaban last dose Timing of rivaroxaban last dose before Andexxa initiation < 8 hrs or Unknown ≥ 8 hrs ≤ 10 mg Low dose: Initial IV Bolus 400 mg at a target rate of 30 mg/min, then IV Infusion: 4 mg/min for up to 100-120 minutes (480 mg) Low dose: Initial IV Bolus 400 mg at a target rate of 30 mg/min; then IV Infusion: 4 mg/min for up to 100-120 minutes > 10 mg or Unknown High dose: Initial IV Bolus: 800 mg at a target rate of 30 mg/min; then IV Infusion: 8 mg/min for up to 100-120 minutes (960 mg) - Andexanet Alpha Pediatric dosing: NO reported pediatric dosing is available. Based on limited experience, the following dosing recommendations may be considered when determining risk vs. benefit of reversal of rivaroxaban. Recommend considering the following dosing in patients < 50kg:
Weight Use of rivaroxaban ≤ 24 hours in patients with normal renal function or up to 48 hours in patient with CrCl <30 mL/min/1.73 m2 12 to 30 kg 100 mg bolus, then 1 mg/min for up to 100-120 minutes 30 to < 50 kg 200 mg bolus, then 2 mg/min for up to 100-120 minutes ≥ 50 kg Use Adult dosing above - Critical site bleeds: Intracranial hemorrhage, including intraparenchymal, subdural, epidural, and subarachnoid hemorrhages; Other CNS hemorrhage, including intraocular, intra- or extra-axial spinal hemorrhages; Pericardial tamponade; Airway, including posterior epistaxis; Hemothorax, intraabdominal bleeding, and retroperitoneal hemorrhage; Extremity bleeds, including intramuscular and intraarticular bleeding concerning for compartment syndrome, bleeding associated with hemodynamic instability, bleeding in a noncompressible vessel (e.g., subclavian)
- Recommended Adult dose:
- Kcentra (prothrombin complex concentrate) 25-50 units/kg/dose (maximum 2000 unit/dose) for severe bleeding or NovoSeven (rFVIIa) 90 mcg/kg may be considered. FEIBA (activated PCC) 50 units/kg would be a last resort due to higher thrombosis risk. They are on formulary at PMCH but are not labeled by the manufacturer for reversal of rivaroxaban.
- In the setting of overdose, also consider administration of activated charcoal (50 g) if within 2 hours of dose.
- Rivaroxaban is NOT dialyzable because it is mostly protein bound.
- Repeat monitoring tests for anticoagulant and platelets, PT, PTT, and fibrinogen after infusing a reversal agent and q 4-6 hours until severe bleeding risk has passed. Determine if and when anticoagulation should be reinitiated and what agent. Monitor patient for thrombosis and bleeding.
Transition Information
- A bridge anticoagulant is not necessary when transitioning from another anticoagulant to rivaroxaban therapy. See separate anticoagulant-specific Clinical Case Manual for transitioning from another specific anticoagulant to rivaroxaban.
- See table for switching from rivaroxaban to another anticoagulant
| From | To | Action |
| Rivaroxaban | Argatroban/Bivalirudin/ Enoxaparin/Fondaparinux/ Heparin | Discontinue rivaroxaban and give the first dose of the other anticoagulant at the time that next rivaroxaban would be due. In cases of high bleeding risk, consider omitting initial bolus when transitioning to heparin infusion. |
| Apixaban, Betrixaban, Dabigatran, or Edoxaban | Discontinue rivaroxaban and give the first dose of the other anticoagulant at the time that the next rivaroxaban dose would have been taken. | |
| Warfarin | Limited data available on switching DOACs to warfarin. Consider coadministering DOAC and warfarin therapy until INR is therapeutic, or stopping DOAC and bridging warfarin with LMWH or UFH if bridging patient is clinically indicated (e.g., start UFH or therapeutic LMWH and warfarin when next dose of rivaroxaban would have been taken). Rivaroxaban can elevate the INR and can complicate INR interpretation, therefore rivaroxaban should be stopped when starting warfarin and consider starting enoxaparin at the time of the next scheduled dose of rivaroxaban until INR ≥ 2. All DOACs affect INR so that initial INR during the transition may not be useful for determining the appropriate dose of warfarin; the INR may be affected by rivaroxaban for 24 hours. Consider starting warfarin and stopping rivaroxaban 3 days later. |
Pregnancy Currently, only Lovenox (enoxaparin) and unfractionated heparin are advised for use in pregnant women. Females of childbearing age must be counseled that DOACs are not approved for use during pregnancy and referred for appropriate contraception if needed. Patient Education & Ongoing Management Discharging IHTC physician/APP is responsible for ensuring adequate follow-up for anticoagulation management has been scheduled prior to patient leaving the hospital.
References
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