| Author | Affiliation |
|---|---|
| Brendan M. Carr, MD, MS | Mayo Clinic, Department of Emergency Medicine, Rochester, Minnesota |
| David J. Roy, PharmD, BCPS | Mayo Clinic, Department of Emergency Medicine, Rochester, Minnesota; Mayo Clinic, Pharmacy Services, Rochester, Minnesota |
| Stacey A. Bangh, PharmD, DABAT | Hennepin County Medical Center, Minneapolis, Minnesota; Minnesota Poison Control System, Minneapolis, Minnesota |
| Thomas R. Hellmich, MD | Mayo Clinic, Department of Emergency Medicine, Rochester, Minnesota |
| Laura E. Walker, MD | Mayo Clinic, Department of Emergency Medicine, Rochester, Minnesota |
Introduction
Case report
Discussion
Conclusion
ABSTRACT
Rivaroxaban, an oral anticoagulant, directly inhibits factor Xa (FXa). A 35-month-old boy was brought to the emergency department 15 minutes after ingesting 200 mg of rivaroxaban (16 mg/kg). Activated charcoal (AC) was administered; the patient was observed with monitoring of plasma anti-FXa levels and discharged the following day after an uneventful hospital observation. We identified two case series and seven case reports of potentially toxic rivaroxaban ingestion in the literature. No serious adverse effects were reported. The present case is the first reported use of anti-FXa monitoring after rivaroxaban ingestion. The magnitude of the effect of AC administration in this patient is unclear.
INTRODUCTION
Rivaroxaban is an oral anticoagulant that directly inhibits factor Xa (FXa). The United States (U.S.) Food and Drug Administration (FDA) has approved its use in adults for prophylaxis and treatment of deep vein thrombosis, pulmonary embolism, and prevention of ischemic stroke in patients with nonvalvular atrial fibrillation. Typical daily doses in adults range from 10 to 30 mg depending on renal function and indication. No FDA-approved indications exist for pediatric patients. A favorable pharmaco-kinetic profile and absence of therapeutic drug monitoring have led to increasing popularity of rivaroxaban over vitamin K antagonists.
Until recently, no antidote was available in the U.S. to reverse the anticoagulant effects of rivaroxaban in an overdose. In May 2018, the FDA approved coagulation FXa (recombinant), inactivated-zhzo for reversal of anticoagulation in patients treated with rivaroxaban or apixaban who are experiencing life-threatening or uncontrolled bleeding. It is not yet widely available for clinical use, however, and it has not been studied in pediatric populations.1
Anti-FXa assays quantitatively measure plasma levels of unfractionated heparin or low-molecular-weight heparin.2
Multiple, commercially available, automated assays exist, and the test is readily available throughout the U.S. Compared with activated partial thromboplastin time (aPTT), a more traditional method of measuring response to heparin therapy, anti-FXa assays provide a more specific measurement of heparin activity. Other proposed advantages include faster time to achieving a therapeutic range for heparin anticoagulation, less variability in testing reagents, and fewer laboratory blood samples drawn compared with the aPTT. Anti-FXa is finalized in a similar amount of time and has been shown to be cost neutral compared with aPTT.3 Although there are no FDA-approved anti-FXa reagents for oral FXa inhibitors, a strong correlation has been shown with rivaroxaban concentrations using a heparin-calibrated anti-FXa assay.1
CASE REPORT
A previously healthy 35-month-old boy (weight, 12.5 kg) was brought to the emergency department (ED) immediately after he was found with partially chewed rivaroxaban tablets in his mouth. His mother reported missing 10 20-mg tablets (200 mg total; approximately 16 mg/kg). The patient had no known family history of bleeding or hypercoagulable disorders.
He was examined within 15 minutes of ingestion by a physician who did not find evidence of bleeding, bruising, or altered mental status. The regional poison control center was then quickly contacted. Activated charcoal (AC) (2 g/kg) was orally administered within 45 minutes of ingestion and was tolerated well by the patient. During the ED stay, a plasma anti-FXa level was obtained approximately four hours after ingestion. The result (>4.00 international units/mL) exceeded the upper limit of the reference range and markedly surpassed the therapeutic window for unfractionated heparin (0.30–0.70 international units/mL).
The patient was admitted and observed overnight. At 13.5 hours after ingestion (a time chosen to correspond with the pediatric hospital service’s morning rounds the following day), the anti-FXa level was rechecked and found to be 1.51 international units/mL. No other laboratory testing was performed by the ED or inpatient teams. The patient was discharged later that day, less than 24 hours after ingestion, without any complications. He did not receive blood products, reversal agents, or additional doses of AC during his stay.
We performed a literature search to identify case reports of rivaroxaban ingestion. All reports of pediatric ingestion are limited to pediatric subsets of two case series drawn from reports to poison control centers with limited details for individual cases. No reports of quantitative monitoring with anti-FXa levels or utility of AC in pediatric patients were identified.
In one case series, two “1.5-year-old” children accidently ingested an unknown quantity of rivaroxaban but did not have further evaluation by a healthcare provider. Both patients were lost to follow-up without any treatment or adverse effects reported.4 The other case series identified 18 reports of one-time exposure in pediatric patients (age <12 years) who did not have adverse effects. An unspecified minority of patients had results of coagulation studies (international normalized ratio [INR], prothrombin time [PT], or partial thromboplastin time) that were all within the reference ranges.5
The other case reports, which involved adults, are summarized in the Table.6-12 AC or prothrombin complex concentrate or both were given empirically in some cases with no report of serious morbidity.
| Age (years) | Sex | Time to presentation | Intentional | Amount of rivaroxaban (mg) | Coingestants | Tests performed | Treatment | Bleeding | Reference |
|---|---|---|---|---|---|---|---|---|---|
| 71 | M | Unknown | Yes | 1,940 | None | PT 60.2 s; INR 7.2; aPTT 55.7 s; BUN 28 mg/dL; Cr 1.2 mg/dL | None | None | Repplinger et al6 |
| 50s | M | 12 ha | No | 300a | None | INR about 2.1; PT 20 s; PTT 40 s | Activated charcoal | None | Sajkov and Gallus7 |
| 28 | F | 3 mo | Yes | Unknown | Unknown | PT 19.2 s; INR 1.8; PTT 52 s; TEG “normal” | Unknown | Abnormal uterine bleeding | Katragadda et al8 |
| 42 | M | 5 h | Yes | 1,400 | 24 g acetaminophen; 1,200 mg codeine; 600 mg diphenhydramine; 8 mg lorazepam; unknown amount of naproxen | INR 2.4; PTT 46 s | Tranexamic acid; 4fPCC | None | Linkins and Moffat9 |
| 63 | M | 2.5 h | Yes | 1,960 | 90 mg diazepam; 1 g quetiapine; 50 mg zolpidem | PT 66 s; aPTT 64 s | Activated charcoal; 4fPCC | None | Lehmann et al10 |
| 23 | M | 12 h | Yes | 1,960 | 31.5 mg phenprocoumon; 1,425 mg diclofenac; 21 g metamizole | PT 34 s; aPTT 128 s | Vitamin K; PCCb; pantoprazole | Single episode of gross hematuria | Pfeiffer et al11 |
| 54 | M | 3 h | Yes | 1,800 | 1,800 mg enoxaparin | PT 21.4 s; aPTT >150 s; INR 1.9 | None | None | Bandali et al12 |
aPTT, activated partial thromboplastin time; BUN, blood urea nitrogen; Cr, creatinine; 4fPCC, four-factor prothrombin complex concentrate; F, female; g, grams; h, hours; INR, international normalized ratio; M, male; mg, milligrams; mo, months; PCC, prothrombin complex concentrate; PT, prothrombin time; PTT, partial thromboplastin time; s, seconds; TEG, thrombolastography; y, years.
aTwo 150-mg doses separated by 12 hours; recognized 10 minutes after the second dose.
bCase report did not specify whether three-factor or four-factor PCC was used.
DISCUSSION
We report the use of serum anti-FXa, a more specific marker of anticoagulation status than PT/INR in FXa inhibitors, as a means to guide management of rivaroxaban ingestion in a pediatric patient. For our patient, the true peak anti-FXa drawn at four hours was unknown, but the result (>4.00 international units/mL) exceeded the upper limit of the reference range. The anti-FXa level 13.5 hours after ingestion decreased to 1.51 international units/mL.
In healthy adult volunteers, maximal inhibition of FXa with rivaroxaban occurs in two to four hours. The bioavailability (66%–100%) is dependent on the dose and state of fasting.13 In healthy adults, a single rivaroxaban tablet has a half-life of six to seven hours. A dose-dependent relationship between the biologic effect and anti-FXa activity has been described.14
For our patient, if the most conservative peak concentration is used (4.00 international units/mL), we observed a 62% reduction in anti-FXa activity over 9.5 hours. It is plausible that AC helped decrease the absorption and bioavailability of rivaroxaban. Administration of AC within two hours after ingestion has been shown to decrease the serum concentration of rivaroxaban relatively quickly, resulting in a 43% reduction over time in the rivaroxaban area under the curve.15
CPC-EM Capsule
What do we already know about this clinical entity?
Rivaroxaban is an anti-factor Xa (FXa) inhibitor used for anticoagulation, and an overdose could be associated with bleeding. Reports of this are rare in adults and almost nonexistent in children.
What makes this presentation of disease reportable?
This is the first case report of a pediatric rivaroxaban ingestion presented in the literature and the first report of anti-FXa testing being used to confirm ingestion and monitor recovery.
What is the major learning point?
Morbidity from rivaroxaban overdose is rare. Also, anti-FXa is a common laboratory test that can be useful in cases of suspected ingestion, in lieu of traditional coagulation studies.
How might this improve emergency medicine practice?
Anti-FXa testing can be considered in diagnosing and treating a suspected rivaroxaban overdose.
It is plausible to attribute the decrease in anti-FXa in our patient to the effect of AC and possible enterohepatic recirculation of rivaroxaban. No evidence is available on the enterohepatic recirculation of rivaroxaban; however, it has been described in animal studies for apixaban and edoxaban, which are in the same therapeutic drug class as rivaroxaban.16,17 One study suggested that AC given eight hours after ingestion decreased the rivaroxaban area under the curve even after drug absorption was complete.12 No conclusions can be made regarding the influence of AC on our patient’s outcome given the lack of data in this population. No adverse effects related to AC administration were observed.
CONCLUSION
In summary, our pediatric patient who accidentally ingested rivaroxaban was treated with early administration of AC and monitored with anti-FXa levels without showing clinically significant morbidity. This case showed the utility of monitoring anti-FXa levels in an ingestion of rivaroxaban and suggested that early use of AC should be considered for pediatric patients who ingest rivaroxaban. Additional pharmacokinetic and toxicokinetic studies of rivaroxaban in pediatric patients are needed to further understand optimal treatment and monitoring.
Documented patient informed consent and/or Institutional Review Board approval has been obtained and filed for publication of this case report.
Footnotes
Section Editor: Steven J. Walsh, MD
Full text available through open access at http://escholarship.org/uc/uciem_cpcem
Address for Correspondence: Brendan M. Carr, MD, MS, Mayo Clinic, Department of Emergency Medicine, 200 1st St SW Rochester MN 55905, Emai: Carr.Brendan@mayo.edu. 2:247 – 250
Submission history: Revision received March 20, 2018; Submitted May 15, 2018; Accepted May 16, 2018
Conflicts of Interest: By the CPC-EM article submission agreement, all authors are required to disclose all affiliations, funding sources and financial or management relationships that could be perceived as potential sources of bias. The authors disclosed none.
REFERENCES
1. ANDEXXA [prescribing information]. 2018. Available at: https://www.fda.gov/downloads/BiologicsBloodVaccines/CellularGeneTherapyProducts/ApprovedProducts/UCM606687.pdf. Accessed May 15, 2018.
2. Gosselin RC, Francart SJ, Hawes EM, et al. Heparin-calibrated chromogenic anti-FXa activity measurements in patients receiving Rivaroxaban: can this test be used to quantify drug level?. Ann Pharmacother. 2015;49(7):777-83.
3. Rosborough TK. Monitoring unfractionated heparin therapy with antifactor Xa activity results in fewer monitoring tests and dosage changes than monitoring with the activated partial thromboplastin time. Pharmacotherapy. 1999;19(6):760-6.
4. Stevenson JW, Minns AB, Smollin C, et al. An observational case series of dabigatran and rivaroxaban exposures reported to a poison control system. Am J Emerg Med. 2014;32(9):1077-84.
5. Spiller HA, Mowry JB, Aleguas A, et al. An Observational study of the factor Xa inhibitors rivaroxaban and apixaban as reported to eight poison centers. Ann Emerg Med. 2016;67(2):189-95.
6. Repplinger DJ, Hoffman RS, Nelson LS, et al. Lack of significant bleeding despite large acute rivaroxaban overdose confirmed with whole blood concentrations. Clin Toxicol (Phila). 2016;54(8):647-9.
7. Sajkov D, Gallus A. Accidental rivaroxaban overdose in a patient with pulmonary embolism: some lessons for managing new oral anticoagulants. Clin Med Insights Case Rep. 2015;8:57-59.
8. Katragadda L, Murphy MC, Harris NS, et al. Steps to diagnosis of a case of surreptitious intake of one of the newer direct oral anticoagulants: a case report and literature review. Blood Coagul Fibrinolysis. 2015;26(5):574-6.
9. Linkins LA, Moffat K. Monitoring the anticoagulant effect after a massive rivaroxaban overdose. J Thromb Haemost. 2014;12(9):1570-71.
10. Lehmann T, Hofer KE, Baumann M, et al. Massive human rivaroxaban overdose. Thromb Haemost. 2014;112(4):834-6.
11. Pfeiffer H, Herbst L, Schwarze B, et al. Massive intoxication with rivaroxaban, phenprocoumon, and diclofenac: a case report. Medicine (Baltimore). 2016;95(44):e5343.
12. Bandali F, Thomas Z, Gozzo Y. 1205: Conservative management of massive rivaroxaban and enoxaparin overdose. Crit Care Med. 2014;42(12):A1642.
13. Xarelto [prescribing information]. 2017. Available at: http://www.janssenlabels.com/package-insert/product-monograph/prescribing-information/XARELTO-pi.pdf. Accessed February 28, 2018.
14. Kubitza D, Becka M, Voith B, et al. Safety, pharmacodynamics, and pharmacokinetics of single doses of BAY 59-7939, an oral, direct factor Xa inhibitor. Clin Pharmacol Ther. 2005;78(4):412-21.
15. Ollier E, Hodin S, Lanoiselee J, et al. Effect of activated charcoal on rivaroxaban complex absorption. Clin Pharmacokinet. 2017;56(7):793-801.
16. Zhang D, Frost CE, He K, et al. Investigating the enteroenteric recirculation of apixaban, a factor Xa inhibitor: administration of activated charcoal to bile duct-cannulated rats and dogs receiving an intravenous dose and use of drug transporter knockout rats. Drug Metab Dispos. 2013;41(4):906-15.
17. Parasrampuria DA, Truitt KE. Pharmacokinetics and pharmacodynamics of edoxaban, a non-vitamin K antagonist oral anticoagulant that inhibits clotting factor Xa. Clin Pharmacokinet. 2016;55(6):641-655.
