Rivaroxaban use in specific populations
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Ahmed Zaghw, M.D. [2]
8 USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
Pregnancy Category C There are no adequate or well-controlled studies of XARELTO in pregnant women, and dosing for pregnant women has not been established. Use XARELTO with caution in pregnant patients because of the potential for pregnancy related hemorrhage and/or emergent delivery with an anticoagulant that is not readily reversible. The anticoagulant effect of XARELTO cannot be reliably monitored with standard laboratory testing. Animal reproduction studies showed no increased risk of structural malformations, but increased post-implantation pregnancy loss occurred in rabbits. XARELTO should be used during pregnancy only if the potential benefit justifies the potential risk to mother and fetus [see Warnings and Precautions (5.7)].
Rivaroxaban crosses the placenta in animals. Animal reproduction studies have shown pronounced maternal hemorrhagic complications in rats and an increased incidence of post‑implantation pregnancy loss in rabbits. Rivaroxaban increased fetal toxicity (increased resorptions, decreased number of live fetuses, and decreased fetal body weight) when pregnant rabbits were given oral doses of ≥10 mg/kg rivaroxaban during the period of organogenesis. This dose corresponds to about 4 times the human exposure of unbound drug, based on AUC comparisons at the highest recommended human dose of 20 mg/day. Fetal body weights decreased when pregnant rats were given oral doses of 120 mg/kg. This dose corresponds to about 14 times the human exposure of unbound drug.
8.2 Labor and Delivery
Safety and effectiveness of XARELTO during labor and delivery have not been studied in clinical trials. However, in animal studies maternal bleeding and maternal and fetal death occurred at the rivaroxaban dose of 40 mg/kg (about 6 times maximum human exposure of the unbound drug at the human dose of 20 mg/day).
8.3 Nursing Mothers
It is not known if rivaroxaban is excreted in human milk. Rivaroxaban and/or its metabolites were excreted into the milk of rats. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from rivaroxaban, a decision should be made whether to discontinue nursing or discontinue XARELTO, taking into account the importance of the drug to the mother.
8.4 Pediatric Use
Safety and effectiveness in pediatric patients have not been established.
8.5 Geriatric Use
Of the total number of patients in the RECORD 1–3 clinical studies evaluating XARELTO, about 54% were 65 years and over, while about 15% were >75 years. In ROCKET AF, approximately 77% were 65 years and over and about 38% were >75 years. In the EINSTEIN DVT, PE and Extension clinical studies approximately 37% were 65 years and over and about 16% were >75 years. In clinical trials the efficacy of XARELTO in the elderly (65 years or older) was similar to that seen in patients younger than 65 years. Both thrombotic and bleeding event rates were higher in these older patients, but the risk-benefit profile was favorable in all age groups [see Clinical Pharmacology (12.3) and Clinical Studies (14)].
8.6 Females of Reproductive Potential
Females of reproductive potential requiring anticoagulation should discuss pregnancy planning with their physician.
8.7 Renal Impairment
In a pharmacokinetic study, compared to healthy subjects with normal creatinine clearance, rivaroxaban exposure increased by approximately 44 to 64% in subjects with renal impairment. Increases in pharmacodynamic effects were also observed [see Clinical Pharmacology (12.3)].
Nonvalvular Atrial Fibrillation
In the ROCKET AF trial, patients with CrCl 30 to 50 mL/min were administered XARELTO 15 mg once daily resulting in serum concentrations of rivaroxaban and clinical outcomes similar to those in patients with better renal function administered XARELTO 20 mg once daily. Patients with CrCl 15 to 30 mL/min were not studied, but administration of XARELTO 15 mg once daily is also expected to result in serum concentrations of rivaroxaban similar to those in patients with normal renal function [see Dosage and Administration (2.3)].
Treatment of DVT and/or PE, and Reduction in the Risk of Recurrence of DVT and of PE
In the EINSTEIN trials, patients with CrCl values <30 mL/min at screening were excluded from the studies. Avoid the use of XARELTO in patients with CrCl <30 mL/min.
Prophylaxis of DVT Following Hip or Knee Replacement Surgery
The combined analysis of the RECORD 1–3 clinical efficacy studies did not show an increase in bleeding risk for patients with CrCl 30 to 50 mL/min and reported a possible increase in total venous thromboemboli in this population. Observe closely and promptly evaluate any signs or symptoms of blood loss in patients with CrCl 30 to 50 mL/min. Avoid the use of XARELTO in patients with CrCl <30 mL/min.
8.8 Hepatic Impairment
In a pharmacokinetic study, compared to healthy subjects with normal liver function, AUC increases of 127% were observed in subjects with moderate hepatic impairment (Child-Pugh B).
The safety or PK of XARELTO in patients with severe hepatic impairment (Child-Pugh C) has not been evaluated [see Clinical Pharmacology (12.3)].
Avoid the use of XARELTO in patients with moderate (Child-Pugh B) and severe (Child-Pugh C) hepatic impairment or with any hepatic disease associated with coagulopathy.[1]
References
Adapted from the FDA Package Insert.