Summary

• The limited available data on XARELTO in pregnant women are insufficient to inform a drug associated risk of adverse developmental outcomes. Use XARELTO with caution in pregnant patients because of the potential for pregnancy related hemorrhage and/or emergent delivery. The anticoagulant effect of XARELTO cannot be reliably monitored with standard laboratory testing. Consider the benefits and risks of XARELTO for the mother and possible risks to the fetus when prescribing XARELTO to a pregnant woman.¹
• XARELTO has been detected in human milk. There are insufficient data to determine the effects of XARELTO on the breastfed child or on milk production.¹
• An ex-vivo study using isolated human placental cotyledons found a rapid transfer of XARELTO across the placental barrier from maternal-to-fetal circulation and fetal-to-maternal circulation.²
• Sessa et al (2019)³ conducted a review of Vigibase^® for direct oral anticoagulants (DOACs) to evaluate adverse events (AEs) in pregnancy. XARELTO did not show a statistically significant difference in spontaneous abortion compared to warfarin when all cases were reviewed.
• Case series^4,5 and case reports^6,7 that discuss the use of XARELTO during pregnancy and lactation are summarized below.
• Additional citations identified during literature search are included under REFERENCES section for your review.^8,9

PRODUCT LABELING

Please refer to the following sections of the enclosed Full Prescribing Information that are relevant to your inquiry: WARNINGS AND PRECAUTIONS, USE IN SPECIFIC POPULATIONS, and PATIENT COUNSELING INFORMATION.¹

Use in Specific Populations

Pregnancy

The limited available data on XARELTO in pregnant women are insufficient to inform a drug associated risk of adverse developmental outcomes. Use XARELTO with caution in pregnant patients because of the potential for pregnancy related hemorrhage and/or emergent delivery. The anticoagulant effect of XARELTO cannot be reliably monitored with standard laboratory testing. Consider the benefits and risks of XARELTO for the mother and possible risks to the fetus when prescribing XARELTO to a pregnant woman.

Adverse outcomes in pregnancy occur regardless of the health of the mother or the use of medications. The estimated background risk of major birth defects and miscarriage for the indicated populations is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2–4% and 15–20%, respectively.

Clinical Considerations

Disease-Associated Maternal and/or Embryo/Fetal Risk

Pregnancy is a risk factor for venous thromboembolism and that risk is increased in women with inherited or acquired thrombophilias. Pregnant women with thromboembolic disease have an increased risk of maternal complications including pre-eclampsia. Maternal thromboembolic disease increases the risk for intrauterine growth restriction, placental abruption and early and late pregnancy loss.

Fetal/Neonatal Adverse Reactions

Based on the pharmacologic activity of Factor Xa inhibitors and the potential to cross the placenta, bleeding may occur at any site in the fetus and/or neonate.

Labor or Delivery

All patients receiving anticoagulants, including pregnant women, are at risk for bleeding and this risk may be increased during labor or delivery. The risk of bleeding should be balanced with the risk of thrombotic events when considering the use of XARELTO in this setting.

Human Data

There are no adequate or well-controlled studies of XARELTO in pregnant women, and dosing for pregnant women has not been established. Post-marketing experience is currently insufficient to determine a XARELTO-associated risk for major birth defects or miscarriage. In an in vitro placenta perfusion model, unbound XARELTO was rapidly transferred across the human placenta.

Animal Data

XARELTO crosses the placenta in animals. XARELTO 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 XARELTO 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 during the period of organogenesis. This dose corresponds to about 14 times the human exposure of unbound drug. In rats, peripartal maternal bleeding and maternal and fetal death occurred at the XARELTO dose of 40 mg/kg (about 6 times maximum human exposure of the unbound drug at the human dose of 20 mg/day).

Lactation

XARELTO has been detected in human milk. There are insufficient data to determine the effects of XARELTO on the breastfed child or on milk production. XARELTO and/or its metabolites were present in the milk of rats. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for XARELTO and any potential adverse effects on the breastfed infant from XARELTO or from the underlying maternal condition.

Animal data

Following a single oral administration of 3 mg/kg of radioactive [¹⁴C]- XARELTO to lactating rats between Day 8 to 10 postpartum, the concentration of total radioactivity was determined in milk samples collected up to 32 hours post-dose. The estimated amount of radioactivity excreted with milk within 32 hours after administration was 2.1% of the maternal dose.

Females and Males of Reproductive Potential

Females of reproductive potential requiring anticoagulation should discuss pregnancy planning with their physician.

The risk of clinically significant uterine bleeding, potentially requiring gynecological surgical interventions, identified with oral anticoagulants, including XARELTO, should be assessed in females of reproductive potential and those with abnormal uterine bleeding.

PHARMACOKINETIC STUDIES

Bapat et al (2015)² conducted an ex-vivo study using isolated human placental cotyledons to determine if XARELTO passively diffuses across the placenta, the rate and extent of this migration, and to estimate fetal drug exposure. Nine cotyledons from different placentae were perfused with 250 ng/mL of XARELTO on the maternal or fetal reservoir only or simultaneously to both.

The addition of XARELTO to the maternal reservoir resulted in a rapid transfer from maternal-to-fetal circulation with a biphasic decline in XARELTO concentrations from the maternal circulation. At 3 hours after administration, the median fetal concentration of XARELTO was 69.5 ng/ml (interquartile range [IQR] 67.9–84.7) and the median fetal-to-maternal ratio was 0.69 (IQR 0.58-0.73).

The addition of XARELTO to the fetal reservoir also resulted in a rapid transfer to the maternal side with a similar biphasic decline in XARELTO concentration from the fetal circulation. The final maternal concentration was 58.2 ng/ml and the final maternal-to-fetal ratio was 0.69 (IQR 0.67-0.71) at 3 hours. When XARELTO 250 ng/mL was added to both the maternal and fetal sides simultaneously, the fetal-to-maternal ratio remained relatively constant over the 3-hour period. Together, this data suggests that unbound XARELTO passively diffuses across the placenta in both directions down a concentration gradient.

database review

Sessa et al (2019)³ conducted a review of Vigibase^® for DOACs to evaluate AEs in pregnancy.

• Vigibase^® is a global database associated with the World Health Organization and uses standardized dictionaries to code events.
• Reports were evaluated from January 01, 1967 to July 13, 2017 having DOACs as suspected/interacting drugs for which there was reported at least one AE included in the standardized MedDRA Query “Pregnancy and neonatal topics”. There were 764 individual cases that met this definition.
  • Cases were evaluated to determine temporal and biological plausibility for all drug-event pairs by looking at the clinical and demographic characteristics.
  • The role of comorbidities on AEs of interest was assessed by using both medical judgment and review of documentation.
  • Drugs were assessed for potential drug-drug interactions that could lead to a pregnancy-related outcome/teratogenic effects.
• Of the 764 cases evaluated, only 60 (7.8%) fit criteria for data extraction.
• In cases with and without alternative causes for the AE, XARELTO (reporting odds ratio [ROR] 2.70; 95% CI 1.79–4.07) and apixaban (ROR 6.76; 95% CI 2.99–15.25) had an increased probability of reporting spontaneous abortion compared to other AEs in comparison to all other drugs. However, in cases without confounders, XARELTO did not show a statistically significant estimation (ROR 1.05; 95% CI 0.54–2.02).
• When all cases were used, XARELTO did not show a statistically significant ROR for spontaneous abortion in comparison to warfarin (ROR 0.79; 95% CI 0.47–1.32). Similar results were observed when the analysis was restricted only to cases without reported alternative causes for spontaneous abortion (ROR 0.86 95% CI 0.37–1.99).
• When only cases without confounders were reviewed, apixaban showed a statistically significant ROR for spontaneous abortion if compared to warfarin (ROR 5.55; 95% CI 2.11–14.63) or XARELTO (ROR 6.45; 95% CI 2.27–18.35).

CASE REPORTs/CASE SERIES

Yamashita et al (2024)⁴ published a case series involving 2 lactating mothers treated with XARELTO 15 mg once daily in Japan. Blood and breast milk samples were collected from the mothers at time 0 and 2 hours after XARELTO administration. The infants were breastfed 2 hours after XARELTO administration to the mothers and blood samples were taken 2 hours after breastfeeding (4 hours after maternal XARELTO administration).

• Case 1 was a 40-year-old woman with a previous history of acute deep vein thrombosis. Three days after delivery of twin children at 37 weeks, she was transitioned from unfractionated heparin to XARELTO. All blood and breastmilk samples were collected 4 days after delivery. Results may be seen in the Table: XARELTO Concentrations in Maternal and Infant Blood Samples and in Breastmilk
• Case 2 was a 34-year-old woman who developed acute deep vein thrombosis at 28 weeks of pregnancy. She was treated with unfractionated heparin and transitioned to XARELTO 3 days after giving birth at 40 weeks of gestation. Blood and breastmilk samples were taken 5 days after delivery. Results may be seen in the Table: XARELTO Concentrations in Maternal and Infant Blood Samples and in Breastmilk

• All plasma XARELTO concentrations in the infants 2 hours after breastfeeding were below the lower limit of quantification.
• At 3 months of follow-up, breastfeeding continued with XARELTO without complications, including no bleeding events.

Muysson et al (2020)⁵ report the drug-concentration profile of XARELTO in milk samples collected from two lactating mothers consuming XARELTO 15 mg twice daily and then subsequently transitioned to 20 mg once daily following a mild stroke and bilateral pulmonary emboli.

• The first lactating mother was a 35-year-old woman weighing 58.9 kg who gave birth at 39 weeks of gestation. Three months postpartum, she was diagnosed with a mild stroke and was initiated on XARELTO 15 mg twice daily for 21 days and then 20 mg once daily thereafter for 6 months.
• The second lactating mother was a 33-year-old woman who gave birth at 39 weeks gestation. Four weeks postpartum, she was diagnosed with bilateral PE and was initiated on XARELTO 15 twice daily for 21 days and then 20 mg once daily thereafter for 6 months.
• Milk samples for the first lactating mother were collected on day 10 of treatment after taking the 15 mg dose twice daily at -0, 1, 3, 5, 8, 10, and 12 hours. Milk samples for the second lactating mother were collected on day 10 of treatment after taking the 15 mg dose twice daily at -0, 1, 2, 4, 8, 10, 12, and 24 hours.
  • Milk samples for the 20 mg dose were collected 7 days after transitioning to the higher dose at -0, 1, 2, 4, 8, 10, 12, and 24 hours (sampling for the 20 mg dose regimen was identical for both patients).
• The average concentration of XARELTO in milk observed in both patients was 0.16 +0.0004 μg/mL taking the 15 mg twice daily dose. The maximum concentration was 0.3 +0.02μg/mL at 1 hour. The estimated infant dose per 12 hours was 0.01 mg/kg and the estimated relative infant dose was 5%.
• The average concentration of XARELTO in milk for the 20 mg dose was 0.07 +0.02 μg/mL. The maximum concentration was 0.26 +0.01 μg/mL at 2 hours. The estimated infant dose per day was 0.01 mg/kg and the estimated relative infant dose was 4%.
• Both patients were advised against breastfeeding once they began XARELTO treatment. They continued to pump to keep up their supply and to donate milk samples to the investigators.

Myers et al (2015)⁶ published a case report involving a 20-year-old female patient who presented for consideration of termination of an unplanned pregnancy while on XARELTO 20 mg once daily for venous thromboembolism (VTE) prevention.

• Initial ultrasound revealed the fetus was 25+ weeks gestation. XARELTO therapy was discontinued, and low molecular weight heparin was initiated.
• The patient continued regular follow-up with fetal scans which showed normal growth and no fetal abnormalities or bleeding.
• She underwent an emergency Caesarean section at 39+ weeks due to spontaneous rupture of membranes. A male baby was delivered without evidence of intracranial hemorrhage. Follow-up examinations were normal.

Konigsbrugge et al (2014)⁷ reported a case involving a 24-year-old female who was found to be 19 weeks gestation while on XARELTO 15 mg once daily for VTE prophylaxis.

• Upon discovery of pregnancy, XARELTO therapy was immediately discontinued and replaced with low molecular weight heparin.
• Routine follow-up was conducted without anomalies. The patient delivered a male infant at 40 weeks without any complications.

LITERATURE SEARCH

A literature search of MEDLINE^®, EMBASE^®, BIOSIS Previews^®, DERWENT^® (and/or other resources, including internal/external databases) pertaining to this topic was conducted on 20 August 2024.