FDA Safety Update: Andexxa Risks Outweigh Benefits After Postmarketing Thromboembolic Events—Market Withdrawal Planned

FDA Updates Safety Assessment of Andexxa After Serious Thromboembolic Events. On December 18, 2025, the U.S. Food and Drug Administration (FDA) issued a safety communication regarding Andexxa (coagulation factor Xa (recombinant), inactivated-zhzo). The agency has reviewed postmarketing safety data showing an increased incidence of thromboembolic events, including serious and fatal outcomes, in patients treated with Andexxa. Based on these findings, the FDA now considers that the risks associated with Andexxa outweigh its benefits in its approved use.

As a result of this assessment, the FDA has informed AstraZeneca of its position, and the company has submitted a request to voluntarily withdraw the biologics license application (BLA) for Andexxa for commercial reasons. AstraZeneca also confirmed plans to cease U.S. commercial sales and manufacturing of Andexxa by December 22, 2025.

Drug Mechanism and Approved Use

Andexxa is a recombinant modified human factor Xa protein designed to reverse the anticoagulant effects of the popular oral factor Xa inhibitors rivaroxaban and apixaban. It was originally granted accelerated approval by the FDA in 2018 for use in patients requiring urgent reversal of anticoagulation due to life-threatening or uncontrolled bleeding. The initial approval included a boxed warning about thromboembolic risk.

Postmarketing Safety Data and ANNEXA-I Results

The FDA’s updated safety evaluation leaned heavily on results from the randomized ANNEXA-I trial (NCT03661528), conducted to verify clinical benefit as required under accelerated approval. In that trial, patients treated with Andexxa had a higher rate of thrombotic events compared with those receiving usual care.

Key findings from the ANNEXA-I trial included:

• A higher incidence of thrombosis in the Andexxa group (14.6%) compared with usual care (6.9%).
• Greater thrombosis-related mortality at 30 days in the Andexxa arm (2.5%) versus the control arm (0.9%).
• More than half of the thrombotic events in the Andexxa group occurred earlier than in the control group.

These safety signals raised significant concern because thrombotic complications can include deep vein thrombosis, pulmonary embolism, stroke, and other life-threatening conditions.

Regulatory History and Evolving Evidence on Andexxa

Since its accelerated approval by the U.S. FDA in May 2018, Andexxa has been the only approved specific reversal agent for major bleeding associated with the factor Xa inhibitors rivaroxaban and apixaban. The approval was based on changes in anti-factor Xa activity in healthy volunteers and carried a boxed warning for thromboembolic risks. Continued approval was contingent on completing postmarketing studies to demonstrate clinical benefit.

In 2023, AstraZeneca reported interim results from the Phase IV ANNEXA-I trial showing superior haemostatic control of bleeding compared with usual care, which initially supported the rationale for further evaluation. At that time, company leadership highlighted Andexxa’s role in addressing urgent bleeding in patients on direct oral anticoagulants, noting its rapid reversal mechanism.

However, when the full data from ANNEXA-I were reviewed by the FDA’s Cellular, Tissue, and Gene Therapies Advisory Committee in November 2024, concerns emerged about the balance of benefits and risks. The committee noted a doubling in thrombotic events and thrombosis-related deaths in the Andexxa arm compared with usual care, raising questions about the clinical meaningfulness of the benefit in the studied population.

Earlier regulatory interactions also reflect this evolving assessment. In late 2024, the FDA issued a complete response letter (CRL) when AstraZeneca sought conversion from accelerated to full approval, citing uncertainties in the confirmatory trial’s safety and efficacy outcomes. At that time, the agency and advisory committee discussed whether modifying the indication or dosing could yield a more favorable risk-benefit profile, though no definitive path was agreed upon.

 Statements from AstraZeneca and the FDA on Future Steps

In the December 18, 2025, safety communication, the FDA reaffirmed its commitment to monitoring biologics’ safety and said it will continue working with AstraZeneca and stakeholders to keep clinicians and the public informed as the product is withdrawn from the U.S. market.

AstraZeneca confirmed that it has voluntarily requested withdrawal of its biologics license application and will end U.S. commercial sales by December 22, 2025, citing commercial reasons in the context of the updated safety findings. The company has not publicly detailed plans for any new trials specifically aimed at addressing the thromboembolic risk seen in ANNEXA-I, but ongoing analysis of the broader dataset and international regulatory discussions may inform future strategies.