Issue to be Considered by FDA Advisory Committee on November 21, 2024, and Discussion May Lead to Andexxa Drug Recall
(Posted by Tom Lamb at Drug Injury Watch)
At its November 21, 2024 meeting, the FDA's Cellular, Tissue, and Gene Therapies Advisory Committee will discuss whether Andexxa risks outweigh benefits. From the October 2024 FDA Briefing Document for that Andexxa Advisory Committee meeting comes this Draft Discussion Question:
ANNEXA-I demonstrated an increased incidence of thrombosis (15.1% versus 6.9%) and thrombosis-related deaths at Day 30 (2.5% versus 0.9%) in the [Andexxa (andexanet)] arm compared to the [usual care (UC)]. Are the serious risks of [Andexxa (andexanet)] acceptable in the indicated population and in the context of the benefit demonstrated in ANNEXA-I?
For some contextual information, we turn to this November 19, 2024 Endpoints News report "Ahead of adcomm, FDA raises safety questions for AstraZeneca’s reversal agent for life-threatening bleeds", by Zachary Brennan, Senior Editor:
[Andexxa (andexanet)], a recombinant modified human factor Xa protein, is for patients treated with [Xarelto (rivaroxaban)] or [Eliquis (apixaban)] when rapid reversal of anticoagulation is needed because of life-threatening or uncontrolled bleeding. That could include, for example, when a patient needed urgent surgery because of a medical emergency or accident.
Last year, AstraZeneca began plans to shift Andexxa to a full approval from its accelerated approval after halting its confirmatory trial early due to these efficacy findings.
But FDA explained how the confirmatory trial, known as ANNEXA-I, revealed “major safety findings” including a “doubling of the rate of thromboses and thrombosis related deaths at Day 30 in the [Andexxa (andexanet)] arm compared with” a standard of care clotting agent known as a prothrombin complex concentrate.
Of the 239 patients treated with [Andexxa (andexanet)], FDA said, 14.6% of patients suffered thrombotic events versus 6.9% in the standard of care arm.
Essentially, as regards the issue of whether Andexxa risks outweigh benefits, the FDA wants this Andexxa Advisory Committee to look into the increased rates of dangerous clotting and clotting-related deaths seen in the ANNEXA-I trial done for Andexxa, compared with a standard of care reversal agent.
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For more specificity, we return to the October 2024 FDA Briefing Document and go to the Topics for Discussion part:
4.1. Increased Risk of Thrombosis of Treatment with [Andexxa (andexanet)]
The rate of thrombotic events among patients treated with [Andexxa (andexanet)] is double the rate of those who were treated with [usual care (UC)]. Of patients treated with andexanet, 14.6% suffered [thrombotic events (TEs)] versus 6.9% in the [usual care (UC)] arm.
Thrombotic events in the [Andexxa (andexanet)] arm tended to occur earlier at median day 3.5, compared with median day 16 in the UC arm. Such early [thrombotic event (TE)] onset may preclude attempts at prophylactic anticoagulant resumption.
Of those patients who resumed prophylactic anticoagulation, 9.6% in the [Andexxa (andexanet)] arm and 5.5% in the UC arm developed TEs. More than half of the 35 patients experiencing a TE after [Andexxa (andexanet)] treatment had their first TE within 3 days of randomization, a period when anticoagulation is generally not feasible due to bleeding concerns, and therefore did not receive prophylactic anticoagulation....
Death rates were comparable between the treatment arms with 28.0% in the [Andexxa (andexanet)] group and 26.3% in the UC arm, however, deaths attributable to TEs were more twice as high in the [Andexxa (andexanet)] arm than in the UC arm.
Even before this Andexxa Advisory Committee meeting was convened, there was speculation that it might lead to an eventual Andexxa drug recall. For example, here is an article published November 20, 2024, by Pink Sheet, "AstraZeneca’s Andexxa Could Be Headed For Withdrawal After US FDA’s Negative Advisory Committee Preview":
AstraZeneca PLC’s Andexxa may face withdrawal after the US Food and Drug Administration raised concerns about its clinical efficacy, as well as serious safety events seen in the anticoagulant reversal agent’s confirmatory study in briefing documents ahead of a 21 November advisory committee.
We will continue to monitor this emerging drug safety issue of whether Andexxa risks outweigh benefits.
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