On October 16,2015, the US Food and Drugs Administration (FDA) granted approval for Praxbind (idarucizumab) an antidote to reverse Pradaxa (dabigatran) effects. Praxbind is a humanized monoclonal antibody fragment that binds to Pradaxa, stopping the powerful Novel Oral Anticoagulant (NOAC) effects, whenever a serious adverse reaction like internal bleeding occurs. But what about Pradaxa’s close brother, the other blood-thinning agent Xarelto (rivaroxaban)?
FDA granted accelerated approval of Praxbind, an injective antidote that can rapidly prevent Pradaxa from seriously harming or even killing a patient. The accelerated approval program allows the FDA to approve drugs that still did not pass the usual amount of clinical trials required for other medications. The idea is to provide patients with these medications as soon as possible when there’s an urgent unmet medical need for a given drug, provided that the clinical trials at least can predict a significant clinical benefit for patients involved. The manufacturer will then submit additional clinical results in due time, to confirm the medication’s effectiveness and safety.
Praxbind was tested on a total of 283 volunteers across three different trials. All the patients involved were healthy persons who did not require a blood-thinning agent, and the test checked their Pradaxa plasma levels after the antidote was administered. Another trial instead involved 123 patients who required Praxbind to reverse Pradaxa’s effects because of an emergency surgery or uncontrolled bleeding event. The test showed that in almost nine patients out of ten the effects of the NOAC were reversed whitin four hours. The most common side effects were either headache in the first group of healthy patients, or confusion, low potassium serum levels, pneumonia and fever in the second group.
FDA approved Pradaxa’s antidote with so much urgency, as since this drug’s approval 5 years ago Pradaxa was deemed responsible for thousands of life-threatening adverse reaction that either seriously harmed or even killed many patients. Internal bleeding caused by the NOACs such as Pradaxa, Xarelto and Eliquis (apixaban) can led to a patient’s death, as there’s no way to control the haemorrhage once it’s started. For this reason, without an antidote readily available, even a simple gastrointestinal bleeding can became a life-threatening hazard that can seriously injury a patient who’s under medication. FDA’s approval of these drugs when no reversal agent was available, was often deemed as a questionable judgment, or at least as an oversight.
The Project On Government Oversight (POGO) published a report in which they explained that: “The result was to accommodate a pharmaceutical company by easing a drug’s passage to market and then deflecting questions about its safety once the product had won approval. The issues ranged from what standards to demand from the manufacturer-sponsored clinical trial used to secure the drug’s approval to what warnings to give patients about potential hazards and what claims to allow in ads for the product.”
On the other hand it’s more than legitimate now to ask if it’s still reasonable for FDA to let pharmaceutical companies to keep marketing the other NOACs that lack a proper antidote, Xarelto and Eliquis. If the need for an antidote was so urgent for Pradaxa, it would be reasonable to think that patient’s safety is at risk with Xarelto and Eliquis. However, Ellis F. Unger, an official in the FDA’s Center for Drug Evaluation and Research explained that they will keep on marketing the drugs nonetheless.
“With reversal agents now available for Pradaxa and warfarin, we have been asked if FDA should continue to allow marketing of anticoagulant drugs that do not have a reversal agent,” Unger explained. “The short answer to that question is yes.”
An antidote for Xarelto is yet under development though. The andexanet alfa antibody produced by Portola Pharmaceuticals was presented on December 9, 2013, at the 55th American Society of Hematology Annual Meeting in New Orleans, showing that this molecule can actually reverse the effects of both Xarelto and Eliquis.
1. Fiercepharma. “FDA approves Praxbind, the first reversal agent for the anticoagulant Pradaxa.” http://www.fiercepharma.com/press-releases/fda-approves-praxbind-first-reversal-agent-anticoagulant-pradaxa
2. Crowther M. A phase 2 randomized, double-blind, placebo-controlled trial demonstrating reversal of rivaroxaban-induced anticoagulation in healthy subjects by andexanet alfa (PRT064445), an antidote for fXa inhibitors. Presented at: American Society of Hematology Annual Meeting; December 9, 2013; New Orleans, LA.
3. “Bleeding with dabigatran, rivaroxaban, apixaban. No antidote, and little clinical experience.” Prescrire Int. 2013 Jun;22(139):155-9.
4. Institute for Safe Medication Practices (ISMP) “QuarterWatch Monitoring FDA MedWatch Reports – Anticoagulants the Leading Reported Drug Risk in 2011 – May 31, 2012 – New Data from 2011 Quarters 3 – 4” http://www.ismp.org/quarterwatch/pdfs/2011Q4.pdf (Accessed June 2015)