FDA on May 3 approved a license from Portola Pharmaceuticals, Inc., of South San Francisco, California, to market the first agency-approved anticoagulation reversal agent for the direct factor Xa inhibitors rivaroxaban and apixaban.
The reversal agent—dubbed coagulation factor Xa (recombinant), inactivated-zhzo—will be marketed as Andexxa. Portola referred to the product as andexanet alfa during clinical development.
The labeling for Andexxa states that it is indicated for the treatment of life-threatening or uncontrolled bleeding resulting from the use of rivaroxaban or apixaban.
Andexxa has not been shown to be effective as a reversal agent for any other factor Xa inhibitors and is not indicated for such use, according to the labeling.
FDA approved the reversal agent on the basis of data on anti–factor Xa activity in healthy volunteers. A clinical study to evaluate the product’s effects on hemostasis in bleeding patients who recently received a factor Xa inhibitor is underway and is described in the labeling.
In healthy volunteers who received Andexxa, the most commonly reported adverse events were infusion-related reactions, usually of mild or moderate severity. Urinary tract infection and pneumonia were the most commonly reported adverse events among clinical trial patients treated with the reversal agent.
Andexxa’s labeling contains a boxed warning about reports of sudden death, thromboembolic and ischemic events, and cardiac arrest occurring within 30 days of administration of the drug to patients in the ongoing study. These adverse events affected 18% of 185 clinical trial participants for whom safety data were available, according to the labeling.
Portola officials announced that Andexxa will be made available in June to about 30–40 hospitals, most of which have served as clinical trial sites.
The company’s 2017 annual report states that initial quantities of the reversal agent are limited to product made at a site that supplies the drug for clinical studies but lacks sufficient capacity for large-scale commercial manufacture.
Portola stated that it is developing a “generation 2” manufacturing process at another site that has greater manufacturing capacity. FDA must approve the manufacturing process and verify that the resulting drug product is comparable to the licensed version of Andexxa before allowing the newer material on the U.S. market; that will occur early next year, company officials predicted.
The reversal agent will be supplied in cartons of 4 single-use vials, each containing 100 mg of lyophilized coagulation factor Xa inactivated. The vials should be refrigerated at 2–8 °C until use.
Instructions in the labeling describe low- and high-dose treatment regimens and the specific circumstances in which each regimen should be used.
Treatment consists of a single 400- or 800-mg i.v. bolus dose infused at a rate of 30 mg/min followed by a single continuous i.v. infusion administered at a rate of 4 or 8 mg/min for up to 2 hours.
The safety and effectiveness of additional doses have not been evaluated in clinical studies, according to the labeling.
The continuous infusion requires the use of a 0.2- or 0.22-µm inline polyethersulfone or equivalent low protein-binding filter and should begin within 2 minutes after the bolus is administered.
Before use, the contents of the required number of vials must be reconstituted with Sterile Water for Injection, USP. Separate doses for administration as a bolus and as a continuous infusion must be prepared as described in the packaging.
After reconstitution, Andexxa is stable in the original vials for up to 8 hours at room temperature or up to 24 hours under refrigeration. Product that is reconstituted and transferred into an i.v. bag is stable at room temperature for up to 8 hours or up to 16 hours if refrigerated.
[This news story appears in the June 15, 2018, issue of AJHP.]
