b'B:8.375"T:7.875"S:7.125"reaction that occurred more frequently than in the placebo group. No serious or severe adverse reactions were reported. The ANNEXA-4 study is an ongoing multinational, prospective, open-label study using ANDEXXA in subjects presenting with acute major bleeding and who have recently received an FXa inhibitor. Coagulation Factor Xa To date, safety data are available for 352 subjects. Sixty-three percent of the 352 subjects were 75 years or older. Subjects had received either apixaban (194/352; (Recombinant), Inactivatedzhzo 55%) or rivaroxaban (128/352; 36%) as anticoagulation treatment for atrial fibrillation (286/352; 81%) or venous thromboembolism (87/352; 25%). In the majority of subjects, ANDEXXA (coagulation factor Xa (recombinant), inactivated-zhzo)ANDEXXA was used to reverse anticoagulant therapy following either an intracranial Lyophilized Powder for Solution for Intravenous Injection hemorrhage (227; 64%) or a gastrointestinal bleed (90; 26%), with the remaining 35 Rx Only subjects (10%) experiencing bleeding at other sites. Subjects were assessed at aBRIEF SUMMARY OF FULL PRESCRIBING INFORMATION.Day 30 follow-up visit following infusion with ANDEXXA. This does not include all the information needed to use ANDEXXAsafely andDeaths effectively. See full Prescribing Information for ANDEXXA. In the ongoing ANNEXA-4 study, of the 352 subjects completing 30-day safety follow-up, there were 54 deaths (15%) occurring prior to the Day 30 visit. The number WARNING: THROMBOEMBOLIC RISKS, ISCHEMIC RISKS, CARDIAC ARREST, ANDof cardiovascular deaths, including three with unknown causes and two that were SUDDEN DEATHS unadjudicated, was 42 of 352 (12%), and the number of non-cardiovascular deaths See full prescribing information for complete boxed warning was 12 (3%). Twenty (37%) subjects died within ten days after the ANDEXXA infusion. Treatment with ANDEXXA has been associated with serious and life-threateningAll subjects died prior to Day 45. Of the 54 subjects who died, the bleeding type was adverse events, including: intracranial bleeding in 37 (69%), gastrointestinal bleeding in 12 (22%), and other Arterial and venous thromboembolic events bleeding types in 5 (9%) subjects.Ischemic events, including myocardial infarction and ischemic stroke Thromboembolic and Ischemic Events Cardiac arrest In the ANNEXA-4 study, 63/352 (18%) subjects experienced one or more of the Sudden deaths following overall thromboembolic events: cerebrovascular accident (CVA) (16/63; Monitor for thromboembolic events and initiate anticoagulation when medically25%), deep venous thrombosis (16/63; 25%), acute myocardial infarction (10/63; 16%), appropriate. Monitor for symptoms and signs that precede cardiac arrest andpulmonary embolism (5/63; 8%), and transient ischemic attack (1/63; 2%). The median provide treatment as needed.time to event was seven days. A total of 33% of subjects with thromboembolic events (21/63) experienced the thromboembolic event during the first three days. Of the 352 INDICATIONS AND USAGE subjects who received ANDEXXA, 223 received at least one anticoagulation dose ANDEXXA is indicated for patients treated with rivaroxaban or apixaban, whenwithin 30 days after treatment. Of these 223, 18 subjects (8%) had a thrombotic event reversal of anticoagulation is needed due to life-threatening or uncontrolled bleeding. and/or ischemic event after resumption.This indication is approved under accelerated approval based on the change fromNo thromboembolic events were observed in 223 healthy volunteers who received FXa baseline in anti-FXa activity in healthy volunteers. An improvement in hemostasis hasinhibitors and were treated with ANDEXXA.not been established. Continued approval for this indication may be contingent uponInfusion-Related Reactions the results of studies that demonstrate an improvement in hemostasis in patients.Infusion-related reactions occurred in 18% (39/223) of ANDEXXA-treated healthy Limitations of Use volunteers vs. 6% (6/94) of placebo-treated subjects. These reactions were characterized ANDEXXA has not been shown to be effective for, and is not indicated for, theby a range of symptoms, including flushing, feeling hot, cough, dysgeusia, and dyspnea. treatment of bleeding related to any FXa inhibitors other than apixaban or rivaroxaban.Symptoms were mild to moderate in severity, and 90% (35/39) did not require treatment. CONTRAINDICATIONSOne subject with a history of hives prematurely discontinued ANDEXXA after developing None. mild hives. Two of 352 (0.6%) subjects in the ANNEXA-4 study experienced an infusion-related reaction.WARNINGS AND PRECAUTIONSImmunogenicityThromboembolic and Ischemic Risks As with all therapeutic proteins, there is the potential for immunogenicity. Using an The thromboembolic and ischemic risks were assessed in 352 bleeding subjects whoelectrochemiluminescence (ECL)-based assay, 145 ANDEXXA-treated healthy subjects received ANDEXXA. Of the 63 subjects who experienced a thrombotic event, thewere tested for antibodies to ANDEXXA as well as for antibodies cross-reacting with median time to first event was 7 days, and 21 subjects experienced the event withinfactor X (FX) and FXa. Low titers of anti-ANDEXXA antibodies were observed in 26/145 the first three days. A total of 63 (18%) experienced 88 thromboembolic or ischemichealthy subjects (17%); 6% (9/145) were first observed at Day 30, with 20 subjects (14%)S:10" T:10.75" B:11"events. Of the 352 subjects who received ANDEXXA, 223 received at least onestill having titers at the last time point (Days 44 to 48). To date, the pattern of antibody anticoagulation dose within 30 days after treatment. Of these 223, 18 subjects (8%) response in subjects in the ongoing ANNEXA-4 study has been similar to that observed had a thrombotic event and/or ischemic event after resumption.in healthy volunteers. Of the 236 subjects with available samples, 6.8% (16/236) Monitor subjects treated with ANDEXXA for signs and symptoms of arterial andhad antibodies against ANDEXXA. None of these anti-ANDEXXA antibodies were venous thromboembolic events, ischemic events, and cardiac arrest. To reduceneutralizing. No neutralizing antibodies cross-reacting with FX or FXa were detectedthromboembolic risk, resume anticoagulant therapy as soon as medically appropriatein healthy subjects (0/145) or in bleeding subjects (0/209) to date. following treatment with ANDEXXA.Detection of antibody formation is highly dependent on the sensitivity and specificity The safety of ANDEXXA has not been evaluated in subjects who experiencedof the assay. Additionally, the observed incidence of antibody (including neutralizing thromboembolic events or disseminated intravascular coagulation within two weeksantibody) positivity in an assay may be influenced by several factors, including assay prior to the life-threatening bleeding event requiring treatment with ANDEXXA. Safetymethodology, sample handling, timing of sample collection, concomitant medications, of ANDEXXA also has not been evaluated in subjects who received prothrombinand underlying disease. For these reasons, comparison of the incidence of antibodies complex concentrates, recombinant factor VIIa, or whole blood products within sevento ANDEXXA with the incidence of antibodies to other products may be misleading. days prior to the bleeding event.USE IN SPECIFIC POPULATIONSRe-elevation or Incomplete Reversal of Anti-FXa Activity PregnancyThe time course of anti-FXa activity following ANDEXXA administration was consistentRisk Summaryamong the healthy volunteer studies and the ANNEXA-4 study in bleeding subjects.There are no adequate and well-controlled studies of ANDEXXA in pregnant women Compared to baseline, there was a rapid and substantial decrease in anti-FXa activityto inform patients of associated risks. Animal reproductive and developmental studies corresponding to the ANDEXXA bolus. This decrease was sustained through the endhave not been conducted with ANDEXXA. of the ANDEXXA continuous infusion. The anti-FXa activity returned to the placeboIn the U.S. general population, the estimated background risk of major birth defects levels approximately two hours after completion of a bolus or continuous infusion.and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, Subsequently, the anti-FXa activity decreased at a rate similar to the clearance of therespectively.FXa inhibitors.Labor or DeliverySeventy-one subjects were anticoagulated with apixaban and had baseline levelsThe safety and effectiveness of ANDEXXA during labor and delivery have not been of anti-FXa activity 150 ng/mL. Nineteen subjects who were anticoagulated withevaluated.rivaroxaban had elevated baseline anti-FXa activity levels 300 ng/mL. Forty-eight of the 71 apixaban-treated subjects (68%) experienced a 90% decrease from baselineLactationanti-FXa activity after administration of ANDEXXA. Ten of the 19 rivaroxaban-treatedRisk Summarysubjects (53%) experienced a 90% decrease from baseline anti-FXa activity afterThere is no information regarding the presence of ANDEXXA in human milk, the effects administration of ANDEXXA. on the breastfed child, or the effects on milk production.Use of Heparin Following Administration of ANDEXXA The developmental and health benefits of breastfeeding should be considered along ANDEXXA may interfere with the anticoagulant effect of heparin. with the mothers clinical need for ANDEXXA and any potential adverse effects on the Use of ANDEXXA as an antidote for heparin has not been established. Avoid usebreastfed child from ANDEXXA or from the underlying maternal condition. of ANDEXXA for the reversal of direct FXa inhibitors (apixaban and rivaroxaban)Pediatric Useprior to heparinization as ANDEXXA may cause unresponsiveness to heparin. IfThe safety and efficacy of ANDEXXA in the pediatric population have not been studied.anticoagulation is needed, use an alternative anticoagulant to heparin. Geriatric UseADVERSE REACTIONS Of the 352 subjects in the ANNEXA-4 study of ANDEXXA, 314 were 65 years of age or The most common adverse reactions ( 5%) in bleeding subjects receiving ANDEXXAolder, and 231 were 75 years of age or older. No overall differences in safety or efficacy were urinary tract infections and pneumonia.were observed between these subjects and younger subjects, and other reported The most common adverse reactions ( 3%) in healthy subjects treated with ANDEXXAclinical experience has not identified differences in responses between elderly and were infusion-related reactions. younger subjects; however, greater sensitivity of some older individuals cannot Clinical Trials Experience be ruled out. The pharmacokinetics of ANDEXXA in healthy older (65 years; n=10) Because clinical trials are conducted under widely varying conditions, adverse reactionsubjects were not different compared to younger (18-45 years; n=10) subjects.rates observed in the clinical trials of a drug cannot be directly compared to rates in thePortola Pharmaceuticals, Inc.clinical trials of another drug and may not reflect the rates observed in clinical practice.In the pooled safety analysis of clinical trials of ANDEXXA, 223 healthy volunteers received FXa inhibitors, followed by treatment with ANDEXXA. The frequency of adverse reactions was similar in the ANDEXXA-treated group (120/223; 54%) and in the placebo-treated group (54/94; 57%). Infusion-related adverse reactions occurredSouth San Francisco, CA 94080 USA in 18% (39/223) of the ANDEXXA-treated group and were the only type of adverseUS License No. 2017US/POR-ADX/0059September 202011439040_Andexxa_Jrnl_Ad_Spread_US_MEDICINE_M1.indd 2 11/20/20 11:39 AM'