FDA label e366faf3-92b5-4c21-8b80-7640fb9c4d47

WARNING: THROMBOEMBOLIC RISKS, ISCHEMIC RISKS, CARDIAC ARREST, AND SUDDEN DEATHS Treatment with ANDEXXA has been associated with serious and life-threatening adverse events, including: ( 5.1 ) • Arterial and venous thromboembolic events • Ischemic events, including myocardial infarction and ischemic stroke • Cardiac arrest • Sudden deaths Monitor for thromboembolic events and initiate anticoagulation when medically appropriate. Monitor for symptoms and signs that precede cardiac arrest and provide treatment as needed. WARNING: THROMBOEMBOLIC RISKS, ISCHEMIC RISKS, CARDIAC ARREST, AND SUDDEN DEATHS See full prescribing information for complete boxed warning Treatment with ANDEXXA has been associated with serious and life-threatening adverse events, including: ( 5.1 ) • Arterial and venous thromboembolic events • Ischemic events, including myocardial infarction and ischemic stroke • Cardiac arrest • Sudden deaths Monitor for thromboembolic events and initiate anticoagulation when medically appropriate. Monitor for symptoms and signs that precede cardiac arrest and provide treatment as needed.

5 WARNINGS AND PRECAUTIONS • Arterial and venous thromboembolic events, ischemic events, and cardiac events, including sudden death, have occurred during treatment with ANDEXXA. Resume anticoagulant therapy as soon as medically appropriate following treatment with ANDEXXA . ( 5.1 ) • Re-elevation or incomplete reversal of anticoagulant activity can occur. ( 5.2 ) 5.1 Thromboembolic and Ischemic Risks The thromboembolic and ischemic risks were assessed in 352 bleeding subjects who received ANDEXXA. Of the 63 subjects who experienced a thrombotic event, the median time to first event was 7 days, and 21 subjects experienced the event within the first three days. A total of 63 (18%) experienced 88 thromboembolic or ischemic events. Of the 352 subjects who received ANDEXXA, 223 received at least one anticoagulation dose within 30 days after treatment. Of these 223, 18 subjects (8%) had a thrombotic event and/or ischemic event after resumption. Monitor subjects treated with ANDEXXA for signs and symptoms of arterial and venous thromboembolic events, ischemic events, and cardiac arrest. To reduce thromboembolic risk, resume anticoagulant therapy as soon as medically appropriate following treatment with ANDEXXA. The safety of ANDEXXA has not been evaluated in subjects who experienced thromboembolic events or disseminated intravascular coagulation within two weeks prior to the life-threatening bleeding event requiring treatment with ANDEXXA. Safety of ANDEXXA also has not been evaluated in subjects who received prothrombin complex concentrates, recombinant factor VIIa, or whole blood products within seven days prior to the bleeding event. 5.2 Re-elevation or Incomplete Reversal of Anti-FXa Activity The time course of anti-FXa activity following ANDEXXA administration was consistent among the healthy volunteer studies and the ANNEXA-4 study in bleeding subjects [see Clinical Studies (14) ] . Compared to baseline, there was a rapid and substantial decrease in anti-FXa activity corresponding to the ANDEXXA bolus. This decrease was sustained through the end of the ANDEXXA continuous infusion. The anti-FXa activity returned to the placebo levels approximately two hours after completion of a bolus or continuous infusion. Subsequently, the anti-FXa activity decreased at a rate similar to the clearance of the FXa inhibitors. Seventy-one subjects were anticoagulated with apixaban and had baseline levels of anti-FXa activity > 150 ng/mL. Nineteen subjects who were anticoagulated with 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 baseline anti-FXa activity after administration of ANDEXXA. Ten of the 19 rivaroxaban subjects (53%) experienced a > 90% decrease from baseline anti-FXa activity after administration of ANDEXXA. 5.3 Use of Heparin Following Administration of ANDEXXA ANDEXXA may interfere with the anticoagulant effect of heparin. Use of ANDEXXA as an antidote for heparin has not been established. Avoid use of ANDEXXA for the reversal of direct FXa inhibitors (apixaban and rivaroxaban) prior to heparinization as ANDEXXA may cause unresponsiveness to heparin. If anticoagulation is needed, use an alternative anticoagulant to heparin.

6 ADVERSE REACTIONS The most common adverse reactions (≥ 5%) in bleeding subjects receiving ANDEXXA were urinary tract infections and pneumonia. The most common adverse reactions (≥ 3%) in healthy subjects treated with ANDEXXA were infusion-related reactions. The most common adverse reactions (≥ 5%) in bleeding subjects receiving ANDEXXA were urinary tract infections and pneumonia. ( 6.1 ) The most common adverse reactions (≥ 3%) in healthy volunteers treated with ANDEXXA were infusion-related reactions. To report SUSPECTED ADVERSE REACTIONS, contact Alexion Pharmaceuticals, Inc. at 1-844-259-6783 or the FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be compared directly to rates in the 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 occurred in 18% (39/223) of the ANDEXXA-treated group and were the only type of adverse 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. 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; 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 was used to reverse anticoagulant therapy following either an intracranial hemorrhage (227; 64%) or a gastrointestinal bleed (90; 26%), with the remaining 35 subjects (10%) experiencing bleeding at other sites. Subjects were assessed at a Day 30 follow-up visit following infusion with ANDEXXA. Deaths 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 of cardiovascular deaths, including three with unknown causes and two that were unadjudicated, was 42 of 352 (12%), and the number of non-cardiovascular deaths was 12 (3%). Twenty (37%) subjects died within ten days after the ANDEXXA infusion. All subjects died prior to Day 45. Of the 54 subjects who died, the bleeding type was intracranial bleeding in 37 (69%), gastrointestinal bleeding in 12 (22%), and other bleeding types in 5 (9%) subjects. Thromboembolic and Ischemic Events In the ANNEXA-4 study, 63/352 (18%) subjects experienced one or more of the following overall thromboembolic events: cerebrovascular accident (CVA) (16/63; 25%), deep venous thrombosis (16/63; 25%), acute myocardial infarction (10/63; 16%), pulmonary embolism (5/63; 8%), and transient ischemic attack (1/63; 2%). The median 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 subjects who received ANDEXXA, 223 received at least one anticoagulation dose within 30 days after treatment. Of these 223, 18 subjects (8%) had a thrombotic event and/or ischemic event after resumption [see Warnings and Precautions (5.1) ] . No thromboembolic events were observed in 223 healthy volunteers who received FXa inhibitors and were treated with ANDEXXA. Infusion-Related Reactions Infusion-related reactions occurred in 18% (39/223) of ANDEXXA-treated healthy volunteers vs. 6% (6/94) of placebo-treated subjects. These reactions were characterized by a range of symptoms, including flushing, feeling hot, cough, dysgeusia, and dyspnea. Symptoms were mild to moderate in severity, and 90% (35/39) did not require treatment. One subject with a history of hives prematurely discontinued ANDEXXA after developing mild hives. Two of 352 (0.6%) subjects in the ANNEXA-4 study experienced an infusion-related reaction. 6.2 Immunogenicity As with all therapeutic proteins, there is the potential for immunogenicity. Using an electrochemiluminescence (ECL)-based assay, 145 ANDEXXA-treated healthy subjects were tested for antibodies to ANDEXXA as well as for antibodies cross-reacting with factor X (FX) and FXa. Low titers of anti-ANDEXXA antibodies were observed in 26/145 healthy subjects (17%); 6% (9/145) were first observed at Day 30, with 20 subjects (14%) still having titers at the last time point (Days 44 to 48). To date, the pattern of antibody response in subjects in the ongoing ANNEXA-4 study has been similar to that observed in healthy volunteers. Of the 236 subjects with available samples, 6.8% (16/236) had antibodies against ANDEXXA. None of these anti-ANDEXXA antibodies were neutralizing. No neutralizing antibodies cross-reacting with FX or FXa were detected in healthy subjects (0/145) or in bleeding subjects (0/209) to date. Detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors, including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to ANDEXXA with the incidence of antibodies to other products may be misleading.