ANDEXXA

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 ) • Unresponsiveness to unfractionated heparin has been reported following ANDEXXA administration. ( 5.2 ) • Re-elevation or incomplete reversal of anticoagulant activity can occur. ( 5.3 ) 5.1 Thromboembolic and Ischemic Risks The thromboembolic and ischemic risks were assessed in 419 bleeding -patients in the ANNEXA-4 study who received ANDEXXA and were treated with apixaban or rivaroxaban. There were 45/419 (10.7%) patients who experienced a thrombotic event. The median time to first event was 10 days, and 17 patients experienced the event within three days of treatment. Of the 419 patients who received ANDEXXA, 266 received at least one anticoagulation dose within 30 days after treatment as a prophylactic measure. Of these 266 patients, 14 patients (5.3%) had a thrombotic event after resumption [ see Adverse Reactions (6.1) ]. Monitor patients 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 [ see Dosage and Administration (2.4) ]. The safety of ANDEXXA has not been evaluated in patients 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 patients who received prothrombin complex concentrates, recombinant factor VIIa, or whole blood products within seven days prior to the bleeding event. 5.2 Unresponsiveness to Unfractionated Heparin Unresponsiveness to unfractionated heparin leading to non-prolongation of activated clotting times and serious thrombotic events has occurred following ANDEXXA administration. [ see Postmarketing Experience (6.2) ]. Do not use ANDEXXA for the reversal of direct FXa inhibitors (apixaban and rivaroxaban) prior to heparinization. If anticoagulation is needed, use an alternative anticoagulant to heparin Use of ANDEXXA as an antidote for heparin has not been established. 5.3 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 patients [ 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. A total of 114 patients from ANNEXA-4 were anticoagulated with apixaban or rivaroxaban and had elevated baseline levels of anti-FXa (>150 ng/mL for apixaban and >300 ng/mL for rivaroxaban). After administration of ANDEXXA, these patients experienced decreased anti-FXa activity levels, with median reductions of 96% for rivaroxaban and 92% for apixaban .

6 ADVERSE REACTIONS The most common adverse reactions (≥ 5%) in bleeding patients receiving ANDEXXA were urinary tract infections and pneumonia. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact AstraZeneca at 1-800-236-9933 or 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 directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. The most common adverse reactions (≥ 5%) in bleeding patients receiving ANDEXXA were urinary tract infections and pneumonia. In Study 3 (ANNEXA-4), four hundred and seventy-seven patients with acute major bleeding were enrolled and received ANDEXXA. Of these 477 patients, 419 patients were treated with apixaban (245/419; 58.5%) or rivaroxaban (174/419; 41.5%). Most patients had received apixaban or rivaroxaban as anticoagulation treatment for atrial fibrillation (348/419; 83%) or venous thromboembolism (65/419; 16%). In the majority of patients, ANDEXXA was used to reverse anticoagulant therapy following either an intracranial hemorrhage (289/419; 69%) or a gastrointestinal bleed (95/419; 23%), with the remaining patients (35/419; 8.4%) experiencing bleeding at other sites. Patients were assessed at a Day 30 follow-up visit following infusion with ANDEXXA. Deaths In the ANNEXA-4 study, of the 419 patients in the safety population who were treated with apixaban or rivaroxaban, there were 75 deaths (18%). There were 37 cardiovascular deaths related to bleeding, 19 deaths that were cardiovascular and not related to bleeding, 14 that were non-cardiovascular, and 5 deaths had an uncertain or unknown cause. The average time to death was 15 days after treatment. All patients died prior to Day 45. Of the 75 patients who died, the initial bleeding event was intracranial bleeding in 55 (73%), gastrointestinal bleeding in 14 (19%), and other bleeding types in 6 (8%)patients. Thromboembolic and Ischemic Events In the Study 3 (ANNEXA-4), 45/419 (10.7%) patients experienced one or more of the following thromboembolic events: cerebrovascular accident (CVA) (19/45; 42%), deep venous thrombosis (11/45; 24%), myocardial infarction (9/45; 20%), pulmonary embolism (5/45; 11%), and transient ischemic attack (1/45; 2%). The median time to event was ten days. A total of 38% of patients with thromboembolic events (17/45) experienced the thromboembolic event during the first three days. Of the 419 patients who received ANDEXXA, 282 (67.3%) received any form of re-anticoagulation within 30 days after treatment. Of these 282 patients, 16 received anticoagulation in response to a thrombotic event, while 266 received the anticoagulation as a prophylactic. Of these 266, 14 patients (5.3%) had a thrombotic event after resumption of anticoagulation; while of the 153 patients who did not receive anticoagulation as a prophylactic, 31 (20.3%) had a thrombotic event. No patient had a thrombotic event after resumption of oral anticoagulation [ see Warnings and Precautions (5.1) ]. Infusion-Related Reactions In the ANNEXA-4 study, 2/419 (0.5%) patients experienced an infusion-related reaction, neither of which were assessed as severe (1 moderate; 1 mild). Reported signs and symptoms were transient and included rigors, chills, hypertension, oxygen desaturation, agitation and confusion. 6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of ANDEXXA. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or stablish a causal relationship to drug exposure. General disorders and administration site conditions: heparin resistance [ see Unresponsiveness to Unfractionated Heparin (5.2) ] and [ see Use with Unfractionated Heparin (7.1) ].