ANDEXXA

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) ].

7 DRUG INTERACTIONS Do not use unfractionated heparin following ANDEXXA administration due to unresponsiveness characterized by non-prolongation of activated clotting times ( 7.1 ). See full prescribing information for details on drug interactions. 7.1 Use with Unfractionated Heparin Unresponsiveness to unfractionated heparin has occurred following ANDEXXA administration, characterized by non-prolongation of activated clotting times and requirement for increased dosing of heparin. Do not use unfractionated heparin following ANDEXXA administration. 7.2 Interference with Anti-FXa Activity Test Current commercial clinical anti-FXa-activity assays are unsuitable for measuring FXa activity following administration of ANDEXXA. Due to the reversible binding of ANDEXXA to the FXa inhibitor, the high sample dilution currently used in commercial clinical assays promotes dissociation of the inhibitor from ANDEXXA, resulting in detection of erroneously elevated anti-FXa activity levels, thereby causing a underestimation of the reversal activity of ANDEXXA.