WARNING: SPINAL/EPIDURAL HEMATOMA Epidural or spinal hematomas may occur in patients treated with betrixaban who are receiving neuraxial anesthesia or undergoing spinal puncture. The risk of these events may be increased by the use of in-dwelling epidural catheters or the concomitant use of medical products affecting hemostasis. These hematomas may result in long-term or permanent paralysis. Consider these risks when scheduling patients for spinal procedures [see Warnings and Precautions (5.2) ]. WARNING: SPINAL/EPIDURAL HEMATOMA See full prescribing information for complete boxed warning. Epidural or spinal hematomas may occur in patients treated with betrixaban who are receiving neuraxial anesthesia or undergoing spinal puncture. The risk of these events may be increased by the use of in-dwelling epidural catheters or the concomitant use of medical products affecting hemostasis. These hematomas may result in long-term or permanent paralysis. Consider these risks when scheduling patients for spinal procedures. ( 5.2 )
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warnings and cautions
5 WARNINGS AND PRECAUTIONS Risk of Bleeding: Can cause serious, potentially fatal bleeding. Promptly evaluate signs and symptoms of blood loss ( 5.1 ) Severe Renal Impairment: Increased risk of bleeding events; reduce BEVYXXA dose ( 2.3 , 5.3 ) Concomitant P-gp Inhibitors: Increased risk of bleeding events; reduce BEVYXXA dose ( 2.2 , 5.4 ) Increased Risk of Thrombosis in Patients with Triple Positive Antiphospholipid Syndrome: BEVYXXA use not recommended. ( 5.5 ) 5.1 Risk of Bleeding BEVYXXA increases the risk of bleeding and can cause serious and potentially fatal bleeding. Promptly evaluate any signs or symptoms of blood loss [see Adverse Reactions (6.1) ] . Concomitant use of drugs affecting hemostasis increases the risk of bleeding. These include aspirin and other antiplatelet agents, other anticoagulants, heparin, thrombolytic agents, selective serotonin reuptake inhibitors, serotonin norepinephrine reuptake inhibitors, and nonsteroidal anti-inflammatory drugs (NSAIDs) [see Drug Interactions (7.3) ] . Advise patients of signs and symptoms of blood loss and to report them immediately and seek emergency care. Promptly evaluate any signs or symptoms of blood loss, and consider the need for blood replacement. Discontinue BEVYXXA in patients with active pathological bleeding. There is no established way to reverse the anticoagulant effect of BEVYXXA, which can be expected to persist for at least 72 hours after the last dose. It is unknown whether hemodialysis removes BEVYXXA. Protamine sulfate, vitamin K, and tranexamic acid are not expected to reverse the anticoagulant activity of BEVYXXA. 5.2 Spinal/Epidural Anesthesia or Puncture When neuraxial anesthesia (spinal/epidural anesthesia) or spinal/epidural puncture is employed, patients treated with antithrombotic agents for prevention of thromboembolic complications are at risk of developing an epidural or spinal hematoma which can result in long-term or permanent paralysis. Do not remove an epidural catheter earlier than 72 hours after the last administration of BEVYXXA. Do not administer the next BEVYXXA dose earlier than 5 hours after the removal of the catheter. If traumatic puncture occurs, delay the administration of BEVYXXA for 72 hours. Monitor patients frequently for signs and symptoms of neurological impairment (e.g., numbness or weakness of the legs, bowel or bladder dysfunction). If neurological compromise is noted, urgent diagnosis and treatment is necessary. Prior to neuraxial intervention, consider the potential benefit versus the risk in anticoagulated patients or in patients to be anticoagulated for thromboprophylaxis. 5.3 Use in Patients with Severe Renal Impairment Patients with severe renal impairment (CrCl ≥ 15 to < 30 mL/min computed by Cockcroft-Gault using actual body weight) taking BEVYXXA may have an increased risk of bleeding events. Reduce dose of BEVYXXA, monitor patients closely, and promptly evaluate any signs or symptoms of blood loss in these patients [see Dosage and Administration (2.3) , Warnings and Precautions (5.1) , Adverse Reactions (6.1) , Use in Specific Populations (8.6) , Clinical Pharmacology (12.3) ] . 5.4 Use in Patients on Concomitant P-gp Inhibitors Patients on concomitant P-gp inhibitors with BEVYXXA may have an increased risk of bleeding. Reduce dose of BEVYXXA in patients receiving or starting P-gp inhibitors. Monitor patients closely, and promptly evaluate any signs or symptoms of blood loss in these patients [see Dosage and Administration (2.2) , Warnings and Precautions (5.1) , Adverse Reactions (6.1) , Drug Interactions (7.1) , Clinical Pharmacology (12.3) ] . Avoid use of BEVYXXA in patients with severe renal impairment receiving concomitant P-gp inhibitors [see Warnings and Precautions (5.3) ]. 5.5 Increased Risk of Thrombosis in Patients with Triple Positive Antiphospholipid Syndrome Direct-acting oral anticoagulants (DOACs), including BEVYXXA, are not recommended for use in patients with triple-positive antiphospholipid syndrome (APS). For patients with APS (especially those who are triple positive [positive for lupus anticoagulant, anticardiolipin, and anti–beta 2- glycoprotein I antibodies]), treatment with DOACs has been associated with increased rates of recurrent thrombotic events compared with vitamin K antagonist therapy.
6 ADVERSE REACTIONS The following clinically significant adverse reactions are described elsewhere in the labeling: Risk of Bleeding [see Warnings and Precautions (5.1 , 5.3 , 5.4) ]. Spinal/Epidural Anesthesia or Puncture [see Boxed Warning and Warnings and Precautions (5.2) ]. Increased Risk of Thrombosis in Patients with Triple Positive Antiphospholipid Syndrome [see Warnings and Precautions (5.5) ]. Most common adverse reaction (incidence > 5%) is bleeding. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Portola Pharmaceuticals at 1-866-777-5947 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 practice. The safety of BEVYXXA was evaluated in the Acute Medically Ill Prevention with Extended Duration Betrixaban (APEX) Study [see Clinical Studies (14) ] , including 3,716 patients treated with BEVYXXA for a median of 36 days compared to 3,716 patients treated with enoxaparin for a median of 9 days. Patients in both treatment groups were followed for safety, including bleeding events, for up to 77 days. Patients randomized to the BEVYXXA arm received BEVYXXA 160 mg orally on Day 1, then 80 mg once daily for 35 to 42 days AND enoxaparin subcutaneous placebo once daily for 6 to 14 days. Patients randomized to the enoxaparin arm received enoxaparin 40 mg subcutaneously once daily for 6 to 14 days AND BEVYXXA placebo orally once daily for 35 to 42 days. Patients with severe renal impairment (creatinine clearance ≥ 15 and < 30 mL/min) received reduced doses of study medications (BEVYXXA 80 mg loading dose, then 40 mg once daily or enoxaparin 20 mg once daily) along with corresponding placebo. Patients taking a concomitant P-gp inhibitor received BEVYXXA 80 mg loading dose, then 40 mg once daily or enoxaparin 40 mg subcutaneously once daily for 6 to 14 days along with corresponding placebo. Hemorrhage The most common adverse reactions with BEVYXXA were related to bleeding (> 5%), with major bleeding occurring in less than 1% of patients (see Table 1 ). Overall, 54% of patients receiving BEVYXXA experienced at least one adverse reaction versus 52% with enoxaparin. The frequency of patients reporting serious adverse reactions was similar between BEVYXXA (18%) and enoxaparin (17%). In the APEX trial, the most frequent reason for treatment discontinuation was bleeding, with an incidence rate of 2.4% for BEVYXXA versus 1.2% for enoxaparin. The primary and secondary safety outcomes in APEX were bleeding-related events. A summary of major and clinically relevant non-major (CRNM) bleeding events in the overall safety population is shown in Table 1. Most CRNM events (86%) were mild to moderate in severity, and the majority (62%) did not require medical intervention. The incidence of fatal bleeding was the same in the BEVYXXA and enoxaparin treatment groups (1 in each group). Table 1: Bleeding Events in APEX through 7 Days after Discontinuation of All Study Drugs (Safety Population) Parameter BEVYXXA (N=3,716) Enoxaparin (N=3,716) BEVYXXA vs. Enoxaparin RR (95% CI) Major Bleeding Major bleeding event was defined as clinically overt bleeding that met one of the following ISTH criteria: a reduction in hemoglobin of at least 2 g/dL within 48 hours of an overt bleeding event; a transfusion of at least two units of whole blood or packed red blood cells; a critical area (e.g., intraocular, intracranial, intraspinal, intramuscular with compartment syndrome, retroperitoneal, intra-articular, or pericardial); or a fatal outcome. Retinal hemorrhages secondary to diabetic retinopathy or conjunctival bleeds did not qualify as major bleeds. 25 (0.67) 21 (0.57) 1.19 (0.67, 2.12) p = 0.554 Gastrointestinal (GI) 19 (0.51) 9 (0.24) Intracranial Hemorrhage 2 (0.05) 7 (0.19) Intraocular 0 (0) 1 (0.03) Fatal Bleeding 1 (0.03) 1 (0.03) CRNM CRNM bleeding was defined as overt bleeding not meeting the criteria for major bleeding but associated with medical intervention, unscheduled contact (visit or telephone call) with a physician, (temporary/permanent) cessation of the study treatment, or associated with discomfort for the patient such as pain or impairment of activities of daily life. 91 (2.45) 38 (1.02) 2.39 (1.64, 3.49) p < 0.001 A summary of major and CRNM bleeding events by dose is shown in Table 2 and Table 3. Table 2: Summary of Adjudicated Major, CRNM, Major or CRNM Bleeding Events through 7 Days after Discontinuation for Patients Receiving 80 mg Parameter BEVYXXA 80 mg (N=2,986) n (%) Enoxaparin 40 mg (N=2,991) n (%) Major 15 (0.50) 16 (0.53) RR (95% CI) 0.94 (0.47, 1.90) CRNM 66 (2.21) 33 (1.10) RR (95% CI) 2.00 (1.32, 3.03) Major or CRNM 81 (2.71) 49 (1.64) RR (95% CI) 1.66 (1.17, 2.35) Table 3: Summary of Adjudicated Major, CRNM, Major or CRNM Bleeding Events through 7 Days after Discontinuation for Patients Receiving 40 mg Severe Renal Impairment Concomitant Use of P-gp Inhibitor Parameter BEVYXXA 40 mg (N=150) n (%) Enoxaparin 20 mg (N=125) n (%) BEVYXXA 40 mg (N=542) n (%) Enoxaparin 40 mg (N=527) n (%) Major 3 (2.00) 1 (0.80) 6 (1.11) 4 (0.76) RR (95% CI) 2.5 (0.26, 23.74) 1.46 (0.41, 5.14) CRNM 6 (4.00) 2 (1.60) 20 (3.69) 3 (0.57) RR (95% CI) 2.5 (0.51, 12.17) 6.5 (1.94, 21.68) Major or CRNM 9 (6.00) 3 (2.40) 26 (4.80) 7 (1.33) RR (95% CI) 2.5 (0.69, 9.04) 3.6 (1.58, 8.25) The most common adverse reactions occurring in ≥ 2% of patients are shown in Table 4. Table 4: Adverse Reactions in APEX Occurring in ≥ 2% of Patients Adverse Reaction BEVYXXA N=3,716 n (%) Enoxaparin N=3,716 n (%) Bleeding-related (all sources) Epistaxis 58 (2) 24 (1) Hematuria 62 (2) 28 (1) Non-bleeding Adverse Reaction Urinary Tract Infection 123 (3) 87 (2) Constipation 110 (3) 102 (3) Hypokalemia 93 (3) 84 (2) Hypertension 89 (2) 80 (2) Headache 74 (2) 59 (2) Nausea 67 (2) 56 (2) Diarrhea 64 (2) 61 (2) Other Adverse Reactions Hypersensitivity Reactions One patient experienced a serious adverse reaction of moderate hypersensitivity.
adverse reactions table
<table ID="table1" width="75%"><caption>Table 1: Bleeding Events in APEX through 7 Days after Discontinuation of All Study Drugs (Safety Population)</caption><col width="25%" align="left" valign="top"/><col width="25%" align="center" valign="middle"/><col width="25%" align="center" valign="middle"/><col width="25%" align="center" valign="middle"/><thead><tr><th styleCode="Lrule Rrule" valign="bottom" align="center">Parameter</th><th styleCode="Rrule" valign="bottom">BEVYXXA (N=3,716)</th><th styleCode="Rrule" valign="bottom">Enoxaparin (N=3,716)</th><th styleCode="Rrule" valign="bottom">BEVYXXA vs. Enoxaparin RR (95% CI)</th></tr></thead><tbody><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="middle"><content styleCode="Bold">Major Bleeding <footnote ID="t1f1">Major bleeding event was defined as clinically overt bleeding that met one of the following ISTH criteria: a reduction in hemoglobin of at least 2 g/dL within 48 hours of an overt bleeding event; a transfusion of at least two units of whole blood or packed red blood cells; a critical area (e.g., intraocular, intracranial, intraspinal, intramuscular with compartment syndrome, retroperitoneal, intra-articular, or pericardial); or a fatal outcome. Retinal hemorrhages secondary to diabetic retinopathy or conjunctival bleeds did not qualify as major bleeds.</footnote></content></td><td styleCode="Rrule">25 (0.67)</td><td styleCode="Rrule">21 (0.57) </td><td styleCode="Rrule">1.19 (0.67, 2.12) p = 0.554</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Gastrointestinal (GI)</td><td styleCode="Rrule">19 (0.51)</td><td styleCode="Rrule">9 (0.24)</td><td styleCode="Rrule"/></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Intracranial Hemorrhage</td><td styleCode="Rrule">2 (0.05)</td><td styleCode="Rrule">7 (0.19)</td><td styleCode="Rrule"/></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Intraocular</td><td styleCode="Rrule">0 (0)</td><td styleCode="Rrule">1 (0.03)</td><td styleCode="Rrule"/></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Fatal Bleeding</td><td styleCode="Rrule">1 (0.03)</td><td styleCode="Rrule">1 (0.03)</td><td styleCode="Rrule"/></tr><tr styleCode="Botrule"><td valign="middle" styleCode="Lrule Rrule"><content styleCode="Bold">CRNM <footnote ID="t1f2">CRNM bleeding was defined as overt bleeding not meeting the criteria for major bleeding but associated with medical intervention, unscheduled contact (visit or telephone call) with a physician, (temporary/permanent) cessation of the study treatment, or associated with discomfort for the patient such as pain or impairment of activities of daily life.</footnote></content></td><td styleCode="Rrule">91 (2.45)</td><td styleCode="Rrule">38 (1.02)</td><td styleCode="Rrule">2.39 (1.64, 3.49) p < 0.001</td></tr></tbody></table>