HIGHLIGHTS OF PRESCRIBING INFORMATION
`
`HIGHLIGHTS OF PRESCRIBING INFORMATION
` These highlights do not include all the information needed to use
`
`
`These highlights do not include all the information needed to use
` BEVYXXA safely and effectively. See full prescribing information for
`
`
`
`
`BEVYXXA safely and effectively. See full prescribing information for
` BEVYXXA.
`
`BEVYXXA.
`
`BEVYXXA ™ (betrixaban) capsules, for oral use
`
`
`
`
`BEVYXXA TM (betrixaban) capsules, for oral use
`Initial U.S. Approval: 2017
`
`
`Initial U.S. Approval: 2017
`
`
` WARNING: SPINAL/EPIDURAL HEMATOMA
`
`
`WARNING: SPINAL/EPIDURAL HEMATOMA
` See full prescribing information for complete boxed warning.
`
`
`
`See full prescribing information for complete boxed warning.
` Epidural or spinal hematomas may occur in patients treated
`
`
`Epidural or spinal hematomas may occur in patients treated
` with betrixaban who are receiving neuraxial anesthesia or undergoing
`
`
`
`
`with betrixaban who are receiving neuraxial anesthesia or undergoing
` spinal puncture. The risk of these events may be increased by the use
`
`
`
`spinal puncture. The risk of these events may be increased by the use
`
` of in-dwelling epidural catheters or the concomitant use of medical
`
`
`
`of in-dwelling epidural catheters or the concomitant use of medical
` products affecting hemostasis. These hematomas may result in long-term
`
`
`products affecting hemostasis. These hematomas may result in long-term
` or permanent paralysis. Consider these risks when scheduling patients
`
`or permanent paralysis. Consider these risks when scheduling patients
`
` for spinal procedures. (5.2)
`
`for spinal procedures. (5.2)
` __________________
` _________________
`INDICATIONS AND USAGE
` INDICATIONS AND USAGE
`BEVYXXA is a factor Xa (FXa) inhibitor indicated for the prophylaxis of
`
`
`
`BEVYXXA is a factor Xa (FXa) inhibitor indicated for the prophylaxis of
`venous thromboembolism (VTE) in adult patients hospitalized for an acute
`
`
`
`venous thromboembolism (VTE) in adult patients hospitalized for an acute
`medical illness who are at risk for thromboembolic complications due to
`
`
`
`
`
`
`
`medical illness who are at risk for thromboembolic complications due to
`moderate or severe restricted mobility and other risk factors for VTE. (1)
`
`
`
`moderate or severe restricted mobility and other risk factors for VTE. (1)
`
`Limitations of Use:
`
`
`
`Limitations of Use:
`Safety and efficacy of BEVYXXA have not been established in patients with
`
`
`
`
`Safety and efficacy of BEVYXXA have not been established in patients with
`prosthetic heart valves because this population has not been studied. (1)
`
`
`
`
`
`
`
`prosthetic heart valves because this population has not been studied. (1)
`
`_______________DOSAGE AND ADMINISTRATION
`
`
` ______________
` DOSAGE AND ADMINISTRATION
`The recommended dose of BEVYXXA is an initial single dose of 160 mg,
`
`
`
`
`
`
`The recommended dose of BEVYXXA is an initial single dose of 160 mg,
`followed by 80 mg once daily, taken at the same time each day with food.
`
`
`
`
`followed by 80 mg once daily, taken at the same time each day with food.
`The recommended duration of treatment is 35 to 42 days. (2.1)
`
`
`
`
`
`
`The recommended duration of treatment is 35 to 42 days. (2.1)
`Reduce dose for patients with severe renal impairment. (2.2)
`•
`
`
`
`Reduce dose for patients with severe renal impairment. (2.2)
`•
`Reduce dose for patients on P-glycoprotein (P-gp) inhibitors. (2.3)
`•
`
`
`
`Reduce dose for patients on P-glycoprotein (P-gp) inhibitors. (2.3)
`•
`
`
`
`FULL PRESCRIBING INFORMATION: CONTENTS *
`
`FULL PRESCRIBING INFORMATION: CONTENTS *
`
`WARNING: SPINAL/EPIDURAL HEMATOMA
`
`WARNING: SPINAL/EPIDURAL HEMATOMA
`1
`INDICATIONS AND USAGE
`
`
`1
`INDICATIONS AND USAGE
`2
`DOSAGE AND ADMINISTRATION
`
`
`2
`DOSAGE AND ADMINISTRATION
`
`2.1 Recommended Dose
`
`2.1 Recommended Dose
`
`
`2.2
`Severe Renal Impairment
`
`Severe Renal Impairment
`2.2
`
`
`2.3 Use with P-gp Inhibitors
`
`
`2.3 Use with P-gp Inhibitors
`2.4 Missed Dose
`
`
`2.4 Missed Dose
`DOSAGE FORMS AND STRENGTHS
`3
`
`
`DOSAGE FORMS AND STRENGTHS
`3
`CONTRAINDICATIONS
`4
`
`
`4
`CONTRAINDICATIONS
`5 WARNINGS AND PRECAUTIONS
`
`
`5 WARNINGS AND PRECAUTIONS
`5.1 Risk of Bleeding
`
`
`5.1 Risk of Bleeding
`5.2
`Spinal/Epidural Anesthesia or Puncture
`
`
`5.2
`Spinal/Epidural Anesthesia or Puncture
`5.3 Use in Patients with Severe Renal Impairment
`
`
`
`5.3 Use in Patients with Severe Renal Impairment
`5.4 Use in Patients on Concomitant P-gp Inhibitors
`
`
`
`5.4 Use in Patients on Concomitant P-gp Inhibitors
`ADVERSE REACTIONS
`
`ADVERSE REACTIONS
`6.1 Clinical Trials Experience
`
`
`6.1 Clinical Trials Experience
`DRUG INTERACTIONS
`
`DRUG INTERACTIONS
`7.1
`Inhibitors of P-gp
`
`
`7.1
`Inhibitors of P-gp
`7.2 Anticoagulants, Antiplatelets, and Thrombolytics
`
`
`
`7.2 Anticoagulants, Antiplatelets, and Thrombolytics
`
`7
`
`7
`
`6
`
`6
`
`
`
`
`•
`•
`
`
`•
`•
`
` _____________
` ______________
`DOSAGE FORMS AND STRENGTHS
`
`DOSAGE FORMS AND STRENGTHS
`Capsules: 40 mg and 80 mg (3)
`
`
`
`
`Capsules: 40 mg and 80 mg (3)
`___________________ CONTRAINDICATIONS ___________________
`
`
`
`
`
`CONTRAINDICATIONS
`
`
`
`Active pathological bleeding. (4)
`•
`• Active pathological bleeding. (4)
`
`
`
`
`Severe hypersensitivity reaction to betrixaban BEVYXXA. (4)
`•
`Severe hypersensitivity reaction to betrixaban BEVYXXA. (4)
`•
`
`
`
`
`_______________WARNINGS AND PRECAUTIONS _______________
`WARNINGS AND PRECAUTIONS
`
`
`
`
`
`Risk of Bleeding: Can cause serious, potentially fatal bleeding.
`•
`Risk of Bleeding: Can cause serious, potentially fatal bleeding.
`•
`Promptly evaluate signs and symptoms of blood loss. (5.1)
`
`Promptly evaluate signs and symptoms of blood loss. (5.1)
`
`
`
`Severe Renal Impairment: Increased risk of bleeding events; reduce
`Severe Renal Impairment: Increased risk of bleeding events; reduce
`
`BEVYXXA dose (2.2, 5.3)
`BEVYXXA dose (2.2, 5.3)
`
`Concomitant P-gp Inhibitors: Increased risk of bleeding events; reduce
`Concomitant P-gp Inhibitors: Increased risk of bleeding events; reduce
`BEVYXXA dose (2.3, 5.4)
`
`BEVYXXA dose (2.3, 5.4)
`
`___________________ ADVERSE REACTIONS ___________________
`
`
`
`
`ADVERSE REACTIONS
`Most common adverse reaction (incidence >5%) is bleeding. (6.1)
`
`
`
`
`
`Most common adverse reaction (incidence >5%) is bleeding. (6.1)
`
`To report SUSPECTED ADVERSE REACTIONS, contact Portola
`
`To report SUSPECTED ADVERSE REACTIONS, contact Portola
`Pharmaceuticals at 1-855-767-7167 or FDA at 1-800-FDA-1088 or
`
`
`
`Pharmaceuticals at 1-855-767-7167 or FDA at 1-800-FDA-1088 or
`www.fda.gov/medwatch.
`
`www.fdagov/medwatch.
`
`___________________ DRUG INTERACTIONS____________________
`
`
`DRUG INTERACTIONS
`P-gp inhibitors increase the blood levels of betrixaban. Reduce
`•
`
`
`
`
`•
`P-gp inhibitors increase the blood levels of betrixaban. Reduce
`BEVYXXA dose. (7.1)
`
`
`
`BEVYXXA dose. (7.1)
`Anticoagulants: Avoid concomitant use. (7.2)
`•
`
`
`
`• Anticoagulants: Avoid concomitant use. (7.2)
` ______________
` _______________
`USE IN SPECIFIC POPULATIONS
`USE IN SPECIFIC POPULATIONS
`Pregnancy: Use only if potential benefit outweighs the potential risk to
`•
`
`
`
`•
`Pregnancy: Use only if potential benefit outweighs the potential risk to
`the mother or fetus (8.1)
`
`the mother or fetus (8.1)
`
`
`
`Renal Impairment: Reduce dose. (8.6)
`•
`Renal Impairment: Reduce dose. (8.6)
`•
`
`
`
`Hepatic impairment: Avoid use (8.7)
`•
`• Hepatic impairment: Avoid use (8.7)
`
`
`
`See 17 for PATIENT COUNSELING INFORMATION and Medication
`See 17 for PATIENT COUNSELING INFORMATION and Medication
`Guide.
`
`Guide.
`
`
`Revised: 6/2017
`Revised: 6/2017
`
`8
`
`8
`
`USE IN SPECIFIC POPULATIONS
`
`USE IN SPECIFIC POPULATIONS
`8.1
`Pregnancy
`
`
`8.1
`Pregnancy
`
`8.2 Lactation
`
`8.2 Lactation
`8.4
`Pediatric Use
`
`
`8.4
`Pediatric Use
`8.5 Geriatric Use
`
`
`8.5 Geriatric Use
`8.6 Renal Impairment
`
`
`8.6 Renal Impairment
`8.7 Hepatic Impairment
`
`
`8.7 Hepatic Impairment
`10 OVERDOSAGE
`
`
`10 OVERDOSAGE
`11 DESCRIPTION
`
`
`11 DESCRIPTION
`12 CLINICAL PHARMACOLOGY
`
`
`12 CLINICAL PHARMACOLOGY
`12.1 Mechanism of Action
`
`
`12.1 Mechanism of Action
`12.2 Pharmacodynamics
`
`
`12.2 Pharmacodynamics
`12.3 Pharmacokinetics
`
`
`12.3 Pharmacokinetics
`13 NONCLINICAL TOXICOLOGY
`
`
`13 NONCLINICAL TOXICOLOGY
`13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
`
`
`
`13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
`14 CLINICAL STUDIES
`
`
`14 CLINICAL STUDIES
`16 HOW SUPPLIED/STORAGE AND HANDLING
`
`
`
`16 HOW SUPPLIED/STORAGE AND HANDLING
`17
`PATIENT COUNSELING INFORMATION
`
`
`17
`PATIENT COUNSELING INFORMATION
`* Sections or subsections omitted from the full prescribing information are
`
`
`
`• Sections or subsections omitted from the full prescribing information are
`not listed.
`
`not listed.
`
`
`
`Reference ID: 4115694 Reference ID: 4115694
`
`
` 1
`1
`
`0001
`
`0001
`
`MYLAN - EXHIBIT 1064
`
`

`

` FULL PRESCRIBING INFORMATION
`
`
`FULL PRESCRIBING INFORMATION
`
`
` WARNING: SPINAL/EPIDURAL HEMATOMA
`
`
`WARNING: SPINAL/EPIDURAL HEMATOMA
` Epidural or spinal hematomas may occur in patients treated with betrixaban who are
`
`
`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
`
`
`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
`
`
`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
`
`
`
`products affecting hemostasis. These hematomas may result in long-term or permanent
` paralysis. Consider these risks when scheduling patients for spinal procedures [see
`
`paralysis. Consider these risks when scheduling patients for spinal procedures [see
`Warnings and Precautions (5.2)].
`
`Warnings and Precautions (5.2)1
`
`
`INDICATIONS AND USAGE
`1
`
`
`INDICATIONS AND USAGE
`1
`BEVYXXA is indicated for the prophylaxis of venous thromboembolism (VTE) in adult patients
`
`
`
`
`BEVYXXA is indicated for the prophylaxis of venous thromboembolism (VTE) in adult patients
`hospitalized for an acute medical illness who are at risk for thromboembolic complications due
`
`
`
`hospitalized for an acute medical illness who are at risk for thromboembolic complications due
`to moderate or severe restricted mobility and other risk factors for VTE [see Clinical Studies
`
`
`
`
`
`to moderate or severe restricted mobility and other risk factors for VTE [see Clinical Studies
`(14)].
`
`(14)]
`
`Limitations of Use:
`
`
`Limitations of Use:
`
`
`
`
`
`
`The safety and effectiveness of BEVYXXA have not been established in patients with prosthetic
`The safety and effectiveness of BEVYXXA have not been established in patients with prosthetic
`
`heart valves because this population has not been studied.
`heart valves because this population has not been studied.
`
`
`2
`2
`
`
`DOSAGE AND ADMINISTRATION
`DOSAGE AND ADMINISTRATION
`
`
`
`Recommended Dose
`2.1
`2.1
`Recommended Dose
`
`
`
`
`
`
`The recommended dose of BEVYXXA is an initial single dose of 160 mg, followed by 80 mg
`The recommended dose of BEVYXXA is an initial single dose of 160 mg, followed by 80 mg
`
`
`
`
`
`once daily. Daily oral doses should be given at the same time of day with food.
`once daily. Daily oral doses should be given at the same time of day with food.
`
`
`
`The recommended duration of treatment is 35 to 42 days.
`The recommended duration of treatment is 35 to 42 days.
`
`
`
`Severe Renal Impairment
`2.2
`Severe Renal Impairment
`2.2
`For patients with severe renal impairment (CrCl ≥ 15 to < 30 mL/min computed by Cockcroft-
`For patients with severe renal impairment (CrCl> 15 to < 30 mL/min computed by Cockcroft-
`
`
`
`
`
`Gault using actual body weight) the recommended dose of BEVYXXA is an initial single dose
`Gault using actual body weight) the recommended dose of BEVYXXA is an initial single dose
`
`
`
`of 80 mg followed by 40 mg once daily [see Warnings and Precautions (5.3), Use in Specific
`
`of 80 mg followed by 40 mg once daily [see Warnings and Precautions (5.3), Use in Specific
`
`Populations (8.6), Clinical Pharmacology (12.3]. The recommended duration of treatment is 35
`
`Populations (8.6), Clinical Pharmacology (12.31. The recommended duration of treatment is 35
`
`to 42 days.
`to 42 days.
`
`
`
`Reference ID: 4115694 Reference ID: 4115694
`
`
` 2
`2
`
`0002
`
`0002
`
`

`

` Use with P-gp Inhibitors
`
`
` 2.3
`Use with P-gp Inhibitors
`2.3
`
` For patients receiving or starting concomitant P-gp inhibitors the recommended dose of
`
`
`For patients receiving or starting concomitant P-gp inhibitors the recommended dose of
` BEVYXXA is an initial single dose of 80 mg followed by 40 mg once daily [see Warnings and
`
`
`
`
`BEVYXXA is an initial single dose of 80 mg followed by 40 mg once daily [see Warnings and
` Precautions (5.4), Drug Interactions (7.1), Clinical Pharmacology (12.3)]. The recommended
`
`
`Precautions (5.4), Drug Interactions (7.1), Clinical Pharmacology (12.3)1 The recommended
` duration of treatment is 35 to 42 days.
`
`duration of treatment is 35 to 42 days.
`
`Missed Dose
`2.4
`
`
`2.4
`Missed Dose
`
` If a dose of BEVYXXA is not taken at the scheduled time, the dose should be taken as soon as
`
`
`If a dose of BEVYXXA is not taken at the scheduled time, the dose should be taken as soon as
` possible on the same day. The BEVYXXA dose should not be doubled to make up for a missed
`
`
`possible on the same day. The BEVYXXA dose should not be doubled to make up for a missed
`
` dose.
`dose.
`
`DOSAGE FORMS AND STRENGTHS
`3
`
`
`DOSAGE FORMS AND STRENGTHS
`3
`40 mg and 80 mg capsules
`
`
`
`
`
`40 mg and 80 mg capsules
`• 80 mg, size 2 hard gelatin capsules are light grey with 80 printed in black, and have a
`
`
`
`
`
`• 80 mg, size 2 hard gelatin capsules are light grey with 80 printed in black, and have a
`blue cap with PTLA printed in white.
`
`blue cap with PTLA printed in white.
`• 40 mg, size 4 hard gelatin capsules are light grey with 40 printed in black, and have a
`
`
`
`
`
`• 40 mg, size 4 hard gelatin capsules are light grey with 40 printed in black, and have a
`light blue cap with PTLA printed in white.
`
`
`light blue cap with PTLA printed in white.
`
`CONTRAINDICATIONS
`4
`
`
`CONTRAINDICATIONS
`4
`BEVYXXA is contraindicated in patients with:
`
`
`BEVYXXA is contraindicated in patients with:
`• Active pathological bleeding [see Warnings and Precautions (5.1) and Adverse
`
`
`
`
`• Active pathological bleeding [see Warnings and Precautions (5.1) and Adverse
`Reactions (6.1)]
`
`
`Reactions (6.1)]
`• Severe hypersensitivity reaction to betrixaban [see Adverse Reactions (6.1)].
`
`
`
`
`
`
`• Severe hypersensitivity reaction to betrixaban [see Adverse Reactions (6.1)1.
`
`5
`
`5
`
`WARNINGS AND PRECAUTIONS
`
`WARNINGS AND PRECAUTIONS
`
`Risk of Bleeding
`5.1
`
`
`Risk of Bleeding
`5.1
`BEVYXXA increases the risk of bleeding and can cause serious and potentially fatal 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)].
`
`
`
`
`Promptly evaluate any signs or symptoms of blood loss [see Adverse Reactions (6.1)1.
`
`Concomitant use of drugs affecting hemostasis increases the risk of bleeding. These include
`
`Concomitant use of drugs affecting hemostasis increases the risk of bleeding. These include
`aspirin and other antiplatelet agents, other anticoagulants, heparin, thrombolytic agents, selective
`
`
`aspirin and other antiplatelet agents, other anticoagulants, heparin, thrombolytic agents, selective
`serotonin reuptake inhibitors, serotonin norepinephrine reuptake inhibitors, and nonsteroidal
`
`serotonin reuptake inhibitors, serotonin norepinephrine reuptake inhibitors, and nonsteroidal
`anti-inflammatory drugs (NSAIDs) [see Drug Interactions (7.2)].
`
`
`
`anti-inflammatory drugs (NSAIDs) [see Drug Interactions (7.2)1.
`
`Advise patients of signs and symptoms of blood loss and to report them immediately and seek
`
`
`
`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
`
`
`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.
`
`
`
`for blood replacement. Discontinue BEVYXXA in patients with active pathological bleeding.
`
`
`
`Reference ID: 4115694 Reference ID: 4115694
`
`
` 3
`3
`
`0003
`
`0003
`
`

`

` There is no established way to reverse the anticoagulant effect of BEVYXXA, which can be
`
`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
`
`
`
`
`
`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
`
`
`removes BEVYXXA. Protamine sulfate, vitamin K, and tranexamic acid are not expected to
` reverse the anticoagulant activity of BEVYXXA.
`
`
`reverse the anticoagulant activity of BEVYXXA.
`
`Spinal/Epidural Anesthesia or Puncture
`5.2
`
`
`
`5.2
`Spinal/Epidural Anesthesia or Puncture
`When neuraxial anesthesia (spinal/epidural anesthesia) or spinal/epidural puncture is employed,
`When neuraxial anesthesia (spinal/epidural anesthesia) or spinal/epidural puncture is employed,
`patients treated with antithrombotic agents for prevention of thromboembolic complications are
`
`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
`
`at risk of developing an epidural or spinal hematoma which can result in long-term or permanent
`paralysis.
`
`paralysis.
`
`Do not remove an epidural catheter earlier than 72 hours after the last administration of
`
`
`
`
`
`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
`
`
`
`
`
`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 TRADENAME for
`
`
`
`
`of the catheter. If traumatic puncture occurs, delay the administration of TRADENAME for
`72 hours.
`
`
`72 hours.
`
`Monitor patients frequently for signs and symptoms of neurological impairment (e.g., numbness
`
`
`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,
`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
`
`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
`
`
`potential benefit versus the risk in anticoagulated patients or in patients to be anticoagulated for
`thromboprophylaxis.
`
`thromboprophylaxis.
`
`Use in Patients with Severe Renal Impairment
`5.3
`
`
`Use in Patients with Severe Renal Impairment
`5.3
`Patients with severe renal impairment (CrCl ≥ 15 to < 30 mL/min computed by Cockcroft-Gault
`
`
`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.
`
`
`
`
`
`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
`
`
`
`
`Reduce dose of BEVYXXA, monitor patients closely, and promptly evaluate any signs or
`symptoms of blood loss in these patients [see Dosage and Administration (2.2), Warnings and
`
`
`
`
`symptoms of blood loss in these patients [see Dosage and Administration (2.2), Warnings and
` Precautions (5.1), Adverse Reactions (6.1), Use in Specific Populations (8.6), Clinical
`
`
`Precautions (5.1), Adverse Reactions (6.1), Use in Specific Populations (8.6), Clinical
` Pharmacology (12.3)].
`
`Pharmacology (12.3)1 .
`
`Use in Patients on Concomitant P-gp Inhibitors
`5.4
`
`
`
`
`Use in Patients on Concomitant P-gp Inhibitors
`5.4
`Patients on concomitant P-gp inhibitors with BEVYXXA may have an increased risk of
`
`
`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
`
`
`
`
`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
`
`
`
`
`
`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),
`
`
`
`
`Dosage and Administration (2.3), Warnings and Precautions (5.1), Adverse Reactions (6.1),
`Drug Interactions (7.1), Clinical Pharmacology (12.3)].
`
`
`Drug Interactions (7.1), Clinical Pharmacology (12.3)1 .
`
`Avoid use of BEVYXXA in patients with severe renal impairment receiving concomitant P-gp
`
`
`
`
`Avoid use of BEVYXXA in patients with severe renal impairment receiving concomitant P-gp
`inhibitors [see Warnings and Precautions (5.3)].
`
`
`
`inhibitors [see Warnings and Precautions (5.3)1.
`
`
`
`Reference ID: 4115694 Reference ID: 4115694
`
`
` 4
`4
`
`0004
`
`0004
`
`

`

` ADVERSE REACTIONS
`
`
` 6
`ADVERSE REACTIONS
`6
` The following serious adverse reactions are described elsewhere in the labeling:
`
`
`
`The following serious adverse reactions are described elsewhere in the labeling:
` • Risk of Bleeding [see Warnings and Precautions (5.1, 5.3, 5.4)].
`
`
`
`
`
`
`• Risk of Bleeding [see Warnings and Precautions (5.1, 5.3, 5.4)].
` • Spinal/Epidural Anesthesia or Puncture [see Boxed Warning and Warnings and
`
`
`
`• Spinal/Epidural Anesthesia or Puncture [see Boxed Warning and Warnings and
`Precautions (5.2)].
`
`Precautions (5.2)].
`
`
`
`Clinical Trials Experience
`6.1
`Clinical Trials Experience
`6.1
`
`
`Because clinical trials are conducted under widely varying conditions, adverse reaction rates
`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
`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.
`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
`
`
`
`
`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
`
`
`
`
`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
`
`
`
`
`
`
`
`
`
`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
`
`
`
`
`
`a median of 9 days. Patients in both treatment groups were followed for safety, including
`bleeding events, for up to 77 days.
`
`
`
`bleeding events, for up to 77 days.
`
`Patients randomized to the BEVYXXA arm received BEVYXXA 160 mg orally on Day 1, then
`
`
`
`
`
`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
`
`
`
`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
`
`
`
`
`
`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.
`
`
`
`
`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
`
`
`
`
`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
`
`
`
`
`
`
`
`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.
`
`
`
`
`
`enoxaparin 20 mg once daily) along with corresponding placebo.
`
`Patients taking a concomitant P-gp inhibitor received BEVYXXA 80 mg loading dose, then
`
`
`
`
`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
`
`
`
`40 mg once daily or enoxaparin 40 mg subcutaneously once daily for 6 to 14 days along with
`corresponding placebo.
`
`corresponding placebo.
`
`Hemorrhage
`
`Hemorrhage
`The most common adverse reactions with BEVYXXA were related to bleeding (> 5%) with
`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).
`
`
`
`major bleeding occurring in less than 1% of patients (see Table 1).
`
`Overall, 54% of patients receiving BEVYXXA experienced at least one adverse reaction vs. 52%
`
`
`
`
`
`Overall, 54% of patients receiving BEVYXXA experienced at least one adverse reaction vs. 52%
`with enoxaparin. The frequency of patients reporting serious adverse reactions was similar
`
`
`
`
`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
`
`
`
`
`
`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 vs.
`
`
`
`
`for treatment discontinuation was bleeding, with an incidence rate of 2.4% for BEVYXXA vs.
`1.2% for enoxaparin.
`
`1.2% for enoxaparin.
`
`The primary and secondary safety outcomes in APEX were bleeding-related events.
`The primary and secondary safety outcomes in APEX were bleeding-related events.
`
`
`
`
`
`Reference ID: 4115694 Reference ID: 4115694
`
`
` 5
`5
`
`0005
`
`0005
`
`

`

` A summary of major and clinically relevant non-major (CRNM) bleeding events in the overall
`
`
`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
`
`
`
`
`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.
`
`severity, and the majority (62%) did not require medical intervention.
`
`The incidence of fatal bleeding was the same in the BEVYXXA and enoxaparin treatment
`
`
`The incidence of fatal bleeding was the same in the BEVYXXA and enoxaparin treatment
`groups (1 in each group).
`
`
`groups (1 in each group).
`
`Table 1:
`
`
`Table 1:
`
`Bleeding Events in APEX through 7 days after Discontinuation of All Study
`
`Bleeding Events in APEX through 7 days after Discontinuation of All Study
`Drugs (Safety Population)
`
`Drugs (Safety Population)
`
` Parameter
`
`Parameter
`
`Major Bleeding a
`
`
`Major Bleeding a
`
` BEVYXXA
`
`BEVYXXA
` (N=3,716)
`
`(N=3,716)
`
` Enoxaparin
`
`Enoxaparin
` (N=3,716)
`
`(N=3,716)
`
`
`25 (0.67)
`25 (0.67)
`
`19 (0.51)
`
`19 (0.51)
`2 (0.05)
`
`2 (0.05)
`0 (0)
`
`0 (0)
`1 (0.03)
`
`1 (0.03)
`
`91 (2.45)
`
`91 (2.45)
`
`
`21 (0.57)
`21 (0.57)
`
`9 (0.24)
`
`9 (0.24)
`7 (0.19)
`
`7 (0.19)
`1 (0.03)
`
`1 (0.03)
`1 (0.03)
`
`1 (0.03)
`
`38 (1.02)
`
`38 (1.02)
`
`
`
`BEVYXXA vs.
`BEVYXXA vs.
`
`Enoxaparin RR
`Enoxaparin RR
`
`(95% CI)
`(95% CI)
`
`
`1.19 (0.67, 2.12)
`1.19 (0.67, 2.12)
`
`p = 0.554
`p = 0.554
`Gastrointestinal (GI)
`
`
`Gastrointestinal (GI)
`Intracranial Hemorrhage
`
`
`Intracranial Hemorrhage
`Intraocular
`
`
`Intraocular
`Fatal Bleeding
`
`
`Fatal Bleeding
`2.39 (1.64, 3.49)
`
`
`Clinically Relevant
`
`2.39 (1.64, 3.49)
`Clinically Relevant
`Non-Major Bleeding b
`
`Non-Major Bleeding b
`p < 0.001
`
`
`p < 0.001
`
` a Major bleeding event was defined as clinically overt bleeding that met one of the following criteria: a
`
`
`
`a Major bleeding event was defined as clinically overt bleeding that met one of the following criteria: a
` reduction in hemoglobin of a least 2 g/dL within 48 hours of an overt bleeding event; a transfusion of at least
`
`
`reduction in hemoglobin of a 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,
`
`
`
`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, pericardial, or a fatal outcome.
`
`
`intramuscular with compartment syndrome, retroperitoneal, intra-articular, pericardial, or a fatal outcome.
` Retinal hemorrhages secondary to diabetic retinopathy or conjunctival bleeds did not qualify as a major bleeds.
`
`Retinal hemorrhages secondary to diabetic retinopathy or conjunctival bleeds did not qualify as a major bleeds.
`b CRNM bleeding was defined as overt bleeding not meeting the criteria for major bleeding but associated with
`
`
`
`
`
`
`
`
`b 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)
`
`
`
`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
`
`
`
`cessation of the study treatment, or associated with discomfort for the patient such as pain or impairment of
`activities of daily life.
`
`
`activities of daily life.
`
`
` A summary of major and CRNM bleeding events by dose is shown in Table 2 and Table 3.
`
`
`
`
`
`
`
`A summary of major and CRNM bleeding events by dose is shown in Table 2 and Table 3.
`
`Reference ID: 4115694
`Reference ID: 4115694
`
`
` 6
`6
`
`0006
`
`0006
`
`

`

` Summary of Adjudicated Major, CRNM, Major or CRNM Bleeding Events
`
`
`Summary of Adjudicated Major, CRNM, Major or CRNM Bleeding Events
` through 7 Days after Discontinuation for Patients Receiving 80 mg
`
`
`
`
`through 7 Days after Discontinuation for Patients Receiving 80 mg
` TRADENAME
`
`Enoxaparin
`
`TRADENAME
`Enoxaparin
`
` 80 mg
` 40 mg
`
`80 mg
`40 mg
` (N=2,986)
`
` (N=2,991)
`
`(N=2,986)
`(N=2,991)
`
` n (%)
` n (%)
`
`n (%)
`n (%)
`
`
` Parameter
`Parameter
`
`
`
`
`Major
`
`Major
`
`15 (0.50)
`
`15 (0.50)
`
`16 (0.53)
`
`16 (0.53)
`
`RR (95% CI)
`
`RR (95% CI)
`
`0.94 (0.47, 1.90)
`
`
`0.94 (0.47, 1.90)
`
`Clinically Relevant
`
`Clinically Relevant
`Non-Major (CRNM)
`
`Non-Major (CRNM)
`
`66 (2.21)
`
`66 (2.21)
`
`33 (1.10)
`
`33 (1.10)
`
`RR (95% CI)
`
`RR (95% CI)
`
`2.00 (1.32, 3.03)
`
`
`2.00 (1.32, 3.03)
`
`Major or CRNM
`
`
`Major or CRNM
`
`81 (2.71)
`
`81 (2.71)
`
`49 (1.64)
`
`
`49 (1.64)
`
`
`RR (95% CI)
`RR (95% CI)
`
`1.66 (1.17, 2.35)
`
`
`1.66 (1.17, 2.35)
`
` Table 2:
`
`
`Table 2:
`
`
`
` Table 3:
`
`Table 3:
`
` Summary of Adjudicated Major, CRNM, Major or CRNM Bleeding Events
`
`
`Summary of Adjudicated Major, CRNM, Major or CRNM Bleeding Events
` through 7 Days after Discontinuation for Patients Receiving 40 mg
`
`
`through 7 Days after Discontinuation for Patients Receiv