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
`SAVAYSA™ safely and effectively. See full prescribing information for
`SAVAYSA safely and effectively. See full prescribing information for
`SAVAYSA.
`SAVAYSA.
`
`SAVAYSA (edoxaban) tablets for oral use
`SAVAYSA (edoxaban) tablets for oral use
`Initial U.S. Approval: 2015
`Initial U.S. Approval: 2015
`
`
`WARNING (A) REDUCED EFFICACY IN NONVALVULAR
`WARNING (A) REDUCED EFFICACY IN NONVALVULAR
`ATRIAL FIBRILLATION PATIENTS WITH CREATININE
`ATRIAL FIBRILLATION PATIENTS WITH CREATININE
`CLEARANCE (CRCL) > 95 ML/MIN
`CLEARANCE (CRCL) > 95 ML/MIN
`(B) PREMATURE DISCONTINUATION OF SAVAYSA
`(B) PREMATURE DISCONTINUATION OF SAVAYSA
`INCREASES THE RISK OF ISCHEMIC EVENTS
`INCREASES THE RISK OF ISCHEMIC EVENTS
`(C) SPINAL/EPIDURAL HEMATOMA
`(C) SPINAL/EPIDURAL HEMATOMA
`See full prescribing information for complete boxed warning.
`See full prescribing information for complete boxed warning.
`(A) REDUCED EFFICACY IN NONVALVULAR ATRIAL
`(A) REDUCED EFFICACY IN NONVALVULAR ATRIAL
`FIBRILLATION PATIENTS WITH CRCL > 95 ML/MIN:
`FIBRILLATION PATIENTS WITH CRCL > 95 ML/MIN:
`SAVAYSA should not be used in patients with CrCL > 95 mL/min.
`SAVAYSA should not be used in patients with CrCL > 95 mL/min.
`In the ENGAGE AF-TIMI 48 study, nonvalvular atrial fibrillation
`In the ENGAGE AF-TIMI 48 study, nonvalvular atrial fibrillation
`patients with CrCL > 95 mL/min had an increased rate of ischemic
`patients with CrCL > 95 mL/min had an increased rate of ischemic
`stroke with SAVAYSA 60 mg once daily compared to patients treated
`stroke with SAVAYSA 60 mg once daily compared to patients treated
`with warfarin. In these patients another anticoagulant should be used
`with warfarin. In these patients another anticoagulant should be used
`(5.1).
`(5.1).
`(B) PREMATURE DISCONTINUATION OF SAVAYSA
`(B) PREMATURE DISCONTINUATION OF SAVAYSA
`INCREASES THE RISK OF ISCHEMIC EVENTS: Premature
`INCREASES THE RISK OF ISCHEMIC EVENTS: Premature
`discontinuation of any oral anticoagulant in the absence of adequate
`discontinuation of any oral anticoagulant in the absence of adequate
`alternative anticoagulation increases the risk of ischemic events. If
`alternative anticoagulation increases the risk of ischemic events. If
`SAVAYSA is discontinued for a reason other than pathological
`SAVAYSA is discontinued for a reason other than pathological
`bleeding or completion of a course of therapy, consider coverage with
`bleeding or completion of a course of therapy, consider coverage with
`another anticoagulant as described in the transition guidance (2.4, 5.2,
`another anticoagulant as described in the transition guidance (2.4, 5.2,
`14).
`14).
`(C) SPINAL/EPIDURAL HEMATOMA: Epidural or spinal
`(C) SPINAL/EPIDURAL HEMATOMA: Epidural or spinal
`hematomas may occur in patients treated with SAVAYSA who are
`hematomas may occur in patients treated with SAVAYSA who are
`receiving neuraxial anesthesia or undergoing spinal puncture. These
`receiving neuraxial anesthesia or undergoing spinal puncture. These
`hematomas may result in long-term or permanent paralysis. Consider
`hematomas may result in long-term or permanent paralysis. Consider
`these risks when scheduling patients for spinal procedures (5.4).
`these risks when scheduling patients for spinal procedures (5.4).
` __________________ INDICATIONS AND USAGE _________________
` INDICATIONS AND USAGE
`SAVAYSA is a factor Xa inhibitor indicated:
`SAVAYSA is a factor Xa inhibitor indicated:
`To reduce the risk of stroke and systemic embolism (SE) in patients with
`To reduce the risk of stroke and systemic embolism (SE) in patients with
`nonvalvular atrial fibrillation (NVAF) (1.1)
`nonvalvular atrial fibrillation (NVAF) (1.1)
`Limitation of Use for NVAF
`•
`•
`Limitation of Use for NVAF
`SAVAYSA should not be used in patients with creatinine clearance
`SAVAYSA should not be used in patients with creatinine clearance
`(CrCL) > 95 mL/min because of increased risk of ischemic stroke
`(CrCL) > 95 mL/min because of increased risk of ischemic stroke
`compared to warfarin at the highest dose studied (60 mg) (1.1)
`compared to warfarin at the highest dose studied (60 mg) (1.1)
`
`SAVAYSA is indicated for the treatment of deep vein thrombosis (DVT) and
`SAVAYSA is indicated for the treatment of deep vein thrombosis (DVT) and
`pulmonary embolism (PE) following 5-10 days of initial therapy with a
`pulmonary embolism (PE) following 5-10 days of initial therapy with a
`parenteral anticoagulant (1.2)
`parenteral anticoagulant (1.2)
`
`
`
`
`
`
`
`
`FULL PRESCRIBING INFORMATION: CONTENTS*
`FULL PRESCRIBING INFORMATION: CONTENTS*
`WARNING: (A) REDUCED EFFICACY IN NONVALVULAR ATRIAL
`WARNING: (A) REDUCED EFFICACY IN NONVALVULAR ATRIAL
`FIBRILLATION PATIENTS WITH RENAL FUNCTION OF CRCL >
`FIBRILLATION PATIENTS WITH RENAL FUNCTION OF CRCL >
`95 ML/MIN (B) PREMATURE DISCONTINUATION OF SAVAYSA
`95 ML/MIN (B) PREMATURE DISCONTINUATION OF SAVAYSA
`INCREASES THE RISK OF ISCHEMIC EVENTS
`INCREASES THE RISK OF ISCHEMIC EVENTS
`(C) SPINAL/EPIDURAL HEMATOMA
`(C) SPINAL/EPIDURAL HEMATOMA
`1
`INDICATIONS AND USAGE
`1
`INDICATIONS AND USAGE
`1.1 Reduction in the Risk of Stroke and Systemic Embolism in
`1.1 Reduction in the Risk of Stroke and Systemic Embolism in
`Nonvalvular Atrial Fibrillation
`Nonvalvular Atrial Fibrillation
`1.2 Treatment of Deep Vein Thrombosis and Pulmonary Embolism
`1.2 Treatment of Deep Vein Thrombosis and Pulmonary Embolism
`DOSAGE AND ADMINISTRATION
`2
`2 DOSAGE AND ADMINISTRATION
`2.1 Nonvalvular Atrial Fibrillation
`2.1 Nonvalvular Atrial Fibrillation
`2.2 Treatment of Deep Vein Thrombosis and Pulmonary Embolism
`2.2 Treatment of Deep Vein Thrombosis and Pulmonary Embolism
`2.3 Administration Information
`2.3 Administration Information
`2.4 Transition to or from SAVAYSA
`2.4 Transition to or from SAVAYSA
`2.5 Discontinuation for Surgery and Other Interventions
`2.5 Discontinuation for Surgery and Other Interventions
`DOSAGE FORMS AND STRENGTHS
`3
`3 DOSAGE FORMS AND STRENGTHS
`4
`CONTRAINDICATIONS
`4
`CONTRAINDICATIONS
`5 WARNINGS AND PRECAUTIONS
`5 WARNINGS AND PRECAUTIONS
`5.1 Reduced Efficacy in Nonvalvular Atrial Fibrillation Patients with
`5.1 Reduced Efficacy in Nonvalvular Atrial Fibrillation Patients with
`CrCL > 95 mL/min
`CrCL > 95 mlJmin
`
`
`
`
`•
`•
`
` ______________ DOSAGE AND ADMINISTRATION_______________
`
`DOSAGE AND ADMINISTRATION
`Treatment of NVAF:
`•
`•
`Treatment of NVAF:
`
`Assess CrCL before initiating therapy (2.1)
`Assess CrCL before initiating therapy (2.1)
`The recommended dose is 60 mg once daily in patients with CrCL >50
`The recommended dose is 60 mg once daily in patients with CrCL >50
`to ≤ 95 mL/min. Do not use SAVAYSA in patients with CrCL > 95
`to < 95 mlJmin. Do not use SAVAYSA in patients with CrCL > 95
`mL/min (2.1)
`mL/min (2.1)
`Reduce dose to 30 mg once daily in patients with creatinine clearance 15
`Reduce dose to 30 mg once daily in patients with creatinine clearance 15
`to 50 mL/min (2.1)
`to 50 mL/min (2.1)
`
`Treatment of DVT and PE:
`Treatment of DVT and PE:
`The recommended dose is 60 mg once daily (2.2)
`The recommended dose is 60 mg once daily (2.2)
`The recommended dose is 30 mg once daily for patients with CrCL 15 to
`The recommended dose is 30 mg once daily for patients with CrCL 15 to
`50 mL/min or body weight less than or equal to 60 kg or who use certain
`50 mL/min or body weight less than or equal to 60 kg or who use certain
`P-gp inhibitors (2.2)
`P-gp inhibitors (2.2)
` _____________ DOSAGE FORMS AND STRENGTHS ______________
`DOSAGE FORMS AND STRENGTHS
`
`Tablets: 60 mg, 30 mg, and 15 mg (3)
`•
`•
`Tablets: 60 mg, 30 mg, and 15 mg (3)
` ___________________ CONTRAINDICATIONS ___________________
`CONTRAINDICATIONS
`
`Active pathological bleeding (4)
`•
`• Active pathological bleeding (4)
`
` _______________ WARNINGS AND PRECAUTIONS _______________
`WARNINGS AND PRECAUTIONS
`
`Bleeding: Serious and potentially fatal bleeding. Promptly evaluate signs
`•
`Bleeding: Serious and potentially fatal bleeding. Promptly evaluate signs
`•
`and symptoms of blood loss (5.2)
`and symptoms of blood loss (5.2)
`• Mechanical heart valves or moderate to severe mitral stenosis: Use is not
`• Mechanical heart valves or moderate to severe mitral stenosis: Use is not
`recommended (5.5)
`recommended (5.5)
`
` ___________________ ADVERSE REACTIONS ___________________
`ADVERSE REACTIONS
`Treatment of NVAF: The most common adverse reactions (≥ 5%) are
`Treatment of NVAF: The most common adverse reactions (2 5%) are
`bleeding and anemia (6.1)
`bleeding and anemia (6.1)
`Treatment of DVT and PE: The most common adverse reactions (≥ 1%) are
`Treatment of DVT and PE: The most common adverse reactions (2 1%) are
`bleeding, rash, abnormal liver function tests and anemia (6.1)
`bleeding, rash, abnormal liver function tests and anemia (6.1)
`To report SUSPECTED ADVERSE REACTIONS, contact Daiichi
`To report SUSPECTED ADVERSE REACTIONS, contact Daiichi
`Sankyo, Inc. at 1-877-437-7763 or FDA at 1-800-FDA-1088 or
`Sankyo, Inc. at 1-877-437-7763 or FDA at 1-800-FDA-1088 or
`www.fda.gov/medwatch.
`www.fda.govimedwatch.
` ___________________ DRUG INTERACTIONS____________________
`DRUG INTERACTIONS
`
`Anticoagulants: Avoid concomitant use (7.1)
`•
`• Anticoagulants: Avoid concomitant use (7.1)
`Rifampin: Avoid concomitant use (7.2)
`•
`•
`Rifampin: Avoid concomitant use (7.2)
`
` ______________ USE IN SPECIFIC POPULATIONS _______________
`USE IN SPECIFIC POPULATIONS
`
`Nursing mothers: Discontinue drug or discontinue nursing (8.3)
`•
`• Nursing mothers: Discontinue drug or discontinue nursing (8.3)
`Impaired renal function (CrCL 15 to 50 mL/min): Reduce dose (2.1, 2.2,
`•
`•
`Impaired renal function (CrCL 15 to 50 mL/min): Reduce dose (2.1, 2.2,
`8.6)
`8.6)
`• Moderate or severe hepatic impairment: Not recommended (8.7)
`• Moderate or severe hepatic impairment: Not recommended (8.7)
`
`See 17 for PATIENT COUNSELING INFORMATION and Medication
`See 17 for PATIENT COUNSELING INFORMATION and Medication
`Guide.
`Guide.
`
`
`Revised: 01/2015
`Revised: 01/2015
`
`6
`6
`
`7
`7
`
`8
`8
`
`5.2
`5.2
`
`Increased Risk of Stroke with Discontinuation of SAVAYSA in
`Increased Risk of Stroke with Discontinuation of SAVAYSA in
`Patients with Nonvalvular Atrial Fibrillation
`Patients with Nonvalvular Atrial Fibrillation
`5.3 Risk of Bleeding
`5.3 Risk of Bleeding
`5.4 Spinal/Epidural Anesthesia or Puncture
`5.4 Spinal/Epidural Anesthesia or Puncture
`5.5 Patients with Mechanical Heart Valves or Moderate to Severe
`5.5 Patients with Mechanical Heart Valves or Moderate to Severe
`Mitral Stenosis
`Mitral Stenosis
`ADVERSE REACTIONS
`ADVERSE REACTIONS
`6.1 Clinical Trials Experience
`6.1 Clinical Trials Experience
`DRUG INTERACTIONS
`DRUG INTERACTIONS
`7.1 Anticoagulants, Antiplatelets, and Thrombolytics
`7.1 Anticoagulants, Antiplatelets, and Thrombolytics
`7.2 P-gp Inducers
`7.2 P-gp Inducers
`7.3 P-gp Inhibitors
`7.3 P-gp Inhibitors
`USE IN SPECIFIC POPULATIONS
`USE IN SPECIFIC POPULATIONS
`8.1 Pregnancy
`8.1 Pregnancy
`8.2 Labor and Delivery
`8.2 Labor and Delivery
`8.3 Nursing Mothers
`8.3 Nursing Mothers
`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
`8.8 Low Body Weight Consideration for Patients treated for DVT
`8.8 Low Body Weight Consideration for Patients treated for DVT
`and/or PE
`and/or PE
`
`0001
`
`0001
`
`MYLAN - EXHIBIT 1063
`
`

`

`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
`14.1 Nonvalvular Atrial Fibrillation
`14.1 Nonvalvular Atrial Fibrillation
`14.2 Treatment of Deep Vein Thrombosis and Pulmonary Embolism
`14.2 Treatment of Deep Vein Thrombosis and Pulmonary Embolism
`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
`*Sections or subsections omitted from the full prescribing information
`are not listed.
`are not listed.
`
`1
`1
`
`
`0002
`
`0002
`
`

`

`
`
`FULL PRESCRIBING INFORMATION
`FULL PRESCRIBING INFORMATION
`WARNING (A) REDUCED EFFICACY IN NONVALVULAR ATRIAL
`WARNING (A) REDUCED EFFICACY IN NONVALVULAR ATRIAL
`FIBRILLATION PATIENTS WITH CREATININE CLEARANCE (CRCL) > 95
`FIBRILLATION PATIENTS WITH CREATININE CLEARANCE (CRCL) > 95
`ML/MIN (B) PREMATURE DISCONTINUATION OF SAVAYSA INCREASES THE
`ML/1VIIN (B) PREMATURE DISCONTINUATION OF SAVAYSA INCREASES THE
`RISK OF ISCHEMIC EVENTS (C) SPINAL/EPIDURAL HEMATOMA
`RISK OF ISCHEMIC EVENTS (C) SPINAL/EPIDURAL HEMATOMA
`A. REDUCED EFFICACY IN NONVALVULAR ATRIAL FIBRILLATION
`A. REDUCED EFFICACY IN NONVALVULAR ATRIAL FIBRILLATION
`PATIENTS WITH CRCL > 95 ML/MIN
`PATIENTS WITH CRCL > 95 ML/1VIIN
`SAVAYSA should not be used in patients with CrCL > 95 mL/min. In the ENGAGE
`SAVAYSA should not be used in patients with CrCL > 95 mL/min. In the ENGAGE
`AF-TIMI 48 study, nonvalvular atrial fibrillation patients with CrCL > 95 mL/min had
`AF-TIMI 48 study, nonvalvular atrial fibrillation patients with CrCL > 95 mL/min had
`an increased rate of ischemic stroke with SAVAYSA 60 mg once daily compared to
`an increased rate of ischemic stroke with SAVAYSA 60 mg once daily compared to
`patients treated with warfarin. In these patients another anticoagulant should be used
`patients treated with warfarin. In these patients another anticoagulant should be used
`[see Dosage and Administration (2.1), Warnings and Precautions (5.1), and Clinical
`[see Dosage and Administration (2.1), Warnings and Precautions (5.1), and Clinical
`Studies (14.1)].
`Studies (14.1)].
`B. PREMATURE DISCONTINUATION OF SAVAYSA INCREASES THE RISK OF
`B. PREMATURE DISCONTINUATION OF SAVAYSA INCREASES THE RISK OF
`ISCHEMIC EVENTS
`ISCHEMIC EVENTS
`Premature discontinuation of any oral anticoagulant in the absence of adequate
`Premature discontinuation of any oral anticoagulant in the absence of adequate
`alternative anticoagulation increases the risk of ischemic events. If SAVAYSA is
`alternative anticoagulation increases the risk of ischemic events. If SAVAYSA is
`discontinued for a reason other than pathological bleeding or completion of a course of
`discontinued for a reason other than pathological bleeding or completion of a course of
`therapy, consider coverage with another anticoagulant as described in the transition
`therapy, consider coverage with another anticoagulant as described in the transition
`guidance [see Dosage and Administration (2.4), Warnings and Precautions (5.2), and
`guidance [see Dosage and Administration (2.4), Warnings and Precautions (5.2), and
`Clinical Studies (14.1)].
`Clinical Studies (14.1)].
`C. SPINAL/EPIDURAL HEMATOMA
`C. SPINAL/EPIDURAL HEMATOMA
`Epidural or spinal hematomas may occur in patients treated with SAVAYSA who are
`Epidural or spinal hematomas may occur in patients treated with SAVAYSA who are
`receiving neuraxial anesthesia or undergoing spinal puncture. These hematomas may
`receiving neuraxial anesthesia or undergoing spinal puncture. These hematomas may
`result in long-term or permanent paralysis. Consider these risks when scheduling
`result in long-term or permanent paralysis. Consider these risks when scheduling
`patients for spinal procedures. Factors that can increase the risk of developing epidural
`patients for spinal procedures. Factors that can increase the risk of developing epidural
`or spinal hematomas in these patients include:
`or spinal hematomas in these patients include:
`• use of indwelling epidural catheters
`use of indwelling epidural catheters
`•
`concomitant use of other drugs that affect hemostasis, such as nonsteroidal
`•
`•
`concomitant use of other drugs that affect hemostasis, such as nonsteroidal
`anti-inflammatory drugs (NSAIDs), platelet inhibitors, other anticoagulants
`anti-inflammatory drugs (NSAIDs), platelet inhibitors, other anticoagulants
`• a history of traumatic or repeated epidural or spinal punctures
`•
`a history of traumatic or repeated epidural or spinal punctures
`• a history of spinal deformity or spinal surgery
`a history of spinal deformity or spinal surgery
`•
`• optimal timing between the administration of SAVAYSA and neuraxial procedures
`•
`optimal timing between the administration of SAVAYSA and neuraxial procedures
`is not known
`is not known
`[see Warnings and Precautions (5.4)].
`[see Warnings and Precautions (5.4)].
`Monitor patients frequently for signs and symptoms of neurological impairment. If
`Monitor patients frequently for signs and symptoms of neurological impairment. If
`neurological compromise is noted, urgent treatment is necessary [see Warnings and
`neurological compromise is noted, urgent treatment is necessary [see Warnings and
`Precautions (5.4)].
`Precautions (5.4)].
`Consider the benefits and risks before neuraxial intervention in patients anticoagulated
`Consider the benefits and risks before neuraxial intervention in patients anticoagulated
`or to be anticoagulated [see Warnings and Precautions (5.4)].
`or to be anticoagulated [see Warnings and Precautions (5.4)].
`
`
`
`
`2
`2
`
`
`0003
`
`0003
`
`

`

`
`
`INDICATIONS AND USAGE
`1
`INDICATIONS AND USAGE
`1
`1.1 Reduction in the Risk of Stroke and Systemic Embolism in Nonvalvular Atrial Fibrillation
`1.1 Reduction in the Risk of Stroke and Systemic Embolism in Nonvalvular Atrial Fibrillation
`
`SAVAYSA is indicated to reduce the risk of stroke and systemic embolism (SE) in patients with
`SAVAYSA is indicated to reduce the risk of stroke and systemic embolism (SE) in patients with
`nonvalvular atrial fibrillation (NVAF).
`nonvalvular atrial fibrillation (NVAF).
`
`Limitation of Use for NVAF
`Limitation of Use for NVAF
`
`SAVAYSA should not be used in patients with CrCL > 95 mL/min because of an increased risk of
`SAVAYSA should not be used in patients with CrCL > 95 mL/min because of an increased risk of
`ischemic stroke compared to warfarin [see Dosage and Administration (2.1), Warnings and Precautions
`ischemic stroke compared to warfarin [see Dosage and Administration (2.1), Warnings and Precautions
`(5.1), Clinical Studies (14.1)].
`(5.1), Clinical Studies (14.1)] .
`
`
`
`1.2 Treatment of Deep Vein Thrombosis and Pulmonary Embolism
`1.2 Treatment of Deep Vein Thrombosis and Pulmonary Embolism
`
`SAVAYSA is indicated for the treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE)
`SAVAYSA is indicated for the treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE)
`following 5 to 10 days of initial therapy with a parenteral anticoagulant.
`following 5 to 10 days of initial therapy with a parenteral anticoagulant.
`
`2 DOSAGE AND ADMINISTRATION
`2 DOSAGE AND ADMINISTRATION
`
`2.1 Nonvalvular Atrial Fibrillation
`2.1 Nonvalvular Atrial Fibrillation
`The recommended dose of SAVAYSA is 60 mg taken orally once daily [see Warnings and Precautions
`The recommended dose of SAVAYSA is 60 mg taken orally once daily [see Warnings and Precautions
`(5.1), Clinical Studies (14.1)]. Assess creatinine clearance, as calculated using the Cockcroft-Gault
`(5.1), Clinical Studies (14.1)] . Assess creatinine clearance, as calculated using the Cockcroft-Gault
`equation*, before initiating therapy with SAVAYSA. Do not use SAVAYSA in patients with CrCL > 95
`equation*, before initiating therapy with SAVAYSA. Do not use SAVAYSA in patients with CrCL > 95
`mL/min.
`mL/min
`Reduce SAVAYSA dose to 30 mg once daily in patients with CrCL 15 to 50 mL/min [see Use in Specific
`Reduce SAVAYSA dose to 30 mg once daily in patients with CrCL 15 to 50 mL/min [see Use in Specific
`Populations (8.6) and Clinical Pharmacology (12.3)].
`Populations (8.6) and Clinical Pharmacology (12.3)] .
`*Cockcroft-Gault CrCL = (140-age) x (weight in kg) x (0.85 if female) / (72 x creatinine in mg/dL).
`*Cockcroft-Gault CrCL = (140-age) x (weight in kg) x (0.85 if female) / (72 x creatinine in mg/dL).
`
`2.2 Treatment of Deep Vein Thrombosis and Pulmonary Embolism
`2.2 Treatment of Deep Vein Thrombosis and Pulmonary Embolism
`
`The recommended dose of SAVAYSA is 60 mg taken orally once daily following 5 to 10 days of initial
`The recommended dose of SAVAYSA is 60 mg taken orally once daily following 5 to 10 days of initial
`therapy with a parenteral anticoagulant [see Clinical Studies (14.2)].
`therapy with a parenteral anticoagulant [see Clinical Studies (14.2)] .
`
`The recommended dose of SAVAYSA is 30 mg once daily in patients with CrCL 15 to 50 mL/min,
`The recommended dose of SAVAYSA is 30 mg once daily in patients with CrCL 15 to 50 mL/min,
`patients who weigh less than or equal to 60 kg, or patients who are taking certain concomitant P-gp
`patients who weigh less than or equal to 60 kg, or patients who are taking certain concomitant P-gp
`inhibitor medications based on clinical study data in this indication [see Clinical Studies (14.2)].
`inhibitor medications based on clinical study data in this indication [see Clinical Studies (14.2)] .
`
`2.3 Administration Information
`2.3 Administration Information
`If a dose of SAVAYSA is missed, the dose should be taken as soon as possible on the same day. Dosing
`If a dose of SAVAYSA is missed, the dose should be taken as soon as possible on the same day. Dosing
`should resume the next day according to the normal dosing schedule. The dose should not be doubled to
`should resume the next day according to the normal dosing schedule. The dose should not be doubled to
`make up for a missed dose.
`make up for a missed dose.
`SAVAYSA can be taken without regard to food [see Clinical Pharmacology (12.3)].
`SAVAYSA can be taken without regard to food [see Clinical Pharmacology (12.3)] .
`
`
`
`3
`3
`
`
`0004
`
`0004
`
`

`

`
`
`2.4 Transition to or from SAVAYSA
`2.4 Transition to or from SAVAYSA
`Transition to SAVAYSA
`Transition to SAVAYSA
`To
`To
`SAVAYSA
`SAVAYSA
`
`SAVAYSA
`SAVAYSA
`
`
`Recommendation
`Recommendation
`Discontinue warfarin and start SAVAYSA when
`Discontinue warfarin and start SAVAYSA when
`the INR is ≤ 2.5
`the INR is < 2.5
`Discontinue current oral anticoagulant and start
`Discontinue current oral anticoagulant and start
`SAVAYSA at the time of the next scheduled dose
`SAVAYSA at the time of the next scheduled dose
`of the other oral anticoagulant
`of the other oral anticoagulant
`Discontinue LMWH and start SAVAYSA at the
`Discontinue LMWH and start SAVAYSA at the
`time of the next scheduled administration of
`time of the next scheduled administration of
`LMWH
`LMWH
`Discontinue the infusion and start SAVAYSA
`Discontinue the infusion and start SAVAYSA
`4 hours later
`4 hours later
`
`SAVAYSA
`SAVAYSA
`
`
`SAVAYSA
`SAVAYSA
`
`
`From
`From
`Warfarin or other
`Warfarin or other
`Vitamin K Antagonists
`Vitamin K Antagonists
`Oral anticoagulants other
`Oral anticoagulants other
`than warfarin or other
`than warfarin or other
`Vitamin K Antagonists
`Vitamin K Antagonists
`Low Molecular Weight
`Low Molecular Weight
`Heparin (LMWH)
`Heparin (LMWH)
`
`Unfractionated heparin
`Unfractionated heparin
`
`
`
`From
`From
`
`SAVAYSA
`SAVAYSA
`
`SAVAYSA
`SAVAYSA
`
`SAVAYSA
`SAVAYSA
`
`SAVAYSA
`SAVAYSA
`
`Transition from SAVAYSA
`Transition from SAVAYSA
`To
`To
`
`Warfarin
`Warfarin
`
`Warfarin
`Warfarin
`
`Recommendation
`Recommendation
`Oral option: For patients taking 60 mg of
`Oral option: For patients taking 60 mg of
`SAVAYSA, reduce the dose to 30 mg and begin
`SAVAYSA, reduce the dose to 30 mg and begin
`warfarin concomitantly. For patients receiving
`warfarin concomitantly. For patients receiving
`30 mg of SAVAYSA, reduce the dose to 15 mg
`30 mg of SAVAYSA, reduce the dose to 15 mg
`and begin warfarin concomitantly. INR must be
`and begin warfarin concomitantly. INR must be
`measured at least weekly and just prior to the daily
`measured at least weekly and just prior to the daily
`dose of SAVAYSA to minimize the influence of
`dose of SAVAYSA to minimize the influence of
`SAVAYSA on INR measurements. Once a stable
`SAVAYSA on INR measurements. Once a stable
`INR ≥ 2.0 is achieved, SAVAYSA should be
`INR > 2.0 is achieved, SAVAYSA should be
`discontinued and the warfarin continued
`discontinued and the warfarin continued
`Parenteral option: Discontinue SAVAYSA and
`Parenteral option: Discontinue SAVAYSA and
`administer a parenteral anticoagulant and warfarin
`administer a parenteral anticoagulant and warfarin
`at the time of the next scheduled SAVAYSA dose.
`at the time of the next scheduled SAVAYSA dose.
`Once a stable INR ≥ 2.0 is achieved the parenteral
`Once a stable INR > 2.0 is achieved the parenteral
`anticoagulant should be discontinued and the
`anticoagulant should be discontinued and the
`warfarin continued
`warfarin continued
`Discontinue SAVAYSA and start the other oral
`Non-Vitamin-
`Non-Vitamin-
`Discontinue SAVAYSA and start the other oral
`anticoagulant at the time of the next dose of
`K-Dependent Oral
`K-Dependent Oral
`anticoagulant at the time of the next dose of
`SAVAYSA
`anticoagulants
`SAVAYSA
`anticoagulants
`Parenteral anticoagulants Discontinue SAVAYSA and start the parenteral
`Parenteral anticoagulants Discontinue SAVAYSA and start the parenteral
`anticoagulant at the time of the next dose of
`anticoagulant at the time of the next dose of
`SAVAYSA
`SAVAYSA
`
`Abbreviations: INR=International Normalized Ratio
`Abbreviations: INR=International Normalized Ratio
`
`2.5 Discontinuation for Surgery and Other Interventions
`2.5 Discontinuation for Surgery and Other Interventions
`Discontinue SAVAYSA at least 24 hours before invasive or surgical procedures because of the risk of
`Discontinue SAVAYSA at least 24 hours before invasive or surgical procedures because of the risk of
`bleeding [see Warnings and Precautions (5.3)].
`bleeding [see Warnings and Precautions (5.3)] .
`If surgery cannot be delayed, there is an increased risk of bleeding. This risk of bleeding should be
`If surgery cannot be delayed, there is an increased risk of bleeding. This risk of bleeding should be
`weighed against the urgency of intervention [see Warnings and Precautions (5.3)].
`weighed against the urgency of intervention [see Warnings and Precautions (5.3)] .
`
`
`
`4
`4
`
`
`0005
`
`0005
`
`

`

`SAVAYSA can be restarted after the surgical or other procedure as soon as adequate hemostasis has been
`SAVAYSA can be restarted after the surgical or other procedure as soon as adequate hemostasis has been
`established noting that the time to onset of pharmacodynamic effect is 1-2 hours [see Warnings and
`established noting that the time to onset of pharmacodynamic effect is 1-2 hours [see Warnings and
`Precautions (5.2)]. Administer a parenteral anticoagulant and then switch to oral SAVAYSA, if oral
`Precautions (5.2)] . Administer a parenteral anticoagulant and then switch to oral SAVAYSA, if oral
`medication cannot be taken during or after surgical intervention.
`medication cannot be taken during or after surgical intervention.
`
`
`
`3 DOSAGE FORMS AND STRENGTHS
`3 DOSAGE FORMS AND STRENGTHS
`• 60 mg, yellow round shaped, film-coated tablets, debossed with DSC L60 on one side
`60 mg, yellow round shaped, film-coated tablets, debossed with DSC L60 on one side
`•
`• 30 mg, pink round shaped, film-coated tablets, debossed with DSC L30 on one side
`30 mg, pink round shaped, film-coated tablets, debossed with DSC L30 on one side
`•
`• 15 mg, orange round shaped, film-coated tablets, debossed with DSC L15 on one side
`15 mg, orange round shaped, film-coated tablets, debossed with DSC L15 on one side
`•
`
`4 CONTRAINDICATIONS
`4 CONTRAINDICATIONS
`SAVAYSA is contraindicated in patients with:
`SAVAYSA is contraindicated in patients with:
`• Active pathological bleeding [see Warnings and Precautions (5.3) and Adverse Reactions (6.1)]
`• Active pathological bleeding [see Warnings and Precautions (5.3) and Adverse Reactions (6.1)]
`
`5 WARNINGS AND PRECAUTIONS
`5 WARNINGS AND PRECAUTIONS
`
`5.1 Reduced Efficacy in Nonvalvular Atrial Fibrillation Patients with CrCL > 95 mL/min
`5.1 Reduced Efficacy in Nonvalvular Atrial Fibrillation Patients with CrCL > 95 mL/min
`SAVAYSA should not be used in patients with CrCL > 95 mL/min. In the randomized ENGAGE AF-
`SAVAYSA should not be used in patients with CrCL > 95 mL/min. In the randomized ENGAGE AF-
`TIMI 48 study, NVAF patients with CrCL > 95 mL/min had an increased rate of ischemic stroke with
`T1MI 48 study, NVAF patients with CrCL > 95 mL/min had an increased rate of ischemic stroke with
`SAVAYSA 60 mg daily compared to patients treated with warfarin. In these patients another
`SAVAYSA 60 mg daily compared to patients treated with warfarin. In these patients another
`anticoagulant should be used [see Dosage and Administration (2.1), Clinical Studies (14.1)].
`anticoagulant should be used [see Dosage and Administration (2.1), Clinical Studies (14.1)] .
`
`Increased Risk of Stroke with Discontinuation of SAVAYSA in Patients with Nonvalvular
`5.2
`Increased Risk of Stroke with Discontinuation of SAVAYSA in Patients with Nonvalvular
`5.2
`Atrial Fibrillation
`Atrial Fibrillation
`Premature discontinuation of any oral anticoagulant in the absence of adequate alternative anticoagulation
`Premature discontinuation of any oral anticoagulant in the absence of adequate alternative anticoagulation
`increases the risk of ischemic events. If SAVAYSA is discontinued for a reason other than pathological
`increases the risk of ischemic events. If SAVAYSA is discontinued for a reason other than pathological
`bleeding or completion of a course of therapy, consider coverage with another anticoagulant as described
`bleeding or completion of a course of therapy, consider coverage with another anticoagulant as described
`in the transition guidance [see Dosage and Administration (2.4) and Clinical Studies (14.1)].
`in the transition guidance [see Dosage and Administration (2.4) and Clinical Studies (14.1)] .
`
`5.3 Risk of Bleeding
`5.3 Risk of Bleeding
`SAVAYSA increases the risk of bleeding and can cause serious and potentially fatal bleeding. Promptly
`SAVAYSA increases the risk of bleeding and can cause serious and potentially fatal bleeding. Promptly
`evaluate any signs or symptoms of blood loss.
`evaluate any signs or symptoms of blood loss.
`Discontinue SAVAYSA in patients with active pathological bleeding.
`Discontinue SAVAYSA in patients with active pathological bleeding.
`Concomitant use of drugs affecting hemostasis may increase the risk of bleeding. These include aspirin
`Concomitant use of drugs affecting hemostasis may increase the risk of bleeding. These include aspirin
`and other antiplatelet agents, other antithrombotic agents, fibrinolytic therapy, and chronic use of
`and other antiplatelet agents, other antithrombotic agents, fibrinolytic therapy, and chronic use of
`nonsteroidal anti-inflammatory drugs (NSAIDs) [see Drug Interactions (7.1)].
`nonsteroidal anti-inflammatory drugs (NSAIDs) [see Drug Interactions (7.1)] .
`There is no established way to reverse the anticoagulant effects of SAVAYSA, which can be expected to
`There is no established way to reverse the anticoagulant effects of SAVAYSA, which can be expected to
`persist for approximately 24 hours after the last dose. The anticoagulant effect of SAVAYSA cannot be
`persist for approximately 24 hours after the last dose. The anticoagulant effect of SAVAYSA cannot be
`
`
`
`5
`5
`
`
`0006
`
`0006
`
`

`

`
`
`reliably monitored with standard laboratory testing. A specific reversal agent for edoxaban is not
`reliably monitored with standard laboratory testing. A specific reversal agent for edoxaban is not
`available. Hemodialysis does not significantly contribute to edoxaban clearance [see Clinical
`available. Hemodialysis does not significantly contribute to edoxaban clearance [see Clinical
`Pharmacology (12.3)]. Protamine sulfate, vitamin K, and tranexamic acid are not expected to reverse the
`Pharmacology (12.3)] . Protamine sulfate, vitamin K, and tranexamic acid are not expected to reverse the
`anticoagulant activity of SAVAYSA.
`anticoagulant activity of SAVAYSA.
`
`Spinal/Epidural Anesthesia or Puncture
`5.4
`Spinal/Epidural Anesthesia or Punctu