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
` ELIQUIS safely and effectively. See full prescribing information for
`
`
`
`
`ELIQUIS safely and effectively. See full prescribing information for
` ELIQUIS.
`
`ELIQUIS.
`
`ELIQUIS (apixaban) tablets for oral use
`
`
`
`
`ELIQUIS® (apixaban) tablets for oral use
`
`
`Initial U.S. Approval: 2012
`Initial U.S. Approval: 2012
`
`
`
`WARNING: (A) DISCONTINUING ELIQUIS IN PATIENTS WITH
`
`WARNING: (A) DISCONTINUING ELIQUIS IN PATIENTS WITH
`
`
`NONVALVULAR ATRIAL FIBRILLATION WITHOUT
`
`NONVALVULAR ATRIAL FIBRILLATION WITHOUT
`
`ADEQUATE CONTINUOUS ANTICOAGULATION INCREASES
`
`ADEQUATE CONTINUOUS ANTICOAGULATION INCREASES
`
`RISK OF STROKE
`
`RISK OF STROKE
`
`(B) SPINAL/EPIDURAL HEMATOMA
`(B) SPINAL/EPIDURAL HEMATOMA
`
`
`
`See full prescribing information for complete boxed warning.
`See full prescribing information for complete boxed warning.
`(A) DISCONTINUING ELIQUIS
` IN PATIENTS WITH
`
`(A) DISCONTINUING ELIQUIS
`IN PATIENTS WITH
`NONVALVULAR
`ATRIAL
` FIBRILLATION WITHOUT
`
`NONVALVULAR
`ATRIAL
`FIBRILLATION WITHOUT
` ADEQUATE CONTINUOUS ANTICOAGULATION INCREASES
`
`ADEQUATE CONTINUOUS ANTICOAGULATION INCREASES
` RISK OF STROKE: Discontinuing ELIQUIS places patients at an
`
`
`RISK OF STROKE: Discontinuing ELIQUIS places patients at an
` increased risk of thrombotic events. An increased rate of stroke was
`
`increased risk of thrombotic events. An increased rate of stroke was
` observed following discontinuation of ELIQUIS in clinical trials in
`
`
`
`observed following discontinuation of ELIQUIS in clinical trials in
` patients with nonvalvular atrial fibrillation. If anticoagulation with
`
`
`
`
`patients with nonvalvular atrial fibrillation. If anticoagulation with
` ELIQUIS must be discontinued for a reason other than pathological
`
`
`ELIQUIS must be discontinued for a reason other than pathological
` bleeding, coverage with another anticoagulant should be strongly
`
`
`bleeding, coverage with another anticoagulant should be strongly
` considered. (2.5, 5.1)
`
`considered. (2.5, 5.1)
`
`
`(B) SPINAL/EPIDURAL HEMATOMA: ELIQUIS use in patients
`(B) SPINAL/EPIDURAL HEMATOMA: ELIQUIS use in patients
`
`undergoing spinal epidural anesthesia or spinal puncture increases the
`undergoing spinal epidural anesthesia or spinal puncture increases the
`
`
`
`
`risk of epidural or spinal hematoma which may cause long-term or
`risk of epidural or spinal hematoma which may cause long-term or
`
` permanent paralysis. Monitor patients frequently for signs and
`
`
`
`
`permanent paralysis. Monitor patients frequently for signs and
` symptoms of neurologic impairment and if observed, treat urgently.
`
`
`
`symptoms of neurologic impairment and if observed, treat urgently.
`Consider the benefits and risks before neuraxial intervention in
`Consider the benefits and risks before neuraxial intervention in
` patients who are or who need to be anticoagulated. (5.3)
`
`
`
`
`
`patients who are or who need to be anticoagulated. (53)
`
`---------------------------RECENT MAJOR CHANGES--------------------------­
`RECENT MAJOR CHANGES
` Boxed Warning
`
`
` 03/2014
`Boxed Warning
`03/2014
` Indications and Usage (1.2)
`
` 03/2014
`
`03/2014
`Indications and Usage (1.2)
` Dosage and Administration (2.1)
`
` 03/2014
`
`Dosage and Administration (2.1)
`03/2014
` Dosage and Administration (2.8)
`
`
` 03/2014
`Dosage and Administration (2.8)
`03/2014
` Warnings and Precautions (5.3)
`
`
`
` 03/2014
`03/2014
`Warnings and Precautions (5.3)
`---------------------------INDICATIONS AND USAGE---------------------------­
`
`INDICATIONS AND USAGE
`
`
` ELIQUIS is a factor Xa inhibitor anticoagulant indicated:
`
`
`
`ELIQUIS is a factor Xa inhibitor anticoagulant indicated:
`
`to reduce the risk of stroke and systemic embolism in patients with
`
`•
`• to reduce the risk of stroke and systemic embolism in patients with
`
`nonvalvular atrial fibrillation. (1.1)
`nonvalvular atrial fibrillation. (1.1)
`• for the prophylaxis of deep vein thrombosis (DVT), which may lead to
`
`• for the prophylaxis of deep vein thrombosis (DVT), which may lead to
`
`
`pulmonary embolism (PE), in patients who have undergone hip or knee
`pulmonary embolism (PE), in patients who have undergone hip or knee
`
`replacement surgery. (1.2)
`replacement surgery. (1.2)
`
`
`
`
`FULL PRESCRIBING INFORMATION: CONTENTS*
`FULL PRESCRIBING INFORMATION: CONTENTS*
`
`
`WARNING: (A) DISCONTINUING ELIQUIS IN PATIENTS WITH
`WARNING: (A) DISCONTINUING ELIQUIS IN PATIENTS WITH
`
`
`NONVALVULAR ATRIAL FIBRILLATION WITHOUT
`NONVALVULAR ATRIAL FIBRILLATION WITHOUT
`
`ADEQUATE CONTINUOUS ANTICOAGULATION INCREASES
`ADEQUATE CONTINUOUS ANTICOAGULATION INCREASES
`
`RISK OF STROKE
`RISK OF STROKE
`
`(B) SPINAL/EPIDURAL HEMATOMA
`
`(B) SPINAL/EPIDURAL HEMATOMA
`
`
`1
`INDICATIONS AND USAGE
`
`1
`INDICATIONS AND USAGE
`
`1.1
`Reduction of Risk of Stroke and Systemic Embolism in
`
`
`Reduction of Risk of Stroke and Systemic Embolism in
`1.1
`
`Nonvalvular Atrial Fibrillation
`Nonvalvular Atrial Fibrillation
`
`Prophylaxis of Deep Vein Thrombosis Following Hip or
`1.2
`
`
`Prophylaxis of Deep Vein Thrombosis Following Hip or
`1.2
`
`Knee Replacement Surgery
`Knee Replacement Surgery
`
`
`2 DOSAGE AND ADMINISTRATION
`
`2 DOSAGE AND ADMINISTRATION
`
`
`2.1
`Recommended Dose
`Recommended Dose
`2.1
`
`
`2.2
`Dosage Adjustments
`Dosage Adjustments
`2.2
`
`
`2.3
`Missed Dose
`Missed Dose
`2.3
`
`2.4
`Temporary Interruption for Surgery and Other
`
`
`
`
`Temporary Interruption for Surgery and Other
`2.4
`
`Interventions
`
`Interventions
`
`
`Converting from or to ELIQUIS
`2.5
`
`Converting from or to ELIQUIS
`2.5
`
`
`Hepatic Impairment
`2.6
`Hepatic Impairment
`2.6
`
`
`Renal Impairment
`2.7
`Renal Impairment
`2.7
`
`
`Administration Options
`2.8
`2.8
`Administration Options
`
`
`3 DOSAGE FORMS AND STRENGTHS
`
`3 DOSAGE FORMS AND STRENGTHS
`
`
`4 CONTRAINDICATIONS
`4 CONTRAINDICATIONS
`
`
`5 WARNINGS AND PRECAUTIONS
`
`5 WARNINGS AND PRECAUTIONS
`
`5.1
`Increased Risk of Stroke with Discontinuation of ELIQUIS
`
`
`Increased Risk of Stroke with Discontinuation of ELIQUIS
`5.1
`
`in Patients with Nonvalvular Atrial Fibrillation
`
`in Patients with Nonvalvular Atrial Fibrillation
`
`
`Bleeding
`5.2
`Bleeding
`5.2
`
`
`
`
`
`
`
`
`
`
`------------------------DOSAGE AND ADMINISTRATION---------------------­
`DOSAGE AND ADMINISTRATION
`
`
`
`
`• Reduction in risk of stroke and systemic embolism in nonvalvular atrial
`• Reduction in risk of stroke and systemic embolism in nonvalvular atrial
`
`fibrillation:
`fibrillation:
`
`
`
`• The recommended dose is 5 mg orally twice daily. (2.1)
`• The recommended dose is 5 mg orally twice daily. (2.1)
`
`
` • In patients with at least 2 of the following characteristics: age ≥80
`• In patients with at least 2 of the following characteristics: age 80
`
`
`
`
`years, body weight ≤60 kg, or serum creatinine ≥1.5 mg/dL, the
`years, body weight <60 kg, or serum creatinine
`mg/dL, the
`
`recommended dose is 2.5 mg orally twice daily. (2.2)
`recommended dose is 2.5 mg orally twice daily. (2.2)
`
`
`
`• Prophylaxis of DVT following hip or knee replacement surgery:
`• Prophylaxis of DVT following hip or knee replacement surgery:
`
`
`
`• The recommended dose is 2.5 mg orally twice daily. (2.1)
`• The recommended dose is 2.5 mg orally twice daily. (2.1)
`----------------------DOSAGE FORMS AND STRENGTHS--------------------­
`DOSAGE FORMS AND STRENGTHS
`
`
`
`
`
`
`• Tablets: 2.5 mg and 5 mg (3)
`• Tablets: 2.5 mg and 5 mg (3)
`------------------------------CONTRAINDICATIONS------------------------------­
`CONTRAINDICATIONS-
`
`
`• Active pathological bleeding (4)
`• Active pathological bleeding (4)
`
`
`
`
`
`• Severe hypersensitivity to ELIQUIS (4)
`• Severe hypersensitivity to ELIQUIS (4)
`
`
`------------------------WARNINGS AND PRECAUTIONS----------------------­
`WARNINGS AND PRECAUTIONS
`
`
`
`
`• ELIQUIS can cause serious, potentially fatal bleeding. Promptly evaluate
`• ELIQUIS can cause serious, potentially fatal bleeding. Promptly evaluate
`
`
`
`signs and symptoms of blood loss. (5.2)
`signs and symptoms of blood loss. (5.2)
`
`
`
`
`• Prosthetic heart valves: ELIQUIS use not recommended. (5.4)
`• Prosthetic heart valves: ELIQUIS use not recommended. (5.4)
`-------------------------------ADVERSE REACTIONS-----------------------------­
`ADVERSE REACTIONS
`
`
`
`
`Most common adverse reactions (>1%) are related to bleeding. (6.1)
`Most common adverse reactions (>1%) are related to bleeding. (6.1)
`
`
`
`
`To report SUSPECTED ADVERSE REACTIONS, contact Bristol-Myers
`To report SUSPECTED ADVERSE REACTIONS, contact Bristol-Myers
`
`
`
`Squibb
`at
`1-800-721-5072
`or FDA
`at
`1-800-FDA-1088
`or
`Squibb at 1-800-721-5072 or FDA at 1-800-FDA-1088 or
`
`www.fda.gov/medwatch.
`www.fdagov/medwatch.
`
`--------------------------------DRUG INTERACTIONS----------------------------­
`DRUG INTERACTIONS
`
`
`
`
`
`
`• Strong dual inhibitors of CYP3A4 and P-gp increase blood levels of
`• Strong dual inhibitors of CYP3A4 and P-gp increase blood levels of
`
`
`
`apixaban: Reduce ELIQUIS dose to 2.5 mg or avoid concomitant use. (2.2,
`apixaban: Reduce ELIQUIS dose to 2.5 mg or avoid concomitant use. (2.2,
`
`7.1, 12.3)
`7.1, 12.3)
`
`
`
`
`
`
`• Simultaneous use of strong dual inducers of CYP3A4 and P-gp reduces
`• Simultaneous use of strong dual inducers of CYP3A4 and P-gp reduces
`
`
`blood levels of apixaban: Avoid concomitant use. (7.2, 12.3)
`blood levels of apixaban: Avoid concomitant use. (7.2, 12.3)
`------------------------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)
`
`
`
`• Pregnancy: Not recommended. (8.1)
`• Pregnancy: Not recommended. (8.1)
`
`
`
`• Severe Hepatic Impairment: Not recommended. (12.2)
`• Severe Hepatic Impairment: Not recommended. (12.2)
`
`
`
`See 17 for PATIENT COUNSELING INFORMATION and Medication
`See 17 for PATIENT COUNSELING INFORMATION and Medication
`
`Guide.
`Guide.
`
`
`Revised: 03/2014
`Revised: 03/2014
`
`
`
`
`
`
`
`Spinal/Epidural Anesthesia or Puncture
`5.3
`
`
`Spinal/Epidural Anesthesia or Puncture
`5.3
`
`
`Patients with Prosthetic Heart Valves
`5.4
`5.4
`Patients with Prosthetic Heart Valves
`
`
`6 ADVERSE REACTIONS
`6 ADVERSE REACTIONS
`
`
`6.1
`Clinical Trials Experience
`
`6.1
`Clinical Trials Experience
`
`
`7 DRUG INTERACTIONS
`
`7 DRUG INTERACTIONS
`
`
`7.1
`Strong Dual Inhibitors of CYP3A4 and P-gp
`
`
`Strong Dual Inhibitors of CYP3A4 and P-gp
`7.1
`
`
`7.2
`Strong Dual Inducers of CYP3A4 and P-gp
`
`
`
`7.2
`Strong Dual Inducers of CYP3A4 and P-gp
`
`
`7.3
`Anticoagulants and Antiplatelet Agents
`7.3
`Anticoagulants and Antiplatelet Agents
`
`
`8 USE IN SPECIFIC POPULATIONS
`8 USE IN SPECIFIC POPULATIONS
`
`
`8.1
`Pregnancy
`Pregnancy
`8.1
`
`
`8.2
`Labor and Delivery
`Labor and Delivery
`8.2
`
`
`8.3
`Nursing Mothers
`Nursing Mothers
`8.3
`
`
`8.4
`Pediatric Use
`8.4
`Pediatric Use
`
`
`8.5
`Geriatric Use
`8.5
`Geriatric Use
`
`8.6
`End-Stage Renal Disease Patients Maintained with
`End-Stage Renal Disease Patients Maintained with
`8.6
`
`Hemodialysis
`Hemodialysis
`
`
`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
`
`
`
`Reference ID: 3470804 Reference ID: 3470804
`
`
` 1
`1
`
`0001
`
`0001
`
`MYLAN - EXHIBIT 1062
`
`

`

`
` 14.1 Reduction of Risk of Stroke and Systemic Embolism in
`
`
`14.1 Reduction of Risk of Stroke and Systemic Embolism in
`
`Nonvalvular Atrial Fibrillation
`Nonvalvular Atrial Fibrillation
`
`
`
`Prophylaxis of Deep Vein Thrombosis Following Hip or
`14.2
`14.2 Prophylaxis of Deep Vein Thrombosis Following Hip or
`
`Knee Replacement Surgery
`Knee Replacement Surgery
`
`
`
`HOW SUPPLIED/STORAGE AND HANDLING
`16
`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.
`
`
`
`Reference ID: 3470804 Reference ID: 3470804
`
`
` 2
`2
`
`0002
`
`0002
`
`

`

`
` FULL PRESCRIBING INFORMATION
`
`
`FULL PRESCRIBING INFORMATION
`
` WARNING: (A) DISCONTINUING ELIQUIS IN PATIENTS WITH NONVALVULAR
`
`
`
`WARNING: (A) DISCONTINUING ELIQUIS IN PATIENTS WITH NONVALVULAR
` ATRIAL FIBRILLATION WITHOUT ADEQUATE CONTINUOUS
`
`
`
`ATRIAL FIBRILLATION WITHOUT ADEQUATE CONTINUOUS
` ANTICOAGULATION INCREASES RISK OF STROKE
`
`
`ANTICOAGULATION INCREASES RISK OF STROKE
`
` (B) SPINAL/EPIDURAL HEMATOMA
`
`(B) SPINAL/EPIDURAL HEMATOMA
`
` (A) DISCONTINUING ELIQUIS IN PATIENTS WITH NONVALVULAR ATRIAL
`
`(A) DISCONTINUING ELIQUIS IN PATIENTS WITH NONVALVULAR ATRIAL
`FIBRILLATION WITHOUT ADEQUATE CONTINUOUS ANTICOAGULATION
`FIBRILLATION WITHOUT ADEQUATE CONTINUOUS ANTICOAGULATION
` INCREASES RISK OF STROKE
`
`INCREASES RISK OF STROKE
`
` Discontinuing ELIQUIS places patients at an increased risk of thrombotic events. An
`
`
`Discontinuing ELIQUIS places patients at an increased risk of thrombotic events. An
` increased rate of stroke was observed following discontinuation of ELIQUIS in clinical
`
`
`
`increased rate of stroke was observed following discontinuation of ELIQUIS in clinical
` trials in patients with nonvalvular atrial fibrillation. If anticoagulation with ELIQUIS
`
`
`
`
`
`trials in patients with nonvalvular atrial fibrillation. If anticoagulation with ELIQUIS
` must be discontinued for a reason other than pathological bleeding, coverage with another
`
`
`must be discontinued for a reason other than pathological bleeding, coverage with another
` anticoagulant should be strongly considered [see Dosage and Administration (2.5) and
`
`
`
`
`anticoagulant should be strongly considered [see Dosage and Administration (2.5) and
` Warnings and Precautions (5.1)].
`
`Warnings and Precautions (5.1)1
`
`(B) SPINAL/EPIDURAL HEMATOMA
`
`(B) SPINAL/EPIDURAL HEMATOMA
`
` When neuraxial anesthesia (epidural/spinal anesthesia) or spinal puncture is employed,
`
`
`When neuraxial anesthesia (epidural/spinal anesthesia) or spinal puncture is employed,
` patients anticoagulated or scheduled to be anticoagulated with low molecular weight
`
`patients anticoagulated or scheduled to be anticoagulated with low molecular weight
` heparins, heparinoids, or Factor Xa inhibitors for prevention of thromboembolic
`
`
`heparins, heparinoids, or Factor Xa inhibitors for prevention of thromboembolic
` complications are at risk of developing an epidural or spinal hematoma which can result in
`
`
`
`complications are at risk of developing an epidural or spinal hematoma which can result in
` long-term or permanent paralysis.
`
`
`long-term or permanent paralysis.
`
`
`The risk of these events may be increased by the use of indwelling epidural catheters for
`The risk of these events may be increased by the use of indwelling epidural catheters for
`
`administration of analgesia or by the concomitant use of drugs affecting hemostasis such as
`administration of analgesia or by the concomitant use of drugs affecting hemostasis such as
`
`nonsteroidal anti-inflammatory drugs (NSAIDs), platelet aggregation inhibitors, or other
`nonsteroidal anti-inflammatory drugs (NSAIDs), platelet aggregation inhibitors, or other
`
`anticoagulants. The risk also appears to be increased by traumatic or repeated epidural or
`anticoagulants. The risk also appears to be increased by traumatic or repeated epidural or
`
`spinal puncture.
`spinal puncture.
`
` Monitor patients for signs and symptoms of neurologic impairment. If neurologic
`
`Monitor patients for signs and symptoms of neurologic impairment. If neurologic
` compromise is noted, urgent treatment is necessary.
`
`
`compromise is noted, urgent treatment is necessary.
`
`
`
`Consider the potential benefit versus risk before neuraxial intervention in patients
`Consider the potential benefit versus risk before neuraxial intervention in patients
`anticoagulated or to be anticoagulated for thromboprophylaxis [see Warnings and
`
`anticoagulated or to be anticoagulated for thromboprophylaxis [see Warnings and
`Precautions (5.3)].
`
`Precautions (5.3)].
`
`
`3
`3
`
`
`
`Reference ID: 3470804 Reference ID: 3470804
`
`0003
`
`0003
`
`

`

`
`
` 1
`1
`
`
` 1.1
`1.1
`
` INDICATIONS AND USAGE
`
`
`INDICATIONS AND USAGE
`
` Reduction of Risk of Stroke and Systemic Embolism in
`
`Reduction of Risk of Stroke and Systemic Embolism in
` Nonvalvular Atrial Fibrillation
`
`Nonvalvular Atrial Fibrillation
`
` ELIQUIS (apixaban) is indicated to reduce the risk of stroke and systemic embolism in patients
`
`
`
`
`
`
`ELIQUIS® (apixaban) is indicated to reduce the risk of stroke and systemic embolism in patients
` with nonvalvular atrial fibrillation.
`
`with nonvalvular atrial fibrillation.
`
`
` 1.2
`1.2
`
` Prophylaxis of Deep Vein Thrombosis Following Hip or Knee
`
`Prophylaxis of Deep Vein Thrombosis Following Hip or Knee
` Replacement Surgery
`
`
`Replacement Surgery
`
` ELIQUIS is indicated for the prophylaxis of deep vein thrombosis (DVT), which may lead to
`
`ELIQUIS is indicated for the prophylaxis of deep vein thrombosis (DVT), which may lead to
` pulmonary embolism (PE), in patients who have undergone hip or knee replacement surgery.
`
`
`
`pulmonary embolism (PE), in patients who have undergone hip or knee replacement surgery.
`
`
` 2
`2
`
`
` 2.1
`2.1
`
` DOSAGE AND ADMINISTRATION
`
`
`DOSAGE AND ADMINISTRATION
`
` Recommended Dose
`
`Recommended Dose
`
` Reduction of Risk of Stroke and Systemic Embolism in Patients with Nonvalvular Atrial
`
`
`Reduction of Risk of Stroke and Systemic Embolism in Patients with Nonvalvular Atrial
` Fibrillation
`
`Fibrillation
`
` The recommended dose of ELIQUIS for most patients is 5 mg taken orally twice daily.
`
`
`The recommended dose of ELIQUIS for most patients is 5 mg taken orally twice daily.
`
` Prophylaxis of Deep Vein Thrombosis Following Hip or Knee Replacement Surgery
`
`
`
`Prophylaxis of Deep Vein Thrombosis Following Hip or Knee Replacement Surgery
`
` The recommended dose of ELIQUIS is 2.5 mg taken orally twice daily. The initial dose should
`
`
`
`The recommended dose of ELIQUIS is 2.5 mg taken orally twice daily. The initial dose should
` be taken 12 to 24 hours after surgery.
`
`be taken 12 to 24 hours after surgery.
`
` In patients undergoing hip replacement surgery, the recommended duration of treatment is 35
`
`
`•
`• In patients undergoing hip replacement surgery, the recommended duration of treatment is 35
`days.
`
`days.
`In patients undergoing knee replacement surgery, the recommended duration of treatment is
`
`
`•
`• In patients undergoing knee replacement surgery, the recommended duration of treatment is
`12 days.
`
`12 days.
`
`
` 2.2
`2.2
`
` Dosage Adjustments
`
`Dosage Adjustments
`
` In patients with nonvalvular atrial fibrillation: The recommended dose of ELIQUIS is 2.5 mg
`
`
`In patients with nonvalvular atrial fibrillation: The recommended dose of ELIQUIS is 2.5 mg
` twice daily in patients with any 2 of the following characteristics:
`
`
`
`
`twice daily in patients with any 2 of the following characteristics:
`
`
`•
`•
`
`age ≥80 years
`
`age 80 years
`
`
`4
`4
`
`
`
`Reference ID: 3470804 Reference ID: 3470804
`
`0004
`
`0004
`
`

`

`
`
`•
`•
`
`•
`•
`
`body weight ≤60 kg
`
`
`body weight 60 kg
`serum creatinine ≥1.5 mg/dL
`
`serum creatinine 1.5 mg/dL
`
`Coadministration with CYP3A4 and P-gp inhibitors: For patients receiving ELIQUIS 5 mg twice
`
`
`
`Coadministration with CYP3A4 and P-gp inhibitors: For patients receiving ELIQUIS 5 mg twice
`daily when ELIQUIS is coadministered with drugs that are strong dual inhibitors of cytochrome
`
`
`
`
`daily when ELIQUIS is coadministered with drugs that are strong dual inhibitors of cytochrome
`P450 3A4 (CYP3A4) and P-glycoprotein (P-gp) (e.g., ketoconazole, itraconazole, ritonavir,
`P450 3A4 (CYP3A4) and P-glycoprotein (P-gp) (e.g., ketoconazole, itraconazole, ritonavir,
`clarithromycin), the recommended dose is 2.5 mg twice daily [see Clinical Pharmacology
`
`
`
`
`clarithromycin), the recommended dose is 2.5 mg twice daily [see Clinical Pharmacology
`(12.3)].
`
`(12.3)] .
`
`In patients already taking 2.5 mg twice daily, coadministration of ELIQUIS with strong dual
`
`
`
`In patients already taking 2.5 mg twice daily, coadministration of ELIQUIS with strong dual
`inhibitors of CYP3A4 and P-gp should be avoided.
`
`
`inhibitors of CYP3A4 and P-gp should be avoided.
`
`
` 2.3
`2.3
`
` Missed Dose
`
`Missed Dose
`
` If a dose of ELIQUIS is not taken at the scheduled time, the dose should be taken as soon as
`
`
`
`
`If a dose of ELIQUIS is not taken at the scheduled time, the dose should be taken as soon as
` possible on the same day and twice-daily administration should be resumed. The dose should not
`
`
`
`possible on the same day and twice-daily administration should be resumed. The dose should not
` be doubled to make up for a missed dose.
`
`be doubled to make up for a missed dose.
`
`
` 2.4
`2.4
`
` Temporary Interruption for Surgery and Other Interventions
`
`
`
`Temporary Interruption for Surgery and Other Interventions
`
` ELIQUIS should be discontinued at least 48 hours prior to elective surgery or invasive
`
`ELIQUIS should be discontinued at least 48 hours prior to elective surgery or invasive
` procedures with a moderate or high risk of unacceptable or clinically significant bleeding.
`
`procedures with a moderate or high risk of unacceptable or clinically significant bleeding.
` ELIQUIS should be discontinued at least 24 hours prior to elective surgery or invasive
`
`ELIQUIS should be discontinued at least 24 hours prior to elective surgery or invasive
` procedures with a low risk of bleeding or where the bleeding would be non-critical in location
`
`
`procedures with a low risk of bleeding or where the bleeding would be non-critical in location
` and easily controlled. Bridging anticoagulation during the 24 to 48 hours after stopping
`
`and easily controlled. Bridging anticoagulation during the 24 to 48 hours after stopping
` ELIQUIS and prior to the intervention is not generally required. ELIQUIS should be restarted
`
`
`ELIQUIS and prior to the intervention is not generally required. ELIQUIS should be restarted
` after the surgical or other procedures as soon as adequate hemostasis has been established.
`
`
`after the surgical or other procedures as soon as adequate hemostasis has been established.
`
`
` 2.5
`2.5
`
` Converting from or to ELIQUIS
`
`
`Converting from or to ELIQUIS
`
` Switching from warfarin to ELIQUIS: Warfarin should be discontinued and ELIQUIS started
`
`
`
`
`
`Switching from warfarin to ELIQUIS: Warfarin should be discontinued and ELIQUIS started
` when the international normalized ratio (INR) is below 2.0.
`
`when the international normalized ratio (INR) is below 2.0.
`
` Switching from ELIQUIS to warfarin: ELIQUIS affects INR, so that initial INR measurements
`
`
`
`
`
`
`Switching from ELIQUIS to warfarin: ELIQUIS affects INR, so that initial INR measurements
` during the transition to warfarin may not be useful for determining the appropriate dose of
`
`
`
`during the transition to warfarin may not be useful for determining the appropriate dose of
` warfarin. If continuous anticoagulation is necessary, discontinue ELIQUIS and begin both a
`
`
`
`
`warfarin. If continuous anticoagulation is necessary, discontinue ELIQUIS and begin both a
` parenteral anticoagulant and warfarin at the time the next dose of ELIQUIS would have been
`
`
`parenteral anticoagulant and warfarin at the time the next dose of ELIQUIS would have been
` taken, discontinuing the parenteral anticoagulant when INR reaches an acceptable range.
`
`
`taken, discontinuing the parenteral anticoagulant when INR reaches an acceptable range.
`
`5
`5
`
`
`
`Reference ID: 3470804 Reference ID: 3470804
`
`0005
`
`0005
`
`

`

`
` Switching between ELIQUIS and anticoagulants other than warfarin: Discontinue one being
`
`
`
`Switching between ELIQUIS and anticoagulants other than warfarin: Discontinue one being
`
` taken and begin the other at the next scheduled dose.
`
`taken and begin the other at the next scheduled dose.
`
`
` 2.6
`2.6
`
` Hepatic Impairment
`
`
`Hepatic Impairment
`
` No dose adjustment is required in patients with mild hepatic impairment.
`
`No dose adjustment is required in patients with mild hepatic impairment.
`
` Because patients with moderate hepatic impairment may have intrinsic coagulation abnormalities
`
`
`Because patients with moderate hepatic impairment may have intrinsic coagulation abnormalities
` and there is limited clinical experience with ELIQUIS in these patients, dosing recommendations
`
`and there is limited clinical experience with ELIQUIS in these patients, dosing recommendations
` cannot be provided [see Clinical Pharmacology (12.2)].
`
`
`cannot be provided [see Clinical Pharmacology (12.2)1 .
`
`ELIQUIS is not recommended in patients with severe hepatic impairment [see Clinical
`ELIQUIS is not recommended in patients with severe hepatic impairment [see Clinical
`Pharmacology (12.3)].
`
`Pharmacology (12.3)1 .
`
`
` 2.7
`2.7
`
` Renal Impairment
`
`Renal Impairment
`
` The dosing adjustment for moderate renal impairment is described above [see Dosage and
`
`
`
`
`The dosing adjustment for moderate renal impairment is described above [see Dosage and
` Administration (2.2)]. The recommended dose for nonvalvular atrial fibrillation patients with
`
`
`
`Administration (2.2)1. The recommended dose for nonvalvular atrial fibrillation patients with
` end-stage renal disease (ESRD) maintained on hemodialysis is 5 mg twice daily. Reduce dose to
`
`end-stage renal disease (ESRD) maintained on hemodialysis is 5 mg twice daily. Reduce dose to
` 2.5 mg twice daily if one of the following patient characteristics (age ≥80 years or body weight
`
`
`
`2.5 mg twice daily if one of the following patient characteristics (age 80 years or body weight
` ≤60 kg) is present [see Use in Specific Populations (8.6) and Clinical Pharmacology (12.3)].
`
`
`
`
`
`
`60 kg) is present [see Use in Specific Populations (8.6) and Clinical Pharmacology (12.3)1 .
`
`
` 2.8
`2.8
`
` Administration Options
`
`Administration Options
`
` For patients who are unable to swallow whole tablets, 5 mg and 2.5 mg ELIQUIS tablets may be
`
`For patients who are unable to swallow whole tablets, 5 mg and 2.5 mg ELIQUIS tablets may be
` crushed and suspended in 60 mL D5W and immediately delivered through a nasogastric tube
`
`crushed and suspended in 60 mL D5W and immediately delivered through a nasogastric tube
` (NGT) [see Clinical Pharmacology (12.3)]. Information regarding the administration of crushed
`
`
`(NGT) [see Clinical Pharmacology (12.3)1 . Information regarding the administration of crushed
` and suspended ELIQUIS tablets swallowed by mouth is not available.
`
`and suspended ELIQUIS tablets swallowed by mouth is not available.
`
`
` 3
`3
`
` DOSAGE FORMS AND STRENGTHS
`
`DOSAGE FORMS AND STRENGTHS
`
` • 2.5 mg, yellow, round, biconvex, film-coated tablets with “893” debossed on one side and
`
`
`
`• 2.5 mg, yellow, round, biconvex, film-coated tablets with "893" debossed on one side and
` “2½” on the other side.
`
`"21/2" on the other side.
`
` • 5 mg, pink, oval-shaped, biconvex, film-coated tablets with “894” debossed on one side and
`
`
`• 5 mg, pink, oval-shaped, biconvex, film-coated tablets with "894" debossed on one side and
` “5” on the other side.
`
`"5" on the other side.
`
`
`6
`6
`
`
`
`Reference ID: 3470804 Reference ID: 3470804
`
`0006
`
`0006
`
`

`

`
`
` 4
`4
`
` CONTRAINDICATIONS
`
`CONTRAINDICATIONS
`
` ELIQUIS is contraindicated in patients with the following conditions:
`
`ELIQUIS is contraindicated in patients with the following conditions:
`
` • Active pathological bleeding [see Warnings and Precautions (5.2) and Adverse Reactions
`
`
`
`
`
`• Active pathological bleeding [see Warnings and Precautions (5.2) and Adverse Reactions
` (6.1)]
`
`(6. 1)I
` • Severe hypersensitivity reaction to ELIQUIS (e.g., anaphylactic reactions) [see Adverse
`
`
`
`
`
`
`• Severe hypersensitivity reaction to ELIQUIS (e.g., anaphylactic reactions) [see Adverse
` Reactions (6.1)]
`
`Reactions (6.1)1
`
`
` 5
`5
`
`
` 5.1
`5.1
`
` WARNINGS AND PRECAUTIONS
`
`WARNINGS AND PRECAUTIONS
`
` Increased Risk of Stroke with Discontinuation of ELIQUIS in
`
`
`
`
`
`
`Increased Risk of Stroke with Discontinuation of ELIQUIS in
` Patients with Nonvalvular Atrial Fibrillation
`
`
`
`Patients with Nonvalvular Atrial Fibrillation
`
` Discontinuing ELIQUIS in the absence of adequate alternative anticoagulation increases the risk
`
`
`
`Discontinuing ELIQUIS in the absence of adequate alternative anticoagulation increases the risk
` of thrombotic events. An increased rate of stroke was observed during the transition from
`
`of thrombotic events. An increased rate of stroke was observed during the transition from
` ELIQUIS to warfarin in clinical trials in patients with nonvalvular atrial fibrillation [see Clinical
`
`
`
`
`
`
`ELIQUIS to warfarin in clinical trials in patients with nonvalvular atrial fibrillation [see Clinical
` Studies (14.1)]. If ELIQUIS must be discontinued for a reason other than pathological bleeding,
`
`Studies (14.1)1 . If ELIQUIS must be discontinued for a reason other than pathological bleeding,
` consider coverage with another anticoagulant [see Dosage and Administration (2.5)].
`
`
`
`
`consider coverage with another anticoagulant [see Dosage and Administration (2.5)1.
`
`
` 5.2
`5.2
`
` Bleeding
`
`Bleeding
`
` ELIQUIS increases the risk of bleeding and can cause serious, potentially fatal, bleeding [see
`
`
`
`
`ELIQUIS increases the risk of bleeding and can cause serious, potentially fatal, bleeding [see
` Dosage and Administration (2.2) and Adverse Reactions (6.1)].
`
`Dosage and Administration (2.2) and 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 (7.3)].
`
`
`anti-inflammatory drugs (NSAIDs) [see Drug Interactions (7.3)1.
`
`
`
`
`
`
`Patients should be made aware of signs and symptoms of blood loss and instructed to report them
`Patients should be made aware of signs and symptoms of blood loss and instructed to report them
`
`
`
`immediately or go to an emergency room. ELIQUIS should be discontinued in patients with
`immediately or go to an emergency room. ELIQUIS should be discontinued in patients with
`
`active pathological hemorrhage.
`active pathological hemorrhage.
`
`
`There is no established way to reverse the anticoagulant effect of apixaban, which can be
`There is no established way to reverse the anticoagulant effect of apixaban, which can be
`
`
`
`expected to persist for at least 24 hours after the last dose, i.e., for about two half-lives. A
`expected to persist for at least 24 hours after the last dose, i.e., for about two half-lives. A
`
`
`
`specific antidote for ELIQUIS is not available. Hemodialysis does not appear to have a
`specific antidote for ELIQUIS is not available. Hemodialysis does not appear to have a
`
`substantial impact on apixaban exposure [see Clinical Pharmacology (12.3)]. Protamine sulfate
`
`
`substantial impact on apixaban exposure [see Clinical Pharmacology (12.3)1 . Protamine sulfate
`
`
`7
`7
`
`
`
`Reference ID: 3470804 Reference ID: 3470804
`
`0007
`
`0007
`
`

`

`
` and vitamin K would not be expected to affect the anticoagulant activity of apixaban. There is no
`
`
`
`
`
`and vitamin K would not be expected to affect the anticoagulant activity of apixaban. There is no
` experience with antifibrinolytic agents (tranexamic ac