HIGHLIGHTS OF PRESCRIBING INFORMATION
`
`
`
` These highlights do not include all the information needed to use
`
` ELIQUIS safely and effectively. See full prescribing information for
`
`
`
`
` ELIQUIS.
`
`ELIQUIS (apixaban) tablets for oral use
`
`
`
`
`
`
`Initial U.S. Approval: 2012
`
`
`
`
`
`WARNING: (A) PREMATURE DISCONTINUATION OF ELIQUIS
`
`
`
`INCREASES THE RISK OF THROMBOTIC EVENTS
`
`(B) SPINAL/EPIDURAL HEMATOMA
`
`
`
`See full prescribing information for complete boxed warning.
`
`
`(A) PREMATURE DISCONTINUATION OF ELIQUIS INCREASES
`
`THE RISK OF THROMBOTIC EVENTS: Premature discontinuation
`
`
`
`
`
`
`of any oral anticoagulant, including ELIQUIS, increases the risk of
`
`thrombotic events. To reduce this risk, consider coverage with another
`
`
`
`
`
`
`
`
`anticoagulant if ELIQUIS is discontinued for a reason other than
`
`
`
`pathological bleeding or completion of a course of therapy. (2.5, 5.1,
`
`14.1)
`
` (B) SPINAL/EPIDURAL HEMATOMA: Epidural or
`
` spinal
`
` hematomas may occur in patients treated with ELIQUIS who are
`
`
`
`
`
`
`
` receiving neuraxial anesthesia or undergoing spinal puncture. These
`
`
`
`
` hematomas may result in long-term or permanent paralysis. Consider
`
`
`
`
`
`
`
`
`
` these risks when scheduling patients for spinal procedures. (5.3)
`
`
`
`---------------------------RECENT MAJOR CHANGES--------------------------­
`
`
` Boxed Warning
`
` 8/2014
`
` Indications and Usage (1.2)
`
` 3/2014
` Indications and Usage (1.3, 1.4, 1.5)
`
`
` 8/2014
`
` Dosage and Administration (2.1)
`
` 8/2014
`
` Dosage and Administration (2.8)
`
` 3/2014
`
`
` Warnings and Precautions (5.1)
`
` 8/2014
`
` Warnings and Precautions (5.3)
`
`
` 3/2014
`
` Warnings and Precautions (5.5)
`
`
` 8/2014
` ---------------------------INDICATIONS AND USAGE---------------------------­
`
`
`
`
` ELIQUIS is a factor Xa inhibitor anticoagulant indicated:
` to reduce the risk of stroke and systemic embolism in patients with
`
`•
`
` nonvalvular atrial fibrillation. (1.1)
`
` • 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. (1.2)
`
` • for the treatment of DVT and PE, and for the reduction in the risk of
`
`
`
`
` recurrent DVT and PE following initial therapy. (1.3, 1.4, 1.5)
`
`
`
`
`
`
`
`------------------------DOSAGE AND ADMINISTRATION---------------------­
`
`
` • Reduction of risk of stroke and systemic embolism in nonvalvular atrial
`
`
`
`
` fibrillation:
`
`
`
` • The recommended dose is 5 mg orally twice daily. (2.1)
`
`
` • 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
`
`
`
`
` recommended dose is 2.5 mg orally twice daily. (2.2)
`
` • Prophylaxis of DVT following hip or knee replacement surgery:
`
`
` • The recommended dose is 2.5 mg orally twice daily. (2.1)
`
`
`
` • Treatment of DVT and PE:
`
`
`
` • The recommended dose is 10 mg taken orally twice daily for 7 days,
`
`
`
` followed by 5 mg taken orally twice daily. (2.1)
` • Reduction in the risk of recurrent DVT and PE following initial therapy:
`
`
`
`
` • The recommended dose is 2.5 mg taken orally twice daily. (2.1)
`
`
`
`
`----------------------DOSAGE FORMS AND STRENGTHS--------------------­
` • Tablets: 2.5 mg and 5 mg (3)
`
`
`
`
`
`
`------------------------------CONTRAINDICATIONS------------------------------­
` • Active pathological bleeding (4)
`
`
`
`
` • Severe hypersensitivity to ELIQUIS (4)
`
`
`
`
` ------------------------WARNINGS AND PRECAUTIONS----------------------­
`
` • ELIQUIS can cause serious, potentially fatal bleeding. Promptly evaluate
`
`
`
` signs and symptoms of blood loss. (5.2)
`
`
`
`
`
` • Prosthetic heart valves: ELIQUIS use not recommended. (5.4)
`
`
`-------------------------------ADVERSE REACTIONS-----------------------------­
`
`
`
`
` Most common adverse reactions (>1%) are related to bleeding. (6.1)
` To report SUSPECTED ADVERSE REACTIONS, contact Bristol-Myers
`
`
`
`
` Squibb
`at
` 1-800-FDA-1088
`
`
`
` 1-800-721-5072
`or FDA
`at
`or
` www.fda.gov/medwatch.
`
`
`--------------------------------DRUG INTERACTIONS----------------------------­
`
`
`
`
`• Strong dual inhibitors of CYP3A4 and P-gp increase blood levels of
`
`
`
`
`
`
`
`apixaban. Reduce dose or avoid coadministration. (2.2, 7.1, 12.3)
`
`
`
`
`
`• Simultaneous use of strong dual inducers of CYP3A4 and P-gp reduces
`
`
`
`
`
`blood levels of apixaban: Avoid concomitant use. (2.2, 7.2, 12.3)
`------------------------USE IN SPECIFIC POPULATIONS----------------------­
`• Pregnancy: Not recommended. (8.1)
`
`
`
`
`• Nursing Mothers: Discontinue drug or discontinue nursing. (8.3)
`
`
`
`
`
`• Severe Hepatic Impairment: Not recommended. (12.2)
`
`
`
`
`
`
`See 17 for PATIENT COUNSELING INFORMATION and Medication
`
`Guide.
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Revised: 8/2014
`
`
`
`
`
`
`
`
`FULL PRESCRIBING INFORMATION: CONTENTS*
`WARNING: (A) PREMATURE DISCONTINUATION OF ELIQUIS
`
`INCREASES THE RISK OF THROMBOTIC EVENTS
`
`
`(B) SPINAL/EPIDURAL HEMATOMA
`
`
`
`INDICATIONS AND USAGE
`1
`
`
`
`Reduction of Risk of Stroke and Systemic Embolism in
`1.1
`
`Nonvalvular Atrial Fibrillation
`
`
`1.2
`Prophylaxis of Deep Vein Thrombosis Following Hip or
`
`Knee Replacement Surgery
`
`
`1.3
`Treatment of Deep Vein Thrombosis
`
`
`Treatment of Pulmonary Embolism
`1.4
`
`
`
`
`1.5
`Reduction in the Risk of Recurrence of DVT and PE
`
`
`2 DOSAGE AND ADMINISTRATION
`
`
`
`2.1
`Recommended Dose
`
`
`2.2
`Dosage Adjustments
`
`
`2.3
`Missed Dose
`
`2.4
`Temporary Interruption for Surgery and Other
`
`
`
`
`Interventions
`
`
`2.5
`Converting from or to ELIQUIS
`
`
`
`Hepatic Impairment
`2.6
`
`
`2.7
`Renal Impairment
`
`
`2.8
`Administration Options
`
`
`3 DOSAGE FORMS AND STRENGTHS
`
`
`
`4 CONTRAINDICATIONS
`
`
`5 WARNINGS AND PRECAUTIONS
`
`
`Increased Risk of Thrombotic Events after Premature
`5.1
`
`
`
`Discontinuation
`
`Reference ID: 3614224
`
`
`
` 1
`
`
`5.2
`
`5.3
`
`5.4
`
`5.5
`
`
`Bleeding
`
`Spinal/Epidural Anesthesia or Puncture
`
`
`
`Patients with Prosthetic Heart Valves
`Acute PE in Hemodynamically Unstable Patients or
`
`
`Patients who Require Thrombolysis or Pulmonary
`
`
`
`Embolectomy
`
`
`6 ADVERSE REACTIONS
`
`
`Clinical Trials Experience
`6.1
`
`
`
`7 DRUG INTERACTIONS
`
`
`
`7.1
`Strong Dual Inhibitors of CYP3A4 and P-gp
`
`
`
`
`Strong Dual Inducers of CYP3A4 and P-gp
`7.2
`
`
`
`
`
`
`7.3
`Anticoagulants and Antiplatelet Agents
`
`
`8 USE IN SPECIFIC POPULATIONS
`
`
`8.1
`Pregnancy
`
`
`8.2
`Labor and Delivery
`
`
`8.3
`Nursing Mothers
`
`
`8.4
`Pediatric Use
`
`
`8.5
`Geriatric Use
`
`8.6
`End-Stage Renal Disease Patients Maintained with
`
`Hemodialysis
`
`
`10 OVERDOSAGE
`
`
`11 DESCRIPTION
`
`
`12 CLINICAL PHARMACOLOGY
`
`
`12.1 Mechanism of Action
`
`
`
`12.2
`Pharmacodynamics
`
`
`12.3
`Pharmacokinetics
`
`

`

`
`
`13 NONCLINICAL TOXICOLOGY
`
`
`
`13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
`
`
`14
`CLINICAL STUDIES
`
`
`
`14.1 Reduction of Risk of Stroke and Systemic Embolism in
`
`Nonvalvular Atrial Fibrillation
`
`
`
`14.2
`Prophylaxis of Deep Vein Thrombosis Following Hip or
`
`Knee Replacement Surgery
`
`
`
`
`
`
`Treatment of DVT and PE and Reduction in the Risk of
`14.3
`
`Recurrence of DVT and PE
`
`
`
`16
`HOW SUPPLIED/STORAGE AND HANDLING
`
`
`
`17
`PATIENT COUNSELING INFORMATION
`
`
`
`
`* Sections or subsections omitted from the full prescribing information
`
`
`are not listed.
`
`Reference ID: 3614224
`
`
`
` 2
`
`

`

`
` FULL PRESCRIBING INFORMATION
`
`
`
`
`
`
` WARNING: (A) PREMATURE DISCONTINUATION OF ELIQUIS INCREASES THE
`
`
`
`
` RISK OF THROMBOTIC EVENTS
`
`
`
`
`
`
` (B) SPINAL/EPIDURAL HEMATOMA
`
`
`
`
`
` (A) PREMATURE DISCONTINUATION OF ELIQUIS INCREASES THE RISK OF
`
` THROMBOTIC EVENTS
`
`
`
`
` Premature discontinuation of any oral anticoagulant, including ELIQUIS, increases the
`
` risk of thrombotic events. If anticoagulation with ELIQUIS is discontinued for a reason
`
`
`
`
` other than pathological bleeding or completion of a course of therapy, consider coverage
`
`
` with another anticoagulant [see Dosage and Administration (2.5), Warnings and Precautions
`
`
` (5.1), and Clinical Studies (14.1)].
`
`
`
`
` (B) SPINAL/EPIDURAL HEMATOMA
`
` Epidural or spinal hematomas may occur in patients treated with ELIQUIS who are
`
`
`
`
`
`
`
`
` receiving neuraxial anesthesia or undergoing spinal puncture. These hematomas may
` 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 or spinal
`
`
`
` hematomas in these patients include:
`
`
`• use of indwelling epidural catheters
`
`
`• concomitant use of other drugs that affect hemostasis, such as nonsteroidal anti-
`
`
`
`
`inflammatory drugs (NSAIDs), platelet inhibitors, other anticoagulants
`
`• a history of traumatic or repeated epidural or spinal punctures
`
`
`
`
`• a history of spinal deformity or spinal surgery
`
`
` • optimal timing between the administration of ELIQUIS and neuraxial procedures is
`
`
` not known
`
`
`
`
`
`[see Warnings and Precautions (5.3)]
`
`
`
`
`Monitor patients frequently for signs and symptoms of neurological impairment. If
`neurological compromise is noted, urgent treatment is necessary [see Warnings and
`
`
`Precautions (5.3)].
`
`
`
`
`
`
`Consider the benefits and risks before neuraxial intervention in patients anticoagulated or
`to be anticoagulated [see Warnings and Precautions (5.3)].
`
`
`
`3
`
`
`Reference ID: 3614224
`
`

`

`
` 1
`
`
`
`
`
` 1.1
`
`
`
` INDICATIONS AND USAGE
`
`
`
`
` Reduction of Risk of Stroke and Systemic Embolism in
` Nonvalvular Atrial Fibrillation
`
`
` ELIQUIS (apixaban) is indicated to reduce the risk of stroke and systemic embolism in patients
`
`
`
`
` with nonvalvular atrial fibrillation.
`
`
`
`
`
`
`
`
`
` 1.2
`
`
`
` Prophylaxis of Deep Vein Thrombosis Following Hip or Knee
`
`
` Replacement Surgery
`
`
` 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.
`
`
`
` 1.3
`
`
`
` Treatment of Deep Vein Thrombosis
`
`
`
` ELIQUIS is indicated for the treatment of DVT.
`
`
`
` 1.4
`
`
`
` Treatment of Pulmonary Embolism
`
`
`
` ELIQUIS is indicated for the treatment of PE.
`
`
`
` 1.5
`
`
`
` Reduction in the Risk of Recurrence of DVT and PE
`
`
`
`
`
` ELIQUIS is indicated to reduce the risk of recurrent DVT and PE following initial therapy.
`
`
`
`
`
` 2
`
`
`
` 2.1
`
`
`
` DOSAGE AND ADMINISTRATION
`
`
`
`
`
` Recommended Dose
`
`
`
` Reduction of Risk of Stroke and Systemic Embolism in Patients with Nonvalvular Atrial
`
` Fibrillation
`
`
`
` The recommended dose of ELIQUIS for most patients is 5 mg taken orally twice daily.
`
`
`
`4
`
`
`Reference ID: 3614224
`
`

`

`
` 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
`
`
` be taken 12 to 24 hours after surgery.
`
`
`
`
`•
`
`
`•
`
`
`
` In patients undergoing hip replacement surgery, the recommended duration of treatment is 35
`
` days.
` In patients undergoing knee replacement surgery, the recommended duration of treatment is
`
` 12 days.
`
`
`
` Treatment of DVT and PE
`
`
`
`
`
`
`
` The recommended dose of ELIQUIS is 10 mg taken orally twice daily for 7 days, followed by
`
`
`
` 5 mg taken orally twice daily.
`
`
`
`
`
` Reduction in the Risk of Recurrence of DVT and PE
`
`
`
`
`
`
`
` The recommended dose of ELIQUIS is 2.5 mg taken orally twice daily after at least 6 months of
`
` treatment for DVT or PE [see Clinical Studies (14.3)].
`
`
`
`
`
`
` 2.2
`
`
`
` Dosage Adjustments
`
`
` 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:
`
`
`
`
`
`
`
`
`•
`
`•
`
`•
`
`
` age ≥80 years
`
` body weight ≤60 kg
`
` serum creatinine ≥1.5 mg/dL
`
`
`
`
`
`
`
` Coadministration with strong dual CYP3A4 and P-gp inhibitors: For patients receiving
`
`
`
`
` ELIQUIS doses greater than 2.5 mg twice daily, reduce the dose by 50% 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, clarithromycin) [see
`
`
` Clinical Pharmacology (12.3)].
`
`
` In patients already taking 2.5 mg twice daily, avoid coadministration of ELIQUIS with strong
`
`
`
`
`
` dual inhibitors of CYP3A4 and P-gp [see Drug Interactions (7.1)].
`
`
`
`
`
`5
`
`
`Reference ID: 3614224
`
`

`

`
` 2.3
`
`
`
`
`
` Missed Dose
`
`
`
`
`
` 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
`
`
` be doubled to make up for a missed dose.
`
`
`
` 2.4
`
`
`
` Temporary Interruption for Surgery and Other Interventions
`
`
`
`
`
`
` 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.
`
`
` 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
`
` 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
`
`
` after the surgical or other procedures as soon as adequate hemostasis has been established.
`
`
`
`
`
`
` 2.5
`
`
`
` Converting from or to ELIQUIS
`
`
`
` Switching from warfarin to ELIQUIS: Warfarin should be discontinued and ELIQUIS started
`
`
`
` when the international normalized ratio (INR) is below 2.0.
`
`
`
`
`
`
`
`
` 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
`
`
` 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
`
`
`
` taken, discontinuing the parenteral anticoagulant when INR reaches an acceptable range.
`
`
`
`
` Switching between ELIQUIS and anticoagulants other than warfarin: Discontinue one being
`
`
`
` taken and begin the other at the next scheduled dose.
`
`
`
`
`
`
`
` 2.6
`
`
`
` Hepatic Impairment
`
`
`
`
`
` No dose adjustment is required in patients with mild hepatic impairment.
`
`
`
` Because patients with moderate hepatic impairment may have intrinsic coagulation abnormalities
`
` and there is limited clinical experience with ELIQUIS in these patients, dosing recommendations
`
` cannot be provided [see Clinical Pharmacology (12.2)].
`
`
`6
`
`
`Reference ID: 3614224
`
`

`

`
`ELIQUIS is not recommended in patients with severe hepatic impairment [see Clinical
`
` Pharmacology (12.3)].
`
`
`
` 2.7
`
`
`
` Renal Impairment
`
`
`
`
`
`
` The dosing adjustment for patients with moderate renal impairment and nonvalvular atrial
` fibrillation is described above [see Dosage and Administration (2.2)]. 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 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)].
`
`
`
`
`
` No dose adjustment is required for the following indications:
`
`
`
`
`•
`
`
`•
`
`
` for the prophylaxis of DVT, which may lead to PE, in patients who have undergone hip or
` knee replacement surgery.
`
`
`
`
`
`
`
`
` for the treatment of DVT and PE, and for the reduction in the risk of recurrent DVT and PE.
`
`
`
`
`
` 2.8
`
`
`
` Administration Options
`
`
` 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
` (NGT) [see Clinical Pharmacology (12.3)]. Information regarding the administration of crushed
`
`
`
` and suspended ELIQUIS tablets swallowed by mouth is not available.
`
`
`
`
` 3
`
`
`
` DOSAGE FORMS AND STRENGTHS
`
`
`
` • 2.5 mg, yellow, round, biconvex, film-coated tablets with “893” debossed on one side and
`
`
` “2½” on the other side.
`
`
`
`
`
` • 5 mg, pink, oval-shaped, biconvex, film-coated tablets with “894” debossed on one side and
`
`
` “5” on the other side.
`
`
`
` 4
`
`
`
` CONTRAINDICATIONS
`
`
`
` ELIQUIS is contraindicated in patients with the following conditions:
`
`7
`
`
`Reference ID: 3614224
`
`

`

`
`
`
`
`
`
`
`
`
` • Active pathological bleeding [see Warnings and Precautions (5.2) and Adverse Reactions
`
`
` (6.1)]
` • Severe hypersensitivity reaction to ELIQUIS (e.g., anaphylactic reactions) [see Adverse
`
`
` Reactions (6.1)]
`
`
`
`
`
`
`
`
`
`
`
`
`
` 5
`
`
`
` 5.1
`
`
`
` WARNINGS AND PRECAUTIONS
`
`
` Increased Risk of Thrombotic Events after Premature
`
` Discontinuation
`
`
`
`
`
`
` Premature discontinuation of any oral anticoagulant, including 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 ELIQUIS to warfarin in clinical trials in atrial
`
`
`
` fibrillation patients. If ELIQUIS is discontinued for a reason other than pathological bleeding or
`
`
` completion of a course of therapy, consider coverage with another anticoagulant [see Dosage
`
`
` and Administration (2.5) and Clinical Studies (14.1)].
`
`
`
`
`
` 5.2
`
`
`
` Bleeding
`
` ELIQUIS increases the risk of bleeding and can cause serious, potentially fatal, bleeding [see
`
`
` Dosage and Administration (2.2) and Adverse Reactions (6.1)].
`
`
`
`
`
`
`
`
`
`
`
` Concomitant use of drugs affecting hemostasis increases the risk of bleeding. These include
`
` aspirin and other antiplatelet agents, other anticoagulants, heparin, thrombolytic agents, selective
`
`
`
`serotonin reuptake inhibitors, serotonin norepinephrine reuptake inhibitors, and nonsteroidal
`
` anti-inflammatory drugs (NSAIDs) [see Drug Interactions (7.3)].
`
`
` Advise patients of signs and symptoms of blood loss and to report them immediately or go to an
`
`
`
`
`
`
` emergency room. Discontinue ELIQUIS in patients with active pathological hemorrhage.
`
`
`
` 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 drug half-lives. 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
`
`
` and vitamin K are not expected to affect the anticoagulant activity of apixaban. There is no
`
`
`
` experience with antifibrinolytic agents (tranexamic acid, aminocaproic acid) in individuals
`
`
` receiving apixaban. There is neither scientific rationale for reversal nor experience with systemic
`
`
`
` hemostatics (desmopressin and aprotinin) in individuals receiving apixaban. Use of procoagulant
`
`8
`
`
`Reference ID: 3614224
`
`

`

`
` reversal agents such as prothrombin complex concentrate, activated prothrombin complex
`
`
` concentrate, or recombinant factor VIIa may be considered but has not been evaluated in clinical
`
` studies. Activated oral charcoal reduces absorption of apixaban, thereby lowering apixaban
`
`
` plasma concentration [see Overdosage (10)].
`
`
`
`
`
`
` 5.3
`
`
`
` Spinal/Epidural Anesthesia or Puncture
`
`
`
`
` When neuraxial anesthesia (spinal/epidural anesthesia) or spinal/epidural puncture is employed,
`
` patients treated with antithrombotic agents for prevention of thromboembolic complications are
` at risk of developing an epidural or spinal hematoma which can result in long-term or permanent
`
`
` paralysis.
`
`
`
`
` The risk of these events may be increased by the postoperative use of indwelling epidural
`
`
` catheters or the concomitant use of medicinal products affecting hemostasis. Indwelling epidural
`
` or intrathecal catheters should not be removed earlier than 24 hours after the last administration
`
`
` of ELIQUIS. The next dose of ELIQUIS should not be administered earlier than 5 hours after the
`
`
` removal of the catheter. The risk may also be increased by traumatic or repeated epidural or
`
`
`
` spinal puncture. If traumatic puncture occurs, delay the administration of ELIQUIS for 48 hours.
`
`
` Monitor patients frequently for signs and symptoms of neurological impairment (e.g., numbness
`
` or weakness of the legs, bowel, or bladder dysfunction). If neurological compromise is noted,
`
` urgent diagnosis and treatment is necessary. Prior to neuraxial intervention the physician should
`
`
` consider the potential benefit versus the risk in anticoagulated patients or in patients to be
`
` anticoagulated for thromboprophylaxis.
`
`
`
` 5.4
`
`
`
` Patients with Prosthetic Heart Valves
`
`
`
` The safety and efficacy of ELIQUIS have not been studied in patients with prosthetic heart
`
`
`
`
` valves. Therefore, use of ELIQUIS is not recommended in these patients.
`
`
`
`
`
` 5.5
`
` Acute PE in Hemodynamically Unstable Patients or Patients
`
`
` who Require Thrombolysis or Pulmonary Embolectomy
`
`
` Initiation of ELIQUIS is not recommended as an alternative to unfractionated heparin for the
`
` initial treatment of patients with PE who present with hemodynamic instability or who may
`
` receive thrombolysis or pulmonary embolectomy.
`
`
`
`9
`
`
`Reference ID: 3614224
`
`

`

`
` 6
`
`
`
`
`
` ADVERSE REACTIONS
`
`
`
` The following serious adverse reactions are discussed in greater detail in other sections of the
`
` prescribing information.
`
`
`•
`
`
`
`
`
`
` Increased risk of thrombotic events after premature discontinuation [see Warnings and
`
`
` Precautions (5.1)]
` • Bleeding [see Warnings and Precautions (5.2)]
`
`
`
` • Spinal/epidural anesthesia or puncture [see Warnings and Precautions (5.3)]
`
`
`
`
`
`
`
`
`
`
`
`
` 6.1
`
`
`
` Clinical Trials Experience
`
`
`
`
`
`
` Because clinical trials are conducted under widely varying conditions, adverse reaction rates
`
` observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials
`
` of another drug and may not reflect the rates observed in practice.
`
`
`
`
`
`
`
`
`
`
` Reduction of Risk of Stroke and Systemic Embolism in Nonvalvular Atrial Fibrillation
`
`
`
`
`
` The safety of ELIQUIS was evaluated in the ARISTOTLE and AVERROES studies [see
`
`
`
`
` Clinical Studies (14)], including 11,284 patients exposed to ELIQUIS 5 mg twice daily and 602
`
`
`
`
`
`
`
`
` patients exposed to ELIQUIS 2.5 mg twice daily. The duration of ELIQUIS exposure was ≥12
`
`
`
`
`
`
`
`
`
`
`
` months for 9375 patients and ≥24 months for 3369 patients in the two studies. In ARISTOTLE,
`
`
`
`
`
`
` the mean duration of exposure was 89 weeks (>15,000 patient-years). In AVERROES, the mean
`
`
` duration of exposure was approximately 59 weeks (>3000 patient-years).
`
`
`
`
` The most common reason for treatment discontinuation in both studies was for bleeding-related
`
`
`
`
`
`
` adverse reactions; in ARISTOTLE this occurred in 1.7% and 2.5% of patients treated with
` ELIQUIS and warfarin, respectively, and in AVERROES, in 1.5% and 1.3% on ELIQUIS and
`
`
`
`
` aspirin, respectively.
`
` Bleeding in Patients with Nonvalvular Atrial Fibrillation in ARISTOTLE and AVERROES
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` Tables 1 and 2 show the number of patients experiencing major bleeding during the treatment
`
` period and the bleeding rate (percentage of subjects with at least one bleeding event per year) in
`
`
` ARISTOTLE and AVERROES.
`
`
`
`10
`
`
`Reference ID: 3614224
`
`

`

`
`
` Major bleeding was defined as clinically overt bleeding that was accompanied by one or more of
`
`
`
`
`
` the following: a decrease in hemoglobin of 2 g/dL or more; a transfusion of 2 or more units of
`
` packed red blood cells; bleeding that occurred in at least one of the following critical sites:
`
` intracranial, intraspinal, intraocular, pericardial, intra-articular, intramuscular with compartment
` syndrome, retroperitoneal; or bleeding that was fatal. Intracranial hemorrhage included
`
`
`
`
` intracerebral (hemorrhagic stroke), subarachnoid, and subdural bleeds.
`
`
`
`
` Bleeding Events in Patients with Nonvalvular Atrial Fibrillation in
`
` ARISTOTLE
`
`
`
`
`
`
`
`
`
` Table 1:
`
`
`
`
`
`
` ELIQUIS
`
` N=9088
`n (%/year)
`
`
` 327 (2.13)
`
` 128 (0.83)
`
` 52 (0.33)
`
`
`32 (0.21)
` 10 (0.06)
`
`
` 318 (2.08)
`
`
` Warfarin
`
` N=9052
`n (%/year)
`
`
` 462 (3.09)
`
` 141 (0.93)
`
` 125 (0.82)
`
`
`
`22 (0.14)
` 37 (0.24)
`
`
` 444 (3.00)
`
`
`
` Hazard Ratio
`
` (95% CI*)
`
`
`
` P-value
`
`
`
` 0.69 (0.60, 0.80)
`
`
` 0.89 (0.70, 1.14)
` 0.41 (0.30, 0.57)
`
`
`
`
`1.42 (0.83, 2.45)
` 0.27 (0.13, 0.53)
`
`
`
` 0.70 (0.60, 0.80)
`
`
`
` <0.0001
`
`-
`
`-
`
`-
`
`-
` <0.0001
`
`
`
` Major†
` Gastrointestinal (GI)‡
`
`
` Intracranial
`
`
` Intraocular§
`
`Fatal¶
`
`
` CRNM**
`
`
`
` * Confidence interval.
`† International Society on Thrombosis and Hemostasis (ISTH) major bleed assessed by sequential testing strategy
`
`
`
`
`
`
`for superiority designed to control the overall type I error in the trial.
`‡ GI bleed includes upper GI, lower GI, and rectal bleeding.
`
`
`§ Intraocular bleed is within the corpus of the eye (a conjunctival bleed is not an intraocular bleed).
`
`
`
`
`¶ Fatal bleed is an adjudicated death because of bleeding during the treatment period and includes both fatal
`
`
`
`
`
`
`
`
`extracranial bleeds and fatal hemorrhagic stroke.
`
`
`** CRNM = clinically relevant nonmajor bleeding.
`
`
`
`Events associated with each endpoint were counted once per subject, but subjects may have contributed events to
`
`
`
`
`multiple endpoints.
`
`
`
`
`
` In ARISTOTLE, the results for major bleeding were generally consistent across most major
`
` subgroups including age, weight, CHADS2 score (a scale from 0 to 6 used to estimate risk of
`
`
`
`
`stroke, with higher scores predicting greater risk), prior warfarin use, geographic region,
`
`
`
`ELIQUIS dose, type of atrial fibrillation (AF), and aspirin use at randomization (Figure 1).
`
`
`
`
`Subjects treated with apixaban with diabetes bled more (3.0% per year) than did subjects without
`
`
`
`diabetes (1.9% per year).
`
`11
`
`
`Reference ID: 3614224
`
`

`

`
`Figure 1:
`
`
`Major Bleeding Hazard Ratios by Baseline Characteristics –
`
`ARISTOTLE Study
`
`
`12
`
`
`
`
`
`Reference ID: 3614224
`
`
`

`

`
` Table 2:
`
`
`
` Bleeding Events in Patients with Nonvalvular Atrial Fibrillation in
`
`
` AVERROES
`
`
`
`
`
`
`
`
`
` Hazard Ratio
`
`
` (95% CI)
`
`
`
` P-value
`
`
` ELIQUIS
`
` Aspirin
`
` N=2798
`
` N=2780
`
` n (%/year)
`
` n (%/year)
`
` 0.07
`
`
` 1.54 (0.96, 2.45)
`
` 29 (0.92)
`
` 45 (1.41)
`
` Major
`
`
`
` 0.99 (0.23, 4.29)
` 5 (0.16)
`
` 5 (0.16)
`
` Fatal
`
`
`
`
` 0.99 (0.39, 2.51)
`
` 11 (0.35)
`
` 11 (0.34)
`
`
`
` Intracranial
`
` Events associated with each endpoint were counted once per subject, but subjects may have contributed events to
`
` multiple endpoints.
`
`
`
`
`--
`
`
`
`
`
`
`
` Other Adverse Reactions
`
`
`
` Hypersensitivity reactions (including drug hypersensitivity, such as skin rash, and anaphylactic
`
`
`
`
`
` reactions, such as allergic edema) and syncope were reported in <1% of patients receiving
` ELIQUIS.
`
`
`
`
` Prophylaxis of Deep Vein Thrombosis Following Hip or Knee Replacement Surgery
`
`
`
`
`
`
`
`
`
`
`
` The safety of ELIQUIS has been evaluated in 1 Phase II and 3 Phase III studies including 5924
`
` patients exposed to ELIQUIS 2.5 mg twice daily undergoing major orthopedic surgery of the
`
` lower limbs (elective hip replacement or elective knee replacement) treated for up to 38 days.
`
`
`
`
`
`
` In total, 11% of the patients treated with ELIQUIS 2.5 mg twice daily experienced adverse
`
` reactions.
`
` Bleeding results during the treatment period in the Phase III studies are shown in Table 3.
`
`
`
` Bleeding was assessed in each study beginning with the first dose of double-blind study drug.
`
`13
`
`
`Reference ID: 3614224
`
`

`

`
` Table 3:
`
`
`
` Bleeding
`
` Endpoint*
`
`
`
` Bleeding During the Treatment Period in Patients Undergoing
`
`
`
` Elective Hip or Knee Replacement Surgery
`
`
`
`
` ADVANCE-3
`
` Hip Replacement Surgery
`
`ELIQUIS
`Enoxaparin
`
`
`2.5 mg po bid
`40 mg sc qd
`
`
`35±3 days
`35±3 days
`
`
`
`
`ADVANCE-2
`
`Knee Replacement Surgery
`ELIQUIS
`Enoxaparin
`
`
`2.5 mg po bid
`40 mg sc qd
`
`
`12±2 days
`12±2 days
`
`
`
`
`First dose
`12 to 24
`
`hours post
`
`surgery
`N=2673
`
`22 (0.82%)†
`
`
`
`
`
`First dose
`
`9 to 15
`hours prior
`
`to surgery
`N=2659
`
`18 (0.68%)
`
`
`
`First dose
`12 to 24
`
`hours post
`
`surgery
`N=1501
`
`9 (0.60%)‡
`
`
`
`First dose
`
`9 to 15
`hours prior
`
`to surgery
`N=1508
`
`14 (0.93%)
`
`
`
`ADVANCE-1
`
`Knee Replacement Surgery
`ELIQUIS
`Enoxaparin
`
`
`2.5 mg po bid
`30 mg sc
`
`
`q12h
`
`12±2 days
`
`12±2 days
`
`
`First dose
`12 to 24
`
`hours post
`
`surgery
`N=1588
`
`22 (1.39%)
`
`
`
`First dose
`12 to 24
`
`hours post
`
`surgery
`N=1596
`
`11 (0.69%)
`
`
`
`
`
`
`
`0
`13 (0.49%)
`
`
`
`0
`10 (0.38%)
`
`
`
`0
`8 (0.53%)
`
`
`
`0
`9 (0.60%)
`
`
`
`0
`10 (0.63%)
`
`
`
`1 (0.06%)
`16 (1.01%)
`
`
`16 (0.60%)
`
`
`14 (0.53%)
`
`
`5 (0.33%)
`
`
`9 (0.60%)
`
`
`9 (0.56%)
`
`
`18 (1.13%)
`
`
`
`1 (0.04%)
`
`
`1 (0.04%)
`
`
`1 (0.07%)
`
`
`2 (0.13%)
`
`
`1 (0.06%)
`
`
`4 (0.25%)
`
`
`129 (4.83%)
`
`
`134 (5.04%)
`
`
`53 (3.53%)
`
`
`72 (4.77%)
`
`
`46 (2.88%)
`
`
`68 (4.28%)
`
`
`126 (8.36%)
`
`
`85 (5.33%)
`
`
`108 (6.80%)
`
`All treated
`
`Major
`
`(including
`
`surgical site)
`
`
`Fatal
`Hgb
`
`
`decrease
`≥2 g/dL
`
`
`Transfusion
`of ≥2 units
`
`RBC
`
`
`Bleed at
`critical site§
`
`Major
`
`+ CRNM¶
`
`
`
`
`
`104 (6.93%)
`313 (11.71%) 334 (12.56%)
`All
`
`
`
`* All bleeding criteria included surgical site bleeding.
`† Includes 13 subjects with major bleeding events that occurred before the first dose of apixaban (administered 12
`
`
`
`
`
`to 24 hours post surgery).
`‡ Includes 5 subjects with major bleeding events that occurred before the first dose of apixaban (administered 12 to
`
`
`
`
`
`24 hours post surgery).
`§ Intracranial, intraspinal, intraocular, pericardial, an operated joint requiring re-operation or intervention,
`
`
`
`intramuscular with compartment syndrome, or retroperitoneal. Bleeding into an operated joint requiring re-
`
`
`
`operation or intervention was present in all patients with this category of bleeding. Events and event rates include
`
`
`
`one enoxaparin-treated patient in ADVANCE-1 who also had intracranial hemorrhage.
`¶ CRNM = clinically relevant nonmajor.
`
`
`
`
`Adverse reactions occurring in ≥1% of patients undergoing hip or knee replacement surgery in
`
`
`
`
` the 1 Phase II study and the 3 Phase III studies are listed in Table 4.
`
`14
`
`
`Reference ID: 3614224
`
`

`

`
` Table 4:
`
`
`
` Nausea
`
`Anemia (including postoperative and hemorrhagic anemia,
`
`and respective laboratory parameters)
`
`Contusion
`
`Hemorrhage (including hematoma, and vaginal and urethral
`
`hemorrhage)
`
`Postprocedural hemorrhage (including postprocedural
`
`hematoma, wound hemorrhage, vessel puncture site
`
`
`hematoma and catheter site hemorrhage)
`
`Transaminases increased (including alanine aminotransferase
`increased and alanine aminotransferase abnormal)
`
`Aspartate aminotransferase increased
`
`Gamma-glutamyltransferase increased
`
`
` Adverse Reactions Occurring in ≥1% of Patients in Either Group
`
`
` Undergoing Hip or Knee Replacement Surgery
`
`
`
` ELIQUIS, n (%)
` 2.5 mg po bid
`
`
`
` N=5924
`
` 153 (2.6)
`153 (2.6)
`
`
`Enoxaparin, n (%)
`
` 40 mg sc qd or
`
` 30 mg sc q12h
`
` N=5904
`
` 159 (2.7)
`178 (3.0)
`
`
`
`
`83 (1.4)
`
`67 (1.1)
`
`
`54 (0.9)
`
`
`50 (0.8)
`
`
`47 (0.8)
`
`38 (0.6)
`
`
`115 (1.9)
`
`81 (1.4)
`
`
`60 (1.0)
`
`
`71 (1.2)
`
`
`69 (1.2)
`
`65 (1.1)
`
`
`
`
` Less common adverse reactions in apixaban-treated patients undergoing hip or knee replacement
`
`
`
`
` surgery occurring at a frequency of ≥0.1% to <1%:
`
`
`
`
` Blood and lymphatic system disorders: thrombocytopenia (including platelet count decreases)
`
`
`
`
`
`
` Vascular disorders: hypotension (including procedural hypotension)
`
`
`
`
`
`
` Respiratory, thoracic, and mediastinal disorders: epistaxis
`
`
`
`
`
`
` Gastrointestinal disorders: gastrointestinal hemorrhage (including hematemesis and melena),
`
`
` hematochezia
`
`
`
`
`
` Hepatobiliary disorders: liver function test abnormal, blood alkaline phosphatase increased,
`
` blood bilirubin increased
`
`
`
`
`
`
`
` Renal and urinary disorders: hematuria (including respective laboratory parameters)
`
`
`
` Injury, poisoning, and procedural complications: wound secretion, incision-site hemorrhage
`
`
` (including