`These highlights do not include all the information needed to use ELIQUIS
`safely and effectively. See full prescribing information for ELIQUIS.
`
`ELIQUIS(cid:147)(cid:147) (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. (2.4, 5.1,
`14.1)
`spinal
`(B) SPINAL/EPIDURAL HEMATOMA: Epidural or
`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---------------------------
`Warnings and Precautions (5.2)
`6/2018
`---------------------------INDICATIONS AND USAGE----------------------------
`ELIQUIS is a factor Xa inhibitor indicated:
`(cid:120) to reduce the risk of stroke and systemic embolism in patients with
`nonvalvular atrial fibrillation. (1.1)
`(cid:120) 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)
`(cid:120) 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----------------------
`(cid:120) Reduction of risk of stroke and systemic embolism in nonvalvular atrial
`fibrillation:
`(cid:120) The recommended dose is 5 mg orally twice daily. (2.1)
`(cid:120) In patients with at least 2 of the following characteristics: age greater
`than or equal to 80 years, body weight less than or equal to 60 kg, or
`
`serum creatinine greater than or equal to 1.5 mg/dL, the recommended
`dose is 2.5 mg orally twice daily. (2.1)
`(cid:120) Prophylaxis of DVT following hip or knee replacement surgery:
`(cid:120) The recommended dose is 2.5 mg orally twice daily. (2.1)
`(cid:120) Treatment of DVT and PE:
`(cid:120) The recommended dose is 10 mg taken orally twice daily for 7 days,
`followed by 5 mg taken orally twice daily. (2.1)
`(cid:120) Reduction in the risk of recurrent DVT and PE following initial therapy:
`(cid:120) The recommended dose is 2.5 mg taken orally twice daily. (2.1)
`----------------------DOSAGE FORMS AND STRENGTHS---------------------
`(cid:120) Tablets: 2.5 mg and 5 mg (3)
`------------------------------CONTRAINDICATIONS-------------------------------
`(cid:120) Active pathological bleeding (4)
`(cid:120) Severe hypersensitivity to ELIQUIS (4)
`------------------------WARNINGS AND PRECAUTIONS-----------------------
`(cid:120) ELIQUIS can cause serious, potentially fatal, bleeding. Promptly evaluate
`signs and symptoms of blood loss. An agent to reverse the anti-factor Xa
`activity of apixaban is available. (5.2)
`(cid:120) 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
`1-800-721-5072
`or FDA
`at
`1-800-FDA-1088
`or
`www.fda.gov/medwatch.
`--------------------------------DRUG INTERACTIONS-----------------------------
`(cid:120) Combined P-gp and strong CYP3A4 inhibitors increase blood levels of
`apixaban. Reduce ELIQUIS dose or avoid coadministration. (2.5, 7.1, 12.3)
`(cid:120) Simultaneous use of combined P-gp and strong CYP3A4 inducers reduces
`blood levels of apixaban: Avoid concomitant use. (7.2, 12.3)
`------------------------USE IN SPECIFIC POPULATIONS-----------------------
`(cid:120) Pregnancy: Not recommended. (8.1)
`(cid:120) Nursing Mothers: Discontinue drug or discontinue nursing. (8.3)
`(cid:120) Severe Hepatic Impairment: Not recommended. (8.7, 12.2)
`See 17 for PATIENT COUNSELING INFORMATION and Medication
`Guide.
`
`Revised: 6/2018
`
`1
`
`FULL PRESCRIBING INFORMATION: CONTENTS*
`WARNING: (A) PREMATURE DISCONTINUATION OF ELIQUIS
`INCREASES THE RISK OF THROMBOTIC EVENTS
`(B) SPINAL/EPIDURAL HEMATOMA
`INDICATIONS AND USAGE
`1.1
`Reduction of Risk of Stroke and Systemic Embolism in
`Nonvalvular Atrial Fibrillation
`1.2
`Prophylaxis of Deep Vein Thrombosis Following Hip or
`Knee Replacement Surgery
`1.3
`Treatment of Deep Vein Thrombosis
`1.4
`Treatment of Pulmonary Embolism
`1.5
`Reduction in the Risk of Recurrence of DVT and PE
`2 DOSAGE AND ADMINISTRATION
`2.1
`Recommended Dose
`2.2
`Missed Dose
`2.3
`Temporary Interruption for Surgery and Other
`Interventions
`Converting from or to ELIQUIS
`2.4
`Combined P-gp and Strong CYP3A4 Inhibitors
`2.5
`Administration Options
`2.6
`3 DOSAGE FORMS AND STRENGTHS
`4 CONTRAINDICATIONS
`5 WARNINGS AND PRECAUTIONS
`5.1
`Increased Risk of Thrombotic Events after Premature
`Discontinuation
`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
`
`5.2
`5.3
`5.4
`5.5
`
`Reference ID: 4283723
`
`1
`
`6
`
`7
`
`ADVERSE REACTIONS
`6.1
`Clinical Trials Experience
`DRUG INTERACTIONS
`7.1
`Combined P-gp and Strong CYP3A4 Inhibitors
`7.2
`Combined P-gp and Strong CYP3A4 Inducers
`7.3
`Anticoagulants and Antiplatelet Agents
`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
`Renal Impairment
`8.7
`Hepatic Impairment
`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
`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
`
`8
`
`14.2
`
`BMS 2018
`MYLAN v. BMS
`IPR2018-00892
`
`
`
`17 PATIENT COUNSELING INFORMATION
`
`* Sections or subsections omitted from the full prescribing information
`are not listed.
`
`Reference ID: 4283723
`
`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 (2.4), 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:
`(cid:120) use of indwelling epidural catheters
`concomitant use of other drugs that affect hemostasis, such as nonsteroidal anti-
`(cid:120)
`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)]
`impairment. If
`Monitor patients frequently for signs and symptoms of neurological
`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)].
`
`(cid:120)
`(cid:120)
`(cid:120)
`
`3
`
`Reference ID: 4283723
`
`
`
`1
`1.1
`
`INDICATIONS AND USAGE
`Reduction of Risk of Stroke and Systemic Embolism in
`Nonvalvular Atrial Fibrillation
`
`ELIQUIS(cid:147) (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
`DOSAGE AND ADMINISTRATION
`2.1
`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.
`The recommended dose of ELIQUIS is 2.5 mg twice daily in patients with at least two of the
`following characteristics:
`age greater than or equal to 80 years
`body weight less than or equal to 60 kg
`serum creatinine greater than or equal to 1.5 mg/dL
`
`(cid:120)
`(cid:120)
`(cid:120)
`
`4
`
`Reference ID: 4283723
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`
`
`Prophylaxis of Deep Vein Thrombosis Following Hip or Knee Replacement Surgery
`
`(cid:120)
`
`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
`
`(cid:120)
`
`The recommended dose of ELIQUIS is 10 mg taken orally twice daily for the first 7 days of
`therapy. After 7 days, the recommended dose is 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
`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.
`2.3
`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 [see Warnings and
`Precautions (5.2)]. 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.
`2.4
`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
`
`5
`
`Reference ID: 4283723
`
`
`
`warfarin. One approach is to 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 from ELIQUIS to anticoagulants other than warfarin (oral or parenteral): Discontinue
`ELIQUIS and begin taking the new anticoagulant other than warfarin at the usual time of the next
`dose of ELIQUIS.
`Switching from anticoagulants other than warfarin (oral or parenteral) to ELIQUIS: Discontinue
`the anticoagulant other than warfarin and begin taking ELIQUIS at the usual time of the next dose
`of the anticoagulant other than warfarin.
`2.5
`Combined P-gp and Strong CYP3A4 Inhibitors
`For patients receiving ELIQUIS doses of 5 mg or 10 mg twice daily, reduce the dose by 50% when
`ELIQUIS is coadministered with drugs that are combined P-glycoprotein (P-gp) and strong
`cytochrome P450 3A4 (CYP3A4) inhibitors (e.g., ketoconazole, itraconazole, ritonavir) [see
`Clinical Pharmacology (12.3)].
`In patients already taking 2.5 mg twice daily, avoid coadministration of ELIQUIS with combined
`P-gp and strong CYP3A4 inhibitors [see Drug Interactions (7.1)].
`2.6
`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 water, 5% dextrose in water (D5W), or apple juice, or mixed with
`applesauce and promptly administered orally [see Clinical Pharmacology (12.3)]. Alternatively,
`ELIQUIS tablets may be crushed and suspended in 60 mL of water or D5W and promptly delivered
`through a nasogastric tube [see Clinical Pharmacology (12.3)].
`Crushed ELIQUIS tablets are stable in water, D5W, apple juice, and applesauce for up to 4 hours.
`3
`DOSAGE FORMS AND STRENGTHS
`
`(cid:120)
`
`(cid:120)
`
`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.
`CONTRAINDICATIONS
`4
`ELIQUIS is contraindicated in patients with the following conditions:
`
`6
`
`Reference ID: 4283723
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`
`
`5
`5.1
`
`(cid:120) Active pathological bleeding [see Warnings and Precautions (5.2) and Adverse Reactions
`(6.1)]
`(cid:120) Severe hypersensitivity reaction to ELIQUIS (e.g., anaphylactic reactions) [see Adverse
`Reactions (6.1)]
`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 (2.4) 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 (2.1) 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.
`Reversal of Anticoagulant Effect
`
`An agent to reverse the anti-factor Xa activity of apixaban is available. The pharmacodynamic
`effect of ELIQUIS can be expected to persist for at least 24 hours after the last dose, i.e., for about
`two drug half-lives. Prothrombin complex concentrate (PCC), activated prothrombin complex
`concentrate or recombinant factor VIIa may be considered, but have not been evaluated in clinical
`studies [see Clinical Pharmacology (12.2)]. When PCCs are used, monitoring for
`the
`anticoagulation effect of apixaban using a clotting test (PT, INR, or aPTT) or anti-factor Xa (FXa)
`activity is not useful and is not recommended. Activated oral charcoal reduces absorption of
`apixaban, thereby lowering apixaban plasma concentration [see Overdosage (10)].
`
`7
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`Reference ID: 4283723
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`
`
`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 no experience with systemic
`hemostatics (desmopressin and aprotinin) in individuals receiving apixaban, and they are not
`expected to be effective as a reversal agent.
`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, or 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.
`
`8
`
`Reference ID: 4283723
`
`
`
`(cid:120)
`
`ADVERSE REACTIONS
`6
`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)]
`(cid:120) Bleeding [see Warnings and Precautions (5.2)]
`(cid:120) 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 Patients with 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 (cid:116)12 months for
`9375 patients and (cid:116)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 100
`patient-years) in ARISTOTLE and AVERROES.
`
`9
`
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`
`Hazard Ratio
`(95% CI)
`
`P-value
`
`Bleeding Events in Patients with Nonvalvular Atrial Fibrillation in
`ARISTOTLE*
`ELIQUIS
`Warfarin
`N=9088
`N=9052
`n (per 100 pt-year)
`n (per 100 pt-year)
`Major†
`<0.0001
`0.69 (0.60, 0.80)
`462 (3.09)
`327 (2.13)
`Intracranial (ICH)‡
`-
`0.41 (0.30, 0.57)
`125 (0.82)
`52 (0.33)
`Hemorrhagic stroke§
`-
`0.51 (0.34, 0.75)
`74 (0.49)
`38 (0.24)
`-
`0.29 (0.16, 0.51)
`51 (0.34)
`15 (0.10)
`Other ICH
`Gastrointestinal (GI)¶
`-
`0.89 (0.70, 1.14)
`141 (0.93)
`128 (0.83)
`-
`0.27 (0.13, 0.53)
`37 (0.24)
`10 (0.06)
`Fatal**
`-
`0.13 (0.05, 0.37)
`30 (0.20)
`4 (0.03)
`Intracranial
`-
`0.84 (0.28, 2.15)
`7 (0.05)
`6 (0.04)
`Non-intracranial
`* Bleeding events within each subcategory were counted once per subject, but subjects may have contributed events
`to multiple endpoints. Bleeding events were counted during treatment or within 2 days of stopping study treatment
`(on-treatment period).
`† Defined as clinically overt bleeding accompanied by one or more of the following: a decrease in hemoglobin of (cid:116)2
`g/dL, a transfusion of 2 or more units of packed red blood cells, bleeding at a critical site: intracranial, intraspinal,
`intraocular, pericardial, intra-articular, intramuscular with compartment syndrome, retroperitoneal or with fatal
`outcome.
`‡ Intracranial bleed includes intracerebral, intraventricular, subdural, and subarachnoid bleeding. Any type of
`hemorrhagic stroke was adjudicated and counted as an intracranial major bleed.
`§ On-treatment analysis based on the safety population, compared to ITT analysis presented in Section 14.
`¶ GI bleed includes upper GI, lower GI, and rectal bleeding.
`**Fatal bleeding is an adjudicated death with the primary cause of death as intracranial bleeding or non-intracranial
`bleeding during the on-treatment period.
`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, 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).
`
`Table 1:
`
`10
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`
`
`
`Figure 1:
`
`Major Bleeding Hazard Ratios by Baseline Characteristics –
`ARISTOTLE Study
`
`Note: The figure above presents effects in various subgroups, all of which are baseline characteristics and all of which
`were prespecified, if not the groupings. The 95% confidence limits that are shown do not take into account how many
`comparisons were made, nor do they reflect the effect of a particular factor after adjustment for all other factors.
`Apparent homogeneity or heterogeneity among groups should not be over-interpreted.
`
`11
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`Table 2:
`
`Bleeding Events in Patients with Nonvalvular Atrial Fibrillation in
`AVERROES
`
`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.
`
`Hazard Ratio
`(95% CI)
`
`P-value
`
`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.
`
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`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(cid:114)3 days
`35(cid:114)3 days
`
`ADVANCE-2
`Knee Replacement Surgery
`ELIQUIS
`Enoxaparin
`2.5 mg po bid
`40 mg sc qd
`12(cid:114)2 days
`12(cid:114)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(cid:114)2 days
`12(cid:114)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
`(cid:116)2 g/dL
`Transfusion
`of (cid:116)2 units
`RBC
`Bleed at
`critical site§
`Major
`+ CRNM¶
`104 (6.93%)
`334 (12.56%)
`313 (11.71%)
`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 (cid:116)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.
`
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`Table 4:
`
`Adverse Reactions Occurring in (cid:116)(cid:116)1% of Patients in Either Group
`Undergoing Hip or Knee Replacement Surgery
`ELIQUIS, n (%)
`2.5 mg po bid
`
`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
`
`N=5924
`153 (2.6)
`153 (2.6)
`
`83 (1.4)
`67 (1.1)
`
`54 (0.9)
`
`50 (0.8)
`
`47 (0.8)
`38 (0.6)
`
`Enoxaparin, n (%)
`40 mg sc qd or
`30 mg sc q12h
`N=5904
`159 (2.7)
`178 (3.0)
`
`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 (cid:116)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 incision-site hematoma), operative hemorrhage
`Less common adverse reactions in apixaban-treated patients undergoing hip or knee replacement
`surgery occurring at a frequency of <0.1%:
`
`14
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`Reference ID: 4283723
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`
`
`Gingival bleeding, hemoptysis, hypersensitivity, muscle hemorrhage, ocular hemorrhage
`(including conjunctival hemorrhage), rectal hemorrhage
`Treatment of DVT and PE and Reduction in the Risk of Recurrence of DVT or PE
`
`The safety of ELIQUIS has been evaluated in the AMPLIFY and AMPLIFY-EXT studies,
`including 2676 patients exposed to ELIQUIS 10 mg twice daily, 3359 patients exposed to
`ELIQUIS 5 mg twice daily, and 840 patients exposed to ELIQUIS 2.5 mg twice daily.
`Common adverse reactions ((cid:116)1%) were gingival bleeding, epistaxis, contusion, hematuria, rectal
`hemorrhage, hematoma, menorrhagia, and hemoptysis.
`AMPLIFY Study
`
`The mean duration of exposure to ELIQUIS was 154 days and to enoxaparin/warfarin was 152
`days in the AMPLIFY study. Adverse reactions related to bleeding occurred in 417 (15.6%)
`ELIQUIS-treated patients compared to 661 (24.6%) enoxaparin/warfarin-treated patients. The
`discontinuation rate due to bleeding events was 0.7% in the ELIQUIS-treated patients compared
`to 1.7% in enoxaparin/warfarin-treated patients in the AMPLIFY study.
`In the AMPLIFY study, ELIQUIS was statistically superior to enoxaparin/warfarin in the primary
`safety endpoint of major bleeding (relative risk 0.31, 95% CI [0.17, 0.55], P-value <0.0001).
`Bleeding results from the AMPLIFY study are summarized in Table 5.
`
`Table 5:
`
`Major
`
`Bleeding Results in the AMPLIFY Study
`ELIQUIS
`Enoxaparin/Warfarin
`N=2676
`N=2689
`n (%)
`n (%)
`15 (0.6)
`49 (1.8)
`
`Relative Risk (95% CI)
`
`0.31 (0.17, 0.55)
`p<0.0001
`
`103 (3.9)
`CRNM*
`115 (4.3)
`Major + CRNM
`313 (11.7)
`Minor
`402 (15.0)
`All
`* CRNM = clinically relevant nonmajor bleeding.
`Events associated with each endpoint were counted once per subject, but subjects may have contributed events to
`multiple endpoints.
`
`215 (8.0)
`261 (9.7)
`505 (18.8)
`676 (25.1)
`
`Adverse reactions occurring in (cid:116)1% of patients in the AMPLIFY study are listed in Table 6.
`
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`Reference ID: 4283723
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`
`
`Table 6:
`
`Epistaxis
`Contusion
`Hematuria
`Menorrhagia
`Hematoma
`Hemoptysis
`Rectal hemorrhage
`Gingival bleeding
`
`Adverse Reactions Occurring in (cid:116)(cid:116)1% of Patients Treated for DVT
`and PE in the AMPLIFY Study
`ELIQUIS
`N=2676
`n (%)
`77 (2.9)
`49 (1.8)
`46 (1.7)
`38 (1.4)
`35 (1.3)
`32 (1.2)
`26 (1.0)
`26 (1.0)
`
`Enoxaparin/Warfarin
`N=2689
`n (%)
`146 (5.4)
`97 (3.6)
`102 (3.8)
`30 (1.1)
`76 (2.8)
`31 (1.2)
`39 (1.5)
`50 (1.9)
`
`AMPLIFY-EXT Study
`
`The mean duration of exposure to ELIQUIS was approximately 330 days and to placebo was 312
`days in the AMPLIFY-EXT study. Adverse reactions related to bleeding occurred in 219 (13.3%)
`ELIQUIS-treated patients compared to 72 (8.7%) placebo-treated patients. The discontinuation
`rate due to bleeding events was approximately 1% in the ELIQUIS-treated patients compared to
`0.4% in those patients in the placebo group in the AMPLIFY-EXT study.
`Bleeding results from the AMPLIFY-EXT study are summarized in Table 7.
`
`Table 7:
`
`Bleeding Results in the AMPLIFY-EXT Study
`ELIQUIS 2.5 mg bid
`ELIQUIS 5 mg bid
`N=840
`N=811
`n (%)
`n (%)
`2 (0.2)
`1 (0.1)
`Major
`25 (3.0)
`34 (4.2)
`CRNM*
`27 (3.2)
`35 (4.3)
`Major + CRNM
`75 (8.9)
`98 (12.1)
`Minor
`94 (11.2)
`121 (14.9)
`All
`* CRNM = clinically relevant nonmajor bleeding