Case 1:17-cv-00401-LPS Document 1-2 Filed 04/10/17 Page 1 of 45 PageID #: 21
`Case 1:17-cv—00401-LPS Document 1-2 Filed 04/10/17 Page 1 of 45 PagelD #: 21
`
`
`
`EXHIBIT B
`
`EXHIBIT B
`
`

`

`Case 1:17-cv-00401-LPS Document 1-2 Filed 04/10/17 Page 2 of 45 PageID #: 22
`
`
`
` • 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. (2.1)
`
` • 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 ELIQUIS dose or avoid coadministration. (2.5, 7.1,
`
`
`
`
`
`
`12.3)
`
`• Simultaneous use of strong dual inducers of CYP3A4 and P-gp reduces
`
`
`
`
`
`
`blood levels of apixaban: Avoid concomitant use. (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. (8.7, 12.2)
`
`
`
`
`See 17 for PATIENT COUNSELING INFORMATION and Medication
`
`
`
`Guide.
`
`
` 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. (2.4, 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--------------------------­
`
`
` Dosage and Administration (2.6)
`
` 7/2016
`
`
`
` 7/2016
` Warnings and Precautions (5.2)
` ---------------------------INDICATIONS AND USAGE---------------------------­
`
`
`
` ELIQUIS is a factor Xa inhibitor 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:
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Revised: 07/2016
`
`
`
`
`
`
`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
`Missed Dose
`
`2.3
`Temporary Interruption for Surgery and Other
`
`
`
`
`Interventions
`
`
`2.4
`Converting from or to ELIQUIS
`
`
`
`Strong Dual Inhibitors of CYP3A4 and P-glycoprotein
`2.5
`
`
`
`
`2.6
`Administration Options
`
`
`3 DOSAGE FORMS AND STRENGTHS
`
`
`
`4 CONTRAINDICATIONS
`
`
`5 WARNINGS AND PRECAUTIONS
`
`
`Increased Risk of Thrombotic Events after Premature
`5.1
`
`
`
`Discontinuation
`
`
`5.2
`Bleeding
`
`
`Spinal/Epidural Anesthesia or Puncture
`5.3
`
`
`
`
`5.4
`Patients with Prosthetic Heart Valves
`
`Reference ID: 3961165
`
`
`
` 1
`
`
`5.5
`
`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
`
`
`
`
`7.2
`Strong Dual Inducers of CYP3A4 and P-gp
`
`
`
`
`
`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
`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
`
`

`

`
`
`
`
`Case 1:17-cv-00401-LPS Document 1-2 Filed 04/10/17 Page 3 of 45 PageID #: 23
`
`
`17 PATIENT COUNSELING INFORMATION
`
`
`
`
`
`* Sections or subsections omitted from the full prescribing information
`
`
`are not listed.
`
`
` Prophylaxis of Deep Vein Thrombosis Following Hip or
`14.2
`
`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
`
`
`Reference ID: 3961165
`
`
`
` 2
`
`

`

`Case 1:17-cv-00401-LPS Document 1-2 Filed 04/10/17 Page 4 of 45 PageID #: 24
`
`
` 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:
`
`
`
`
`
`
`
`
`
`
`• 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: 3961165
`
`

`

`Case 1:17-cv-00401-LPS Document 1-2 Filed 04/10/17 Page 5 of 45 PageID #: 25
`
`
` 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.
` Prophylaxis of Deep Vein Thrombosis Following Hip or Knee
`
` 1.2
`
`
` 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.
` Treatment of Deep Vein Thrombosis
`
`
` 1.3
` ELIQUIS is indicated for the treatment of DVT.
`
`
` Treatment of Pulmonary Embolism
` 1.4
` ELIQUIS is indicated for the treatment of PE.
`
`
`
`
` Reduction in the Risk of Recurrence of DVT and PE
` 1.5
` 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 ≥80 years
`
`
` • body weight ≤60 kg
`
`
` serum creatinine ≥1.5 mg/dL
`
`•
`
`
`
`
`4
`
`Reference ID: 3961165
`
`

`

`Case 1:17-cv-00401-LPS Document 1-2 Filed 04/10/17 Page 6 of 45 PageID #: 26
`
`
` 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 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)].
`
` Missed Dose
`
`
` 2.2
`
`
`
`
` 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.
` Temporary Interruption for Surgery and Other Interventions
`
`
`
`
` 2.3
`
` 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.
`
`
` Converting from or to ELIQUIS
`
`
`
` 2.4
`
` 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: 3961165
`
`

`

`Case 1:17-cv-00401-LPS Document 1-2 Filed 04/10/17 Page 7 of 45 PageID #: 27
`
`
` 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.
` Strong Dual Inhibitors of CYP3A4 and P-glycoprotein
`
`
`
` 2.5
` 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 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)].
`
`
` Administration Options
`
`
` 2.6
`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.
` DOSAGE FORMS AND STRENGTHS
`
`
`
` 3
` • 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.
`
`
`6
`
`Reference ID: 3961165
`
`
`
`
`
`
`
`
`
`

`

`Case 1:17-cv-00401-LPS Document 1-2 Filed 04/10/17 Page 8 of 45 PageID #: 28
`
`
` CONTRAINDICATIONS
` 4
`
`
` ELIQUIS is contraindicated in patients with the following conditions:
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` • 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)]
` 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)].
`
`
`
` Bleeding
`
` 5.2
` 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
`
`
`
`
`
`
`
` 5
`
`
` 5.1
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` A specific antidote for ELIQUIS is not available, and there is no established way to reverse
`
`
`
`
`
`
`
`bleeding in patients taking ELIQUIS. 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. Use of
`
`
`
`procoagulant reversal agents, such as prothrombin complex concentrate (PCC), activated
`
`
`prothrombin complex concentrate or recombinant factor VIIa, may be considered but has not
`
`
`been evaluated in clinical studies [see Clinical Pharmacology (12.2)]. When PCCs are used,
`
`
`
`
`
`7
`
`Reference ID: 3961165
`
`

`

`
`
`
`
`Case 1:17-cv-00401-LPS Document 1-2 Filed 04/10/17 Page 9 of 45 PageID #: 29
`
`
`
`
`
`
`
`
` 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)].
`
`
`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.
`
`
`
`
` Spinal/Epidural Anesthesia or Puncture
`
`
` 5.3
`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.
` Patients with Prosthetic Heart Valves
`
`
`
` 5.4
`
`
`
` 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.
`
`
`
`
`
`
`
`
`
`
`8
`
`Reference ID: 3961165
`
`

`

`Case 1:17-cv-00401-LPS Document 1-2 Filed 04/10/17 Page 10 of 45 PageID #: 30
`
`
` 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.
`
`
` 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)]
`
` • 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 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 ≥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.
`
`
`
`9
`
`Reference ID: 3961165
`
`

`

`Case 1:17-cv-00401-LPS Document 1-2 Filed 04/10/17 Page 11 of 45 PageID #: 31
`
`
` 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.
`
`
`
`
`
` Table 1:
`
`
` Bleeding Events in Patients with Nonvalvular Atrial Fibrillation in
`
` ARISTOTLE*
`
`
`
`
`
`
`
`
`
`
` Hazard Ratio
`
` (95% CI)
`
`
`
` P-value
`
`
` 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
`
`
`
`
`
`≥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).
`
`
`
`
`
`
`
`
`
`
`
`10
`
`Reference ID: 3961165
`
`

`

`Case 1:17-cv-00401-LPS Document 1-2 Filed 04/10/17 Page 12 of 45 PageID #: 32
`
`
` 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 pre-specified, 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
`
`Reference ID: 3961165
`
`

`

`Case 1:17-cv-00401-LPS Document 1-2 Filed 04/10/17 Page 13 of 45 PageID #: 33
`
`
` 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.
`
`
`12
`
`Reference ID: 3961165
`
`

`

`Case 1:17-cv-00401-LPS Document 1-2 Filed 04/10/17 Page 14 of 45 PageID #: 34
`
` Bleeding During the Treatment Period in Patients Undergoing
`
`
`
` Elective Hip or Knee Replacement Surgery
`
`
`
`
`
`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%)
`
`
`
`ADVANCE-2
`
`Knee Replacement Surgery
`ELIQUIS
`Enoxaparin
`
`2.5 mg po bid
`40 mg sc qd
`
`12±2 days
`12±2 days
`
`
`
`
`
` ADVANCE-3
`
` Hip Replacement Surgery
`
`ELIQUIS
`Enoxaparin
`
`2.5 mg po bid
`40 mg sc qd
`
`35±3 days
`35±3 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%)
`
`
`
` Table 3:
`
`
`
` Bleeding
`
` Endpoint*
`
`
`
`
`
`
`
`
`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.
`
`
`13
`
`Reference ID: 3961165
`
`

`

`Case 1:17-cv-00401-LPS Document 1-2 Filed 04/10/17 Page 15 of 45 PageID #: 35
`
`
` Table 4:
`
`
`
` 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)
`
`
` 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
`
`
`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 comm