vte assessment crf (using wells'
appendix 4.5 visit 3 (post-op)

Was visit conducted? Yes No Was visit conducted 14 days post-op (+/- 4 days)? Yes No If no, complete deviation log for visit outside window (unless early discontinuation)  
| Vitals Blood Pressure Pulse Temperature Respiratory rate Height Weight Calculate BMI : Weight (kg) / (Height (m) )2   |
|-----------------------------------------------------------------------------------------------------------------------|  
Confirm Subject Cancer diagnosis (based on final pathology):
Malignancy is: ☐BENIGN ☐BORDERLINE ☐MALIGNANT
Diagnosis Origin:  
  
☐Uterine/Endometrial  
  
  
Is subject meeting standard post-op milestones? Yes No Has subject been hospitalized or to the emergency department since discharge?  
Yes No Has subject experienced a major bleeding or CRNM event since last visit?  
Yes No If yes, indicate Bleeding event: __________________________  
$$\mathrm{{i}}\mathrm{{t}}\mathrm{{Z}}$$  
Date Bleeding event: ______________________
Has subject experienced a VTE event since last visit? Yes No If yes, indicate:
VTE event type: _______________________ Date VTE event: _______________________ Medication prescribed _________________________________
Does subject complain of any pain in legs or chest? Yes No Was assessment of VTE conducted Yes No If Yes, Complete VTE CRF
If subject reported a major bleeding of VTE event, discontinue study and complete discontinuation CRF.  
Medication Adherence (applicable if subject discontinued study treatment) Did subject return Medication Bottles/syringes? Yes No N/A
Total UNUSED returned __________ (\# days unused out of 28 days)
Did subject meet medication compliance per bottle/syringe indication? (not > 2 days UNUSED)
Yes No N/A
Did Subject return Subject Diaries for review? Yes No N/A Did subject meet medication compliance per diary? (not > 2 days of missed medication)
Yes No N/A
Schedule subject to return at day 28 (+/- 4 **days). Instruct subject to return all** medication and dairies at that time.  
AE and Medical Adherence Completed By: _________ (Initials)
vte assessment crf (using wells'
appendix 4.6 visit 4 (end

$$\mathsf{N i o}$$
$$\mathbf{Y}\mathbf{e}\mathbf{s}$$  
Was visit conducted? Yes No Was visit conducted 28 days from V1 (+/- 4 days)? Yes No If no, complete deviation log for visit outside window (unless early discontinuation) Was subject discontinued early from study? Yes No  
| Physical Assessment Blood Pressure Pulse Temperature Respiratory rate Height Weight  Calculate BMI Weight (kg)   (Height (m) )2   |        |          |
|-----------------------------------------------------------------------------------------------------------------------------------|--------|----------|
| Review of Systems  Head and Neck                                                                                                  | Normal | Abnormal |
| Cardiovascular                                                                                                                    | Normal | Abnormal |
| Pulmonary/Chest                                                                                                                   | Normal | Abnormal |
| Abdomen                                                                                                                           | Normal | Abnormal |
| Gastrointestinal                                                                                                                  | Normal | Abnormal |
| Genitourinary                                                                                                                     | Normal | Abnormal |
| Musculoskeletal                                                                                                                   | Normal | Abnormal |
| Lymphadenopathy                                                                                                                   | Normal | Abnormal |
| Skin                                                                                                                              | Normal | Abnormal |
| Neurological                                                                                                                      | Normal | Abnormal |
| Hematological                                                                                                                     | Normal | Abnormal |
| Psychiatric                                                                                                                       | Normal | Abnormal |
| Overall Physical assessment                                                                                                       | Normal | Abnormal |  
Did subject physical health change from baseline? Yes No  
$$\mathrm{\mathrm{\bf~Recorded~by:~}}\ -$$
$$({\mathrm{initials}})$$
Recorded by: ______ (initials)
vte assessment crf (using wells'
bleeding/vte assessment

Has subject been hospitalized or to the emergency department since last visit?  
Yes No Has subject experienced a major bleeding or CRNM event since last visit?  
Yes No If yes, indicate:
Bleeding event: _______________________  
$$\mathrm{\Deltate\Bleedif}$$  
$$\mathbb{N}\mathbb{O}$$
$=\;\hdots\;\;\;\hdots$  .
Date Bleeding event: ______________________
Has subject experienced a VTE event since last visit? Yes No  
$${\mathrm{If~yes,~indicicate:}}\atop{\mathrm{V}}$$  
VTE event type: _______________________  
$$\begin{array}{c}{{\mathrm{ate:}}}\\ {{\sqrt{\top}\vdash\mathrm{event}\vdash}}\end{array}$$
date lorte event .
bleeding/vte assessment

Date VTE event: _______________________  
$\Phi$ is a criterion zero.
$\mathbf{a}$
$${\mathrm{Medication~pn}}$$
$$\mathbf{Y}\mathbf{e}\mathbf{s}$$  
$$\mathrm{{\mathrm{t}}}\mathrm{{e}}\mathrm{{d}}$$  
Medication prescribed: ________________________________
Does subject complain of any pain in legs or chest? Yes No  
Was assessment of VTE conducted Yes No
**Yes**  **If Yes, Complete VTE CRF**
If subject reported a major bleeding of VTE event, discontinue study and complete discontinuation CRF.  
Was QOL assessment conducted? Yes No Have subject complete QOL
Was Satisfaction assessment conducted? Yes No Have subject complete satisfaction
date lorte event .
medication adherence

Did subject return Medication Bottles/syringes(?)? Yes No  
| Total UNUSED returned   | __________ (# days unused out of 28 days)   |                                 |
|-------------------------|---------------------------------------------|---------------------------------|
| Pills only:             | # expected returned: 4 pills                | # pills returned total: _______ |  
Did subject meet medication compliance per bottle/syringe indication? (not > 2 days UNUSED)
Yes No Did Subject return Subject Diaries? Yes No Did subject meet medication compliance per diary? (not > 2 days of missed medication)
Yes No AE and Medical Adherence Completed By: _________ (Initials)
date lorte event .
visit 4.7 visit 5 (follow-up/90

Was visit conducted? Yes No  
| Vitals Blood Pressure Pulse Temperature Respiratory rate Height Weight Calculate BMI : Weight (kg) / (Height (m) )2   |
|-----------------------------------------------------------------------------------------------------------------------|  
$$\mathbf{Y}\mathbf{e}\mathbf{s}$$
$$\mathbb{N}\mathbb{O}$$  
Recorded by: _____ (initials)
Is subject meeting standard post-op milestones? Yes No Has subject been hospitalized or to the emergency department since last visit?  
Yes No Has subject experienced a major bleeding or CRNM event since last visit?  
Yes No If yes, indicate:
Bleeding event: _______________________  
Date Bleeding event: ______________________
Has subject experienced a VTE event since last visit? Yes No If yes, indicate:
VTE event type: _______________________  
Date VTE event: _______________________ Medication prescribed: ________________________________
Does subject complain of any pain in legs or chest? Yes No Was assessment of VTE conducted? Yes No  
  
**If Yes, Complete VTE**
CRF
AR assessment completed By: _________
(Initials)
date lorte event .
visit 4.8 unanticipated event visit

Reason for UAE: __________________________________________________ (report AEs per protocol)  
| Vitals Blood Pressure Pulse Temperature Respiratory rate Height Weight  Calculate BMI   | Weight (kg)    |
|-----------------------------------------------------------------------------------------|----------------|
|                                                                                         | (Height (m) )2 |  
Recorded by: ______ (initials)
Has subject been hospitalized or to the emergency department since last visit?  
Yes No Has subject experienced a major bleeding or CRNM event since last visit?  
Yes No If yes, indicate:
Bleeding event: _______________________ Date Bleeding event: ______________________
Has subject experienced a VTE event since last visit? Yes No If yes, indicate:
VTE event type: _______________________ Date VTE event: _______________________ Medication prescribed: ________________________________
Does subject complain of any pain in legs or chest? Yes No Was assessment of VTE conducted Yes No If Yes, Complete VTE CRF  
Was study medication stopped?  
  
If Yes, indicate: Date stopped: _____________________  
  
Stopped by: ☐Investigator ☐Subject  
  
  
  
  
If subject reported a major bleeding of VTE event, discontinue study and complete discontinuation CRF and V4 End of Treatment. Was subject discontinued early from study? Yes No AE assessment completed By: _________
(Initials)
Appendix 4.9 Early Discontinuation CRF Reason for Early Discontinuation:  
  
  
   
☐Medication Non-Compliance
☐Contradiction to Study Medication ☐Lost to Follow-up/Withdrawal
☐Death
☐Investigator Discretion ☐Other: _____________________________
Date of study discontinuation: __________________  
 Was study medication stopped?  
Yes No  
If Yes, indicate: Date stopped: _____________________
Stopped by: ☐Investigator ☐Subject
Was End of Treatment (V4) conducted Yes No  
  
  
  
Complete V4 CRF Recorded by: _________ (Initials)  
  
Subject has been discontinued from participation in study. ___________________________________________ Date: _______________ Investigator signature
date lorte event .
appendix 5 subject diary

| Complaints                         |                                                                                                  |     |       |       |       |       |      |
|------------------------------------|--------------------------------------------------------------------------------------------------|-----|-------|-------|-------|-------|------|
| Reason for Other                   | Reviewed by:                                                                                     |     |       |       |       |       |      |
| )ther Medications
you took today                                    |                                                                                                  |     |       |       |       |       |      |
| ime you took
2nd dose of
medicaiton
[PILLS ONLY]                                    | __                                                                                               | __  |       |       |       |       |      |
| __                                 | __                                                                                               | __  | __    | am    |       |       |      |
| - did not take
medication                                    | Birdol Mellers Squibb Protocol CV185-394; COMIRB Protocol; 14-1574; Version 1.0 Date 30-Sep-2014 |     |       |       |       |       |      |
| __                                 | __                                                                                               | __  | __    | __    | __    | __    |      |
| ime you took
study
medication                                    | ndication                                                                                        |     |       |       |       |       |      |
| ))                                 | s N                                                                                              | s N | s 12  | s N 2 | s N   | s N   | s in |
| □ □ □                              | □□                                                                                               | □□  | □ □ □ | □□    | □ □ □ | □ □ □ |      |
| Study Day                          |                                                                                                  |     |       |       |       |       |      |
| Date                               |                                                                                                  |     |       |       |       |       |      |
| Protocol CV185-394; COMIRB 15-0187 |                                                                                                  |     |       |       |       |       |      |
appendix 6 apixaban investigator brochure
appendix 5 subject diary

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 (apixaban) (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**
1-800-721-5072 or FDA at 1-800-FDA-1088 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
5.2 Bleeding 5.3 Spinal/Epidural Anesthesia or Puncture 5.4 Patients with Prosthetic Heart Valves 5.5 Acute PE in Hemodynamically Unstable Patients or Patients who Require Thrombolysis or Pulmonary Embolectomy
(B) SPINAL/EPIDURAL **HEMATOMA**
1 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 Dosage Adjustments 2.3 Missed Dose 2.4 Temporary Interruption for Surgery and Other Interventions 2.5 Converting from or to ELIQUIS
2.6 Hepatic Impairment 2.7 Renal Impairment 2.8 Administration Options 3 DOSAGE FORMS AND STRENGTHS
4 CONTRAINDICATIONS
5 WARNINGS AND **PRECAUTIONS**
5.1 Increased Risk of Thrombotic Events after Premature Discontinuation 6 ADVERSE **REACTIONS**
6.1 Clinical Trials Experience 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 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 14.3 Treatment of DVT and PE and Reduction in the Risk of 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.  
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)].*
1 INDICATIONS AND **USAGE** 1.1 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 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.  
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)]*.  
83 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)].*
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)].*
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.
appendix 6 apixaban investigator brochure
eliquis (apixaban) eliquis (apixaban) 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)]*
5 WARNINGS AND PRECAUTIONS
5.1 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 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.  
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)]*
appendix 6 apixaban investigator brochure
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.  
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.  
Table 1: Bleeding Events in Patients with Nonvalvular Atrial Fibrillation in ARISTOTLE
ELIQUIS **Warfarin**
N=9088 N=9052 n (%/year) n **(%/year)**
Major† 327 (2.13) 462 (3.09)  
| ARISTOTLE              | ELIQUIS    | Warfarin   |                           |         |
|------------------------|------------|------------|---------------------------|---------|
| N=9088                 | N=9052     |            |                           |         |
| n (%/year) n (%/year)  |            |            |                           |         |
| Major†                 | 327 (2.13) | 462 (3.09) | Hazard Ratio (95% CI*)    | P-value |
| 0.69 (0.60, 0.80)      | <0.0001    |            |                           |         |
| Gastrointestinal (GI)‡ | 128 (0.83) | 141 (0.93) | 0.89 (0.70, 1.14)         | -       |
| Intracranial           | 52 (0.33)  | 125 (0.82) | 0.41 (0.30, 0.57)         | -       |
| Intraocular§           | 32 (0.21)  | 22 (0.14)  | 1.42 (0.83, 2.45)         | -       |
| Fatal¶                 | 10 (0.06)  | 37 (0.24)  | 0.27 (0.13, 0.53)         | -       |
| CRNM**                 | 318 (2.08) | 444 (3.00) | 0.70 (0.60, 0.80) <0.0001 |         |  
* 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).  
Table 2: Bleeding Events in Patients with Nonvalvular Atrial **Fibrillation** in  
  
Major 45 (1.41) 29 (0.92) 1.54 (0.96, 2.45) 0.07Nausea 153 (2.6) 159 (2.7)  
Intracranial 11 (0.34) 11 (0.35) 0.99 (0.39, 2.51) -  
Anemia (including postoperative and hemorrhagic  
anemia, and respective laboratory parameters)  
153 (2.6) 178 (3.0)  
Events associated with each endpoint were counted once per subject, but subjectsContusion 83 (1.4) 115 (1.9)  
| AVERROES                                                                                                                             | ELIQUIS    | Aspirin      |                   |    |
|--------------------------------------------------------------------------------------------------------------------------------------|------------|--------------|-------------------|----|
| N=2798                                                                                                                               | N=2780     | Hazard Ratio |                   |    |
| n (%/year)                                                                                                                           | n (%/year) | (95% CI)     | P-value           |    |
| Fatal                                                                                                                                | 5 (0.16)   | 5 (0.16)     | 0.99 (0.23, 4.29) | -  |
| Intracranial                                                                                                                         | 11 (0.34)  | 11 (0.35)    | 0.99 (0.39, 2.51) | -  |
| may have contributed events to multiple endpoints. Other Adverse Reactions Protocol CV185-394; COMIRB 15-0187 Version 9.0, 1/27/2020 |            |              |                   |    |  
Other Adverse Reactions  
Hypersensitivity reactions (including drug hypersensitivity, such as skin rash, and anaphylactic reactions, such as allergic Version 9.0, 1/27/2020  
85
appendix 6 apixaban investigator brochure
eliquis (apixaban) eliquis (apixaban)

Figure 1: Major Bleeding Hazard Ratios by Baseline Characteristics –
ARISTOTLE **Study**
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 doubleblind study drug.  
Fatal 0 0 0 0 0 1  
(0.06%)  
Hgb decrease  
≥2 g/dL  
13  
(0.49%)  
10  
(0.38%)  
8  
(0.53%)  
9  
(0.60%)  
10  
(0.63%)  
16  
(1.01%)  
Transfusion of  
≥2 units RBC  
16  
(0.60%)  
14  
(0.53%)  
5  
(0.33%)  
9  
(0.60%)  
9  
(0.56%)  
18  
(1.13%)  
Bleed at  
critical site§  
1  
(0.04%)  
1  
(0.04%)  
1  
(0.07%)  
2  
(0.13%)  
1  
(0.06%)  
4  
(0.25%)  
Major  
+ CRNM¶129  
(4.83%)  
134  
(5.04%)  
53  
(3.53%)  
72  
(4.77%)  
46  
(2.88%)  
68  
(4.28%)  
All 313  
(11.71%)  
334  
(12.56%)  
104  
(6.93%)  
126  
(8.36%)  
85  
(5.33%)  
108  
(6.80%)  
* 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.  
Table 4: Adverse Reactions Occurring in ≥1% of Patients in Either Group  
Undergoing Hip or Knee Replacement Surgery  
| Table 3:                                                                                                                                                                                                                                                                                        | Bleeding During the Treatment Period in Patients Undergoing Elective Hip or Knee Replacement Surgery ADVANCE-3 ADVANCE-2 ADVANCE-1   |                                                                                      |                                          |         |         |         |
|-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|--------------------------------------------------------------------------------------------------------------------------------------|--------------------------------------------------------------------------------------|------------------------------------------|---------|---------|---------|
| Bleeding                                                                                                                                                                                                                                                                                        | Hip Replacement                                                                                                                      | Knee Replacement                                                                     | Knee Replacement                         |         |         |         |
| Endpoint*                                                                                                                                                                                                                                                                                       | Surgery                                                                                                                              | Surgery                                                                              | Surgery                                  |         |         |         |
| Enoxaparin                                                                                                                                                                                                                                                                                      |                                                                                                                                      |                                                                                      |                                          |         |         |         |
| ELIQUIS 2.5 mg                                                                                                                                                                                                                                                                                  | 40 mg sc qd                                                                                                                          |                                                                                      |                                          |         |         |         |
| po bid 35±3 days                                                                                                                                                                                                                                                                                | 35±3 days                                                                                                                            | Enoxaparin                                                                           |                                          |         |         |         |
| ELIQUIS 2.5 mg                                                                                                                                                                                                                                                                                  | 30 mg sc q12h                                                                                                                        |                                                                                      |                                          |         |         |         |
| po bid 12±2 days                                                                                                                                                                                                                                                                                | 12±2 days                                                                                                                            |                                                                                      |                                          |         |         |         |
| First dose 12 to 24  hours post  surgery                                                                                                                                                                                                                                                        | Enoxaparin                                                                                                                           |                                                                                      |                                          |         |         |         |
| ELIQUIS 2.5 mg                                                                                                                                                                                                                                                                                  | 40 mg sc qd                                                                                                                          |                                                                                      |                                          |         |         |         |
| po bid 12±2 days                                                                                                                                                                                                                                                                                | 12±2 days                                                                                                                            | First dose 12 to 24  hours post  surgery                                             |                                          |         |         |         |
| All treated                                                                                                                                                                                                                                                                                     | N=2673                                                                                                                               | N=2659                                                                               | N=1501                                   | N=1508  | N=1596  | N=1588  |
| Major                                                                                                                                                                                                                                                                                           | (0.82%)†                                                                                                                             | 18                                                                                   |                                          |         |         |         |
| 22                                                                                                                                                                                                                                                                                              | (0.60%)‡                                                                                                                             | 14                                                                                   |                                          |         |         |         |
| 9                                                                                                                                                                                                                                                                                               | 11                                                                                                                                   | 22                                                                                   |                                          |         |         |         |
| (including                                                                                                                                                                                                                                                                                      | (0.68%)                                                                                                                              | (0.93%)                                                                              | (0.69%)                                  | (1.39%) |         |         |
| surgical site)                                                                                                                                                                                                                                                                                  | First dose 9 to 15  hours prior  to surgery                                                                                          | First dose 12 to 24  hours post  surgery First dose 9 to 15  hours prior  to surgery | First dose 12 to 24  hours post  surgery |         |         |         |
| Fatal                                                                                                                                                                                                                                                                                           | 0                                                                                                                                    | 0                                                                                    | 0                                        | 0       | 0       | 1       |
| (0.06%)                                                                                                                                                                                                                                                                                         |                                                                                                                                      |                                                                                      |                                          |         |         |         |
| Hgb decrease                                                                                                                                                                                                                                                                                    | 13                                                                                                                                   | 10                                                                                   | 8                                        | 9       | 10      | 16      |
| ≥2 g/dL                                                                                                                                                                                                                                                                                         | (0.49%)                                                                                                                              | (0.38%)                                                                              | (0.53%)                                  | (0.60%) | (0.63%) | (1.01%) |
| Transfusion of                                                                                                                                                                                                                                                                                  | 16                                                                                                                                   | 14                                                                                   | 5                                        | 9       | 9       | 18      |
| ≥2 units RBC                                                                                                                                                                                                                                                                                    | (0.60%)                                                                                                                              | (0.53%)                                                                              | (0.33%)                                  | (0.60%) | (0.56%) | (1.13%) |
| Bleed at                                                                                                                                                                                                                                                                                        | 1                                                                                                                                    | 1                                                                                    | 1                                        | 2       | 1       | 4       |
| critical site§                                                                                                                                                                                                                                                                                  | (0.04%)                                                                                                                              | (0.04%)                                                                              | (0.07%)                                  | (0.13%) | (0.06%) | (0.25%) |
| Major + CRNM¶                                                                                                                                                                                                                                                                                   | 129                                                                                                                                  | 134                                                                                  | 53                                       | 72      | 46      | 68      |
| (4.83%)                                                                                                                                                                                                                                                                                         | (5.04%)                                                                                                                              | (3.53%)                                                                              | (4.77%)                                  | (2.88%) | (4.28%) |         |
| All                                                                                                                                                                                                                                                                                             | 313                                                                                                                                  | 334                                                                                  | 104                                      | 126     | 85      | 108     |
| (11.71%)                                                                                                                                                                                                                                                                                        | (12.56%)                                                                                                                             | (6.93%)                                                                              | (8.36%)                                  | (5.33%) | (6.80%) |         |
| * 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 |                                                                                                                                      |                                                                                      |                                          |         |         |         |  
  
| Undergoing Hip or Knee Replacement Surgery ELIQUIS, n (%) 2.5 mg po bid N=5924                                                                                              | Enoxaparin, n (%) 40 mg sc qd or 30 mg sc q12h N=5904   |           |             |      |
|-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------|---------------------------------------------------------|-----------|-------------|------|
| Anemia (including postoperative and hemorrhagic                                                                                                                             | 153 (2.6)                                               | 178 (3.0) |             |      |
| anemia, and respective laboratory parameters) 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.                                                                                                                                                          |                                                         |           |             |      |  
ELIQUIS® (apixaban) ELIQUIS® **(apixaban)**  
| Hemorrhage (including hematoma, and vaginal and urethral hemorrhage)                                                                        | 67 (1.1)   | 81 (1.4)   |
|---------------------------------------------------------------------------------------------------------------------------------------------|------------|------------|
| Postprocedural hemorrhage (including postprocedural hematoma, wound hemorrhage, vessel puncture site hematoma and catheter site hemorrhage) | 54 (0.9)   | 60 (1.0)   |  
(Continued) Undergoing Hip or Knee Replacement Surgery Table 6: Adverse Reactions Occurring in ≥1% **of Patients Treated for**  
DVT and PE in the AMPLIFY **Study**  
| Enoxaparin, n (%) 40 mg sc qd or 30 mg sc q12h N=5904              |                                     |          |
|--------------------------------------------------------------------|-------------------------------------|----------|
| Transaminases increased (including alanine                         | 50 (0.8)                            | 71 (1.2) |
| aminotransferase increased and alanine  aminotransferase abnormal) | ELIQUIS, n (%) 2.5 mg po bid N=5924 |          |
| Aspartate aminotransferase increased                               | 47 (0.8)                            | 69 (1.2) |
| Gamma-glutamyltransferase increased                                | 38 (0.6)                            | 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 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%:
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 (≥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/warfarintreated 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.  
Epistaxis 13 (1.5) 29 (3.6) 9 (1.1)  
Table 5: Bleeding Results in the AMPLIFY **Study** Hematuria 12 (1.4) 17 (2.1) 9 (1.1)  
ELIQUIS Enoxaparin/Warfarin Relative **Risk** Hematoma 13 (1.5) 16 (2.0) 10 (1.2)  
N=2676 N=2689 (95% CI) Contusion 18 (2.1) 18 (2.2) 18 (2.2)  
n (%) n (%) Gingival bleeding 12 (1.4) 9 (1.1) 3 (0.4)  
Major 15 (0.6) 49 (1.8) 0.31 (0.17, 0.55)  
p<0.0001 Other Adverse Reactions  
CRNM* 103 (3.9) 215 (8.0) Less common adverse reactions in ELIQUIS-treated patients in the AMPLIFY or  
Major + CRNM 115 (4.3) 261 (9.7) AMPLIFY-EXT studies occurring at a frequency of ≥0.1% to <1%:  
Minor 313 (11.7) 505 (18.8) Blood and lymphatic system *disorders:* hemorrhagic anemia  
All 402 (15.0) 676 (25.1) Gastrointestinal *disorders:* hematochezia, hemorrhoidal hemorrhage, gastrointestinal  
* CRNM = clinically relevant nonmajor bleeding.  
Events associated with each endpoint were counted once per subject, but subjects may have contributed events to multiple endpoints.  
Table 4: Adverse Reactions Occurring in ≥1% of Patients in Either **Group** Adverse reactions occurring in ≥1% of patients in the AMPLIFY study are listed in Table 6.  
| 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)   |
|----------------------------------------------------------------------------------------------------------------------------------|---------------------------------------------------------------------------------------------------------------|
| Epistaxis  Contusion  Hematuria  Menorrhagia  Hematoma  Hemoptysis Rectal hemorrhage Gingival bleeding                           |                                                                                                               |  
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.  
| Major CRNM* Major + CRNM  Minor All   |
|---------------------------------------|  
Table 7: Bleeding Results in the AMPLIFY-EXT **Study**
* CRNM = clinically relevant nonmajor bleeding.  
Events associated with each endpoint were counted once per subject, but subjects may have contributed events to multiple endpoints.  
| Placebo N=826  n (%) 4 (0.5) 19 (2.3) 22 (2.7) 58 (7.0) 74 (9.0)   |
|--------------------------------------------------------------------|  
| ELIQUIS 2.5 mg  N=840  n (%) 2 (0.2) 25 (3.0) 27 (3.2) 75 (8.9) 94 (11.2)   | ELIQUIS 5 mg  N=811  n (%) 1 (0.1) 34 (4.2) 35 (4.3) 98 (12.1) 121 (14.9)   |
|-----------------------------------------------------------------------------|-----------------------------------------------------------------------------|  
Adverse reactions occurring in ≥1% of patients in the AMPLIFY-EXT study are listed in Table 8.  
| Table 8:   | Adverse Reactions Occurring in ≥1% of Patients Undergoing Extended Treatment for DVT and PE in the AMPLIFY-EXT Study ELIQUIS 2.5 mg  N=840  n (%) ELIQUIS 5 mg  N=811  n (%) Placebo N=826  n (%)   |          |         |
|------------|-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|----------|---------|
| Epistaxis  | 13 (1.5)                                                                                                                                                                                            | 29 (3.6) | 9 (1.1) |  
hemorrhage, hematemesis, melena, anal hemorrhage Injury, poisoning, and procedural *complications:* wound hemorrhage, postprocedural hemorrhage, traumatic hematoma, periorbital hematoma Musculoskeletal and connective tissue *disorders:* muscle hemorrhage Reproductive system and breast disorders: vaginal hemorrhage, metrorrhagia, menometrorrhagia, genital hemorrhage ELIQUIS® (apixaban) ELIQUIS® **(apixaban)**
Vascular *disorders:* hemorrhage Skin and subcutaneous tissue *disorders:* ecchymosis, skin hemorrhage, petechiae Eye disorders: conjunctival hemorrhage, retinal hemorrhage, eye hemorrhage Investigations: blood urine present, occult blood positive, occult blood, red blood cells urine positive General disorders and administration-site *conditions:* injection-site hematoma, vessel puncture-site hematoma 7 DRUG **INTERACTIONS**
Apixaban is a substrate of both CYP3A4 and P-gp. Inhibitors of CYP3A4 and P-gp increase exposure to apixaban and increase the risk of bleeding. Inducers of CYP3A4 and P-gp decrease exposure to apixaban and increase the risk of stroke and other thromboembolic events.  
7.1 Strong Dual Inhibitors of CYP3A4 and **P-gp** For patients receiving ELIQUIS doses greater than 2.5 mg twice daily, the dose of ELIQUIS should be decreased by 50% when it is coadministered with drugs that are strong dual inhibitors of CYP3A4 and P-gp (e.g., ketoconazole, itraconazole, ritonavir, or clarithromycin) [see Dosage and Administration (2.2) and Clinical Pharmacology
(12.3)].  
For patients receiving ELIQUIS at a dose of 2.5 mg twice daily, avoid coadministration with strong dual inhibitors of CYP3A4 and P-gp [see Dosage and Administration *(2.2)* and Clinical Pharmacology *(12.3)].*
7.2 Strong Dual Inducers of CYP3A4 and **P-gp** Avoid concomitant use of ELIQUIS with strong dual inducers of CYP3A4 and P-gp (e.g., rifampin, carbamazepine, phenytoin, St. John's wort) because such drugs will decrease exposure to apixaban [see Clinical Pharmacology *(12.3)].*
7.3 Anticoagulants and Antiplatelet **Agents** Coadministration of antiplatelet agents, fibrinolytics, heparin, aspirin, and chronic NSAID use increases the risk of bleeding.  
APPRAISE-2, a placebo-controlled clinical trial of apixaban in high-risk, post-acute coronary syndrome patients treated with aspirin or the combination of aspirin and clopidogrel, was terminated early due to a higher rate of bleeding with apixaban compared to placebo. The rate of ISTH major bleeding was 2.77% per year with apixaban versus 0.62% per year with placebo in patients receiving single antiplatelet therapy and was 5.91% per year with apixaban versus 2.50% per year with placebo in those receiving dual antiplatelet therapy.  
In ARISTOTLE, concomitant use of aspirin increased the bleeding risk on ELIQUIS from 1.8% per year to 3.4% per year and the bleeding risk on warfarin from 2.7% per year to 4.6% per year. In this clinical trial, there was limited (2.3%) use of dual antiplatelet therapy with ELIQUIS.
appendix 6 apixaban investigator brochure
8 use in specific populations

There are no adequate and well-controlled studies of ELIQUIS in pregnant women.  
Treatment is likely to increase the risk of hemorrhage during pregnancy and delivery.  
ELIQUIS should be used during pregnancy only if the potential benefit outweighs the potential risk to the mother and fetus. Treatment of pregnant rats, rabbits, and mice after implantation until the end of gestation resulted in fetal exposure to apixaban, but was not associated with increased risk for fetal malformations or toxicity. No maternal or fetal deaths were attributed to bleeding. Increased incidence of maternal bleeding was observed in mice, rats, and rabbits at maternal exposures that were 19, 4, and 1 times, respectively, the human exposure of unbound drug, based on area under plasma-concentration time curve
(AUC) comparisons at the maximum recommended human dose (MRHD) of 10 mg
(5 mg twice daily).  
8.2 Labor and **Delivery**
Safety and effectiveness of ELIQUIS during labor and delivery have not been studied in clinical trials. Consider the risks of bleeding and of stroke in using ELIQUIS in this setting [see Warnings and Precautions *(5.2)]*. Treatment of pregnant rats from implantation (gestation Day 7) to weaning (lactation Day 21) with apixaban at a dose of 1000 mg/kg (about 5 times the human exposure based on unbound apixaban) did not result in death of offspring or death of mother rats during labor in association with uterine bleeding. However, increased incidence of maternal bleeding, primarily during gestation, occurred at apixaban doses of
≥25 mg/kg, a dose corresponding to ≥1.3 times the human exposure.  
8.3 Nursing **Mothers** It is unknown whether apixaban or its metabolites are excreted in human milk. Rats excrete apixaban in milk (12% of the maternal dose).  
Women should be instructed either to discontinue breastfeeding or to discontinue ELIQUIS therapy, taking into account the importance of the drug to the mother.  
8.4 Pediatric Use Safety and effectiveness in pediatric patients have not been established.  
8.5 Geriatric Use Of the total subjects in the ARISTOTLE and AVERROES clinical studies, >69% were 65 and older, and >31% were 75 and older. In the ADVANCE-1, ADVANCE-2, and ADVANCE-3 clinical studies, 50% of subjects were 65 and older, while 16% were 75 and older. In the AMPLIFY and AMPLIFY-EXT clinical studies, >32% of subjects were 65 and older and >13% were 75 and older. No clinically significant differences in safety or effectiveness were observed when comparing subjects in different age groups.  
8.6 End-Stage Renal Disease Patients Maintained with **Hemodialysis**
Patients with ESRD with or without hemodialysis were not studied in clinical efficacy and safety studies with ELIQUIS; therefore, the dosing recommendation for patients
appendix 6 apixaban investigator brochure
version 9.0 1/27/2020 89 eliquis

with nonvalvular atrial fibrillation is based on pharmacokinetic and pharmacodynamic
(anti-Factor Xa activity) data in subjects with ESRD maintained on dialysis. The recommended dose for ESRD patients maintained with hemodialysis is 5 mg orally twice daily. For ESRD patients maintained with hemodialysis with one of the following patient characteristics, age ≥80 years or body weight ≤60 kg, reduce dose to 2.5 mg twice daily [see Dosage and Administration (2.7) and Clinical Pharmacology *(12.2,*
12.3)].  
10 OVERDOSAGE
There is no antidote to ELIQUIS. Overdose of ELIQUIS increases the risk of bleeding
[see Warnings and Precautions *(5.2)]*.  
In controlled clinical trials, orally administered apixaban in healthy subjects at doses up to 50 mg daily for 3 to 7 days (25 mg twice daily for 7 days or 50 mg once daily for 3 days) had no clinically relevant adverse effects.  
In healthy subjects, administration of activated charcoal 2 and 6 hours after ingestion of a 20-mg dose of apixaban reduced mean apixaban AUC by 50% and 27%, respectively. Thus, administration of activated charcoal may be useful in the management of apixaban overdose or accidental ingestion.  
11 DESCRIPTION
ELIQUIS (apixaban), a factor Xa (FXa) inhibitor, is chemically described as 1-(4-methoxyphenyl)-7-oxo-6-[4-(2-oxopiperidin-1-yl)phenyl]-4,5,6,7-tetrahydro1H-pyrazolo[3,4-c]pyridine-3-carboxamide. Its molecular formula is C25H25N5O4, which corresponds to a molecular weight of 459.5. Apixaban has the following structural formula:
Apixaban is a white to pale-yellow powder.At physiological pH (1.2–6.8), apixaban does  
  
not ionize; its aqueous solubility across the physiological pH range is ~0.04 mg/mL.  
ELIQUIS tablets are available for oral administration in strengths of 2.5 mg and 5 mg of apixaban with the following inactive ingredients: anhydrous lactose, microcrystalline cellulose, croscarmellose sodium, sodium lauryl sulfate, and magnesium stearate. The film coating contains lactose monohydrate, hypromellose, titanium dioxide, triacetin, and yellow iron oxide (2.5 mg tablets) or red iron oxide (5 mg tablets).
appendix 6 apixaban investigator brochure
12 clinical pharmacology 12.1 mechanism

Apixaban is a selective inhibitor of FXa. It does not require antithrombin III for antithrombotic activity. Apixaban inhibits free and clot-bound FXa, and prothrombinase activity. Apixaban has no direct effect on platelet aggregation, but indirectly inhibits platelet aggregation induced by thrombin. By inhibiting FXa, apixaban decreases thrombin generation and thrombus development.  
12.2 Pharmacodynamics As a result of FXa inhibition, apixaban prolongs clotting tests such as prothrombin time (PT), INR, and activated partial thromboplastin time (aPTT). Changes observed in these clotting tests at the expected therapeutic dose, however, are small, subject to a high degree of variability, and not useful in monitoring the anticoagulation effect of apixaban.  
The Rotachrom® Heparin chromogenic assay was used to measure the effect of apixaban on FXa activity in humans during the apixaban development program.  
A concentration-dependent increase in anti-FXa activity was observed in the dose range tested and was similar in healthy subjects and patients with AF.  
This test is not recommended for assessing the anticoagulant effect of apixaban.  
Pharmacodynamic Drug Interaction *Studies* Pharmacodynamic drug interaction studies with aspirin, clopidogrel, aspirin and clopidogrel, prasugrel, enoxaparin, and naproxen were conducted. No pharmacodynamic interactions were observed with aspirin, clopidogrel, or prasugrel
[see Warnings and Precautions *(5.2)]*. A 50% to 60% increase in anti-FXa activity was observed when apixaban was coadministered with enoxaparin or naproxen.  
Specific *Populations* Renal *impairment:* Anti-FXa activity adjusted for exposure to apixaban was similar across renal function categories.  
Hepatic *impairment:* Changes in anti-FXa activity were similar in patients with mildto-moderate hepatic impairment and healthy subjects. However, in patients with moderate hepatic impairment, there is no clear understanding of the impact of this degree of hepatic function impairment on the coagulation cascade and its relationship to efficacy and bleeding. Patients with severe hepatic impairment were not studied.
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eliquis (apixaban) eliquis (apixaban)

Cardiac Electrophysiology Apixaban has no effect on the QTc interval in humans at doses up to 50 mg.  
12.3 Pharmacokinetics Apixaban demonstrates linear pharmacokinetics with dose-proportional increases in exposure for oral doses up to 10 mg.  
Absorption The absolute bioavailability of apixaban is approximately 50% for doses up to 10 mg of ELIQUIS. Food does not affect the bioavailability of apixaban. Maximum concentrations
(Cnzc) of apixaban appear 3 to 4 hours after oral administration of ELIQUIS. At doses 25 mg, apixaban displays dissolution-limited absorption with decreased bioavailability. Following administration of a crushed 5 mg ELIQUIS tablet that was suspended in 60 mL D5W and delivered through a nasogastric tube (NGT), exposure was similar to that seen in other clinical trials involving healthy volunteers receiving a single oral 5 mg tablet dose.  
Distribution Plasma protein binding in humans is approximately 87%. The volume of distribution (Vss) is approximately 21 liters. Metabolism Approximately 25% of an orally administered apixaban dose is recovered in urine and feces as metabolites. Apixaban is metabolized mainly via CYP3A4 with minor contributions from CYP1A2, 2C8, 2C9, 2C19, and 2J2. O-demethylation and hydroxylation at the 3-oxopiperidinyl moiety are the major sites of biotransformation.  
Unchanged apixaban is the major drug-related component in human plasma; there are no active circulating metabolites.  
Elimination Apixaban is eliminated in both urine and feces. Renal excretion accounts for about 2% of total clearance. Biliary and direct intestinal excretion contributes to elimination of apixaban in the feces.  
Apixaban has a total clearance of approximately 3.3 L/hour and an apparent half-life of approximately 12 hours following oral administration.  
Apixaban is a substrate of transport proteins: P-gp and breast cancer resistance protein.  
Drug Interaction Studies In vitro apixaban studies at concentrations significantly greater than therapeutic CYP2C9, CYP2D6, CYP3A4/5, or CYP2C19, nor induction effect on the activity of CYP1A2, CYP2B6, or CYP3A4/5 were observed. Therefore, apixaban is not expected to alter the metabolic clearance of coadministered drugs that are metabolized by these enzymes. Apixaban is not a significant inhibitor of P-gp.  
The effects of coadministered drugs on the pharmacokinetics of apixaban and associated dose recommendations are summarized in Figure 2 [see also Warnings and Precautions (5.2) and Drug Interactions (7)].  
Effect of Coadministered Drugs on the Pharmacokinetics of Figure 2:
Interacting Drug Strong CYP3A4 and P-gp Inhibitor  
  
In dedicated studies conducted in healthy subjects, famotidine, atenolol, prasugrel, and enoxaparin did not meaningfully alter the pharmacokinetics of apixaban In studies conducted in healthy subjects, apixaban did not meaningfully alter the pharmacokinetics of digoxin, naproxen, atenolol, prasugrel, or acetylsalicylic acid.  
Specific Populations The effects of level of renal impairment, age, body weight, and level of hepatic impairment on the pharmacokinetics of apixaban are summarized in Figure 3.
appendix 6 apixaban investigator brochure
figure 3

Effect of Specific Populations on the Pharmacokinetics of Apixaban  
| PK                               | Fold Change and 90% Cl   | Recommendation                    |     |
|----------------------------------|--------------------------|-----------------------------------|-----|
| Population Description           |                          |                                   |     |
| End-Stage Renal                  | No dose adjustment       |                                   |     |
| Disease "/Normal                 | AUC                      |                                   |     |
| Renal Impairment:                | No dose adjustment       |                                   |     |
| Severe1/Normal                   | MC                       |                                   |     |
| Renal Impairment:                | No dose adjustment       |                                   |     |
| Moderate/Normal                  | AUC                      |                                   |     |
| Rengl Impairment                 | No dose adjustment       |                                   |     |
| Population Description AUCNormal |                          |                                   |     |
| A9                               | No dose adjustment       |                                   |     |
| 265 years/18-40 years AUC        | ---                      |                                   |     |
| Body Weight:                     | No dose adjustment       |                                   |     |
| ≥120 kg/65-85 kg                 | AUC                      |                                   |     |
| Body Weight:                     | No dose adjustment       |                                   |     |
| ≤50 kg/65-85 kg                  | AUC                      |                                   |     |
| Hepatic Impairment:              | Dosing recommendation    |                                   |     |
| Moderate/Normal                  | cannot be provided       |                                   |     |
| AIC                              |                          |                                   |     |
| Hepatic Impairment:              | No dose adjustment       |                                   |     |
| Mild/Normal
End-Stage Renal                                  | AUC                      | No dose adjustment                |     |
| Disease'/Normal                  | AC                       | Change Relative to Reference 12.0 |     |
| Renal Impairment:                | No dose adjustment       |                                   |     |
| Severe1/Normal                   | AUC                      |                                   |     |
| Renal Impairment:                | No dose adjustment       |                                   |     |
| Moderate/Normal                  | MC                       |                                   |     |
| Renal Impairment                 | No dose adjustment       |                                   |     |
| MdNormal                         | AUC                      |                                   |     |
| A08                              | No dose adjustment       |                                   |     |
| 265 years/18-40 years AUC        |                          |                                   |     |
| Body Weight                      | No dose adjustment       |                                   |     |
| ≥120 kg/65-85 kg                 | AUC                      |                                   |     |
| Body Weight:                     | No dose adjustment       |                                   |     |
| ≤ 50 kg/65-85 kg                 | AUC                      |                                   |     |
| Hepatic Impairment:              | Dosing recommendation    |                                   |     |
| Moderate/Normal                  | AUC                      | cannot be provided                |     |
| Hepatic Impairment:              | No dose adjustment       |                                   |     |
| Mild/Normal
End-Stage Renal                                  | AN                       | No dose adjustment                |     |
| Dis:ase*/Normal                  | AUC                      | 0.5                               | 2.0 |
| Renal Impairment:                | No dose adjustment       |                                   |     |
| Severe1/Normal                   | WC                       |                                   |     |
| Renal Impairment:                | No dose adjustment       |                                   |     |
| Moderate/Normal                  | AUC                      |                                   |     |
| Renal Impairment                 | No dose adjustment       |                                   |     |
| Mld/Normal                       | AUC                      |                                   |     |
| A08                              | No dose adjustment       |                                   |     |
| 265 years/18-40 years AUC        |                          |                                   |     |
| Body Weight:                     | No dose adjustment       |                                   |     |
| ≥120 kg/65-85 kg                 | AUC                      |                                   |     |
| Body Weight:                     | No dose adjustment       |                                   |     |
| ≤50 kg/65-85 kg                  | AUC                      |                                   |     |
| Hepatic Impairment:              | Dosing recommendation    |                                   |     |
| cannot be provided               |                          |                                   |     |
| Moderate/Normal                  | AUC                      |                                   |     |
| Hepatic Impairment:              | No dose adjustment       |                                   |     |
| MIld/Normal                      | AUC                      | 0.5                               | 2.0 |  
* ESRD subjects maintained with chronic and stable hemodialysis; reported PK
findings are following single dose of apixaban post hemodialysis. † Creatinine clearance 15 to 29 mL/min. ‡ Dashed vertical lines illustrate pharmacokinetic changes that were used to inform dosing recommendations.  
| Ketoconazole 400 mg                                     | Cmax AUC                                                          | See Drug Interactions (7.1)   |     |
|---------------------------------------------------------|-------------------------------------------------------------------|-------------------------------|-----|
| Other CYP3A4 and P-gp Inhibitors Diltiazem 360 mg       | Cmax AUC                                                          |                               |     |
| Naproxen 500 mg                                         | Cmax AUC                                                          |                               |     |
| Strong CYP3A4 and P-gp Inducer Rifampin 600 mg Cmax AUC | No dose adjustment No dose adjustment See Drug Interactions (7.2) |                               |     |
| 0.5                                                     | 1.0                                                               | 1.5                           | 2.0 |  
  
Change Relative to **Reference***  
  
  
* Dashed vertical lines illustrate pharmacokinetic changes that were used to inform dosing recommendations. Dosing recommendations were also informed by clinical considerations [see Warnings and Precautions (5.2) and Drug Interactions (7)].
appendix 6 apixaban investigator brochure
eliquis (apixaban) eliquis (apixaban) a

showed no meaningful difference.  
The results across pharmacokinetic studies in normal subjects showed no differences in apixaban pharmacokinetics among White/Caucasian, Asian, and Black/African American subjects. No dose adjustment is required based on race/ethnicity. In subjects with ESRD, a 4-hour hemodialysis session with a dialysate flow rate of 500 mL/min and a blood flow rate in the range of 350 to 500 mL/min started 2 hours after administration of a single 5 mg dose of apixaban, the AUC of apixaban was 17% greater compared to those with normal renal function. The dialysis clearance of apixaban is approximately 18 mL/min resulting in a 14% decrease in exposure due to Ketoconazole 400 mg Cmax AUC
hemodialysis compared to off-dialysis period.  
Protein binding was similar (92%-94%) between healthy controls and the on-dialysis and off-dialysis periods.  
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of **Fertility**
Carcinogenesis: Apixaban was not carcinogenic when administered to mice and rats for up to 2 years. The systemic exposures (AUCs) of unbound apixaban in male and female mice at the highest doses tested (1500 and 3000 mg/kg/day) were 9 and 20 times, respectively, the human exposure of unbound drug at the MRHD of 10 mg/day.  
Systemic exposures of unbound apixaban in male and female rats at the highest dose tested (600 mg/kg/day) were 2 and 4 times, respectively, the human exposure.  
Mutagenesis: Apixaban was neither mutagenic in the bacterial reverse mutation (Ames) assay, nor clastogenic in Chinese hamster ovary cells in *vitro*, in a 1-month in vivo/in *vitro* cytogenetics study in rat peripheral blood lymphocytes, or in a rat micronucleus study in *vivo*.  
Impairment of *Fertility:* Apixaban had no effect on fertility in male or female rats when given at doses up to 600 mg/kg/day, a dose resulting in exposure levels that are 3 and 4 times, respectively, the human exposure.  
Apixaban administered to female rats at doses up to 1000 mg/kg/day from implantation through the end of lactation produced no adverse findings in male offspring
(F1 generation) at doses up to 1000 mg/kg/day, a dose resulting in exposure that is 5 times the human exposure. Adverse effects in the F1-generation female offspring were limited to decreased mating and fertility indices at 1000 mg/kg/day.  
14 CLINICAL **STUDIES**
14.1 Reduction of Risk of Stroke and Systemic Embolism in Nonvalvular
appendix 6 apixaban investigator brochure
atrial fibrillation

ARISTOTLE
Evidence for the efficacy and safety of ELIQUIS was derived from ARISTOTLE, a multinational, double-blind study in patients with nonvalvular AF comparing the effects of ELIQUIS and warfarin on the risk of stroke and non-central nervous system (CNS) systemic embolism. In ARISTOTLE, patients were randomized to ELIQUIS
5 mg orally twice daily (or 2.5 mg twice daily in subjects with at least 2 of the following characteristics: age ≥80 years, body weight ≤60 kg, or serum creatinine ≥1.5 mg/dL) or to warfarin (targeted to an INR range of 2.0–3.0).  
Patients had to have one or more of the following additional risk factors for stroke:
- prior stroke or transient ischemic attack (TIA)
- prior systemic embolism
- age ≥75 years
- arterial hypertension requiring treatment
- diabetes mellitus
- heart failure ≥New York Heart Association Class 2 - left ventricular ejection fraction ≤40%
The primary objective of ARISTOTLE was to determine whether ELIQUIS 5 mg twice daily (or 2.5 mg twice daily) was effective (noninferior to warfarin) in reducing the risk of stroke (ischemic or hemorrhagic) and systemic embolism. Superiority of ELIQUIS
to warfarin was also examined for the primary endpoint (rate of stroke and systemic embolism), major bleeding, and death from any cause.  
A total of 18,201 patients were randomized and followed on study treatment for a median of 89 weeks. Forty-three percent of patients were vitamin K antagonist
(VKA) "naive," defined as having received ≤30 consecutive days of treatment with warfarin or another VKA before entering the study. The mean age was 69 years and the mean CHADS2 score (a scale from 0 to 6 used to estimate risk of stroke, with higher scores predicting greater risk) was 2.1. The population was 65% male, 83%
Caucasian, 14% Asian, and 1% Black. There was a history of stroke, TIA, or non-CNS
systemic embolism in 19% of patients. Concomitant diseases of patients in this study included hypertension 88%, diabetes 25%, congestive heart failure (or left ventricular ejection fraction ≤40%) 35%, and prior myocardial infarction 14%. Patients treated with warfarin in ARISTOTLE had a mean percentage of time in therapeutic range
(INR 2.0–3.0) of 62%. ELIQUIS was superior to warfarin for the primary endpoint of reducing the risk of stroke and systemic embolism (Table 9 and Figure 4). Superiority to warfarin was primarily attributable to a reduction in hemorrhagic stroke and ischemic strokes with hemorrhagic conversion compared to warfarin. Purely ischemic strokes occurred with similar rates on both drugs.  
ELIQUIS also showed significantly fewer major bleeds than warfarin [see Adverse Reactions *(6.1)].*  
| ELIQUIS                                                            | Warfarin                          |                              |                   |
|--------------------------------------------------------------------|-----------------------------------|------------------------------|-------------------|
| N=9120                                                             | N=9081                            | Hazard Ratio (95% CI)        | P-value           |
| n (%/year) n (%/year)                                              |                                   |                              |                   |
| Stroke or systemic embolism 212 (1.27)                             | 265 (1.60) 0.79 (0.66, 0.95) 0.01 |                              |                   |
| Stroke                                                             | 199 (1.19)                        | 250 (1.51) 0.79 (0.65, 0.95) |                   |
| 140 (0.83)                                                         | 136 (0.82) 1.02 (0.81, 1.29)      |                              |                   |
| Ischemic without  hemorrhage Ischemic with  hemorrhagic conversion | 12 (0.07)                         | 20 (0.12)                    | 0.60 (0.29, 1.23) |
| Hemorrhagic                                                        | 40 (0.24)                         | 78 (0.47)                    | 0.51 (0.35, 0.75) |  
ELIQUIS® (apixaban) ELIQUIS® **(apixaban)**
$3400\%$  34015.  
  
$\tau$I 4.
All-cause death was assessed using a sequential testing strategy that allowed testing for superiority if effects on earlier endpoints (stroke plus systemic embolus and major bleeding) were demonstrated. ELIQUIS treatment resulted in a significantly lower rate of all-cause death (p = 0.046) than did treatment with warfarin, primarily because of a reduction in cardiovascular death, particularly stroke deaths. Non-vascular death rates were similar in the treatment arms.  
In ARISTOTLE, the results for the primary efficacy endpoint were generally consistent across most major subgroups including weight, CHADS2 score (a scale from 0 to 6 used to predict risk of stroke in patients with AF, with higher scores predicting greater risk), prior warfarin use, level of renal impairment, geographic region, ELIQUIS dose, type of AF, and aspirin use at randomization (Figure 5).  
Table 9: Key Efficacy Outcomes in Patients with Nonvalvular Atrial Fibrillation in ARISTOTLE **(Intent-to-Treat Analysis)**
ELIQUIS
N=9120 n (%/year)
Warfarin N=9081 n **(%/year)**
Hazard Ratio
(95% CI) **P-value** Version 9.0, 1/27/2020 92 ELIQUIS® (apixaban) ELIQUIS® **(apixaban)**
Unknown 14 (0.08) 21 (0.13) 0.65 (0.33, 1.29)
Systemic embolism 15 (0.09) 17 (0.10) 0.87 (0.44, 1.75)
The primary endpoint was based on the time to first event (one per subject). Component counts are for subjects with any event, not necessarily the first.
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At the end of the ARISTOTLE study, warfarin patients who completed the study were generally maintained on a VKA with no interruption of anticoagulation. ELIQUIS
patients who completed the study were generally switched to a VKA with a 2-day period of coadministration of ELIQUIS and VKA, so that some patients may not have been adequately anticoagulated after stopping ELIQUIS until attaining a stable and therapeutic INR. During the 30 days following the end of the study, there were 21 stroke or systemic embolism events in the 6791 patients (0.3%) In the ELIQUIS
arm compared to 5 in the 6569 patients (0.1%) in the warfarin arm fsee Dosage and Administration (2.5)].  
AVERROES
In AVERROES, patients with nonvalvular atrial fibrillation thought not to be candidates for warfarin therapy were randomized to treatment with ELIQUIS 5 mg orally twice daily (or 2.5 mg twice daily in selected patients) or aspirin 81 to 324 mg once daily. The primary objective of the study was to determine if ELIQUIS was superior to aspirin for preventing the composite outcome of stroke or systemic embolism. AVERROES
was stopped early on the basis of a prespecified interim analysis showing a significant reduction in stroke and systemic embolism for ELIQUIS compared to aspirin that was associated with a modest increase in major bleeding (Table 10) [see Adverse Reactions (6.1)].  
Table 10:
Key Efficacy Outcomes in Patients with Nonvalvular Atrial  
| Fibrillation in AVERROES              |                                       |              |                   |
|---------------------------------------|---------------------------------------|--------------|-------------------|
| ELIQUIS                               | Aspirin                               |              |                   |
| N=2807                                | N=2791                                | Hazard Ratio |                   |
| n (%/year)   n (%/year)               | (95% Cl)                              | P-value      |                   |
| Stroke or systemic embolism 51 (1.62) | 13 (3.63)   0.45 (0.32, 0.62) <0.0001 |              |                   |
| Stroke                                |                                       |              |                   |
| Ischemic or                           | 43 (1.37)                             | 97 (3.11)    | 0.44 (0.31, 0.63) |
| undetermined                          |                                       |              |                   |
| Hemorrhagic                           | 6 (0.19)                              | 9 (0.28)     | 0.67 (0.24, 1.88) |
| Systemic embolism                     | 2 (0.06)                              | 13 (0.41)    | 0.15 (0.03, 0.68) |
| MI                                    | 24 (0.76)                             | 28 (0.89)    | 0.86 (0.50, 1.48) |
| 0.79 (0.62, 1.02)                     |                                       |              |                   |
| All-cause death                       | 11 (3.51)                             | 140 (4.42)   | 0.068             |
| Vascular death                        | 84 (2.65)                             | 96 (3.03)    | 0.87 (0.65, 1.17) |  
Prophylaxis of Deep Vein Thrombosis Following Hip or Knee 14.2 Replacement Surgery The clinical evidence for the effectiveness of ELIQUIS is derived from the ADVANCE-1, ADVANCE-2, and ADVANCE-3 clinical trials in adult patients undergoing elective hip (ADVANCE-3) or knee (ADVANCE-2 and ADVANCE-1) replacement surgery. A total of 1,659 patients were randomized in 3 double-blind, multi-national studies. Included in this total were 1866 patients age 75 or older, 1161 patients with low body weight
(s60 kg), 2528 patients with Body Mass Index ≥ 33 kg/m 2 , and 625 patients with severe or moderate renal impairment.  
In the ADVANCE-3 study, 5407 patients undergoing elective hip replacement surgery were randomized to receive either ELIQUIS 2.5 mg orally twice daily or enoxaparin 40 mg subcutaneously once daily. The first dose of ELIQUIS was given 12 to 24 hours post surgery, whereas enoxaparin was started 9 to 15 hours prior to surgery. Treatment duration was 32 to 38 days.  
In patients undergoing elective knee replacement surgery, ELIQUIS 2.5 mg orally twice daily was compared to enoxaparin 40 mg subcutaneously once daily (ADVANCE-2, N=3057) or enoxaparin 30 mg subcutaneously every 12 hours (ADVANCE-1, N=3195).  
In the ADVANCE-2 study, the first dose of ELIQUIS was given 12 to 24 hours post surgery, whereas enoxaparin was started 9 to 15 hours prior to surgery. In the ADVANCE-1 study, both ELIQUIS and enoxaparin were initiated 12 to 24 hours post surgery. Treatment duration in both ADVANCE-2 and ADVANCE-1 was 10 to 14 days.  
In all 3 studies, the primary endpoint was a composite of adjudicated asymptomatic and symptomatic DVT, nonfatal PE, and all-cause death at the end of the double-blind intended treatment period. In ADVANCE-3 and ADVANCE-2, the primary endpoint was tested for noninferiority, then superiority, of ELIQUIS to enoxaparin.  In ADVANCE-1, the primary endpoint was tested for noninferiority of ELIQUIS to enoxaparin.  
The efficacy data are provided in Tables 11 and 12
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eliquis (apixaban) eliquis (apixaban)

| Treatment Period for Patients Undergoing Elective Hip Replacement Surgery* ADVANCE-3 Relative Risk (95% CI)  P-value                                                  |              |            |             |
|-----------------------------------------------------------------------------------------------------------------------------------------------------------------------|--------------|------------|-------------|
| Number of Patients                                                                                                                                                    | N=1949       | N=1917     |             |
| Total VTE†/All-cause death                                                                                                                                            | 27 (1.39%)   | 74 (3.86%) | 0.36 (0.22, |
| (0.95, 2.02)                                                                                                                                                          | (3.08, 4.83) | 0.54)      |             |
| p<0.0001                                                                                                                                                              |              |            |             |
| Number of Patients                                                                                                                                                    | N=2708       | N=2699     |             |
| All-cause death                                                                                                                                                       | 3 (0.11%)    | 1 (0.04%)  |             |
| (0.02, 0.35)                                                                                                                                                          | (0.00, 0.24) |            |             |
| PE                                                                                                                                                                    | 3 (0.11%)    | 5 (0.19%)  |             |
| (0.02, 0.35)                                                                                                                                                          | (0.07, 0.45) |            |             |
| Symptomatic DVT                                                                                                                                                       | 1 (0.04%)    | 5 (0.19%)  |             |
| (0.00, 0.24)                                                                                                                                                          | (0.07, 0.45) |            |             |
| Number of Patients                                                                                                                                                    | N=2196       | N=2190     |             |
| Proximal DVT‡                                                                                                                                                         | 7 (0.32%)    | 20 (0.91%) |             |
| (0.14, 0.68)                                                                                                                                                          | (0.59, 1.42) |            |             |
| Number of Patients                                                                                                                                                    | N=1951       | N=1908     |             |
| Distal DVT‡                                                                                                                                                           | 20 (1.03%)   | 57 (2.99%) |             |
| (0.66, 1.59)                                                                                                                                                          | (2.31, 3.86) |            |             |
| * Events associated with each endpoint were counted once per subject but subjects  Events During 35-Day Enoxaparin ELIQUIS Treatment Period 2.5 mg po bid 40 mg sc qd |              |            |             |  
* Events associated with each endpoint were counted once per subject but subjects may have contributed events to multiple endpoints. † Total VTE includes symptomatic and asymptomatic DVT and PE. ‡ Includes symptomatic and asymptomatic DVT.
appendix 6 apixaban investigator brochure
14.3 treatment of dvt and

DVT and PE
Efficacy and safety of ELIQUIS for the treatment of DVT and PE, and for the reduction in the risk of recurrent DVT and PE following 6 to 12 months of anticoagulant treatment was derived from the AMPLIFY and AMPLIFY-EXT studies. Both studies were randomized, parallel-group, double-blind trials in patients with symptomatic proximal DVT and/or symptomatic PE. All key safety and efficacy endpoints were adjudicated in a blinded manner by an independent committee.  
AMPLIFY
The primary objective of AMPLIFY was to determine whether ELIQUIS was noninferior to enoxaparin/warfarin for the incidence of recurrent VTE (venous thromboembolism)
or VTE-related death. Patients with an objectively confirmed symptomatic DVT and/or PE were randomized to treatment with ELIQUIS 10 mg twice daily orally for 7 days followed by ELIQUIS 5 mg twice daily orally for 6 months, or enoxaparin 1 mg/kg twice daily subcutaneously for at least 5 days (until INR ≥2) followed by warfarin (target INR range 2.0-3.0) orally for 6 months. Patients who required thrombectomy, insertion of a caval filter, or use of a fibrinolytic agent, and patients with creatinine clearance
<25 mL/min, significant liver disease, an existing heart valve or atrial fibrillation, or active bleeding were excluded from the AMPLIFY study. Patients were allowed to enter the study with or without prior parenteral anticoagulation (up to 48 hours).  
A total of 5244 patients were evaluable for efficacy and were followed for a mean of 154 days in the ELIQUIS group and 152 days in the enoxaparin/warfarin group.  
The mean age was 57 years. The AMPLIFY study population was 59% male, 83% Caucasian, 8% Asian, and 4% Black. For patients randomized to warfarin, the mean percentage of time in therapeutic range (INR 2.0-3.0) was 60.9%.  
Approximately 90% of patients enrolled in AMPLIFY had an unprovoked DVT or PE at baseline. The remaining 10% of patients with a provoked DVT or PE were required to have an additional ongoing risk factor in order to be randomized, which included previous episode of DVT or PE, immobilization, history of cancer, active cancer, and known prothrombotic genotype.  
ELIQUIS was shown to be noninferior to enoxaparin/warfarin in the AMPLIFY study for the primary endpoint of recurrent symptomatic VTE (nonfatal DVT
or nonfatal PE) or VTE-related death over 6 months of therapy (Table 13).  
Table 13: Efficacy Results in the AMPLIFY **Study**  
| Table 12:                     | Summary of Key Efficacy Analysis Results During the Intended  Treatment Period for Patients Undergoing Elective Knee  Replacement Surgery* ADVANCE-1 ADVANCE-2   |                                   |              |            |
|-------------------------------|------------------------------------------------------------------------------------------------------------------------------------------------------------------|-----------------------------------|--------------|------------|
| Events during 12-day          | ELIQUIS                                                                                                                                                          |                                   |              |            |
| treatment                     | 2.5 mg                                                                                                                                                           |                                   |              |            |
| period                        | po bid                                                                                                                                                           | Relative  Risk  (95% CI)  P-value |              |            |
| Number of                     | N=1157                                                                                                                                                           | N=1130                            | N=976        | N=997      |
| Patients                      | Relative  Risk                                                                                                                                                   | ELIQUIS                           |              |            |
| (95% CI)                      | 2.5 mg                                                                                                                                                           |                                   |              |            |
| P-value                       | po bid                                                                                                                                                           |                                   |              |            |
| Enoxaparin 30 mg  sc q12h     | Enoxaparin 40 mg  sc qd                                                                                                                                          |                                   |              |            |
| Total VTE†/  All-cause  death | 104 (8.99%)  100 (8.85%)  1.02 (0.78, 147 (15.06%)  243 (24.37%)  0.62 (0.51, (7.47, 10.79) (7.33, 10.66) 1.32) NS (12.95, 17.46) (21.81, 27.14) 0.74)  p<0.0001 |                                   |              |            |
| Number of                     | N=1599                                                                                                                                                           | N=1596                            | N=1528       | N=1529     |
| Patients All-cause            | 3 (0.19%)                                                                                                                                                        | 3 (0.19%)                         | 2 (0.13%)    | 0 (0%)     |
| death                         | (0.04, 0.59) (0.04, 0.59)                                                                                                                                        | (0.01, 0.52)                      | (0.00, 0.31) |            |
| PE                            | 16 (1.0%)                                                                                                                                                        | 7 (0.44%)                         | 4 (0.26%)    | 0 (0%)     |
| (0.61, 1.64) (0.20, 0.93)     | (0.08, 0.70)                                                                                                                                                     | (0.00, 0.31)                      |              |            |
| Symptomatic 3 (0.19%)         | 7 (0.44%)                                                                                                                                                        | 3 (0.20%)                         | 7 (0.46%)    |            |
| DVT                           | (0.04, 0.59) (0.20, 0.93)                                                                                                                                        | (0.04, 0.61)                      | (0.20, 0.97) |            |
| Number of                     | N=1254                                                                                                                                                           | N=1207                            | N=1192       | N=1199     |
| Patients Proximal             | 9 (0.72%)                                                                                                                                                        | 11 (0.91%)                        | 9 (0.76%)    | 26 (2.17%) |
| DVT‡                          | (0.36, 1.39) (0.49, 1.65)                                                                                                                                        | (0.38, 1.46)                      | (1.47, 3.18) |            |
| Number of                     | N=1146                                                                                                                                                           | N=1133                            | N=978        | N=1000     |
| Patients Distal               | 83 (7.24%)  91 (8.03%)                                                                                                                                           | 142 (14.52%)  239 (23.9%)         |              |            |
| DVT‡                          | (5.88, 8.91) (6.58, 9.78)                                                                                                                                        | (12.45, 16.88) (21.36, 26.65)     |              |            |  
The efficacy profile of ELIQUIS was generally consistent across subgroups of interest for this indication (e.g., age, gender, race, body weight, renal impairment).  
| VTE or VTE-related death*  DVT† PE† VTE-related death†  VTE or all-cause death  VTE or CV-related death   | ELIQUIS  N=2609  n 59 (2.3%) 22 (0.8%) 27 (1.0%) 12 (0.4%) 84 (3.2%) 61 (2.3%)   | Enoxaparin/Warfarin N=2635  n 71 (2.7%) 35 (1.3%) 25 (0.9%) 16 (0.6%) 104 (4.0%) 77 (2.9%)   | Relative Risk (95% CI) 0.84 (0.60, 1.18) 0.82 (0.61, 1.08) 0.80 (0.57, 1.11)   |
|-----------------------------------------------------------------------------------------------------------|----------------------------------------------------------------------------------|----------------------------------------------------------------------------------------------|--------------------------------------------------------------------------------|  
ELIQUIS® (apixaban) ELIQUIS® **(apixaban)**
* Noninferior compared to enoxaparin/warfarin (P-value <0.0001). †Events associated with each endpoint were counted once per subject, but subjects may have contributed events to multiple endpoints.  
In the AMPLIFY study, patients were stratified according to their index event of PE (with or without DVT) or DVT (without PE). Efficacy in the initial treatment of VTE was consistent between the two subgroups.  
AMPLIFY-EXT
Patients who had been treated for DVT and/or PE for 6 to 12 months with anticoagulant therapy without having a recurrent event were randomized to treatment with ELIQUIS
2.5 mg orally twice daily, ELIQUIS 5 mg orally twice daily, or placebo for 12 months. Approximately one-third of patients participated in the AMPLIFY study prior to enrollment in the AMPLIFY-EXT study.  
A total of 2482 patients were randomized to study treatment and were followed for a mean of approximately 330 days in the ELIQUIS group and 312 days in the placebo group. The mean age in the AMPLIFY-EXT study was 57 years. The study population was 57% male, 85% Caucasian, 5% Asian, and 3% Black.  
The AMPLIFY-EXT study enrolled patients with either an unprovoked DVT or PE at baseline (approximately 92%) or patients with a provoked baseline event and one additional risk factor for recurrence (approximately 8%). However, patients who had experienced multiple episodes of unprovoked DVT or PE were excluded from the AMPLIFY-EXT study. In the AMPLIFY-EXT study, both doses of ELIQUIS were superior to placebo in the primary endpoint of symptomatic, recurrent VTE (nonfatal DVT or nonfatal PE), or all-cause death (Table 14).  
| Table 14:                                                           | Effica c y Results in the AMPLIF Y-EXT Study Relative Risk (95% CI) ELIQUIS ELIQUIS 2.5 mg 5 mg vs Placebo vs Placebo n (%)   |                                                            |
|---------------------------------------------------------------------|-------------------------------------------------------------------------------------------------------------------------------|------------------------------------------------------------|
| Recurrent VTE or  all -cause de ath DVT*  PE * All -cause de ath    | ELIQUIS ELIQUIS Placebo 2.5 mg 5 mg N=840 N=813 N=829 32 (3.8) 34 (4.2) 96 (11.6)                                             | 0.3 3 (0.22 , 0.48) 0.3 6 (0.25 , 0.53) p<0.000 1 p<0.0001 |
| 19 (2.3)                                                            | 28 (3.4)                                                                                                                      | 72 (8.7)                                                   |
| 23 (2.7)                                                            | 25 (3.1)                                                                                                                      | 37 (4.5)                                                   |
| 22 (2.6)                                                            | 25 (3.1)                                                                                                                      | 33 (4.0)                                                   |
| * P atients with more than one event are counted in multiple r ows. |                                                                                                                               |                                                            |
appendix 6 apixaban investigator brochure
16 how supplied/storage and handling

ELIQUIS(apixaban) tablets areavailable as listed in the table below.  
| Tablet                                                                                                                 | Tablet                                                       | Tablet                                                      |                                              |          |
|------------------------------------------------------------------------------------------------------------------------|--------------------------------------------------------------|-------------------------------------------------------------|----------------------------------------------|----------|
| Strength                                                                                                               | Color/Shape                                                  | Markings                                                    | Package Size                                 | NDC Code |
| 2.5 mg  Yell o w , round,  biconvex                                                                                    | Debossed with  "893" on one side  and "2½" on the other side | Bottles of 60 Bottles of 180                                |                                              |          |
| Hospital Unit -Dose Blister Pack age  of 100 Bottles of 60 Bottles of 180 Hospital Unit -Dose Blister Pack age  of 100 | 0003 -0893 -21 0003 -0893 -41 0003 -0893 -31                 |                                                             |                                              |          |
| 5 mg                                                                                                                   | Pink, oval,  biconvex                                        | Debossed with  "894" on one side  and "5" on the other side | 0003 -0894 -21 0003 -0894 -41 0003 -0894 -31 |          |
appendix 6 apixaban investigator brochure
storage and handling

Storeat 20°C to 25°C (68°F-77°F); excursions permitted between 15°C and 30°C
(59°F-86°F) [see USP Controlled RoomTemperature].
appendix 6 apixaban investigator brochure
17 patient counseling information

See FDA-approvedpatient labeling (Medication *Guide).*
Advisepatients of the following:
- They should not discontinue ELIQUIS without talking to their physician first. - They should be informed that it might take longer than usual for bleeding to stop, and they may bruise or bleed more easily when treated with ELIQUIS.  
Advisepatients about how to recognize bleeding or symptoms of hypovolemia and of the urgent need to reportany unusual bleeding to their physician.  
- They should tell their physicians and dentists they are taking ELIQUIS,
and/orany other product known to affect bleeding (including nonprescription products, such as aspirin or NSAIDs), beforeany surgery or medical or dental procedure is scheduled and beforeany new drug is taken.  
- If thepatient ishaving neuraxial anesthesia or spinal puncture, inform the patient towatch for signs and symptoms of spinal or epidural hematomas, such as numbness or weakness of the legs, orbowel or bladderdysfunction
[seeWarnings and Precautions *(5.3)]*. Ifany of these symptoms occur, the patient should contact his or her physician immediately.  
- They should tell their physicians if they are pregnant or plan to become pregnant or are breastfeeding or intend to breastfeed during treatment with ELIQUIS [see Use in SpecificPopulations (8.1, *8.3)].*
- If a dose is missed, 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 fora missed dose.  
Manufactured by: Bristol-Myers Squibb Company Princeton, New Jersey 08543 USA
Marketed by: Bristol-Myers Squibb Company Princeton, New Jersey 08543 USA and Pfizer Inc NewYork, NewYork 10017 USA Rotachrom
® isa registered trademark of Diagnostica Stago.  
1289808A1/ 1289807A1/ 1298500A1
medication guide
what is the most important

People with atrial fibrillation (a type of irregular heartbeat) are at an increased risk of forming a blood clot in the heart, which can travel to the brain, causing a stroke, or to other parts of the body. ELIQUIS lowers your chance of having a stroke by helping to prevent clots from forming. If you stop taking ELIQUIS, you may have increased risk of forming a clot in your blood.
medication guide
do not stop taking eliquis

ELIQUIS may need to be stopped, if possible, prior to surgery or a medical or dental procedure. Ask the doctor who prescribed ELIQUIS for you when you should stop taking it. Your doctor will tell you when you may start taking ELIQUIS again after your surgery or procedure. If you have to stop taking ELIQUIS, your doctor may prescribe another medicine to help prevent a blood clot from forming.  
- ELIQUIS can cause **bleeding** which can be serious and rarely may lead to death. This is because ELIQUIS is a blood thinner medicine that reduces blood clotting.
You may have a higher risk of bleeding if you take ELIQUIS and take other medicines that increase your risk of bleeding, including:  
- aspirin or aspirin-containing products - long-term (chronic) use of nonsteroidal anti-inflammatory drugs
(NSAIDs)
- warfarin sodium (COUMADIN®, JANTOVEN®)  
- any medicine that contains heparin - selective serotonin reuptake inhibitors (SSRIs) or serotonin norepinephrine reuptake inhibitors (SNRIs)
- other medicines to help prevent or treat blood clots
medication guide
eliquis (apixaban)

Tell your doctor if you take any of these medicines. Ask your doctor or pharmacist if you are not sure if your medicine is one listed above.  
While taking ELIQUIS: - you may bruise more easily - it may take longer than usual for any bleeding to stop
medication guide
call your doctor or get

- unexpected bleeding, or bleeding that lasts a long time, such as:
- unusual bleeding from the gums
- nosebleeds that happen often - menstrual bleeding or vaginal bleeding that is heavier than normal
- bleeding that is severe or you cannot control - red, pink, or brown urine - red or black stools (looks like tar) - cough up blood or blood clots  
- vomit blood or your vomit looks like coffee grounds
- unexpected pain, swelling, or joint pain - headaches, feeling dizzy or weak
medication guide
- eliquis is not for

- **Spinal or epidural blood clots (hematoma).** People who take a blood thinner medicine (anticoagulant) like ELIQUIS, and have medicine injected into their spinal and epidural area, or have a spinal puncture have a risk of forming a blood clot that can cause long-term or permanent loss of the ability to move (paralysis). Your risk of developing a spinal or epidural blood clot is higher if: - a thin tube called an epidural catheter is placed in your back to give you certain medicine
medication guide
eliquis (apixaban) eliquis

- you take NSAIDs or a medicine to prevent blood from clotting
- you have a history of difficult or repeated epidural or spinal punctures
- you have a history of problems with your spine or have had surgery on your spine
If you take ELIQUIS and receive spinal anesthesia or have a spinal puncture, your doctor should watch you closely for symptoms of spinal or epidural blood clots or bleeding. Tell your doctor right away if you have tingling, numbness, or muscle weakness, especially in your legs and feet.
medication guide
what is eliquis?

ELIQUIS is a prescription medicine used to:  
- reduce the risk of stroke and blood clots in people who have atrial fibrillation.  
- reduce the risk of forming a blood clot in the legs and lungs of people who have just had hip or knee replacement surgery.  
- treat blood clots in the veins of your legs (deep vein thrombosis) or lungs (pulmonary embolism), and reduce the risk of them occurring again.
It is not known if ELIQUIS is safe and effective in children.
medication guide
who should not take eliquis?

- currently have certain types of abnormal bleeding.  
- have had a serious allergic reaction to ELIQUIS. Ask your doctor if you are not sure.
medication guide
what should i tell my

- have kidney or liver problems
- have any other medical condition - have ever had bleeding problems
- are pregnant or plan to become pregnant.  
It is not known if ELIQUIS will harm your unborn baby. Version 9.0, 1/27/2020 101
- are breastfeeding or plan to breastfeed. It is not known if ELIQUIS passes into your breast milk. You and your doctor should decide if you will take ELIQUIS or breastfeed. You should not do both.  
Tell all of your doctors and dentists that you are taking ELIQUIS. They should talk to the doctor who prescribed ELIQUIS for you, before you have any surgery, medical or dental procedure. Tell your doctor about all the medicines you take, **including** prescription and overthe-counter medicines, vitamins, and herbal supplements. Some of your other medicines may affect the way ELIQUIS works. Certain medicines may increase your risk of bleeding or stroke when taken with ELIQUIS. See "What is the most important information I should know about ELIQUIS?" Know the medicines you take. Keep a list of them to show your doctor and pharmacist when you get a new medicine.
medication guide
how should i take eliquis?

- Take ELIQUIS twice every day with or without food.  
- Do not change your dose or stop taking ELIQUIS unless your doctor tells you to.  
- If you miss a dose of ELIQUIS, take it as soon as you remember. Do not take more than one dose of ELIQUIS at the same time to make up for a missed dose.  
- Your doctor will decide how long you should take ELIQUIS. Do not **stop** taking it without first talking with your doctor. If you are taking ELIQUIS for atrial fibrillation, stopping ELIQUIS **may increase** your risk of having a **stroke**.  
ELIQUIS® (apixaban) **ELIQUIS®**
- Do not run out of ELIQUIS. **Refill**
your prescription before you run out. When leaving the hospital following hip or knee replacement, be sure that you will have ELIQUIS available to avoid missing any doses.  
- If you take too much ELIQUIS, call your doctor or go to the nearest hospital emergency room right away.  
- Call your doctor or healthcare provider right away if you fall or injure yourself, especially if you hit your head. Your doctor or healthcare provider may need to check you.
medication guide
what are the possible side

- ELIQUIS can cause a skin rash or severe allergic reaction. Call your doctor or get medical help right away if you have any of the following symptoms: - chest pain or tightness - swelling of your face or tongue - trouble breathing or wheezing - feeling dizzy or faint
Tell your doctor if you have any side effect that bothers you or that does not go away. These are not all of the possible side effects of ELIQUIS. For more information, ask your doctor or pharmacist. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA1088.  
How should I **store**
medication guide
eliquis? what are the ingredients

Active ingredient: apixaban. Inactive ingredients: anhydrous lactose, microcrystalline cellulose, croscarmellose sodium, sodium lauryl sulfate, and magnesium stearate. The film coating contains lactose monohydrate, hypromellose, titanium dioxide, triacetin, and yellow iron oxide (2.5 mg tablets) or red iron oxide (5 mg tablets). This Medication Guide has been approved by the U.S. Food and Drug Administration. Manufactured by: Bristol-Myers Squibb Company Princeton, New Jersey 08543 USA Marketed by: Bristol-Myers Squibb Company Princeton, New Jersey 08543 USA and Pfizer Inc New York, New York 10017 USA COUMADIN® is a registered trademark of Bristol-Myers Squibb Pharma Company. All other trademarks are property of their respective companies. 1289808A1 / 1289807A1 / 1298500A1 1295958A 1 Store ELIQUIS at room temperature between 68°F to 77°F (20°C to 25°C).
medication guide
keep eliquis and all medicines

Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use ELIQUIS for a condition for which it was not prescribed. Do not give ELIQUIS to other people, even if they have the same symptoms that you have. It may harm them. If you would like more information, talk with your doctor. You can ask your pharmacist or doctor for information about ELIQUIS that is written for health professionals.  
For more information call 1-855-354-7847 (1-855-ELIQUIS) or go to www.ELIQUIS.com. Revised August 2014 432US14BR00805-06-01