CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`
`APPLICATION NUMBER:
`
`202155Orig1s000
`
`RISK ASSESSMENT and RISK MITIGATION
`REVIEW(S)
`
`
`
`
`

`

`Department of Health and Human Services
`Public Health Service
`Food and Drug Administration
`Center for Drug Evaluation and Research
`Office of Surveillance and Epidemiology
`Office of Medication Error Prevention and Risk Management
`
`Final Risk Evaluation and Mitigation Strategy (REMS) Review
`
`December 27, 2012
`Date:
`Reema Mehta, PharmD, MPH
`Team Leader:
`Division of Risk Management
`
`Claudia Manzo, PharmD
`Division Director
`Division of Risk Management
`
`Eliquis® (apixaban)
`Drug Name(s):
`Factor Xa Inhibitor
`Therapeutic Class:
`2.5 mg and 5 mg oral tablets
`Dosage and Route:
`Application Type/Number: NDA 202-155
`Applicant/sponsor:
`Bristol-Myers Squibb
`OSE RCM #:
`2012-2311
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`*** This document contains proprietary and confidential information that should not be
`released to the public. ***
`
`
`
`Reference ID: 3237199
`
`

`

`CONTENTS
`
`1
`
`INTRODUCTION....................................................................................................... 1
`1.1
`Background......................................................................................................... 1
`1.2
`Regulatory History.............................................................................................. 1
`2 MATERIALS REVIEWED ........................................................................................ 3
`2.1
`Data and Information Sources ............................................................................ 3
`3 RESULTS OF REVIEW OF PROPOSED ELIQUIS RISK EVALUATION AND
`MITIGATION STRATEGY............................................................................................... 3
`3.1
`Overview of Clinical Program............................................................................ 3
`3.2
`Safety Concerns .................................................................................................. 3
`3.3
`Goals ................................................................................................................... 4
`3.4
`REMS Elements.................................................................................................. 4
`3.5
`REMS Assessment Plan...................................................................................... 6
`4 DISCUSSION AND CONCLUSIONS....................................................................... 6
`5 RECOMMENDATIONS............................................................................................. 7
`ATTACHMENTS............................................................................................................... 7
`
`Reference ID: 3237199
`
`

`

`1
`INTRODUCTION
`This is the Division of Risk Management’s (DRISK) final review of Bristol-Myers
`Squibb (BMS) proposed Risk Evaluation and Mitigation Strategy (REMS) for NDA 202-
`155, Eliquis® (abixiban). This review addressed the proposed REMS received on
`December 21, 2012.
`The REMS proposed by the Sponsor contains a communication plan with a Dear
`Healthcare Professional (DHCP) letter, letter to Professional Organizations, and REMS
`website.
`
`1.1 BACKGROUND
`Eliquis (apixaban), a new molecular entity, is an orally available direct inhibitor of
`activated Factor Xa (FXa). The proposed indication for Eliquis is the prevention of
`stroke and systemic embolism in patients with nonvalvular atrial fibrillation. Eliquis is
`available as 2.5 mg and 5 mg tablets, and the recommended dose is 5 mg taken twice
`daily.
`The serious risk of concern is that discontinuing Eliquis in the absence of adequate
`anticoagulation places patients at an increased risk of thrombotic events, including stroke.
`An increased rate of stroke was observed during the transition from Eliquis to warfarin in
`clinical trials in atrial fibrillation patients. If Eliquis must be discontinued for a reason
`other than pathological bleeding, prescribers should consider administering another
`anticoagulant.
`
`1.2 REGULATORY HISTORY
`On September 28, 2011, BMS submitted NDA 202-155 for the proposed indication to
`reduce the risk of stroke, systemic embolism,
` in patients with nonvalvular atrial
`fibrillation.
`In accordance with section 505-1 of the Food, Drug, and Cosmetic Act, the Division of
`Cardiovascular and Renal Products (DCRP) and the Division of Risk Management
`(DRISK) determined that a REMS for Eliquis was required to ensure that the benefits of
`the drug outweigh the increased risk of thrombotic events, including stroke, if Eliquis is
`discontinued.
`On February 3, 2012, the DCRP sent the sponsor a REMS Notification Letter, which
`included the following requirements for the proposed REMS:
`1. Communication Plan
`The communication plan must include, at minimum, the following:
` Dear Healthcare Professional letter distributed to appropriate prescribers
` Eliquis REMS website
` Letters to Professional Organizations
`2. Timetable for Submission of Assessments: The proposed REMS must include a
`timetable for submission of assessments that shall be no less frequent than 18 months,
`3 years, and 7 years after the REMS is initially approved.
`
`Reference ID: 3237199
`
`(b) (4)
`
`

`

`On February 13, 2012, the sponsor submitted the proposed REMS (Seq. No. 0040) that
`included a communication plan with the requirements described in the REMS
`Notification Letter. No additional risk mitigation strategies for the REMS were proposed
`by the sponsor.
`After review of the application, DCRP found that the sponsor’s pivitol trial
`(ARISTOTLE) demonstrated clinically significant efficacy for Eliquis in the population
`studied. However, a significant rate (estimated to be approximately 10%) of medication
`errors (wrong active drug, placebo instead of active, active instead of placebo) was
`observed in the ARISTOTLE trial. On June 22, 2012, DCRP issued a Complete Response
`Letter informing the sponsor that the application cannot be reviewed in its present form
`and requested that the sponsor submit additional information on data management and
`verification from the ARISTOTLE trial. The REMS was not reviewed during this review
`cycle.
`On September 17, 2012, the sponsor submitted a NDA Resubmission in response to the
`Complete Response Letter. The resubmission did not include the proposed REMS as a
`component of the application.
`On November 26, 2012, BMS was notified that the resubmission must include a REMS
`for review by the Agency. On November 29, 2012, the sponsor submitted the proposed
`REMS (Supplement 81/Sequence 0077). DRISK reviewed the submission and provided
`BMS with interim comments on December 20, 2012. A summary of the substantive
`comments is as follows:
` The address on the REMS document must be replaced with the physical address of
`the location where the REMS will be managed.
` Communication plan: The target audience for the DHCP letter was revised to include
`emergency medicine physicians, internal medicine physicians, and primary practice
`physicians. The target audience for the Dear Professional Society letter was revised
`to include the Association of Emergency Physicians (AEP). Additionally, the
`requirement to distribute REMS materials via sales representatives and medical
`science liaisons was removed to align the REMS document with current internal
`policy.
` DHCP Letter and Letter to Professional Societies: These REMS materials were
`revised to align with the current proposed label and internal standards regarding
`content and format.
` REMS website: The REMS document must include the REMS website as a
`component of the REMS. The landing page for the REMS website is appended to the
`REMS document. Additionally, comments regarding the content of the website were
`provided to improve the usability of the site.
`BMS sent clarifying questions via email on December 20, 2012 regarding the REMS
`supporting document, in particular the REMS assessment plan and timetable for
`submission of assessments, and corrections to the toll-free number on the Medication
`Guide and REMS letters. On December 20, 2012, the Agency recommended the
`following revisions: (1) the requirement to report on postmarketing commitments can be
`removed from the REMS assessment plan; (2) the table accompanying the timetable for
`
`Reference ID: 3237199
`
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`

`

`submission of assessments should be removed from the REMS supporting document; and
`(3) the updates to the toll-free number are acceptable. The sponsor incorporated the
`recommended revisions and resubmitted the proposed REMS on December 21, 2012.
`On December 27, 2012, DCRP sent the Sponsor a revised label, which included
`clarifying language regarding the apparent half-life of apixiban after repeated
`administration. These revisions impacted the REMS DHCP letter and Letter to
`Professional Societies; therefore, the Sponsor was requested to resubmit these materials
`with the revisions incorporated. The sponsor resubmitted the 2 letters on
`December 27, 2012 via email.
`
`2 MATERIALS REVIEWED
`
`2.1 DATA AND INFORMATION SOURCES
` Bristol-Myers Squibb proposed REMS for Eliquis (apixaban) received
`December 21, 2012 (Sequence 84)
` Division of Risk Management Interim Comments Set #1 for Eliquis (apixaban), dated
`December 20, 2012.
`
`3 RESULTS OF REVIEW OF PROPOSED ELIQUIS RISK EVALUATION
`AND MITIGATION STRATEGY
`
`3.1 OVERVIEW OF CLINICAL PROGRAM
`ARISTOTLE is the primary support for the approval of apixaban for its proposed
`indication, the reduction in risk of stroke and systemic embolism in patients with
`nonvalvular atrial fibrillation. It was a large (18,201 subjects), double-blind (double
`dummy), randomized, global, event driven trial comparing apixaban 5 mg bid (with a
`lower dose for patients with at least 2 of 3 pre-specified risk factors for bleeding) to
`warfarin titrated to a target INR of 2.0 to 3.0. The primary efficacy endpoint was
`noninferiority of apixaban to warfarin for time to the composite of stroke or systemic
`embolism. This endpoint was met. In an additional analysis that was allowed under the
`study’s pre-specified hierarchical analysis plan, apixaban was also superior to warfarin.
`
`3.2 SAFETY CONCERNS
`The serious risk of concern is that discontinuing Eliquis in the absence of adequate
`anticoagulation places patients at an increased risk of thrombotic events, including stroke.
`An increased rate of stroke was observed during the transition from Eliquis to warfarin in
`clinical trials in atrial fibrillation patients. If Eliquis must be discontinued for a reason
`other than pathological bleeding, prescribers should consider administering another
`anticoagulant.
`DCRP and DRISK agree that the REMS for Eliquis should be comparable to the
`currently approved REMS for Xarelto® (rivaroxaban), which is a drug in the same class
`with similar mechanism of action and safety concern. The currently approved REMS for
`Xarelto contains a communication plan and informs healthcare providers (HCPs) of the
`increased risk of thrombotic events without adequate anticoagulation and that Xarelto
`
`Reference ID: 3237199
`
` 3
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`

`

`should be taken with the evening meal. Food does not affect the bioavailability of
`Eliquis; therefore, it is not a subject of the proposed REMS.
`
`3.3 GOALS
`The goal of the ELIQUIS REMS is to inform healthcare providers (HCPs) about:
`
`the increased risk of thrombotic events, including stroke, in patients with nonvalvular
`atrial fibrillation when discontinuing ELIQUIS without introducing an adequate
`alternative anticoagulant
`the importance of following the recommendations in the US Prescribing Information
`(USPI) on how to convert patients with nonvalvular atrial fibrillation from ELIQUIS
`to warfarin or other anticoagulants.
`
`
`
`3.4 REMS ELEMENTS
`
`3.4.1 Communication Plan
`Bristol-Myers Squibb will implement a communication plan to HCPs to support
`implementation of this REMS.
`1. Dear Healthcare Professional Letter
`A Dear Healthcare Professional (DHCP) Letter will be distributed by direct mail or
`electronic delivery to HCPs including: cardiologists, neurologists, emergency medicine
`physicians, internal medicine physicians, primary care physicians, nurse practitioners,
`physician assistants, and pharmacists. The letter will be distributed within 60 days of
`approval of ELIQUIS. Annual letters will be sent within 60 days of the anniversary date
`of approval for ELIQUIS every year for two additional years and within 60 days of FDA
`approval of any substantial safety update. The DHCP Letter will also be provided to FDA
`MedWatch at these times. A copy of the USPI and Medication Guide will accompany the
`DHCP Letter.
`In addition, the DHCP Letter, USPI and Medication Guide will also be available on the
`ELIQUIS REMS website and upon request.
`The DHCP letter is part of the REMS and is appended.
`2. ELIQUIS REMS Website
`Within 30 days of REMS approval, Bristol-Myers Squibb will post information for HCPs
`and patients on the ELIQUIS REMS website (http://www.ELIQUISREMS.com). This
`information will remain on the website for a period of 2 years.
`The content of the print or web-based material will include the following:
` Goal of the REMS
`
`Reference ID: 3237199
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`

`
`Information about the risk
` US Prescribing Information for ELIQUIS
` Medication Guide for ELIQUIS
` DHCP Letter (for a period of 2 years)
`The ELIQUIS REMS website is part of the REMS and is appended.
`3. Letters to Professional Organizations
`A Professional Organization Letter will be distributed by direct mail or electronic
`delivery within 60 days of the REMS approval date. This communication to professional
`organizations will include the same information as that contained in the DHCP Letter.
`Bristol-Myers Squibb will request that these organizations disseminate this information to
`their members. Bristol-Myers Squibb will communicate the letter to the leadership of the
`following professional organizations:
` American Heart Association (AHA)
`
` American College of Cardiologists (ACC)
`
` Heart Rhythm Society (HRS)
`
` Society for Cardiovascular Angiography and Interventions (SCAI)
`
` American Academy of Neurology (AAN)
`
` American Neurological Association (ANA)
`
` National Institute of Neurological Disorders and Stroke (NINDS)
`
` American Stroke Association (ASA)
`
` National Stroke Association (NSA)
`
` American Association of Neuromuscular & Electrodiagnostic Medicine (AANEM)
`
` Association of Emergency Physicians (AEP)
`
` American College of Chest Physicians (ACCP)
`
` Association of Black Cardiologists (ABC)
`
` American Academy of Family Physicians (AAFP)
`
` American College of Physicians (ACP)
`
` Society of General Internal Medicine (SGIM)
`
` 5
`
`Reference ID: 3237199
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`

`

` National Medical Association (NMA)
`
` American Academy of Nurse Practitioners (AANP)
`
` American Academy of Physician Assistants (AAPA)
`
` American College of Clinical Pharmacy (ACCP)
`
` American Society of Health-System Pharmacists (ASHP)
`
` American Pharmacists Association (APhA)
`
` National Association of Chain Drug Stores (NACDS)
`
` American Association of Critical-Care Nurses (AACN)
`
` National Association of Clinical Nurse Specialists (NACNS)
`
`The USPI and the Medication Guide will be provided in conjunction with the letter.
`The Professional Organization Letter is part of the REMS and is appended.
`
`3.4.2 Timetable for Submission of Assessments
`Bristol-Myers Squibb will submit REMS Assessments to the FDA at 18 months, 3 years,
`and 7 years from the date of the REMS approval. To facilitate inclusion of as much
`information as possible while allowing reasonable time to prepare the submission, the
`reporting interval covered by each assessment should conclude no earlier than 60 days
`before the submission date for that assessment. Bristol-Myers Squibb will submit each
`assessment so that it will be received by the FDA on or before the due date.
`
`3.5 REMS ASSESSMENT PLAN
`The assessment plan must include, but is not limited to, the following components:
`1. A report on the distribution of DHCP letters and Professional Organization Letters
`2. An evaluation of healthcare providers’ awareness and understanding of the serious
`risks associated with ELIQUIS (for example, through surveys of healthcare
`providers).
`3. With respect to the REMS goals, an assessment of the extent to which the REMS is
`meeting its goals or whether the goals or other elements should be modified.
`
`4 DISCUSSION AND CONCLUSIONS
`In conclusion, the amended REMS for Eliquis (abixiban), received December 27, 2012,
`contains the appropriate and agreed upon revisions on the REMS components as
`stipulated by the Agency on December 20, 2012, December 21, 2012, and
`December 27, 2012. The REMS Supporting Document outlines the information and
`
`Reference ID: 3237199
`
` 6
`
`

`

`content that the applicant will use to assess the effectiveness of the Eliquis REMS in
`achieving the goals.
`Therefore, the Eliquis REMS is compliant under FDAAA and acceptable to the Office of
`Surveillance and Epidemiology, the Division of Risk Management.
`
`5 RECOMMENDATIONS
`The OSE, DRISK recommends approval of the Eliquis REMS, received
`December 27, 2012, as appended to this review.
`In addition, we recommend the REMS assessment plan described above be included in
`the REMS Approval Letter.
`Any substantive changes to the label that impact the REMS materials should be provided
`to DRISK for further review.
`
`ATTACHMENTS
`
`Attachment A – REMS Document
`
`Reference ID: 3237199
`
` 7
`
`10 Page(s) has been Withheld in Full as b4 (CCI/TS) immediately following this page
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`REEMA J MEHTA
`12/27/2012
`
`GARY H SLATKO
`12/27/2012
`
`Reference ID: 3237199
`
`

`

`Department of Health and Human Services
`Public Health Service
`Food and Drug Administration
`Center for Drug Evaluation and Research
`Office of Surveillance and Epidemiology
`Office of Medication Error Prevention and Risk Management
`
`Interim Comments on Risk Evaluation and Mitigation Strategy (REMS)
`Set # 1
`
`Date:
`
`December 20, 2012
`
`Danielle Smith, PharmD, M.S., Risk Management Analyst
`Reviewer(s):
`DRISK
`
`Reema Mehta, PharmD, MPH
`Team Leader
`DRISK
`
`Claudia Manzo, PharmD
`Division Director
`DRISK
`
`Eliquis (apixaban)
`Drug Name(s):
`Factor Xa Inhibitor
`Therapeutic Class:
`2.5 mg and 5 mg oral tablets
`Dosage and Route:
`Application Type/Number: NDA 202-155
`Submission Number:
`Seq. No. 0077
`Applicant/sponsor:
`Bristol-Myers Squibb
`OSE RCM #:
`2012-2311
`
`
`
`
`
`
`
`
`
`
`
`*** This document contains proprietary and confidential information that should not be
`released to the public. ***
`
`Reference ID: 3234951
`
`

`

`CONTENTS
`
`INTRODUCTION....................................................................................................... 1
`1
`2 BACKGROUND......................................................................................................... 1
`3 REGULATORY hISTORY......................................................................................... 1
`4 Materials Reviewed ..................................................................................................... 2
`4.1
`Submissions ........................................................................................................ 2
`4.2
`Other Materials Informing The Review.............................................................. 2
`5 SUMMARY OF APPLICANT’S PROPOSED REMS .............................................. 2
`I. Goal ............................................................................................................................. 2
`II.
`REMS Elements...................................................................................................... 3
`A.
`Communication Plan........................................................................................... 3
`B.
`Timetable for Submission of Assessments ......................................................... 5
`6 RECOMMENDATIONS FOR THE REVIEW DIVISION........................................ 6
`7 COMMENTS FOR THE APPLICANT...................................................................... 6
`7.1
`General Comments.............................................................................................. 8
`ATTACHMENTS............................................................................................................... 9
`
`Reference ID: 3234951
`
`

`

`1
`INTRODUCTION
`This Division of Risk Management (DRISK) Interim Comments Review evaluates and
`communicates required revisions to the proposed Risk Evaluation and Mitigation
`Strategy (REMS) submitted by Bristol-Myers Squibb (BMS) for Eliquis® (apixaban),
`received on November 29, 2012.
`The REMS proposed by the Sponsor contains a communication plan with a Dear
`Healthcare Professional (DHCP) letter, letter to Professional Organizations, and REMS
`website.
`
`2 BACKGROUND
`Eliquis (apixaban), a new molecular entity, is an orally available direct inhibitor of
`activated Factor X (Factor Xa or FXa). Its proposed indication is the prevention of stroke
`and systemic embolism in patients with nonvalvular atrial fibrillation. It is available as
`2.5 mg and 5 mg tablets, and the recommended dose is 5 mg taken twice daily.
`The serious risk of concern is that discontinuing Eliquis in the absence of adequate
`anticoagulation places patients at an increased risk of thrombotic events, including stroke.
`An increased rate of stroke was observed during the transition from Eliquis to warfarin in
`clinical trials in atrial fibrillation patients. If Eliquis must be discontinued for a reason
`other than pathological bleeding, prescribers should consider administering another
`anticoagulant.
`3 REGULATORY HISTORY
`On September 28, 2011, BMS submitted NDA 202-155 for the proposed indication to
`reduce the risk of stroke, systemic embolism,
` in patients with nonvalvular atrial
`fibrillation.
`In accordance with section 505-1 of the Food, Drug, and Cosmetic Act, the Division of
`Cardiovascular and Renal Products (DCRP) and the Division of Risk Management
`(DRISK) determined that a REMS for Eliquis was required to ensure that the benefits of
`the drug outweigh the increased risk of thrombotic events, including stroke, if Eliquis is
`discontinued.
`On February 3, 2012, the DCRP sent the sponsor a REMS Notification Letter, which
`included the following requirements for the proposed REMS:
`
`
`1. Communication Plan:
`The communication plan must include, at minimum, the following:
` Dear Healthcare Professional letter distributed to appropriate prescribers
` Eliquis REMS website
` Letters to Professional Organizations
`2. Timetable for Submission of Assessments: The proposed REMS must include a
`timetable for submission of assessments that shall be no less frequent than 18
`months, 3 years, and 7 years after the REMS is initially approved.
`
`
`
` 1
`
`Reference ID: 3234951
`
`(b) (4)
`
`

`

`On February 13, 2012, the sponsor submitted the proposed REMS (Seq. No. 0040) that
`included a communication plan with the requirements described in the REMS
`Notification Letter. No additional risk mitigation strategies for the REMS were proposed
`by the sponsor.
`After review of the application, DCRP found that the sponsor’s pivitol trial
`(ARISTOTLE) demonstrated clinically significant efficacy for Eliquis in the population
`studied. However, a significant rate (estimated to be approximately 10%) of medication
`errors (wrong active drug, placebo instead of active, active instead of placebo) was
`observed in the ARISTOTLE trial. On June 22, 2012, DCRP issued a Complete
`Response Letter (informing the sponsor that the application cannot be reviewed in its
`present form and requested that the sponsor submit additional information on data
`management and verification from the ARISTOTLE trial. The REMS was not reviewed
`during this review cycle.
`On September 17, 2012, the sponsor submitted a NDA Resubmission in response to the
`Complete Response Letter. The resubmission did not include the proposed REMS as a
`component of the application.
`On November 26, 2012, BMS was notified that the resubmission must include a REMS
`for review by the Agency. On November 29, 2012, the sponsor submitted the proposed
`REMS (Supplement 81/Sequence 0077), which is the focus of this review.
`4 MATERIALS REVIEWED
`4.1 SUBMISSIONS
` Bristol-Myers Squibb proposed REMS (Supplement 81/Sequence 0077) for Eliquis
`(apixaban), received November 29, 2012
`4.2 OTHER MATERIALS INFORMING THE REVIEW
` Office of Compliance/REMS Compliance Team Review of the REMS for Eliquis,
`dated December 18, 2012
` Draft Prescribing Information for Eliquis (apixaban), dated December 19, 2012
` Xarelto (rivaroxaban) REMS, approved July 12, 2012
`5 SUMMARY OF APPLICANT’S PROPOSED REMS
`DCRP and DRISK agree that the REMS for Eliquis should be comparable to the
`currently approved REMS for Xarelto (rivaroxaban), which is a drug in the same class
`with similar mechanism of action and safety concern. The currently approved REMS for
`Xarelto contains a communication plan and informs healthcare providers (HCPs) of the
`increased risk of thrombotic events without adequate anticoagulation and that Xarelto
`should be taken with the evening meal. Food does not affect the bioavailability of
`Eliquis; therefore, it is not a subject of the proposed REMS.
`I.
`GOAL
`The goal of the ELIQUIS REMS is to inform HCPs that discontinuing ELIQUIS in the
`absence of adequate anticoagulation places patients with nonvalvular atrial fibrillation at
`an increased risk of thrombotic events, including stroke, and to direct HCPs to follow the
`
` 2
`
`Reference ID: 3234951
`
`

`

`recommendations in the US Prescribing Information (USPI) on how to convert patients
`with nonvalvular atrial fibrillation from ELIQUIS to warfarin or other anticoagulants.
`Reviewer’s Comments:
`The applicant’s goal is not identical to that of Xarelto’s REMS due to product
`labeling differences. However, the applicant’s proposed editorial changes do not
`alter the interpretation of the intended goal. To improve clarity of the message,
`DRISK recommends presenting the goals as a bulleted list. These revisions are
`described in Section 7, Comments for the Applicant.
`
`II. REMS ELEMENTS
`
`A. Communication Plan
`
`Bristol-Myers Squibb will implement a communication plan to HCPs to support
`implementation of this REMS.
`1. Dear Healthcare Professional Letter
`A DHCP Letter will be distributed by mail to HCPs including: cardiologists, neurologists,
`internists, family practice physicians, nurse practitioners, physician assistants, and
`pharmacists. The letter will be distributed within 60 days, 12 months, and 24 months after
`approval of the REMS, and in the event of any substantial safety update. The DHCP
`Letter will also be provided to FDA MedWatch at these times. A copy of the USPI and
`Medication Guide will accompany the DHCP Letter.
`
`
`
`The DHCP letter is part of the REMS and is appended.
`Reviewer’s Comments:
`To ensure the same target audience is addressed with the Eliquis REMS as compared
`to the Xarelto REMS, the applicant should:
` add ‘emergency medicine physicians’ to the targeted healthcare professionals
`receiving the letter
` replace ‘internists’ with ‘internal medicine physicians’ and ‘family practice
`physicians’ with ‘primary practice physicians’.
`The section also includes revisions that incorporate comments from the Office of
`Compliance/REMS Compliance Team to ensure the enforceability of the REMS.
`Furthermore, the current policy is for REMS to not specifically require that the
`REMS materials be distributed via sales representatives and medical science liasons.
`Therefore, this requirement must be removed from the REMS.
` The aforementioned revisions are described in Section 7, Comments for the
`Applicant.
`
` 3
`
`Reference ID: 3234951
`
`(b) (4)
`
`

`

`
`
`2. ELIQUIS REMS Website
`Within 30 days of REMS approval, Bristol-Myers Squibb will post information for HCPs
`and
`patients
`on
`the
`ELIQUIS
`REMS
`website
`. This information will remain on the
`
`website for a period of 2 years.
`The content of the print or web-based material will include the following:
` Goal of the REMS
`
`Information about the risk
` US Prescribing Information for ELIQUIS
` Medication Guide for ELIQUIS
` DHCP Letter (for a period of 2 years)
`Reviewer’s Comments:
` The applicant did not include a statement indicating that the website is a part
`of the REMS; therefore, the following sentence after the bulleted list must be
`included:
`The ELIQUIS REMS website is part of the REMS and is appended.
` Current policy is for the REMS website to have a unique web address from the
`product website. The applicant must revise the proposed URL address for the
`REMS website to www.ELIQUISREMS.com, or something similar.
` The content of the REMS website is a replicate of the proposed Dear
`Healthcare Professional Letter. This does not meet the current format and
`content standards for REMS websites. Therefore, the content of the REMS
`website must be revised for clarity and consistency with the current standards
`and practices for REMS websites.
`The aforementioned revisions are described in Section 7, Comments for the
`Applicant.
`
`
`
`3. Letters to Professional Organizations
`A Professional Organization Letter will be distributed by e-mail within 60 days of the
`REMS approval date. This communication to professional organizations will include the
`same information as that contained in the DHCP Letter. Bristol-Myers Squibb will
`request that these organizations disseminate this information to their members. Bristol-
`Myers Squibb will communicate the letter to the leadership of the following professional
`organizations:
` American Heart Association (AHA)
` American College of Cardiologists (ACC)
`
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`
`Reference ID: 3234951
`
`(b) (4)
`
`

`

` Heart Rhythm Society (HRS)
` Society for Cardiovascular Angiography and Interventions (SCAI)
` American Academy of Neurology (AAN)
` American Neurological Association (ANA)
` National Institute of Neurological Disorders and Stroke (NINDS)
` American Stroke Association (ASA)
` National Stroke Association (NSA)
` American Association of Neuromuscular & Electrodiagnostic Medicine (AANEM)
` American College of Chest Physicians (ACCP)
` Association of Black Cardiologists (ABC)
` American Academy of Family Physicians (AAFP)
` American College of Physicians (ACP)
` Society of General Internal Medicine (SGIM)
` National Medical Association (NMA)
` American Academy of Nurse Practitioners (AANP)
` American Academy of Physician Assistants (AAPA)
` American College of Clinical Pharmacy (ACCP)
` American Society of Health-System Pharmacists (ASHP)
` American Pharmacists Association (APhA)
` National Association of Chain Drug Stores (NACDS)
` American Association of Critical-Care Nurses (AACN)
` National Association of Clinical Nurse Specialists (NACNS)
`The USPI and the Medication Guide will be provided in conjunction with the letter.
`The Professional Organization Letter is part of the REMS and is appended.
`Reviewer’s Comment:
`The applicant should add the ‘Association of the Emergency Physicians’ to the list of
`professional organizations to remain consistent with list of professional organizations
`targeted in the Xarelto REMS. The aforementioned revisions are described in Section
`7, Comments for the Applicant.
`
`B. Timetable for Submission of Assessments
`
`Bristol-Myers Squibb will submit REMS Assessments to the FDA at 18 months, 3 years,
`and 7 years from the date of the REMS approval. To facilitate inclusion of as much
`
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`Reference ID: 3234951
`
`

`

`information as possible while allowing reasonable time to prepare the submission, the
`reporting interval covered by each assessment should conclude no earlier than 60 days
`before the submission date for that assessment. Bristol-Myers Squibb will submit each
`assessment so that it will be received by the FDA on or before the due date.
`Reviewer’s Comment:
`The proposed timetable is acceptable; therefore, no further comments are
`provided on the Timetable for Submission of Assessments.
`
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` RECOMMEN