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`Trade Name:
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`Generic Name:
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`CENTER FOR DRUG EVALUATION AND RESEARCH
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`Approval Package for:
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`APPLICATION NUMBER:
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`202155Orig1s002
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` Eliquis 2.5 and 5 mg Tablets
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`apixaban
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`Bristol-Myers Squibb
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`January 30, 2014
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`ELIQUIS is a factor Xa inhibitor anticoagulant indicated
`to reduce the risk of stroke and systemic embolism in
`patients with nonvalvular atrial fibrillation.
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`Sponsor:
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`Approval Date:
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`Indications:
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`

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`CENTER FOR DRUG EVALUATION AND RESEARCH
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`202155Orig1s002
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`CONTENTS
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`Reviews / Information Included in this NDA Review.
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`
`
`Approval Letter
`Other Action Letters
`Labeling
`REMS
`Summary Review
`Officer/Employee List
`Office Director Memo
`Cross Discipline Team Leader Review
`Medical Review(s)
`Chemistry Review(s)
`Environmental Assessment
`Pharmacology Review(s)
`Statistical Review(s)
`Microbiology / Virology Review(s)
`Clinical Pharmacology/Biopharmaceutics Review(s)
`Other Reviews
`Risk Assessment and Risk Mitigation Review(s)
`Proprietary Name Review(s)
`Administrative/Correspondence Document(s)
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`X
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`X
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`X
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`X
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`

`

`
`
`CENTER FOR DRUG EVALUATION AND
`RESEARCH
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`
`
`APPLICATION NUMBER:
`202155Orig1s002
`APPROVAL LETTER
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`DEPARTMENT OF HEALTH AND HUMAN SERVICES
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` NDA 202155/S-002
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`Food and Drug Administration
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`Silver Spring MD 20993
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`SUPPLEMENT APPROVAL
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`Bristol-Myers Squibb
`ATTENTION: Linda Gambone, Ph.D.
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`Associate Director, Global Regulatory Sciences
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`P.O. Box 4000
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`Princeton, NJ 08543-4000
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`
`Dear Dr. Gambone:
`
`
`Please refer to your Supplemental New Drug Application (sNDA) dated April 29, 2013, received April
`29, 2013, submitted under section 505(b) of the Federal Food, Drug, and Cosmetic Act (FDCA) for
`Eliquis (apixaban) 2.5 and 5 mg Tablets.
`
`This Prior Approval supplemental new drug application provides verbiage to better differentiate
`temporary interruption vs. discontinuation, new information and dosing recommendations for patient with
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`end stage renal disease, and to include data from a drug-drug interaction study with prasugrel. The
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`agreed upon changes to the Full Prescribing Information (FPI) language are as follows:
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`
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` The title of subsection 2.3 was changed to “Temporary Interruption for Surgery and Other
`Interventions”
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` The subsection of DOSAGE AND ADMINISTRATION, 2.7 Renal Impairment, was changed
`from:
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`“The dosing adjustment for moderate renal impairment is described above [see Dosage and
`Administration (2.2)]. No data inform use in patients with creatinine clearance <15 mL/min or on
`dialysis.”
`
`
`To
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`“The dosing adjustment for moderate renal impairment is described above [see Dosage and
`Administration (2.2)].The recommended dose for patients with end-stage renal disease (ESRD)
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`maintained on hemodialysis is 5 mg twice daily. Reduce dose to 2.5 mg twice daily if one of the
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`following patient characteristics (age 80 years or body weight 60 kg) is present [see Use in
`Specific Population (8.6) and Clinical Pharmacology (12.3)].”
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`Reference ID: 3445066
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`

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`NDA 202155/S-002 – Approval Letter
`Page 2
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` A new subsection within USE IN SPECIFIC POPULATIONS was added. This new subsection,
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`8.6 End-Stage Renal Disease Patients Maintained with Hemodialysis, reads:
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`“Patients with ESRD with or without hemodialysis were not studied in clinical efficacy and safety
`studies with ELIQUIS; therefore, the dosing recommendation 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
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`Dosage and Administration (2.7), Clinical Pharmacology (12.2, 12.3)].”
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`
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`In subsection 12.3, Pharmacokinetics, Figure 3, “Effect of Specific Populations on the
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`Pharmacokinetics of Apixaban” was replaced with the below:
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` * ESRD subjects maintained with chronic and stable hemodialysis; Reported PK findings are following
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` single dose of apixaban post hemodialysis.
`† Creatinine clearance 15 to 29 mL/min.
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`‡ Dashed vertical lines illustrate pharmacokinetic changes that were used to inform dosing
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`recommendations.
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`  There were also a few minor editorial and formatting changes made to throughout the FPI.
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` The HIGHLIGHTS and Table of Contents were amended to reflect these changes to the FPI.
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`Reference ID: 3445066
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`

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`NDA 202155/S-002 – Approval Letter
`Page 3
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`
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`APPROVAL & LABELING
`We have completed our review of this supplemental application, as amended. It is approved, effective on
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`the date of this letter, for use as recommended in the enclosed, agreed-upon labeling text.
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`CONTENT OF LABELING
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`As soon as possible, but no later than 14 days from the date of this letter, submit the content of labeling
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`[21 CFR 314.50(l)] in structured product labeling (SPL) format using the FDA automated drug
`registration and listing system (eLIST), as described at
`http://www.fda.gov/ForIndustry/DataStandards/StructuredProductLabeling/default.htm. Content of
`labeling must be identical to the enclosed labeling (text for the package insert and Medication Guide),
`with the addition of any labeling changes in pending “Changes Being Effected” (CBE) supplements, as
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`well as annual reportable changes not included in the enclosed labeling.
`
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`Information on submitting SPL files using eList may be found in the guidance for industry titled “SPL
`Standard for Content of Labeling Technical Qs and As at
`http://www.fda.gov/downloads/DrugsGuidanceComplianceRegulatoryInformation/Guidances/UCM0723
`92.pdf
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`The SPL will be accessible from publicly available labeling repositories.
`
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`Also within 14 days, amend all pending supplemental applications that includes labeling changes for this
`NDA, including CBE supplements for which FDA has not yet issued an action letter, with the content of
`labeling [21 CFR 314.50(l)(1)(i)] in MS Word format, that includes the changes approved in this
`supplemental application, as well as annual reportable changes and annotate each change. To facilitate
`review of your submission, provide a highlighted or marked-up copy that shows all changes, as well as a
`clean Microsoft Word version. The marked-up copy should provide appropriate annotations, including
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`supplement number(s) and annual report date(s).
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`REQUIRED PEDIATRIC ASSESSMENTS
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`Under the Pediatric Research Equity Act (PREA) (21 U.S.C. 355c), all applications for new active
`ingredients, new indications, new dosage forms, new dosing regimens, or new routes of administration are
`required to contain an assessment of the safety and effectiveness of the product for the claimed
`indication(s) in pediatric patients unless this requirement is waived, deferred, or inapplicable.
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`Because none of these criteria apply to your application, you are exempt from this requirement.
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`REPORTING REQUIREMENTS
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`We remind you that you must comply with reporting requirements for an approved NDA (21 CFR 314.80
`and 314.81).
`
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`Reference ID: 3445066
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`

`

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`
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`Sincerely,
`
`{See appended electronic signature page}
`
`Mary Ross Southworth, Pharm.D.
`Deputy Director for Safety
`Division of Cardiovascular and Renal Products
`Office of Drug Evaluation I
`Center for Drug Evaluation and Research
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`NDA 202155/S-002 – Approval Letter
`Page 4
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`If you have any questions, please contact:
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`Alison Blaus, RAC
`Regulatory Project Manager
`(301) 796-1138
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`ENCLOSURE:
`Content of Labeling
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`
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`Reference ID: 3445066
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`

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`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`ALISON L BLAUS
`01/30/2014
`
`MARY R SOUTHWORTH
`01/30/2014
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`Reference ID: 3445066
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`