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`DEPARTMENT OF HEALTH AND HUMAN SERVICES
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` NDA 202155-S011
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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
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`ATTENTION: Sekayi Mushonga, PharmD
`Director, US Regulatory Liaison CV & Metabolics
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`P.O. Box 4000
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`Princeton, NJ 08543-4000
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`Dear Dr. Mushonga:
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`Please refer to your Supplemental New Drug Application (sNDA) dated 15 December 2014, received 15
`December 2014, submitted under section 505(b) of the Federal Food, Drug, and Cosmetic Act (FDCA)
`for Eliquis (apixaban) 2.5 and 5 mg Tablets.
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`We acknowledge receipt of your amendments dated 24 March and 28 April 2015.
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`This Prior Approval supplemental new drug application proposes changes to labeling which is aimed to
`harmonize the presentation of safety and efficacy data in the labels for all recently approved non-vitamin
`K-dependent oral anticoagulants (NOACs). The agreed upon changes are as follows:
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`1. In Section 6, ADVERSE REACTIONS, the presentation of the bleeding events was amended to
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`appear as follows. To eliminate redundancy, some information that once appeared prior to the
`bleeding table (and in the table) was also deleted:
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`Reference ID: 3817488
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` NDA 202155-S011
`Page 2
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`Table 1:
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`Bleeding Events in Patients with Nonvalvular Atrial Fibrillation in
`ARISTOTLE*
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`‡
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`Hazard Ratio
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`(95% CI)
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`P-value
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` Warfarin
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` ELIQUIS
`N=9052
`N=9088
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`n (per 100 pt-year) n (per 100 pt-year)
`Major†
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`<0.0001
`0.69 (0.60, 0.80)
`462 (3.09)
`327 (2.13)
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` Intracranial (ICH)‡
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`-
`0.41 (0.30, 0.57)
`125 (0.82)
`52 (0.33)
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`Hemorrhagic stroke§
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`-
`0.51 (0.34, 0.75)
`74 (0.49)
`38 (0.24)
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`-
`0.29 (0.16, 0.51)
`51 (0.34)
`15 (0.10)
`Other ICH
` Gastrointestinal (GI)¶
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`-
`0.89 (0.70, 1.14)
`141 (0.93)
`128 (0.83)
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`-
`0.27 (0.13, 0.53)
`37 (0.24)
`10 (0.06)
`Fatal**
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`-
`0.13 (0.05, 0.37)
`30 (0.20)
`4 (0.03)
`Intracranial
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`-
`0.84 (0.28, 2.15)
`7 (0.05)
`6 (0.04)
`Non-intracranial
`* Bleeding events within each subcategory were counted once per subject, but subjects may have contributed
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`events to multiple endpoints. Bleeding events were counted during treatment or within 2 days of stopping study
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`treatment (on-treatment period).
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`† Defined as clinically overt bleeding accompanied by one or more of the following: a decrease in hemoglobin of
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`2 g/dL, a transfusion of 2 or more units of packed red blood cells, bleeding at a critical site: intracranial,
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`intraspinal, intraocular, pericardial, intra-articular, intramuscular with compartment syndrome, retroperitoneal or
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`with fatal outcome.
`Intracranial bleed includes intracerebral, intraventricular, subdural, and subarachnoid bleeding. Any type of
`hemorrhagic stroke was adjudicated and counted as an intracranial major bleed.
`§ On-treatment analysis based on the safety population, compared to ITT analysis presented in Section 14.
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`¶ GI bleed includes upper GI, lower GI, and rectal bleeding.
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`** Fatal bleeding is an adjudicated death with the primary cause of death as intracranial bleeding or non-intracranial
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`bleeding during the on-treatment period.
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`Reference ID: 3817488
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` NDA 202155-S011
`Page 3
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`2. The following forest plot in Section 6 was amended to include only the following subgroups and
`presented in include n/N(%/yr) for apixaban and warfarin, the hazard ratio, and to remove the
`p-value. An overall effect line was also added to the plot. The population used was On-Treatment
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`plus 2 days:
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`Figure 1: Major Bleeding Hazard Ratios by Baseline Characteristics –
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` ARISTOTLE Study
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`Reference ID: 3817488
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` NDA 202155-S011
`Page 4
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` 3. The following standard cautionary paragraph was included at the bottom of the forest plot:
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`Note: The figure above presents effects in various subgroups, all of which are baseline
`characteristics and all of which were pre-specified, if not the groupings. The 95% confidence
`limits that are shown do not take into account how many comparisons were made, nor do they
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`reflect the effect of a particular factor after adjustment for all other factors. Apparent
`homogeneity or heterogeneity among groups should not be over-interpreted.
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` 4. In Section 14, CLINICAL STUDIES, the forest plot was amended to include the same
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`subgroups as the plot in Section 6 and also to present the data in an identical way as Section 6.
`The population used to generate the forest plot, however, is different than that in Section 6. The
`population used in Section 14 was Intent-to-Treat (ITT).
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`5. In the HIGHLIGHTS, the Recent Major Changes section was updated to remove any changes
`that were outside of 1 year. The corresponding vertical line in the full prescribing information
`noting the changes was therefore also removed.
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`6. Other minor editorial changes were also made throughout the label.
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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), with the addition of any
`labeling changes in pending “Changes Being Effected” (CBE) supplements, as well as annual reportable
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`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
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`clean Microsoft Word version. The marked-up copy should provide appropriate annotations, including
`supplement number(s) and annual report date(s).
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`Reference ID: 3817488
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` NDA 202155-S011
`Page 5
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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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`If you have any questions, please contact:
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`Alison Blaus, RAC
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`Senior Regulatory Project Manager
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`(301) 796-1138
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`Sincerely,
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`{See appended electronic signature page}
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`Mary Ross Southworth, Pharm.D.
`Deputy Director for Safety
`Division of Cardiovascular and Renal Products
`Office of Drug Evaluation I
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`Center for Drug Evaluation and Research
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`ENCLOSURE:
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`Content of Labeling
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`Reference ID: 3817488
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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/
`----------------------------------------------------
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`ALISON L BLAUS
`09/09/2015
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`MARY R SOUTHWORTH
`09/10/2015
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`Reference ID: 3817488
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