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`DEPARTMENT OF HEALTH AND HUMAN SERVICES
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` NDA 022024/S-012
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` NDA 022024/S-013
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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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` Takeda Pharmaceutical U.S.A., Inc.
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` Attention: Esha Desai, MS, RAC (US, EU)
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` Manager, Global Regulatory Affairs Development
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` One Takeda Parkway
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` Deerfield, IL 60015
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`Dear Ms. Desai:
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`Please refer to your Supplemental New Drug Applications (sNDAs) and your amendments,
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`submitted pursuant to section 505(b)(2) of the Federal Food, Drug, and Cosmetic Act (FDCA)
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`for ActoPlus Met XR (pioglitazone and metformin hydrochloride extended release) tablets.
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`Supplement 012
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`This Prior Approval sNDA, dated and received July 30, 2015, provides for updates to the
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`Warnings and Precautions section of the package insert (PI) to include information on bladder
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`cancer risk based on additional information from a 10-year study and changes to the PI to
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`comply with the Pregnancy and Lactation Labeling Rule (PLLR).
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`Supplement 013
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`We also refer to our letter dated April 8, 2016, notifying you, under Section 505(o)(4) of the
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`FDCA, of new safety information that we believe should be included in the labeling. This
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`information pertains to the lower risk of lactic acidosis in certain patients with renal impairment
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`who use products containing metformin.
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`This Changes Being Effected sNDA, dated and received May 5, 2016, provides for revisions to
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`the labeling for ActoPlus Met XR consistent with our April 8, 2016, letter and the changes
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`agreed upon in our October 3, 2016, correspondence.
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`APPROVAL & LABELING
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`We have completed our review of these supplemental applications, as amended. They are
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`approved, effective on the date of this letter, for use as recommended in the enclosed, agreed-
`upon labeling text and with the minor editorial revisions listed below and indicated in the
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`enclosed labeling.
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`Reference ID: 4026186
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`

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` NDA 022024/S-012
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` NDA 022024/S-013
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` Page 2
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` • The revision date listed for the Highlights of Prescribing Information was updated to
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` reflect the date of approval of these supplements.
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` • The revision date listed for Recent Major Changes, Urinary Bladder Tumors, was
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`updated to reflect the date of approval of these supplements.
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`WAIVER OF HIGHLIGHTS SECTION
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`Please note that we have previously granted a waiver of the requirements of 21 CFR
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`201.57(d)(8) regarding the length of Highlights of prescribing information.
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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
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`labeling [21 CFR 314.50(l)] in structured product labeling (SPL) format using the FDA
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`automated drug registration and listing system (eLIST), as described
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`at http://www.fda.gov/ForIndustry/DataStandards/StructuredProductLabeling/default.htm.
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`Content of labeling must be identical to the enclosed labeling (text for the package insert and
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`Medication Guide) with the addition of any labeling changes in pending “Changes Being
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`Effected” (CBE) supplements, as well as annual reportable changes not included in the enclosed
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`labeling.
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`Information on submitting SPL files using eLIST may be found in the guidance for industry
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`titled “SPL Standard for Content of Labeling Technical Qs and As”
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`at http://www.fda.gov/downloads/DrugsGuidanceComplianceRegulatoryInformation/Guidances/
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`UCM072392.pdf.
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` The SPL will be accessible via publicly available labeling repositories.
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` Also within 14 days, amend all pending supplemental applications for this NDA, including CBE
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` 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 with the revisions
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` indicated above 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
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`marked-up copy that shows all changes, as well as a clean Microsoft Word version. The marked-
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`up copy should provide appropriate annotations, including supplement number(s) and annual
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`report date(s).
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`Reference ID: 4026186
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` NDA 022024/S-012
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` NDA 022024/S-013
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` Page 3
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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
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` administration are required to contain an assessment of the safety and effectiveness of the
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` product for the claimed indication(s) in pediatric patients unless this requirement is waived,
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` deferred, or inapplicable.
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`Because none of these criteria apply to your applications, you are exempt from this requirement.
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`FULFILLMENT OF POSTMARKETING REQUIREMENT
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`We have received your submission dated August 28, 2014, containing the final report for the
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`following postmarketing requirement listed in the August 4, 2011, approval letter for sNDA
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`022024/S-007:
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`1783-1
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`Continuation and modification of your ten-year epidemiological study assessing
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`whether treatment with pioglitazone hydrochloride is associated with an increased
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`risk of bladder cancer in men and women with diabetes.
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`We have reviewed your submission and conclude that the above requirement was fulfilled.
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`This completes all of your postmarketing requirements acknowledged in our August 4, 2011,
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`letter.
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`PROMOTIONAL MATERIALS
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`You may request advisory comments on proposed introductory advertising and promotional
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`labeling. To do so, submit the following, in triplicate, (1) a cover letter requesting advisory
`comments, (2) the proposed materials in draft or mock-up form with annotated references, and
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`(3) the package insert(s) to:
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`OPDP Regulatory Project Manager
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`Food and Drug Administration
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`Center for Drug Evaluation and Research
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`Office of Prescription Drug Promotion (OPDP)
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`5901-B Ammendale Road
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`Beltsville, MD 20705-1266
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`Alternatively, you may submit a request for advisory comments electronically in eCTD format.
`For more information about submitting promotional materials in eCTD format, see the draft
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`Guidance for Industry (available
`at: http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidance
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`s/UCM443702.pdf ).
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`Reference ID: 4026186
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` NDA 022024/S-012
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` NDA 022024/S-013
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` Page 4
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` You must submit final promotional materials and package insert(s), accompanied by a Form
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` FDA 2253, at the time of initial dissemination or publication [21 CFR 314.81(b)(3)(i)]. Form
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` FDA 2253 is available
` at http://www.fda.gov/downloads/AboutFDA/ReportsManualsForms/Forms/UCM083570.pdf.
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`Information and Instructions for completing the form can be found
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`at http://www.fda.gov/downloads/AboutFDA/ReportsManualsForms/Forms/UCM375154.pdf.
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`For more information about submission of promotional materials to the Office of Prescription
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`Drug Promotion (OPDP),
`see http://www.fda.gov/AboutFDA/CentersOffices/CDER/ucm090142.htm.
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`All promotional materials that include representations about your drug product must be promptly
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`revised to be consistent with the labeling changes approved in this supplement, including any
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`new safety information [21 CFR 314.70(a)(4)]. The revisions in your promotional materials
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`should include prominent disclosure of the important new safety information that appears in the
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`revised package labeling. Within 7 days of receipt of this letter, submit your statement of intent
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`to comply with 21 CFR 314.70(a)(4) to the address above, by fax to 301-847-8444, or
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`electronically in eCTD format. For more information about submitting promotional materials in
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`eCTD format, see the draft Guidance for Industry (available
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`at: http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidance
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`s/UCM443702.pdf ).
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`REPORTING REQUIREMENTS
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`We remind you that you must comply with reporting requirements for an approved NDA
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`(21 CFR 314.80 and 314.81).
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`If you have any questions, call Liz Godwin, Regulatory Project Manager, at (240) 402-3438.
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`Sincerely,
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`{See appended electronic signature page}
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`Jennifer Rodriguez Pippins, M.D., M.P.H.
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`Deputy Director for Safety
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`Division of Metabolism and Endocrinology Products
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`Office of Drug Evaluation II
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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: 4026186
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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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`JENNIFER R PIPPINS
`12/12/2016
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`Reference ID: 4026186
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