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`DEPARTMENT OF HEALTH AND HUMAN SERVICES
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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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`NDA 22024/S-002
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`Takeda Global Research & Development Center, Inc.
`Attention: Jessica Y. Lee, Ph.D.
`Manager, Regulatory Affairs
`One Takeda Parkway
`Deerfield, IL 60015-2235
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`Dear Dr. Lee:
`
`Please refer to your supplemental new drug application (sNDA) dated November 19, 2009,
`received November 20, 2009, submitted under section 505(b) of the Federal Food, Drug, and
`Cosmetic Act (FDCA) for ACTOPLUS MET XR (pioglitazone hydrochloride + metformin
`hydrochloride extended-release) fixed-dose combination tablets, 15 mg/1000 mg and
`30 mg/1000 mg.
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`We acknowledge receipt of your amendments dated April 16, 2010, and December 3
`and 9, 2010; and your risk evaluation and mitigation strategy (REMS) assessment dated
`November 19, 2010.
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`This supplemental new drug application provides for a proposed modification to the approved
`REMS for ACTOPLUS MET XR (pioglitazone hydrochloride + metformin hydrochloride
`extended release).
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`We have completed our review of this supplemental application, as amended. It is approved,
`effective on the date of this letter, for use as recommended in the enclosed, agreed-upon labeling
`text.
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`We note that your December 3, 2010, submission includes final printed labeling (FPL) for your
`Medication Guide. We have not reviewed this FPL. You are responsible for assuring that the
`wording in this printed labeling is identical to that of the approved content of labeling in the
`structured product labeling (SPL) format.
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`As soon as possible, but no later than 14 days from the date of this letter, submit, using the FDA
`automated drug registration and listing system (eLIST), the content of labeling
`[21 CFR 314.50(l)] in structured product labeling (SPL) format, as described at
`http://www.fda.gov/ForIndustry/DataStandards/StructuredProductLabeling/default.htm, that is
`identical to the enclosed labeling (text for the package insert and text for the Medication Guide)
`and include the labeling changes proposed in any pending “Changes Being Effected” (CBE)
`supplements and any annual reportable changes not included in the enclosed labeling.
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`Reference ID: 2882265
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`

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` NDA 22024/S-002
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`Page 2
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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” at
`http://www.fda.gov/downloads/DrugsGuidanceComplianceRegulatoryInformation/Guidances/U
`CM072392.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 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.
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`We request that the labeling approved today be available on your website within 10 days of
`receipt of this letter.
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`RISK EVALUATION AND MITIGATION STRATEGY REQUIREMENTS
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`The REMS for ACTOPLUS MET XR (pioglitazone hydrochloride + metformin hydrochloride
`extended release) was originally approved on May 12, 2009. The REMS consists of a
`Medication Guide, and a timetable for submission of assessments of the REMS. Your proposed
`modification to the REMS consists of a stand-alone Medication Guide for ACTOPLUS MET XR
`which will replace the combination Medication Guide that was originally approved for both
`ACTOPLUS MET (pioglitazone hydrochloride + metformin hydrochloride) and ACTOPLUS
`MET XR. A stand-alone Medication Guide and REMS modification were previously approved
`for ACTOPLUS MET on October 21, 2009.
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`Your proposed modified REMS, submitted on December 9, 2010, and appended to this letter, is
`approved. The timetable for submission of assessments of the REMS and your REMS
`assessment plan will remain the same as that approved on May 12, 2009.
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`We remind you that assessments of an approved REMS must include, under section 505­
`1(g)(3)(B) and (C), information on the status of any post approval study or clinical trial required
`under section 505(o) or otherwise undertaken to investigate a safety issue. With respect to any
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`such post approval study, you must include the status of such study, including whether any
`difficulties completing the study have been encountered. With respect to any such post approval
`clinical trial, you must include the status of such clinical trial, including whether enrollment has
`begun, the number of participants enrolled, the expected completion date, whether any
`difficulties completing the clinical trial have been encountered, and registration information with
`respect to requirements under subsections (i) and (j) of section 402 of the Public Health Service
`Act. You can satisfy these requirements in your REMS assessments by referring to relevant
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`information included in the most recent annual report required under section 506B and 21 CFR
`314.81(b)(2)(vii) and including any material or significant updates to the status information since
`the annual report was prepared. Failure to comply with the REMS assessments provisions in
`section 505-1(g) could result in enforcement action.
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`Reference ID: 2882265
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` NDA 22024/S-002
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`Page 3
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`We also remind you that in addition to the assessments submitted according to the timetable
`included in the approved REMS, you must submit a REMS assessment and may propose a
`modification to the approved REMS when you submit a supplemental application for a new
`indication for use as described in section 505-1(g)(2)(A) of FDCA.
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`If you currently distribute or plan to distribute an authorized generic product under this NDA,
`you will also need to submit a REMS, REMS supporting document, and any required appended
`documents for that authorized generic, to this NDA. In other words, you must submit a complete
`proposed REMS that relates only to the authorized generic product. Review and approval of the
`REMS is required before you may market your product.
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`Prominently identify the submission containing the REMS assessments or proposed
`modifications with the following wording in bold capital letters at the top of the first page of the
`submission as appropriate:
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`NDA 22024 REMS ASSESSMENT
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`NEW SUPPLEMENT FOR NDA 22024
`PROPOSED REMS MODIFICATION
`REMS ASSESSMENT
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`NEW SUPPLEMENT (NEW INDICATION FOR USE)
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`FOR NDA 22024
`REMS ASSESSMENT
`PROPOSED REMS MODIFICATION (if included)
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`If you do not submit electronically, please send 5 copies of REMS-related submissions.
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`LETTERS TO HEALTH CARE PROFESSIONALS
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`If you decide to issue a letter communicating important safety related information about this drug
`product (i.e., a “Dear Health Care Professional” letter), we request that you at least 24 hours
`prior to issuing the letter, an electronic copy of the letter to this NDA, to
`CDERMedWatchSafetyAlerts@fda.hhs.gov, and to the following address:
`
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`MedWatch
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`Office of Special Health issues
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`Food and Drug Administration
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`10903 New Hampshire Ave
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`Building 32, Mail Stop 5353
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`Silver Spring MD 20993
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`Reference ID: 2882265
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`

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`Sincerely,
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`{See appended electronic signature page}
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`
`
` Parks,
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` M.D.
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` NDA 22024/S-002
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`Page 4
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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 call Ms. Jena Weber, Regulatory Project Manager, at
`301-796-1306.
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`Enclosures:
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`Medication Guide (updated)
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`REMS
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`Package insert (no changes with this supplement, version approved May 12, 2009,
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`under original NDA 022024)
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`
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`H.
`Mary
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`Director
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`Division of Metabolism and Endocrinology Products
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`Office of Drug Evaluation II
`Center for Drug Evaluation and Research
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`Reference ID: 2882265
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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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`MARY H PARKS
`12/22/2010
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`Reference ID: 2882265
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