CENTER FOR DRUG EVALUATION AND
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`CENTER FOR DRUG EVALUATION AND
`RESEARCH
`RESEARCH
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`APPLICATION NUMBER:
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`22-024
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`APPLICA TION NUMBER:
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`APPROVAL LETTER
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`APPROVAL LETTER
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`22-024
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`DEPARTMENT OF HEALTH & HUMAN SERVICES
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`Public Health Service
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`Food and Drug Administration
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`Rockville, MD 20857
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` NDA APPROVAL
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`NDA 22-024
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`Takeda Global Research & Development Center, Inc.
`Attention: Sandra Cosner, R.Ph.
`Program Manager, Regulatory Affairs
`675 N. Field Drive
`Lake Forest, IL 60045
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`Dear Ms. Cosner:
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`Please refer to your new drug application (NDA) dated March 31, 2006, received April 3, 2006,
`submitted pursuant to section 505(b)(2) of the Federal Food, Drug, and Cosmetic Act (FDCA)
`for ACTOPLUS MET XR (pioglitazone hydrochloride and 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 submissions dated February 6, 2007, and February 29, April 30,
`May 9, October 7 (2 submissions), 16, and 28, November 24, and December 10, 2008, and
`February 11, March 11, and 25, and April 1, 2009.
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`The April 30, 2008, submission constituted a complete response to our February 2, 2007, action
`letter.
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`ACTOPLUS MET XR is indicated as an adjunct to diet and exercise to improve glycemic
`control in adults with type 2 diabetes mellitus who are already treated with pioglitazone and
`metformin or who have inadequate glycemic control on pioglitazone alone or metformin alone.
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`We have completed our review of this application, as amended. It is approved, effective on the
`date of this letter, for use as recommended in the enclosed agreed-upon labeling text (text for the
`package insert and Medication Guide submitted March 25, 2009, and carton and container labels
`submitted December 10, 2008).
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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, please submit the
`content of labeling [21 CFR 314.50(l)] in structured product labeling (SPL) format as described
`at http://www.fda.gov/oc/datacouncil/spl.html that is identical to the enclosed labeling (text for
`the package insert and Medication Guide).
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`

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`NDA 22-024
`Page 2
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`Upon receipt, we will transmit that version to the National Library of Medicine for
`public dissemination. For administrative purposes, please designate this submission,
`“SPL for approved NDA 22-024.”
`
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`CARTON AND IMMEDIATE CONTAINER LABELS
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`We acknowledge your December 10, 2008, submission containing printed carton and container
`labels. Submit final printed carton and container labels that are identical to the enclosed carton
`and immediate container labels as soon as they are available, but no more than 30 days after they
`are printed. Please submit these labels electronically according to the guidance for industry titled
`Providing Regulatory Submissions in Electronic Format – Human Pharmaceutical Product
`Applications and Related Submissions Using the eCTD Specifications (October 2005). For
`administrative purposes, designate this submission “Final Printed Carton and Container
`Labels for approved NDA 22-024.” Approval of this submission by FDA is not required before
`the labeling is used.
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`Marketing the product with FPL that is not identical to the approved labeling text may render the
`product misbranded and an unapproved new drug.
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`PEDIATRIC RESEARCH EQUITY ACT (PREA)
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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 in pediatric patients unless this requirement is waived,
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`deferred, or inapplicable.
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`We are granting a full waiver for the pediatric study requirement citing safety concerns with
`pioglitazone hydrochloride, one of the active ingredients in ACTOPLUS MET XR, in the
`pediatric population.
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`RISK EVALUTION AND MITIGATION STRATEGY REQUIREMENTS
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`Title IX, Subtitle A, Section 901 of the Food and Drug Administration Amendments Act of 2007
`(FDAAA) amends the Federal Food, Drug, and Cosmetic Act (FDCA) to authorize FDA to
`require the submission of a Risk Evaluation and Mitigation Strategy (REMS) if FDA determines
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`that such a strategy is necessary to ensure that the benefits of the drug outweigh the risks (section
`505-1(a)(1)). This provision took effect on March 25, 2008.
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`In accordance with section 505-1 of FDCA, as one element of a REMS, FDA may require the
`development of a Medication Guide as provided for under 21 CFR Part 208. Pursuant to 21 CFR
`Part 208, FDA has determined that ACTOPLUS MET XR poses a serious and significant public
`health concern requiring the distribution of a Medication Guide. The Medication Guide is
`necessary for patients’ safe and effective use of ACTOPLUS MET XR.
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`NDA 22-024
`Page 3
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`FDA has determined that ACTOPLUS MET XR is a product that has serious risks (relative to
`benefits) of which patients should be made aware because information concerning the risks could
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`affect patients’ decisions to use, or continue to use ACTOPLUS MET XR. Under 21 CFR 208,
`you are responsible for ensuring that the Medication Guide is available for distribution to
`patients who are dispensed ACTOPLUS MET XR.
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`Your proposed REMS, appended to this letter, submitted on October 16, 2008, is approved. The
`REMS consists of the Medication Guide included with this letter and the timetable for
`submission of assessments of the REMS.
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`Your assessment of the REMS should include an evaluation of:
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`a. Patients’ understanding of the serious risks of ACTOPLUS MET XR
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`b. A report on periodic assessments of the distribution and dispending of the Medication
`Guide in accordance with 21 CFR 208.24
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`c. A report on failures to adhere to distribution and dispensing requirements, and
`corrective actions taken to address noncompliance
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`Prominently identify submissions containing REMS assessments or proposed REMS
`modifications with the following wording in bold capital letters at the top of the first page of the
`submission:
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`NDA 22-024 REMS ASSESSMENT
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`NEW SUPPLEMENT FOR NDA 22-024
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`PROPOSED REMS MODIFICATION
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`<other supplement identification> [if included]
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`<REMS ASSESSMENT> [if included]
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`If you do not submit electronically, please send 5 copies of submissions related to your REMS.
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`Reference is made to your amendments dated October 20, 2008, to NDA 21-073 for Actos
`(pioglitazone) Tablets, and to NDA 21-925 for Duetact (pioglitazone/glimepiride fixed-dose
`combination) Tablets, which contain a proposed Medication Guide and REMS. These
`amendments are under review.
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`PROMOTIONAL MATERIALS
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`You may request advisory comments on proposed introductory advertising and promotional
`labeling. To do so, submit, in triplicate, a cover letter requesting advisory comments, the
`proposed materials in draft or mock-up form with annotated references, and the package insert
`to:
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`Food and Drug Administration
`Center for Drug Evaluation and Research
`Division of Drug Marketing, Advertising, and Communications
`5901-B Ammendale Road
`Beltsville, MD 20705-1266
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`

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`NDA 22-024
`Page 4
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`As required under 21 CFR 314.81(b)(3)(i), you must submit final promotional materials, and the
`package insert(s), at the time of initial dissemination or publication, accompanied by a Form
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`FDA 2253. For instruction on completing the Form FDA 2253, see page 2 of the Form. For
`more information about submission of promotional materials to the Division of Drug Marketing,
`Advertising, and Communications (DDMAC), see www.fda.gov/cder/ddmac.
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`METHODS VALIDATION
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`We have not completed validation of the regulatory methods. However, we expect your
`continued cooperation to resolve any problems that may be identified.
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`LETTERS TO HEALTH CARE PROFESSIONALS
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`If you issue a letter communicating important safety related information about this drug product
`(i.e., a “Dear Health Care Professional” letter), we request that you submit an electronic copy of
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`the letter to both this NDA and to the following address:
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`MedWatch
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`Food and Drug Administration
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`Suite 12B05
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`5600 Fishers Lane
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`Rockville, MD 20857
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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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`Sincerely,
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`{See appended electronic signature page}
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`
`Mary H. Parks, MD
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` Director
`Division of Metabolism and Endocrinology Products
`Office of Drug Evaluation II
`Center for Drug Evaluation and Research
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`Enclosures: Package Insert, Medication Guide, REMS, Carton Labels, Container Labels
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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 Parks
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`5/12/2009 09:12:37 PM
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