CENTER FOR DRUG EVALUATION AND
`RESEARCH
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`APPLICATION NUMBER:
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`OTHER ACTION LETTER(s)
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`22-024
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`DEPARTMENT OF HEALTH & HUMAN SERVICES
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`Public Health Service
`Food and Drug Administration
`Rockville, MD 20857
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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
`One Takeda Parkway
`Deerfield, IL 60015-2235
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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 for ACTOPLUS
`MET™ XR (pioglitazone HCl/metformin HCl 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 June 30, October 17, November 3 and 30, and
`December 20, 2006, and January 29, 2007.
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`We completed our review of this application and it is approvable. Before the application may be
`approved, it will be necessary for you to correct the deficiencies cited by our investigator during a
`recent inspection of the drug product (metformin HCl) manufacturing facility at Andrx
`Pharmaceuticals, Inc.(4955 Orange Drive, Ft. Lauderdale, FL 33314), for this application. Our field
`investigator conveyed deficiencies to the facility representative. Satisfactory resolution to these
`deficiencies is required before this application may be approved.
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`In addition, it will be necessary for you to submit revised draft labeling that addresses the general
`comment and includes changes to the CLINICAL PHARMACOLOGY section, Pharmacokinetics
`and Drug Metabolism, Absorption and Bioavailability subsection summarized below.
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`General Comment:
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`You have proposed one set of prescribing information for both ACTOPLUS MET™ and
`ACTOPLUS MET™ XR. Two doses of ACTOPLUS MET™ XR are proposed:
`pioglitazone/metformin extended-release 15 mg/1000 mg and 30 mg/1000 mg. The usual
`maximum recommended dose of pioglitazone is 45 mg given once daily, while the maximum
`daily dose of metformin is 2000 mg. This information should be clearly stated in the DOSING
`and ADMINISTRATION section. You also propose that either dose of ACTOPLUS MET
`XR may be used as the initial dose; a titrated maximal dose should be stated in the prescribing
`information.
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`The different doses of pioglitazone and metformin in ACTOPLUS MET™ and ACTOPLUS
`MET™ XR
`should
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`highlighted. ACTOPLUS MET™
`tablets
`contain
`pioglitazone/metformin 15 mg/500 mg and 15 mg/850 mg, while ACTOPLUS MET™ XR
`tablets consist of pioglitazone/metformin XR 15 mg/1000 mg and 30 mg/1000 mg.
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`NDA 22-024
`Page 2
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`Under the CLINICAL PHARMACOLOGY section, Pharmacokinetics and Drug Metabolism,
`Absorption and Bioavailability subsection, the following changes need to be made (underline
`indicates new language inserted and strikethrough indicates deletion of language:
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`If additional information relating to the safety or effectiveness of this drug becomes available, revision
`of the labeling may be required.
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`Within 10 days after the date of this letter, you are required to amend this application, notify us of your
`intent to file an amendment, or follow one of your other options under 21 CFR 314.110. If you do not
`follow one of these options, we will consider your lack of response a request to withdraw the
`application under 21 CFR 314.65. Any amendment should respond to all the deficiencies listed. We
`will not process a partial reply as a major amendment nor will the review clock be reactivated until all
`deficiencies have been addressed.
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`The drug product may not be legally marketed until you have been notified in writing that this
`application is approved.
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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, M.D.
`Director
`Division of Metabolism and Endocrinology Products
`Office of Drug Evaluation II
`Center for Drug Evaluation and Research
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`“Time to peak serum concentration was prolonged by approximately 3 and 2 hours
`pioglitazone and metformin under fed conditions.”
`respectively for
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`(b)
`(4)
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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
`2/2/2007 01:28:22 PM
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