CENTER FOR DRUG EVALUATION AND
`
`CENTER FOR DRUG EVALUATION AND
`RESEARCH
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`RESEARCH
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`APPLICATION NUMBER:
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`22-024
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`APPLICA TION NUMBER:
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`MEDICAL REVIEW(S)
`MEDICAL REVIEWQSQ
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` 22-024
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`MEDICAL TEAM LEADER MEMO
`Completed May 1, 2009
`
`Hylton V. Joffe, M.D., M.M.Sc.
`
`
`NDA: 22-024
`Sponsor: Takeda
`Drug: Actoplus Met XR (pioglitazone plus extended-release metformin fixed
`dose combination tablets)
`
`
`Proposed Indication: 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
`
`Primary Medical Reviewers:
`
`Joanna Zawadzki, M.D.
`Karen M. Mahoney, M.D.
`
`
`
`Actoplus Met XR is a fixed-dose combination tablet consisting of pioglitazone and
`extended-release metformin that permits once daily dosing. The new drug
`application (NDA) for Actoplus Met XR was submitted on June 30, 2006. The
`Division issued an approvable letter because of deficiencies at the manufacturing
`facility where the metformin component is produced.
`
`Takeda has subsequently submitted a complete response to the approvable
`letter, which is the subject of this memorandum. Please see Dr. Karen
`Mahoney’s acting clinical team leader memorandum, dated November 28, 2008,
`which is attached to this document as an appendix and which summarizes the
`pertinent findings from the discipline reviews of the complete response.
`
`As mentioned by Dr. Mahoney, the manufacturing deficiencies have been
`rectified. Dr. Mahoney also discusses the revisions to the package insert and the
`implementation of Risk Evaluation and Mitigation Strategies (REMS) with a
`medication guide for the boxed warning of heart failure.
`
`The Division and the sponsor have reached agreement on the wording for the
`package insert and medication guide (see finalized label and medication guide
`that will be appended to the approval letter for this NDA). Of note, the Pediatric
`Review Committee (PeRC) agreed with the Division’s plan to grant a full waiver
`for this product (email communication from Mr. George Greeley, dated January
`8, 2009) but requested additional language in the “Pediatric Use” section of the
`package insert explaining why Actoplus Met XR is not recommended for use in
`children.
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`1
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`The current memo will address all outstanding issues that had not yet been
`resolved at the time of Dr. Mahoney’s review.
`
`
`1. The pediatric text has been revised to explain why Actoplus Met XR is not
`recommended for use in children. The revised text states “Use in pediatric
`patients is not recommended for the treatment of diabetes due to lack of
`long-term safety data. Risks including fractures and other adverse effects
`associated with pioglitazone, one of the components of ACTOPLUS MET
`and ACTOPLUS MET XR, have not been determined in this population
`(see WARNINGS and PRECAUTIONS).”
`
`
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`
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`2. The Medication Guide now includes the following statement pertaining to
`bladder cancer listed under “What are other possible side effects of
`ACTOPLUS MET and ACTOPLUS MET XR?”: “In studies of pioglitazone
`(one of the medicines in ACTOPLUS MET and ACTOPLUS MET XR),
`bladder cancer occurred in a few more people who were taking
`pioglitazone than in people who were taking other diabetes medicines.
`There were too few cases to know if the bladder cancer was related to
`pioglitazone.”
`
`
`3. The Division of Medication Error Prevention and Analysis (DMEPA)
`requested revisions to the proposed container labels and carton labeling
`to decrease the potential for selection errors and to increase readability.
`The sponsor revised these labels accordingly, and DMEPA agreed with
`the revisions (see review of Jinhee Lee, Pharm.D., December 17, 2008).
`
`
`4. The draft approval letter, including the FDA Amendments Act (FDAAA)
`language regarding REMS and labeling were reviewed and cleared by the
`Safety Requirements Team.
`
`5. The Actoplus Met XR tradename was re-evaluated during this review
`cycle and determined to be acceptable (see review of Ms. Cathy Miller).
`
`
`Recommendation: The Actoplus Met XR NDA can be approved.
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`2
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`REVIEW MEMORANDUM
`
`28 Nov 08
`
`Karen Murry Mahoney, MD, FACE
`Acting Diabetes Team Leader, Division of Metabolism and Endocrinology Products
`(DMEP)
`
`Re: Clinical Review of Full Prescribing Information and Medication Guide for NDA
`
`22024 ActoPlus Met XR® (pioglitazone hydrochloride and metformin
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`hydrochloride, fixed-dose combination tablets, extended release formulation)
`
`The previous reviewer for this application was unable to complete the review, and
`therefore a memorandum by the acting team leader is being entered.
`
`On 30 Jun 2006, Takeda Global Research and Development submitted NDA 22024, for
`an extended release formulation of ActoPlus Met XR®, hereafter referred to as APMX.
`This was submitted pursuant to section 505(b)(2) of the Federal Food, Drug and
`Cosmetic Act, and consisted of two bioequivalence studies, a food effect study, and
`information on Chemistry, Manufacturing and Controls. Clinical Pharmacology review
`concluded that the bioequivalence and food effect studies were adequate, but a field
`inspection identified deficiencies at the manufacturing facility at Andrx Pharmaceuticals,
`where the metformin component of the combination product is produced. On 2 Feb
`2007, DMEP issued an approvable letter, citing the following deficiencies:
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`Please see Dr. Chien-Hua Niu’s Chemistry, Manufacturing and Controls review memo.
`On 30 Oct 2008, the Office of Compliance provided confirmation that a repeat
`Establishment Evaluation (inspection) had been performed, and the previously identified
`deficiencies had been corrected.
`
`Dr. Jaya Vaidyanathan, the Clinical Pharmacology reviewer, has confirmed that edits to
`the Full Prescribing Information (FPI) adequately address the deficiencies noted in the
`approvable letter.
`
`On 14 Aug 2007, a Boxed Warning regarding heart failure risk had been added to the
`Full Prescribing Information for Actos® (pioglitazone hydrochloride). This Boxed
`Warning is also required for the APMX label, and in discussions with the DMEP Safety
`Team, and the Safety Requirements Team of the Office of New Drugs in the Center for
`Drug Evaluation and Research, it was determined that this Boxed Warning necessitated a
`Patient Medication Guide (Med Guide) for pioglitazone-containing products.
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`This memo documents the significant changes to the APMX FPI, and discusses the Med
`Guide language.
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`Changes to the Full Prescribing Information:
`• A Boxed Warning for heart failure has been added to the beginning of the FPI. It
`is identical to that approved for Actos® (pioglitazone hydrochloride).
`• The previous Boxed Warning for lactic acidosis has been moved to the beginning
`of the label. Boxed Warnings are to be placed at the beginning of labels, and this
`is consistent with other metformin-containing combination products. The
`language of the lactic acidosis Boxed Warning has been edited to be consistent
`with that of other metformin-containing products.
`In the DESCRIPTION section, and in the CLINICAL PHARMACOLOGY
`section (Pharmacokinetics and Drug Metabolism, Absorption and Bioavailability
`subsection) language has been added to clarify the differences between the
`ActoPlus Met immediate release formulation, and the APMX extended release
`formulation.
`• The different doses of pioglitazone and metformin in the immediate release and
`extended release formulations are now clarified in tabular form.
`• The requested statement regarding the time to peak concentration under fed
`conditions has been added.
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`•
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`(b)
`(4)
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`•
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`•
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`Information on gemfibrozil and rifampin drug-drug interaction studies have been
`added, consistent with interim additions to the Actos® label.
`• Consistent with the Actos® label, a contraindication has been added for initiation
`of ActoPlus Met (APM) or APMX in patients with New York Heart Association
`functional Class III or IV heart failure.
`In the WARNINGS section, language regarding heart failure has been added,
`again consistent with the Actos® label.
`In the PRECAUTIONS section, as statement has been added that there have been
`no clinical studies establishing conclusive evidence of macrovascular risk
`reduction with APM, APMX, or any other anti-diabetic drug. This statement is in
`the label of all oral agents used to treat type 2 diabetes mellitus.
`• Also in the PRECAUTIONS section, information has been added regarding
`macular edema and fractures, consistent with recent additions to the Actos® label.
`Information on bladder cancer in clinical trials has been added, also consistent
`with recent additions to the Actos® label.
`• Cardiovascular safety data from the PROactive trial have been added, consistent
`with the Actos® label.
`• The DOSAGE AND ADMINISTRATION section has been augmented to clarify
`dosing differences for APM and APMX.
`• Under the Special Populations subsection, statements have been added that APM
`and APMX should only be used in patients with normal renal function, and that
`use in children is not recommended.
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`•
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`•
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`Medication Guide Language:
`
`Please see the clinical review of the Medication Guide for Avandamet® (rosiglitazone
`maleate and metformin hydrochloride, NDA 21410, supplement 025, Division File
`System archive 1 Aug 08). This APMX Medication Guide strongly parallels that for
`Avandamet®, except that information regarding the safety signal for myocardial ischemic
`events with rosiglitazone has been omitted.
`
`The Medication Guide emphasizes patient information regarding heart failure and lactic
`acidosis. As with the Avandamet® med guide, the APMX med guide information
`regarding lactic acidosis has been modified to make it more useful to patients in helping
`them to avoid the conditions under which lactic acidosis occurs, because most cases of
`lactic acidosis can be avoided if the drug is taken properly.
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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/
`---------------------
`Karen Mahoney
`11/28/2008 01:14:22 PM
`MEDICAL OFFICER
`Acting Diabetes Team Leader
`
`

`

`---------------------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed electronically and
`this page is the manifestation of the electronic signature.
`---------------------------------------------------------------------------------------------------------------------
` /s/
`---------------------
`Hylton Joffe
`5/1/2009 11:17:32 AM
`MEDICAL OFFICER
`
`Mary Parks
`5/1/2009 03:24:35 PM
`MEDICAL OFFICER
`Concur w/ Dr. Joffe's recommendations
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`

`

`
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`MEDICAL OFFICER REVIEW
`
`Division of Metabolism and Endocrinology Products (HFD-510)
`
`Application
`Type:
`
`Commercial NDA 505 (b)(2)
`Dated 3/31/06
`
`Application #: NDA 22-024
`
`Electronic submission
`\\Cdsesub1\n22024\N 000\2
`006-03-31
`
`Sponsor: Takeda Global Research &
`Development Center,Inc. (TGRD)
`
`3031400
`Pharmaceutical
`Fixed-dose combination
`Category:
`Peroxisome proliferator-activated
`receptor (PPAR) α γ agonist or
`Thiazolidinedione +
`Biguanide
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`
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`Indication:
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`
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`Reviewer: Joanna K. Zawadzki, M.D.
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`Proprietary
`Name:
`
`Route of
`Administration:
`
`Dosage:
`
`Related
`Application:
`
`Date Review
`Completed:
`
`ACTOPLUS MET™ XR
`Fixed-dose combination tablet
`ACTOS® (pioglitazone HCl)
`NDA 21-073 Takeda Pharm. N.A.
`FORTAMET® (metformin HCl
`extended release) NDA-21-574 Andrx
`Labs,LLC
`[also called AD-4833XT]
`
`oral
`
`Pioglitazone/metformin
`15 mg/1000 mg
`30 mg/1000 mg
`ACTOPLUS MET (Takeda)
`(NDA 21-842 approved 8/29/05)
`pioglitazone/metformin fixed-dose
`tablets) 15mg/500mg and 15mg/850mg
`January 12, 2007
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`REVIEW SUMMARY:
`
`See review.
`
`OUTSTANDING ISSUES: Please see labeling comments to minimize possible confusion between ACTOPLUS MET
`XR and ACTOPLUS MET, both for clinicians and patients. The labeling comments should be forwarded to the sponsor.
`The sponsor’s submitted prescribing information is attached as a reference for other FDA reviewers, but “red-lined”
`FDA comments have not been included in it.
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`RECOMMENDED REGULATORY ACTION:
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`SIGNATURES:
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`NDA, Efficacy/Label supplement :
`Approve with labeling changes
`Date: January 12, 2007
`Medical Reviewer: Joanna K. Zawadzki, M.D.
`.
` Division Director: Mary Parks, M.D. Date: .
`
`1
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`(b) (4)
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`Review Summary
`
`The sponsor has submitted reports for two bioequivalence studies and a food effect study
`in support of the proposed fixed-dose combination tablet ACTOPLUS MET™ XR
`(pioglitazone plus extended release metformin):
`• Open-label, randomized, crossover study to assess the bioequivalence of the
`fixed-dose pioglitazone 15 mg/metformin extended release 1000 mg tablet to that
`of individual pioglitazone 15 mg and metformin XR 1000 mg tablets.
`• Open-label, randomized, crossover study to assess the bioequivalence of the
`fixed-dose pioglitazone 30 mg/metformin extended release 1000 mg combination
`tablet to that of individual pioglitazone 15 mg and metformin XR 1000 mg
`tablets.
`• Open-label, randomized, crossover, food-effect study to determine the effect of
`food on the exposure of pioglitazone and metformin after administration of the
`fixed-dose pioglitazone 15 mg/metformin extended release 1000 mg combination
`tablet.
`As a 505(b)(2) application, the review and approval of this application rely on
`information from studies not conducted by or for the sponsor (TGRD) and a right of
`reference has not been obtained. A pediatric waiver is requested.
`
`The primary review for this application was completed by clinical pharmacology (Jaya
`Vaidyanathan, Ph.D.), who recommended approval of ACTOPLUS MET™ XR
`(pioglitazone plus extended release metformin). I concur with her recommendation.
`
`The proposed indication for ACTOPLUS MET XR is the same as for ACTOPLUS
`MET (NDA 21-842 approved 8/29/05, which comprises pioglitazone/metformin
`15mg/500mg and 15mg/850mg fixed-dose tablets): “adjunct to diet and exercise to
`improve glycemic control in patients with type 2 diabetes who are already treated with a
`combination of pioglitazone and metformin or whose diabetes is not adequately
`controlled with metformin alone, or for those patients who have initially responded to
`pioglitazone alone and require additional glycemic control.” Even though ACTOPLUS
`MET™ XR (pioglitazone plus extended release metformin) may replace treatment with
`ACTOPLUS MET, there is no direct comparison between these two drugs, and the doses
`of metformin differ.
` The standard comparison that is recommended to show
`bioequivalence is a comparison of the combination drug to the constituent drugs, as was
`done in this application.
`
`Extended-release metformin (FORTAMET®, Andrx Labs,LLC) was approved as NDA-
`21-574 (April 27, 2004). Metformin extended release given once daily was compared to
`the marketed reference immediate release metformin drug, Glucophage (Bristol Myers
`Squib) given twice daily. Dose equivalency for doses lower than 1000 mg was not
`established, and only the 1000 mg tablet was approved. The clinical reviewer of that
`application (R. Misbin, M.D.) hypothesized that the increasing dose was associated with
`decreasing absorption, and that this phenomenon accounted for some of the difference
`seen between the two products. For this reason, Glucophage 1000 mg given twice daily
`appeared to be more effective than Fortamet 2000 mg given once daily. However, this
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`2
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`difference was small, and it was offset by the convenience and theoretical likelihood of
`greater compliance with once-daily rather than twice-daily dosing.
`
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`Labeling Comments
`
`The sponsor has 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. The sponsor proposes that
`either dose of ACTOPLUS MET XR may be used as the initial dose and a titrated
`maximal dose is not stated in the prescribing information. The maximum daily dose
`should be stated.
`
`The different doses of pioglitazone and metformin in ACTOPLUS MET™ and
`ACTOPLUS MET™ XR should be highlighted. ACTOPLUS MET™ tablets are
`pioglitazone/metformin 15 mg/500 mg and 15 mg/850 mg, while ACTOPLUS MET™
`XR tablets are pioglitazone/metformin XR 15 mg/1000 mg and 30 mg/1000 mg.
`
`The CLINICAL PHARMACOLOGY section states: Pioglitazone is a potent and
`highly selective agonist for peroxisome proliferator-activated receptor-gamma (PPARγ)
`(lines 98-99 of submitted PI). This information is incorrect and should be modified to
`indicate that pioglitazone is an agonist for both peroxisome proliferator-activated
`receptors-gamma and alpha (PPARγa). In the PRECAUTIONS: Carcinogenesis,
`Mutagenesis, Impairment of Fertility section, the prescribing information states
`
`
`. This wording is misleading and should also be corrected.
`
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`Recommendation
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`The labeling comments should be forwarded to the sponsor.
`
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`Appendix: Sponsor’s submitted Prescribing Information
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`
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`cc: M. Parks, M.D., R. Misbin, M.D., J. Vaidyanathan, Ph.D., J. Weber, E. Galliers, L.
`AlJuburi
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`3
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`(b) (4)
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`32 pp. withheld immediately following this page
`as draft labeling (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/
`---------------------
`Joanna Zawadzki
`1/12/2007 06:41:36 PM
`MEDICAL OFFICER
`
`Mary Parks
`1/14/2007 12:42:36 PM
`MEDICAL OFFICER
`see additional comments on this application in division director
`memo
`
`