CENTER FOR DRUG EVALUATION AND
`
`CENTER FOR DRUG EVALUATION AND
`RESEARCH
`RESEARCH
`
`
`
`
`
`
`APPLICATION NUMBER:
`
`22-024
`
`
`APPLICA TION NUMBER:
`
`OTHER REVIEW(S)
`OTHER REVIEW! S!
`
`
`
`
`
` 22-024
`
`

`

`REGULATORY PROJECT MANAGER REVIEW
`
`
`
`Division of Metabolism and Endocrinology Products
`
`
`
`
`
`
`Application Number: NDA 22-024
`
`Name of Drug: Actoplus Met XR (pioglitazone HCl + metformin HCl) Fixed-Dose
`Combination Tablets
`
`Sponsor: Takeda Global Research & Development Center, Inc.
`
`Submission Date (AZ): April 30, 2008
`
`Material Reviewed:
`
`Submission Date
`December 10, 2008
`
`Receipt Date
`December 11, 2008
`
`March 26, 2009
`
`Document Type
`Revised carton & container
`labels
`
`Revised PI and Med Guide
`
`March 25, 2009
`
`
`Background and Summary
`
`
`This new drug application provides for the use of ACTOPLUS MET XR 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.
`
`
`An approvable letter was issued to this NDA file on February 2, 2007. Takeda responded with a
`major amendment (AZ) on April 30, 2008.
`
`Final carton and container labels were submitted on December 10, 2008. These were found
`acceptable as noted in the review from DMEPA dated December 17, 2008.
`
`The agreed-upon FDA/Takeda PI and Med Guide labels were submitted on
`March 25, 2009.
`
`Review:
`
`Package Insert: Acceptable; FDA comments sent to Takeda on 3/18/09; compared to
`revised submission from company dated 3/25/09. Takeda accepted and inserted changes as
`requested. No discrepancies noted.
`
`
`

`

`Med Guide Acceptable; FDA comments sent on 3/18/09, compared to revised submission
`from Takeda dated 3/25/09. No discrepancies noted from FDA requested version. Takeda
`accepted and inserted changes as we requested.
`
`Carton & Container Labels: Acceptable as per DMEPA review dated 12/17/08.
`
`Tradename: Acceptable as per DMEPA review dated 4/30/09.
`
`Conclusion:
`
`An approval letter issued for NDA 22-024. SPL was submitted on April 1, 2009. This will be
`forwarded to NLM.
`
`

`

`---------------------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed electronically and
`this page is the manifestation of the electronic signature.
`---------------------------------------------------------------------------------------------------------------------
` /s/
`---------------------
`Jena Weber
`5/15/2009 07:23:10 AM
`CSO
`
`

`

`NDA REGULATORY FILING REVIEW
`(Including Memo of Filing Meeting)
`
`NDA Regulatory Filing Review
`Page 1
`
`
`22-024
`
`Supplement #
`
`
`
`Efficacy Supplement Type SE-
`
`
`
`
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`
` User Fee Goal Date: November 1, 2008
`
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`(b)(1)
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`(b)(1)
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` (b)(2) X
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` (b)(2)
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`NDA #
`
`
`
`Proprietary Name: ACTOPLUS MET XR
`Established Name: pioglitazone + metformin extended-release (FDC)
`Strengths: 15 mg/1000 mg; 30 mg/1000 mg.
`
`
`Applicant: Takeda Global Research & Development Center, Inc.
`Agent for Applicant: NA
`
`Date of Application: April 30, 2008
`Date of Receipt: May 1, 2008
`
`Date clock started after UN:
`Date of Filing Meeting: June 23, 2008
`Filing Date: July 01, 2008
`
`Action Goal Date (optional):
`
`
`Indication requested: This new drug application provides for the use of ACTOPLUS MET XR 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.
`
`
`Type of Original NDA:
`AND (if applicable)
`Type of Supplement:
`
`
`NOTE:
`(1)
`If you have questions about whether the application is a 505(b)(1) or 505(b)(2) application, see
`Appendix A. A supplement can be either a (b)(1) or a (b)(2) regardless of whether the original NDA
`was a (b)(1) or a (b)(2). If the application or efficacy supplement is a (b)(2), complete Appendix B.
`
`Standard
`NO
`3
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` Resubmission after refuse to file? NO
`
`
`
`
`Review Classification:
`Resubmission after withdrawal?
`Chemical Classification: (1,2,3 etc.)
`Other (orphan, OTC, etc.)
`
`Form 3397 (User Fee Cover Sheet) submitted: YES
`
` Exempt (orphan, government)
`
`Paid
`
`
`User Fee Status:
`
` Waived (e.g., small business, public health)
`
`
`NOTE: If the NDA is a 505(b)(2) application, and the applicant did not pay a fee in reliance on the 505(b)(2)
`exemption (see box 7 on the User Fee Cover Sheet), confirm that a user fee is not required by contacting the
`User Fee staff in the Office of Regulatory Policy. The applicant is required to pay a user fee if: (1) the
`product described in the 505(b)(2) application is a new molecular entity or (2) the applicant claims a new
`indication for a use that that has not been approved under section 505(b). Examples of a new indication for a
`use include a new indication, a new dosing regime, a new patient population, and an Rx-to-OTC switch. The
`best way to determine if the applicant is claiming a new indication for a use is to compare the applicant’s
`proposed labeling to labeling that has already been approved for the product described in the application.
`
`Version 6/14/2006
`
`

`

`Highlight the differences between the proposed and approved labeling. If you need assistance in determining
`if the applicant is claiming a new indication for a use, please contact the User Fee staff.
`
`NDA Regulatory Filing Review
`Page 2
`
`
` ●
`
`Is there any 5-year or 3-year exclusivity on this active moiety in any approved (b)(1) or (b)(2)
`
` application?
`
` NO
`If yes, explain:
`
`Note: If the drug under review is a 505(b)(2), this issue will be addressed in detail in appendix B.
`●
`Does another drug have orphan drug exclusivity for the same indication?
`
` NO
`
`
`
`
`
`
`
`
`
`
`If yes, is the drug considered to be the same drug according to the orphan drug definition of sameness
`[21 CFR 316.3(b)(13)]?
` NO
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`If yes, consult the Director, Division of Regulatory Policy II, Office of Regulatory Policy (HFD-007).
`
` ●
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` ●
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` ●
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` ●
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`
`●
`
`●
`
`•
`
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`
`
`Is the application affected by the Application Integrity Policy (AIP)?
`If yes, explain:
`
`If yes, has OC/DMPQ been notified of the submission? YES
`
`Does the submission contain an accurate comprehensive index? YES
`If no, explain:
`
`Was form 356h included with an authorized signature? YES
`If foreign applicant, both the applicant and the U.S. agent must sign.
`
`
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` NO
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`Submission complete as required under 21 CFR 314.50? YES
`If no, explain:
`
`Answer 1, 2, or 3 below (do not include electronic content of labeling as an partial electronic
` submission).
`
`
`1. This application is a paper NDA
`2. This application is an eNDA or combined paper + eNDA
`This application is:
`Combined paper + eNDA
`This application is in: Combined NDA and CTD formats
`
`Does the eNDA, follow the guidance?
` (http://www.fda.gov/cder/guidance/2353fnl.pdf)
`
`If an eNDA, all forms and certifications must be in paper and require a signature.
`If combined paper + eNDA, which parts of the application were submitted in electronic format? ALL
`
`
`
`
`
`
` NO
` YES
`
`
`
`
` YES
`
`
`
`3. This application is an eCTD NDA.
`
`
` NO
`
`If an eCTD NDA, all forms and certifications must either be in paper and signed or be
`electronically signed.
`
`
` Additional comments:
`
`Patent information submitted on form FDA 3542a? YES
`
`
`
`
`
` ●
`
`
`
`
`Version 6/14/2006
`
`
`
`
`
`
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`
`
`
`

`

`
`
` NO
`
`
`
`
`Exclusivity requested?
`NOTE: An applicant can receive exclusivity without requesting it; therefore, requesting exclusivity is
`not required.
`
`NDA Regulatory Filing Review
`Page 3
`
`
`
`Correctly worded Debarment Certification included with authorized signature? YES
`If foreign applicant, both the applicant and the U.S. Agent must sign the certification.
`
`
`
`
`
`
`
`●
`
` ●
`
`
`
`NOTE: Debarment Certification should use wording in FD&C Act section 306(k)(1) i.e.,
`“[Name of applicant] hereby certifies that it did not and will not use in any capacity the services of
`any person debarred under section 306 of the Federal Food, Drug, and Cosmetic Act in connection
`with this application.” Applicant may not use wording such as “To the best of my knowledge . . . .”
`
`● Are the required pediatric assessment studies and/or deferral/partial waiver/full waiver of pediatric
` studies (or request for deferral/partial waiver/full waiver of pediatric studies) included?
`
`
`
`
`
`
`
`
`
`
`
` YES
`
`
` ●
`
` If the submission contains a request for deferral, partial waiver, or full waiver of studies, does the
` application contain the certification required under FD&C Act sections 505B(a)(3)(B) and (4)(A) and
` (B)?
`
`
`
`
`
`
`
`
` YES
`
`
` ●
`
`
`
`
`
` ●
`
`
`
`Field Copy Certification (that it is a true copy of the CMC technical section) YES
`
`(DO notified).
`
`Is this submission a partial or complete response to a pediatric Written Request?
`
`NO
`
`If yes, contact PMHT in the OND-IO
`
`
`
` YES
`Financial Disclosure forms included with authorized signature?
`(Forms 3454 and/or 3455 must be included and must be signed by the APPLICANT, not an
`agent.)
`NOTE: Financial disclosure is required for bioequivalence studies that are the basis for approval.
`
`
`
`
`
`
`
`
`
`
`
`
`
`PDUFA and Action Goal dates correct in tracking system? YES
`If not, have the document room staff correct them immediately. These are the dates EES uses for
`calculating inspection dates.
`
`Drug name and applicant name correct in COMIS? If not, have the Document Room make the
`corrections. Ask the Doc Rm to add the established name to COMIS for the supporting IND if it is not
`already entered.
`
`List referenced IND numbers: 68,462
`
`Are the trade, established/proper, and applicant names correct in COMIS? YES
`If no, have the Document Room make the corrections.
`
` NO
`
`
`
`
`
`
`
` NO
`
` ●
`
` ●
`
`
`
` ●
`
`
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` ●
`
`
`
` ●
`
`
`
`
`●
`
`●
`
`●
`
`
`End-of-Phase 2 Meeting(s)? Date(s)
`If yes, distribute minutes before filing meeting.
`
`Pre-NDA Meeting(s)? Date(s) 11/10/05
`If yes, distribute minutes before filing meeting.
`
`
`Any SPA agreements? Date(s)
`If yes, distribute letter and/or relevant minutes before filing meeting.
`Version 6/14/2006
`
`

`

`
`
`
`Project Management
`
`NDA Regulatory Filing Review
`Page 4
`
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` ●
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`
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` ●
`
`If Rx, for all new NDAs/efficacy supplements submitted on or after 6/30/06:
`
` Was the PI submitted in PLR format? NO
`
`
`If Rx, was electronic Content of Labeling submitted in SPL format? YES
`If no, request in 74-day letter.
`
`
`
`
`
`If no, explain. Was a waiver or deferral requested before the application was received or in the
`submission? If before, what is the status of the request:
`
`
`
`
`
`
`
`If Rx, all labeling (PI, PPI, MedGuide, carton and immediate container labels) has been consulted to
`
` DDMAC? YES
`
`
`
`
`
`●
`
`
`If Rx, trade name (and all labeling) consulted to OSE/DMETS? YES
`
`
`
`
`
`If Rx, MedGuide and/or PPI (plus PI) consulted to ODE/DSRCS?
`
`
`
` ●
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` ●
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`
`●
`
`Risk Management Plan consulted to OSE/IO?
`
`
`If a drug with abuse potential, was an Abuse Liability Assessment, including a proposal for
`●
` scheduling submitted?
` N/A
`
`
`
`
`
`
`
`
` YES
`
`
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` NO
`
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`If Rx-to-OTC Switch or OTC application:
`
` ●
`
`Proprietary name, all OTC labeling/packaging, and current approved PI consulted to
`
` OSE/DMETS?
`
` N/A
`
` ●
`
`If the application was received by a clinical review division, has N/A
`
` DNPCE been notified of the OTC switch application? Or, if received by
` DNPCE, has the clinical review division been notified?
`
`Clinical
`
` ●
`
`If a controlled substance, has a consult been sent to the Controlled Substance Staff?
`
` N/A
`
`
`
`
`
`
`
`
`
`Chemistry
`
` ●
`
`Did applicant request categorical exclusion for environmental assessment? YES
`
` If no, did applicant submit a complete environmental assessment?
` If EA submitted, consulted to EA officer, OPS?
`
`Establishment Evaluation Request (EER) submitted to DMPQ?
`
`YES
`
`
`
`
`
` If a parenteral product, consulted to Microbiology Team?
`
`
`ATTACHMENT
`
`
`N/A
`
`Version 6/14/2006
`
` ●
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`

`

`MEMO OF FILING MEETING
`
`NDA Regulatory Filing Review
`Page 5
`
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`
` Weber
` DRISK/DDMAC/DMEPA/DSRCS
`
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`FILE
`
`
`DATE: 10/7/08
`
`NDA #: 22-024
`
`DRUG NAMES: ActoPlus Met XR
`
`APPLICANT: Takeda
`
`BACKGROUND: Actoplus Met XR is indicated as an 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. This NDA consists of 2 BE studies and 1 food-effect study. Takeda is the holder of the
`approved drug Actos (pioglitazone); Andrx is the holder of Fortamet (metformin extended-release)
`
`ATTENDEES: Zawadzki, Parks, Vaidyanathan, Campbell, Jahng Lee,Weber
`
`ASSIGNED REVIEWERS (including those not present at filing meeting):
`
`Discipline/Organization
`Reviewer
`
`
`
` Joffe/Zawadzki/Mahoney
`
`
`
`Medical:
`
`
`
`
`
`
`Secondary Medical:
`
` NN
`
`
`
`Statistical:
`
`
` NN
`
`
`
`Pharmacology:
`
` NN
`
`
`
`Statistical Pharmacology:
` Al-Hakim/Frasier/Niu
`
`
`
`Chemistry:
`
`
` Niu
`
`Environmental Assessment (if needed):
` Choe/Vaidyanathan
`
`Biopharmaceutical:
`
`
`
` NN
`
`Microbiology, sterility:
`
`
`Microbiology, clinical (for antimicrobial products only): NN
`DSI:
`
`
`
`
`
`OPS:
`
`Regulatory Project Management:
`
`Other Consults:
`
`
`
`
`
`
`
`
`Per reviewers, are all parts in English or English translation? YES
`If no, explain:
`
`CLINICAL
`
`
`
`
`
`
`
`
`
`
`
`
`
`• Clinical site audit(s) needed? NO
`
`If no, explain:
`• Advisory Committee Meeting needed?
`
`NO
`
`
`
`
`
`
`
`
`
`•
`
`
`
`
`
`
`
`
`
`If the application is affected by the AIP, has the division made a recommendation regarding
`whether or not an exception to the AIP should be granted to permit review based on medical
`necessity or public health significance?
` N/A
`
`Version 6/14/2006
`
`

`

`NDA Regulatory Filing Review
`Page 6
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`CLINICAL MICROBIOLOGY N/A
`
`STATISTICS
`
`BIOPHARMACEUTICS
`
`
`
`
` N/A
`
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` FILE
`
`
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`
`
`• Biopharm. study site audits(s) needed? YES
`YES
`
`
`PHARMACOLOGY/TOX N/A
`
`
`
`
`
`
`
`
`
`
`• GLP audit needed? NO
`
` FILE
`
`
`
`
`
`
`CHEMISTRY
`
`
`• Establishment(s) ready for inspection? YES
`• Sterile product? N/A
` If yes, was microbiology consulted for validation of sterilization?
` N/A
`
`
`ELECTRONIC SUBMISSION:
`Any comments: None
`
`REGULATORY CONCLUSIONS/DEFICIENCIES:
`(Refer to 21 CFR 314.101(d) for filing requirements.)
`
`
`
`
` The application is unsuitable for filing. Explain why:
`
`X
`
` The application, on its face, appears to be well-organized and indexed. The application
`appears to be suitable for filing.
`
`
`
`X
`
` No filing issues have been identified.
`
`
`
` Filing issues to be communicated by Day 74. List (optional):
`
`
`
`
`
`
`
`
`
`
`Jena Weber
`Regulatory Project Manager
`
`Version 6/14/2006
`
`

`

`
`
`Appendix B to NDA Regulatory Filing Review
`Questions for 505(b)(2) Applications
`
`NDA Regulatory Filing Review
`Page 7
`
`
`
`
`1. Does the application reference a listed drug (approved drug)? YES
`
`If “No,” skip to question 3.
`
`
`2. Name of listed drug(s) referenced by the applicant (if any) and NDA/ANDA #(s):
`NDA 21-574 (Fortamet); NDA 21-073 (Actos).
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
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`
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`
`
`3. Is this application for a drug that is an “old” antibiotic (as described in the draft guidance implementing
`the 1997 FDAMA provisions? (Certain antibiotics are not entitled to Hatch-Waxman patent listing and
`exclusivity benefits.)
` NO
`
`If “Yes,” skip to question 7.
`
`4. Is this application for a recombinant or biologically-derived product?
` NO
`
`If “Yes “contact your ODE’s Office of Regulatory Policy representative.
`
`5. The purpose of the questions below (questions 5 to 6) is to determine if there is an approved drug
`product that is equivalent or very similar to the product proposed for approval that should be referenced as
`a listed drug in the pending application.
`
`(a) Is there a pharmaceutical equivalent(s) to the product proposed in the 505(b)(2) application that is
`already approved?
` NO
`
`
`
`
`
`
`
`
`(Pharmaceutical equivalents are drug products in identical dosage forms that: (1) contain identical amounts of
`the identical active drug ingredient, i.e., the same salt or ester of the same therapeutic moiety, or, in the case of
`modified release dosage forms that require a reservoir or overage or such forms as prefilled syringes where
`residual volume may vary, that deliver identical amounts of the active drug ingredient over the identical dosing
`period; (2) do not necessarily contain the same inactive ingredients; and (3) meet the identical compendial or
`other applicable standard of identity, strength, quality, and purity, including potency and, where applicable,
`content uniformity, disintegration times, and/or dissolution rates. (21 CFR 320.1(c))
`
`
`
` If “No,” to (a) skip to question 6. Otherwise, answer part (b and (c)).
`
`
`(b) Is the pharmaceutical equivalent approved for the same indication for NO
`
` which the 505(b)(2) application is seeking approval?
`
`
`
` (c) Is the approved pharmaceutical equivalent(s) cited as the listed drug(s)? YES
`
`If “Yes,” (c), list the pharmaceutical equivalent(s) and proceed to question 6.
`
` If “No,” to (c) list the pharmaceutical equivalent and contact your ODE’s Office of Regulatory Policy
`representative.
`Pharmaceutical equivalent(s):
`
`
`
`
`
`
`
`
`
` NO
`
`Version 6/14/2006
`
`

`

`NDA Regulatory Filing Review
`Page 8
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`
`6. (a) Is there a pharmaceutical alternative(s) already approved? NO
`
`(Pharmaceutical alternatives are drug products that contain the identical therapeutic moiety, or its precursor, but
`not necessarily in the same amount or dosage form or as the same salt or ester. Each such drug product
`individually meets either the identical or its own respective compendial or other applicable standard of identity,
`strength, quality, and purity, including potency and, where applicable, content uniformity, disintegration times
`and/or dissolution rates. (21 CFR 320.1(d)) Different dosage forms and strengths within a product line by a
`single manufacturer are thus pharmaceutical alternatives, as are extended-release products when compared with
`immediate- or standard-release formulations of the same active ingredient.)
`
`
`If “No,” to (a) skip to question 7. Otherwise, answer part (b and (c)).
`
`
`(b) Is the pharmaceutical alternative approved for the same indication YES
`
` for which the 505(b)(2) application is seeking approval?
`
`
`
`
` NO
`
`
`
` NO
`
`
`
`
`
`
`
`
`
` (c) Is the approved pharmaceutical alternative(s) cited as the listed drug(s)? YES
`
`If “Yes,” to (c), proceed to question 7.
`
`NOTE: If there is more than one pharmaceutical alternative approved, consult your ODE’s Office of
`Regulatory Policy representative to determine if the appropriate pharmaceutical alternatives are referenced.
`
`
` If “No,” to (c), list the pharmaceutical alternative(s) and contact your ODE’s Office of Regulatory Policy
`representative. Proceed to question 7.
`Pharmaceutical alternative(s):
`
`7. (a) Does the application rely on published literature necessary to support the proposed approval of the drug
`product (i.e. is the published literature necessary for the approval)?
` NO
`
`If “No,” skip to question 8. Otherwise, answer part (b).
`
` (b) Does any of the published literature cited reference a specific (e.g. brand name) product? Note that if
`yes, the applicant will be required to submit patent certification for the product, see question 12.
`
`8. Describe the change from the listed drug(s) provided for in this (b)(2) application (for example, “This
`application provides for a new indication, otitis media” or “This application provides for a change in
`dosage form, from capsules to solution”). This application provides for a fixed-dose combination
`product.
`
`
`9. Is the application for a duplicate of a listed drug and eligible for approval under NO
`
`section 505(j) as an ANDA? (Normally, FDA may refuse-to-file such NDAs
`
`(see 21 CFR 314.101(d)(9)).
`
`10. Is the application for a duplicate of a listed drug whose only difference is NO
` that the extent to which the active ingredient(s) is absorbed or otherwise made
` available to the site of action less than that of the reference listed drug (RLD)?
` (See 314.54(b)(1)). If yes, the application may be refused for filing under
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` 21 CFR 314.101(d)(9)).
`
`11. Is the application for a duplicate of a listed drug whose only difference is NO
` that the rate at which the product’s active ingredient(s) is absorbed or made
` available to the site of action is unintentionally less than that of the RLD (see 21 CFR 314.54(b)(2))?
` If yes, the application may be refused for filing under 21 CFR 314.101(d)(9).
`
`
`
`
`12. Are there certifications for each of the patents listed in the Orange YES
`Book for the listed drug(s) referenced by the applicant (see question #2)?
`(This is different from the patent declaration submitted on form FDA 3542 and 3542a.)
`
`
`
`13. Which of the following patent certifications does the application contain? (Check all that apply and
` identify the patents to which each type of certification was made, as appropriate.)
`
`
`
`
`
`
`
`
`
`
`
`
`
` Not applicable (e.g., solely based on published literature. See question # 7
`
`
`
`
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`
`
` 21 CFR 314.50(i)(1)(i)(A)(1): The patent information has not been submitted to FDA.
` (Paragraph I certification)
`Patent number(s):
`
` 21 CFR 314.50(i)(1)(i)(A)(2): The patent has expired. (Paragraph II certification)
`Patent number(s):
`
` 21 CFR 314.50(i)(1)(i)(A)(3): The date on which the patent will expire. (Paragraph III
`certification)
`Patent number(s):
`
`
`
`
`X
`
`
`
` 21 CFR 314.50(i)(1)(i)(A)(4): The patent is invalid, unenforceable, or will not be infringed
` by the manufacture, use, or sale of the drug product for which the application is submitted.
` (Paragraph IV certification)
`Patent number(s): See below
`
`NOTE: IF FILED, and if the applicant made a “Paragraph IV” certification [21 CFR
`314.50(i)(1)(i)(A)(4)], the applicant must subsequently submit a signed certification stating
`that the NDA holder and patent owner(s) were notified the NDA was filed [21 CFR
`314.52(b)]. The applicant must also submit documentation showing that the NDA holder and
`patent owner(s) received the notification [21 CFR 314.52(e)]. OND will contact you to verify
`that this documentation was received.
`
`Certification under 21 CFR 314.50(i)(1)(i)(A)(4) pertaining to the FORTAMET (metformin
`HCl extended-release) component:
`
`Paragraph IV Certification:
`
`Takeda Global Research & Development Center, Inc. (TGRD) certify that to the best of
`our knowledge and belief that U.S. Patent No. 6,099,859; U.S. Patent No. 6,495,162;
`U.S. Patent No. 6,790,459; U.S. Patent No. 6,866,866 will not be infringed by the
`manufacture, use or sale of ACTOPLUS MET XR (pioglitazone HCl and metformin
`hydrochloride extended-release) tablets for which this application is submitted.
`
`TGRD will comply with the requirements under 314.52(a), by providing a notice to each
`owner of the patent or their respective representatives and to the holder of the approved
`application for the drug product which is claimed by the patent and with the requirements
`under 21 CFR 314.52(c).
`
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`X
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` Written statement from patent owner that it consents to an immediate effective date upon
` approval of the application.
`Patent number(s):
`
` 21 CFR 314.50(i)(1)(ii): No relevant patents.
`
`
`Please note, TGRD has been granted a licensing agreement with Andrx Pharmaceuticals,
`Inc. and subject to the FDA’s filing of the application TGRD will provide notice pursuant
`to 314.52(a).
`
`On behalf of Andrx Labs, LLC. Andrx has a 1 00% ownership in the following US patents,
`which are listed in the FDA publication, Approved Drug Products with Therapeutic
`Equivalence Evaluations (The Orange Book) for NDA 21-574 for FORTAMET (metformin
`HCL extended-release) tablets 500 mg and 1000 mg:
`
`Patent No. Patent Expiration
`6099859 March 20, 2018
`6495162 March 20. 2018
`6790459 March 17, 2021
`6866866 March 17, 2021
`
`The immediate approval of NDA 22-024 for ACTOPLUS MET TM XR by the US Food and
`Drug Administration will not infringe on any of the above listed patents due to inter-company
`license agreements between Andrx and Takeda Phiarmaceutical Corporation. Ltd. and its
`wholly owned subsidiaries, Takeda Pharmaceuticals North America, Inc. (TPNA) and Takeda
`Global Research & Development Center, Inc (TGRD).
`
`Andrx has no objection to the immediate approval of NBA 22-024 for ACTOPLUS MET XR by
`the US Food and Drug Administration prior to the expiration of the exclusivity period for NDA
`21-574.
`
`The following patents that appear in the publication Approved Drug Products with
`Therapeutic Equivalence Evaluations (The Orange Book) will not be infringed by NDA 22-024
`for ACTOPLUS MET XR:
`
`Patent No. Patent Expiration
`4,687,777 Jan 17, 2011
`5,965,584 Jun 19, 2016
`6,150,383 Jun 19, 2016
`6,150,384 Jun 19, 2016
`6,166,042 Jun 19, 2016
`6,166,043 Jun 19, 2016
`6,172,090 Jun 19, 2016
`6,211,205 Jun 19, 2016
`6,271,243 Jun 19, 2016
`6,303,640 Aug 09, 2016
`6,329,404 Jun 19, 2016
`
`No claims of the listed patents will be infringed because Takeda Pharmaceutical Company
`Limited (TPC), the parent company of Takeda Global Research & Development Center, Inc.
`TGRD) and Takeda Pharmaceuticals North America, Inc. (TPNA) has licensed these patents to
`TGRD and TPNA as explained in the attached letter from TPC
`
` 21 CFR 314.50(i)(3): Statement that applicant has a licensing agreement with the patent
`owner (must also submit certification under 21 CFR 314.50(i)(1)(i)(A)(4) above).
`Patent number(s): See above.
`
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` 21 CFR 314.50(i)(1)(iii): The patent on the listed drug is a method of use patent and the
`labeling for the drug product for which the applicant is seeking approval does not include any
`indications that are covered by the use patent as described in the corresponding use code in the
`Orange Book. Applicant must provide a statement that the method of use patent does not
`claim any of the proposed indications. (Section viii statement)
`Patent number(s):
`
`Did the applicant:
`
`14.
`
`
`•
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Identify which parts of the application rely on the finding of safety and effectiveness for a listed
`drug or published literature describing a listed drug or both? For example, pharm/tox section of
`application relies on finding of preclinical safety for a listed drug.
`
`
` YES
`If “Yes,” what is the listed drug product(s)Fortamet & Actos and which sections of the
`505(b)(2) application rely on the finding of safety and effectiveness or on published literature
`about that listed drug: All from original NDA’s.
`Was this listed drug product(s) referenced by the applicant? (see question # 2)
` YES
`
`
`
`
`
`• Submit a bioavailability/bioequivalence (BA/BE) study comparing the proposed product to the
`listed drug(s)?
` YES
`
`
`
`
`
`
`
`
`
`
`
`
`
`15. (a) Is there unexpired exclusivity on this listed drug (for example, 5 year, 3 year, orphan or pediatric
`exclusivity)? Note: this information is available in the Orange Boo