CENTER FOR DRUG EVALUATION AND
`
`CENTER FOR DRUG EVALUATION AND
`RESEARCH
`RESEARCH
`
`
`
`
`
`APPLICATION NUMBER:
`22-024
`
`APPLICATION NUMBER:
`
`CHEMISTRY REVIEW(S)
`CHEMISTRY REVIEW! S}
`
`
`
`
`
`
`
` 22-024
`
`

`

`1 of 4
`
`
`
`2/1/2007
`
`ActoPlus METTM XR
`(pioglitazone HCl/metformin HCl extended release)
`Tablets
`NDA 22-024
`
`Summary of the Basis for the Recommended Action
` from Chemistry, Manufacturing, and Controls
`
`
`Applicant: Takeda Global Research & Development Center, Inc.
`475 Half Day Road
`Lincolnshire, IL 60069
`
`Indication: Adjunct to diet and exercise as a once daily, fixed dose, combination therapy to
`improve glycemic control in patients with type 2 diabetes mellitus.
`
`
`Presentation: The drug product is supplied in two strengths, either 15 mg pioglitazone/1000 mg
`metformin or 30 mg pioglitazone/1000 mg metformin, as extended release tablets
`and is packaged in 30, 60, and 90-count HDPE bottles, with desiccant, as market
`packages or
` as physician samples.
`
`
`EER Status: Withold 18-Jul-2006
`
`Consults:
`
`
`Pharm/Tox – Acceptable (cf. NDA 21-073 and 21-574)
`ClinPharm - Acceptable 4-Jan-2007
`Methods Validation – Method validation package is provided. Samples will be
` requested for method validation study to be conducted by FDA laboratories.
`EA – Categorical exclusion granted under 21 CFR §25.31(a) for both drugs
`DMETS – Acceptable 8-JAN-2007
`
`
`Original Submission:
`Amendments:
`
`
`31-Mar-2006
`03-Nov-2006
`30-Nov-2006
`
`
`Post-Approval Agreements: None
`
`Drug Substances:
`
`
`Pioglitazone HCl
`
`
`
`Pioglitazone is a highly selective and potent agonist for the peroxisome
`proliferator-activated receptor-gamma (PPARγ). Activation of PPARγ nuclear
`receptors regulates the transcription of insulin-related genes involved in the
`control of glucose production, transport, and utilization. Pioglitazone HCl has a
`chemical name of (±)-5-[[4-[2-(5-Ethyl-2- pyridinyl)ethoxy]phenyl]methyl]-2,4-
`thiazolidinedione hydrochloride, a molecular formula of C19H20N2O3S • HCl, and
`molecular weight of 392.90 g/mole. The hydrochloride salt is a white crystalline
`
`(b) (4)
`
`

`

`2 of 4
`
`
`
`2/1/2007
`
`and slightly soluble in ethanol. Water
`powder that is soluble in
`solubility is pH dependent and is <0.01 mg/mL at physiological pH. The drug
`molecule is chiral and the racemate is used in the formulation. The drug
`substance, pioglitazone HCl, is that approved for use in NDA 21-073 for Takeda’s
`Acto® tablets and reference is made to such and its supplements for all chemistry,
`manufacturing, and controls information pertaining to pioglitazone HCl.
`
`The release specifications include appearance, identity, assay, related impurities,
`heavy metals, residual solvents, moisture content, and particle size distribution.
`The proposed regulatory methods have been validated. The reference standard, a
` commercial lot, has been developed, characterized, and purity data
`
`provided.
`
` is
` inside a
`Bulk pioglitazone HCl, packed in
`stable for up to 4 years when stored at room temperature (25°C/60 %RH) or up to
`6 months when stored at elevated temperature (40°C/75%RH).
`
`Metformin HCl
`
`
`
`
`
`Metformin is a biguanide class of antihiperglycemic agent that acts primarily by
`decreasing endogenous hepatic output of glucose by inhibition of
`gluconcogenesis. Metformin HCl has a chemical name of 1,1-Dimethylbiguanide
`hydrochloride, a molecular formula of C4H11N5 • HCl, and a molecular weight of
`165.62 g/mole.
`
`CMC information on the drug substance, metformin HCl, is described in the Type
`II DMF
` detailed information on manufacture, in-process
`controls, analytical procedures and their validation, and stability is included. The
`applicant has summarized information regarding nomenclature, general
`properties, manufacturing sites, acceptance specifications, reference standard,
`batch analysis data, structural elucidation, and stability studies in the NDA.
`
`The release specifications include description, identification, loss on drying,
`residue on ignition, heavy metal, assay, related impurities, residual solvents and
`particle size. These specifications comply with the USP monograph for metformin
`hydrochloride. The drug substance specification differs from the USP monograph
`in
`.
`The reference standard for metformin HCl is commercially available from USP.
`
` inside a
`Bulk metformin HCl, packed in
`stable for up to 5 years at room temperature (25°C/60% RH) or at elevated
`temperature (40°C/75% RH).
`
`, is
`
`
`Conclusion: Drug substance information is acceptable.
`
`
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`

`

`3 of 4
`
`
`
`2/1/2007
`
`
`Drug Product:
`
`The drug product is a fixed dose combination tablet, composed of a metformin HCl extended
`release core that is coated with an immediate release pioglitazone HCl formulation, and is
`available as two strengths with the following description:
`
`
`The 15/1000 tablets contain 15 mg pioglitazone /1000 metformin mg, are white to off-
`white film-coated, round tablets imprinted with "4833X” and "15/1000" in red on one
`side, and weigh 1255 mg.
`
`The 30/1000 tablets contain 30 mg pioglitazone /1000 metformin mg, are white to off-
`white film-coated, round tablets imprinted with "4833X” and "30/1000" in light blue on
`one side, and weigh 1291 mg.
`
`
`Manufacture of the drug product utilizes Andrx's propriety Single Composition Osmotic Tablet
`(SCOT) delivery technology which, in this case, consists of a metformin HCl extended-release
`core that is coated with an immediate-release pioglitazone HCl formulation.
`
`
`
`
`
`(b) (4)
`
`

`

`4 of 4
`
`
`
`2/1/2007
`
`
`The specification for the drug product includes description, identification (HPLC, TLC), assay
`(HPLC), content uniformity, drug release (dissolution), loss on drying, and related
`compounds. The proposed regulatory methods have been validated. The drug product reference
`materials are the same as those used for pioglitazone HCL and metformin HCL drug substances.
`
`Stability data indicate that there are no significant changes in terms of description,
`assay, related compounds, dissolution, loss on drying, and microbial limits when tablets are
`stored under either long-term (25°C/60%) or accelerated (40°C/75%RH) conditions in HDPE
`bottles with closure and desiccant pack and in
`. Photostability
`studies indicate no significant changes for known pioglitazone impurities and metformin
`impurities. However, pioglitazone unknown impurities increased slightly upon exposure to light.
`At high temperature and low humidity, all results met specification.
`
`Based on 12 months of stability data for tablets packaged in HDPE bottles and blister packages
`stored under long-term and accelerated conditions, the requested expiration dating period of 24
`months is acceptable.
`
`Conclusion: Drug product information is acceptable.
`
`Additional Items:
`
`
`All associated Drug Master Files (DMFs) are adequate or the pertinent
`information has been adequately provided in the application.
`
`
`
`
`
`
`The applicant agrees to place one batch annually in the post-approval stability
`program.
`
` A satisfactory response to the CMC labeling comments is pending. Strengths for
`Pioglitazone as free base and metformin as free base appear on label; label
`strengths should agree with the established names pioglitazone HCl and
`metformin HCl.
`
`
`
`Overall Conclusion:
`
`
`From a CMC perspective, the application is Approvable because of
`Withold recommendation from Office of Compliance.
`
`
`
`Blair A. Fraser, Ph.D.
`Director
`DPA I/ONDQA
`
`
`(b) (4)
`
`

`

`---------------------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed electronically and
`this page is the manifestation of the electronic signature.
`---------------------------------------------------------------------------------------------------------------------
` /s/
`---------------------
`Blair Fraser
`2/1/2007 02:02:07 PM
`CHEMIST
`
`

`

`
`
`
`
`
`
`
`
`CHEMISTRY REVIEW
`
`NDA 22-024
`
`ACTOPLUS METTM XR
`(pioglitazone HCl/metformin HCl
`extended-release)
`Tablets
`
`Takeda
`
`
`Chien-Hua Niu, Ph.D.
`ONDQA/DPMA-I
`
`
`
`
`
`
`
`
`
`
`

`

`
`
`
`
`CHEMISTRY REVIEW
`
`
`
`Table of Contents
`
`
`Table of Contents .....................................................................................................2
`
`Chemistry Review Data Sheet.................................................................................3
`
`The Executive Summary .........................................................................................7
`
`I. Recommendations......................................................................................................................7
`A. Recommendation and Conclusion on Approvability.......................................................................7
`B. Recommendation on Phase 4 (Post-Marketing) Commitments, Agreements, and/or Risk
`Management Steps, if Approvable...................................................................................................7
`
`II. Summary of Chemistry Assessments.........................................................................................7
`A. Description of the Drug Product(s) and Drug Substance(s) .............................................................7
`B. Description of How the Drug Product is Intended to be Used........................................................10
`C. Basis for Approvability or Not-Approval Recommendation..........................................................11
`
`III. Administrative.........................................................................................................................11
`A. Reviewer’s Signature......................................................................................................................11
`B. Endorsement Block.........................................................................................................................11
`C. CC Block ........................................................................................................................................11
`
`Chemistry Assessment.......................................................................................... 12
`
` I.. DRUG SUBSTANCE
`II. DRUG PRODUCT
`III. LABELING & PACKAGE INSERT
`IV. Claim Of Categorical Exclusion
`
` V. List Of Deficiencies To Be Communicated
`
`
`
`
`

`

`
`
`
`
`
`
`CHEMISTRY REVIEW
`Chemistry Review Data Sheet
`
`
`
`Chemistry Review Data Sheet
`
`
`
`
`1. NDA 22-024
`
`2. REVIEW #: 2
`
`
`3. REVIEW DATE: February 1, 2007
`
`
`4. REVIEWER: Chien-Hua Niu, Ph.D.
`
`
`
`5. PREVIOUS DOCUMENTS: None
`
`6. SUBMISSION(S) BEING REVIEWED:
`
` Submission Type Document Date
` Amendment 03-NOV-2006
` Amendment 30-NOV-2006
`
`7. NAME & ADDRESS OF APPLICANT:
`
` Name: Takeda Global Research and Development Center, Inc.
` Address: One Takeda Parkway
` Deerfield, IL 60015-2235
`
`8. DRUG PRODUCT NAME/CODE/TYPE:
`
`a) Proprietary Name: ACTOPLUS METTM XR
`b) Non-Proprietary Name (USAN): Pioglitazone HCl
` : Metformine HCl
`c) Code Name/# (ONDC only): 112529-15-4 (CAS registry number for Pioglitazone)
` 1115-70-4 (CAS registry number for Metformine)
`d) Type/Submission Priority (ONDC only):
`• Chem. Type:
`• Submission Priority: 1 S
`
`
`
`
`
`
`
`
`Page 3 of 18
`
`

`

`
`
`
`
`
`
`
`
`CHEMISTRY REVIEW
`Chemistry Review Data Sheet
`
` Tablets
`
`
`9. LEGAL BASIS FOR SUBMISSION: Not applicable
`
`10. PHARMACOL. CATEGORY: Antihyperglycemic agent
`
`11. DOSAGE FORM:
`
`12. STRENGTH/POTENCY: 15 mg pioglitazone/1000 mg metformin ER
` 30 mg pioglitazone/1000 mg metformin ER
`
`13. ROUTE OF ADMINISTRATION: Oral
`
`14. Rx/OTC DISPENSED: _X__Rx ___OTC
`
`15. SPOTS (SPECIAL PRODUCTS ON-LINE TRACKING SYSTEM):
`
`
`
` SPOTS product – Form Completed
`
` X Not a SPOTS product
`
`16. CHEMICAL NAME, STRUCTURAL FORMULA, MOLECULAR
`FORMULA, MOLECULAR WEIGHT:
`
`
`
`Chemical Name: (±)-5-[[4-[2-(5-Ethyl-2-pyridinyl)ethoxy]phenyl]methyl]-2,4-
`thazolidinedione hydrochloride (Pioglitazone HCl)
`
`
` 1,1-Dimethylbiguanide hydrochloride (Metformin HCl)
`
` Structural Formula: Pioglitazone HCl
`
`
`
` Metformin HCl
`
`
`
`
`
`
`
`
` Molecular Formula: Pioglitazone HCl: C19H20N2O3S • HCl
` Metformin HCl: C4H11N5 • HCl
` Molecular Weight: Pioglitazone HCl: 392.90 g/mol
` Metformin HCl: 165.62
`
`Page 4 of 18
`
`

`

`
`
`
`
`CHEMISTRY REVIEW
`Chemistry Review Data Sheet
`
`
`17. RELATED/SUPPORTING DOCUMENTS:
`
`
`A. DMFs:
`
`
`
`ITEM
`REFERENCE
`D
`
`DMF
`#
`
`TYPE
`
`HOLDER
`
` II
`
` IV
`
` III
`
` III
`
` III
`
` III
`
` III
`
` III
`
` III
`
` 1
`
` 1
`
` 3
`
` 3
`
` 3
`
` 3
`
` 3
`
` 3
`
` 3
`
`CODE1 STATUS2
`
`Adequate
`
`DATE
`REVIEW
`COMPLETED
` 11-July -06
`
`Adequate
`
` 10-October-06
`
`Adequate
`
` 07-August-06
`
`Adequate
`
` 07-December-04
`
`Adequate
`
` 01-August-06
`
`Adequate
`
` 07-January-04
`
`Adequate
`
` 23-June-06
`
`Adequate
`
`
`
`Adequate
`
` 10-July-06
`
`
`
`COMMENTS
`
`Review by
`Chien-Hua Niu for
`NDA #22-024
`
`Reviewed by
`Chien-Hua Niu for
`NDA #22-024
`
`Reviewed by
`Josephine Jee for
`NDA #21-991
`Reviewed by Rapti
`Madurawe for
`IND
`Reviewed by
`Josephine Jee for
`NDA 21-991
`Reviewed by
`Monica Cooper for
`NDA 13-174
`Reviewed by
`Josephine Jee for
`NDA #21-991
`Reviewed by Mike
`Adam for NDA
`#21-925
`
`Reviewed by Shulin
`Ding for NDA
`
`
`1 Action codes for DMF Table:
`1 – DMF Reviewed.
`Other codes indicate why the DMF was not reviewed, as follows:
`2 –Type 1 DMF
`3 – Reviewed previously and no revision since last review
`4 – Sufficient information in application
`5 – Authority to reference not granted
`6 – DMF not available
`7 – Other (explain under "Comments")
`
`2 Adequate, Inadequate, or N/A (There is enough data in the application, therefore the DMF did not need
`to be reviewed)
`
`
`
`
`
`
`
`Page 5 of 18
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`

`

`
`
`
`
`B. Other Documents:
`
`
`CHEMISTRY REVIEW
`Chemistry Review Data Sheet
`
`
`
`DOCUMENT
` IND
`
`APPLICATION NUMBER
` 68,462
`
`DESCRIPTION
`Antihyperglycemic Agent
`
`
`
`
`18. STATUS:
`
`ONDQA:
`CONSULTS/ CMC
`RELATED REVIEWS
`Biometrics
`EES
`Pharm/Tox
`
`Biopharm
`LNC
`Methods Validation
`
`DMETS
`EA
`
`
`
`RECOMMENDATION
`Not Reguired
`Pending
`Acceptable (see NDA #21-
`073 and NDA #21-574)
`Acceptable
`N/A
`The method validation
`package will be sent to and
`validated by the FDA
`laboratories
`Acceptable
`Categorical exclusion
`
`DATE
`
`REVIEWER
`
`
`
`
`
`12/27/06
`
`
`
`
`Office of Compliance
`Karen David-Bruno
`
`Jayabharathi Vaidyanathan
`
`Chien-Hua Niu
`
`01/08/07
`
`
`Kanika Vij
`Chien-Hua Niu
`
`Page 6 of 18
`
`

`

`
`
`
`
`
`
`
`B.
`
`
`CHEMISTRY REVIEW
` REVIEW NOTE
`The Chemistry Review for NDA 22-024
`
`The Executive Summary
`
` I. Recommendations
`
`A.
`Recommendation and Conclusion on Approvability
`The application is approvable, pending an acceptable establishment evaluation by the
`Office of Compliance for the manufacturing sites for the drug product at Andrx
`Pharmaceutical Inc.
`
`Recommendation on Phase 4 (Post-Marketing) Commitments, Agreements,
`and/or Risk Management Steps, if Approvable: None
`
`
`II.
`
`
`
`
`
`
`Summary of Chemistry Assessments
`
`A. Description of the Drug Product(s) and Drug Substance(s)
`
`Pioglitazone is a highly selective and potent agonist for the peroxisome proliferator-activated
`receptor-gamma (PPARγ). Activation of PPARγ nuclear receptors regulates the transcription
`of insulin-related genes involved in the control of glucose production, transport, and
`utilization.
`
`Metformin is an antihiperglycemic agent that belongs to the biguanide class. Their mode of
`action is that biguanides act primarily by decreasing endogenous hepatic output of glucose by
`inhibition of gluconcogenesis.
`
`When taken in combination, pioglitazone and metformin together, provide additive benefits
`and lead to improved glycemic control in patient with type 2 diabetes mellitus.
`
`DRUG SUBSTANCE:
`
`Pioglitazone HCl
`
`
`
`All respective CMC information for pioglitazone HCl drug substance is contained with NDA
`21-073 for ACTO tablets, and its related amendments and annual reports. Reference is also
`made to S-006, S-015 and S-019 to this NDA for CMC information on alternate drug
`substance suppliers. Brief summaries of the information are provided in this application,
`including nomenclarture, general properties, manufacturing processes and in-process
`
`
`
`Page 7 of 18
`
`

`

`
`
`
`
`
`
`CHEMISTRY REVIEW
` REVIEW NOTE
`
`
`
`controls, manufacturing and control sites, structural characterization, acceptance
`specifications, reference standards, batch analysis data, and stability studies.
`
`The manufacturing process for pioglitazone HCl is involved in two main stages. The first
`
`The release specifications include appearance, identity, assay, related impurities, heavy
`metals, residual solvents, moisture content, and particle size distribution. Analytical methods
`and their validation studies are summarized. Reference standard, a
` commercial
`lot, is identified and purity data is provided.
`
`The drug product manufacturer (Andrx Pharmaceuticals) will also analyze each receipt of
`drug substance in conformance with in-house specifications. These in-house specifications
`are the same as the drug substance manufacturer’s specifications except for the unit of
`measure
` for the residual solvent test and the addition of an identity test for the
`
`
`
`
`Based on data from ICH stability studies on three (3) commercial lots, pioglitazone HCl is
` in
`stable for up to five years at room temperature when stored in
` at 25°C/60 %RH for a period of up to 48 months and 40°C/75%RH (6
`
`months).
`.
`Metformin HCl is designated chemically as 1,1-dimethylbiguanide hydrochloride. The
`chemical structure and molecular formula for metformin HCl are shown below:
`
`
`
`
`.
`
`
` Type II DMF #
`All CMC information on metformin HCl is referred to
`The applicant has summarized information regarding nomenclature, general properties,
`manufacturing sites, acceptance specifications, reference standard, batch analysis data,
`structural elucidation, and stability studies in NDA submission. Detailed information on
`manufacture, in-process controls, analytical procedures and their validation, and stability is
`included in the approved DMF
`.
`
`Metformin HCl is manufactured and controlled at one site
`
`The release specifications include description, identification, LOD, residue in ignition, heavy
`metal, assay, related impurities, residual solvents and particle size. These specifications were
`recently revised to comply with the new USP monograph for metformin hydrochloride (see
`Chem. Rev. #9 for DMF
`
`
`
`
`
`
`Page 8 of 18
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`

`

`
`
`
`
`
`
`
`
`
` inside
`
`.
`
` and sealed. The
`
` are then
`
`
`CHEMISTRY REVIEW
` REVIEW NOTE
`
`
`
`Compared to the current USP monograph for metformin hydrochloride, the drug substance
`specification implemented by the drug substance manufacturer
` has two
`differences:
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`The reference standard for metformin HCl is commercially available from USP and EP. The
`current USP reference standard Lot # for metformin HCl is H0E136 (cat. #: 1396309).
`
`Metformin HCl is
`stored inside of a
`
`
`Results of the stability studies of Lot CH7149 demonstrate that there have been no
`indications of a decrease in quality or loss in potency in metformin HCl stored for up to 60
`months at 25°C/60% RH and 40°C/75% RH.
`
`DRUG PRODUCT: The proposed drug product, ACTOPlLUS MET XT, is manufactured
`by Andrx Pharmaceuticals Inc. (4955 Orange DR. Ft. Lauderdale, FL 33314). The drug
`product is a fixed dose combination tablet composed of a metformin HCl extended release
`core coating with an immediate release pioglitazone HCl formulation. The two AD-4833XT
`tablet strengths are shown below grade:
`
`Strength
`15 mg/1000 mg
`
`30 mg/1000 mg
`
`Description
`Round white to off-white filmed coated tablet imprinted with "4833X
`and "15/1000" in red on one side
`Round white to off-white filmed coated tablet imprinted with
`"4833X" and "30/1000" in light blue on one side
`
`
`The core tablet dosage form (metformin extended-release formulation) utilizes Andrx's
`propriety Single Composition Osmotic Tablet (SCOT) delivery technology. These Metformin
`XT laser drilled tablets are manufactured by the same manufacturing process as described in
`the approved NDA #21-574 for FORTAMET.
`
`
`The manufacturing process and in-process controls are described in detail.
`
`Both strengths of AD-4833XT tablets are packaged in HDPE bottles (30-, 60-, and 90-count)
`with child-resistant closure for commercial distribution and
` packages for the
`physician samples.
`
`
`
`
`Page 9 of 18
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`

`

`
`
`
`
`
`
`
`
`
`
`CHEMISTRY REVIEW
` REVIEW NOTE
`
`
`
`The proposed release specifications include description, identification (HPLC, TL), assay
`(HPLC), content uniformity, drug release (dissolution), loss on drying, and related
`compounds. The proposed regulatory methods have been validated.
`
`The dissolution test of AD-4833XT tablets was conducted under two sets of conditions.
`
`
`
`Stability tests performed include description, assay, related compounds, dissolution,
`loss on drying, and microbial limits.
`
`DA-4833XT tablets packaged in HDPE bottles with CRC closure, desiccant pack and
` show no significant changes in terms of description,
`assay, related compounds, dissolution, loss on drying, and microbial limited when
`store at long-term conditions (25°C/60%) and accelerated conditions (40°C/75%RH).
`The photostability study indicates that no significant concentration change for
`pioglitazone known impurities
` or metformin
`impurities
` were observed. However,
`pioglitazone unknown impurities increased with exposure to light. At high
`temperature and low humidity, all results met proposed specifications.
`
`Based on 12 months of stability data from samples packaged HDPE bottles and
` stored at ICH long-term and accelerated conditions, an expiration
`dating period of 24 months requested by the firm is acceptable for AD-4833XT
`tablets.
`
`The sponsor has cited a regulation [21 CFR 25.31(b)] to claim a categorical exclusion
`from filling an environmental assessment.
`
`
`
`
`B. Description of How the Drug Product is Intended to be Used
`ACTOPLUS METTM XR consists of metformin extended-release core coated tablet
`with an immediate-release pioglitazone layer used in the management of type 2
`diabetes. The firm indicates that the recommended dosage of ACTOPLUS MET is
`15 mg pioglitazone HCl (as free base) with 1000 mg metformin HCl (15 mg/1000 mg)
`or 30 mg pioglitazone HCl and 1000 mg metformin HCl (30 mg/1000 mg)
`administered once-a-day.
`
`
`
`
`
`
`
`Page 10 of 18
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`

`

`
`
`
`
`CHEMISTRY REVIEW
` REVIEW NOTE
`
`
`
`
`C. Basis for Approvability or Not-Approval Recommendation
`
`
`The recommendation that this application is approvable from a CMC viewpoint is
`based on the following: (1) The CMC information on the drug substance, including
`pioglitazone HCl and metformin HCl, has been thoroughly reviewed for NDA #21-
`073 (ACTO tablets) and NDA #21-574 (FORTAMET XT), respectively and found
`adequate to support the application of NDA #22-024. (2) The two ACTOPLUS MET
`XT tablet strengths, 15 mg/1000 mg and 30 mg/1000 mg, were manufactured using
`SCOT delivery technology to prepare the metformin core tablets and then by
` of the pioglitazone immediate-release formulation on the metformin core.
`The manufacturing process and in-process controls are validated. However, a number
`of chemistry non-approvability requests for information on the in-process controls are
`being made. (3) Three primary stability batches for each dose strengths have been
`manufactured by Andrx Pharmaceuticals Inc. at 4955 Orange Dr., Ft Lauderdale, FL
`33314. Both strengths of tablets are packaged in HDPE bottles with CRC caps and
`. (4) Stability data indicate that no significant changes were observed in terms
`of description, assay, related compounds, dissolution, loss on drying, and microbial
`limits when stored at 25°C/60% RH and 40°C/75% RH for a period of up to 12
`months. and (5) Satisfactory response to IR letter.
`
`Pending Issue: (1). The satisfactory recommendation issued by the Office of
`Compliance for the manufacturing sites for the drug product at Andrx Pharmaceutical
`Inc.
`
`
`III. Administrative
`
`A. Reviewer’s Signature
`
`B. Endorsement Block
`
`
`
`
`
` Chemist Name/Date: Chien-Hua Niu, Ph.D./ONDQA/DPMA-I
`Chemistry Division Director: Name/Date: Blair Fraser, Ph.D. /ONDQA/DPMA-I
`
`
`C. CC Block
`
`
` Dr. Blair Fraser/Dr. Su (Suong) Tran
`Project Manager Name/Date: Jena Weber, OND/HFD-510
`
`
`
`Page 11 of 18
`
`7 pages withheld immediately following this page
`as (b)(4) CCI/TS.
`
`(b) (4)
`
`(b) (4)
`
`

`

`---------------------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed electronically and
`this page is the manifestation of the electronic signature.
`---------------------------------------------------------------------------------------------------------------------
` /s/
`---------------------
`Chien-Hua Niu
`2/1/2007 01:11:10 PM
`CHEMIST
`
`Blair Fraser
`2/1/2007 01:52:19 PM
`CHEMIST
`
`

`

`
`
`
`
`
`
`
`
`CHEMISTRY REVIEW
`
`NDA 22-024
`
`ACTOPLUS METTM XR
`(pioglitazone HCl/metformin HCl
`extended-release)
`Tablets
`
`Takeda
`
`
`Chien-Hua Niu, Ph.D.
`ONDQA/DPMA-I
`
`
`
`
`
`
`
`
`
`
`

`

`
`
`
`
`CHEMISTRY REVIEW
`
`
`
`Table of Contents
`
`
`Table of Contents .....................................................................................................2
`
`Chemistry Review Data Sheet.................................................................................3
`
`The Executive Summary .........................................................................................7
`
`I. Recommendations......................................................................................................................7
`A. Recommendation and Conclusion on Approvability.......................................................................7
`B. Recommendation on Phase 4 (Post-Marketing) Commitments, Agreements, and/or Risk
`Management Steps, if Approvable...................................................................................................7
`
`II. Summary of Chemistry Assessments.........................................................................................7
`A. Description of the Drug Product(s) and Drug Substance(s) .............................................................7
`B. Description of How the Drug Product is Intended to be Used........................................................10
`C. Basis for Approvability or Not-Approval Recommendation..........................................................10
`
`III. Administrative.........................................................................................................................11
`A. Reviewer’s Signature......................................................................................................................11
`B. Endorsement Block.........................................................................................................................11
`C. CC Block ........................................................................................................................................11
`
`Chemistry Assessment.......................................................................................... 12
`
` I.. DRUG SUBSTANCE
`II. DRUG PRODUCT
`III. LABELING & PACKAGE INSERT
`IV. Claim Of Categorical Exclusion
`
` V. List Of Deficiencies To Be Communicated
`
`
`
`
`

`

`
`
`
`
`
`
`CHEMISTRY REVIEW
`Chemistry Review Data Sheet
`
`
`
`Chemistry Review Data Sheet
`
`
`
`
`1. NDA 21-912
`
`
`2. REVIEW #: 1
`
`
`3. REVIEW DATE: October 13, 2006
`
`
`4. REVIEWER: Chien-Hua Niu, Ph.D.
`
`
`
`5. PREVIOUS DOCUMENTS: None
`
`6. SUBMISSION(S) BEING REVIEWED:
`
` Submission Type Document Date
` Original 31-MAR-2006
`
`7. NAME & ADDRESS OF APPLICANT:
`
` Name: Takeda Global Research and Development Center, Inc.
` Address: 475 Half Day Road
` Lincolnshire, IL 60069
`
`8. DRUG PRODUCT NAME/CODE/TYPE:
`
`a) Proprietary Name: ACTOPLUS METTM XR
`b) Non-Proprietary Name (USAN): Pioglitazone HCl
` : Metformine HCl
`c) Code Name/# (ONDC only): 112529-15-4 (CAS registry number for Pioglitazone)
` 1115-70-4 (CAS registry number for Metformine)
`d) Type/Submission Priority (ONDC only):
`• Chem. Type:
`• Submission Priority: 1 S
`
`
`
`
`
`
`
`
`Page 3 of 80
`
`

`

`
`
`
`
`
`
`
`
`CHEMISTRY REVIEW
`Chemistry Review Data Sheet
`
` Tablets
`
`
`9. LEGAL BASIS FOR SUBMISSION: Not applicable
`
`10. PHARMACOL. CATEGORY: Antihyperglycemic agent
`
`11. DOSAGE FORM:
`
`12. STRENGTH/POTENCY: 15 mg pioglitazone/1000 mg metformin ER
` 30 mg pioglitazone/1000 mg metformin ER
`
`13. ROUTE OF ADMINISTRATION: Oral
`
`14. Rx/OTC DISPENSED: _X__Rx ___OTC
`
`15. SPOTS (SPECIAL PRODUCTS ON-LINE TRACKING SYSTEM):
`
`
`
` SPOTS product – Form Completed
`
` X Not a SPOTS product
`
`16. CHEMICAL NAME, STRUCTURAL FORMULA, MOLECULAR
`FORMULA, MOLECULAR WEIGHT:
`
`
`
`Chemical Name: (±)-5-[[4-[2-(5-Ethyl-2-pyridinyl)ethoxy]phenyl]methyl]-2,4-
`thazolidinedione hydrochloride (Pioglitazone HCl)
`
`
` 1,1-Dimethylbiguanide hydrochloride (Metformin HCl)
`
` Structural Formula: Pioglitazone HCl
`
`
`
` Metformin HCl
`
`
`
`
`
`
`
`
` Molecular Formula: Pioglitazone HCl: C19H20N2O3S • HCl
` Metformin HCl: C4H11N5 • HCl
` Molecular Weight: Pioglitazone HCl: 392.90 g/mol
` Metformin HCl: 165.62
`
`Page 4 of 80
`
`

`

`
`
`
`
`CHEMISTRY REVIEW
`Chemistry Review Data Sheet
`
`
`17. RELATED/SUPPORTING DOCUMENTS:
`
`
`A. DMFs:
`
`
`
`DMF
`#
`
`TYPE
`
`HOLDER
`
` II
`
` IV
`
` III
`
` III
`
` III
`
` III
`
` III
`
` III
`
` III
`
`ITEM
`REFERENCE
`D
`Metformin HCl
`
`
`CODE1 STATUS2
`
`Adequate
`
`DATE
`REVIEW
`COMPLETED
` 11-July -06
`
` 1
`
` 1
`
` 3
`
` 3
`
` 3
`
` 3
`
` 3
`
` 3
`
`Adequate
`
` 10-October-06
`
`Adequate
`
` 07-August-06
`
`Adequate
`
` 07-December-04
`
`Adequate
`
` 01-August-06
`
`Adequate
`
` 07-January-04
`
`Adequate
`
` 23-June-06
`
`Adequate
`
`
`
`
`
` 3
`
`Adequate
`
` 10-July-06
`
`
`
`COMMENTS
`
`Review by
`Chien-Hua Niu for
`NDA #22-024
`
`Reviewed by
`Chien-Hua Niu for
`NDA #22-024
`
`Reviewed by
`Josephine Jee for
`NDA #21-991
`Reviewed by Rapti
`Madurawe for
`IND
`Reviewed by
`Josephine Jee for
`NDA 21-991
`Reviewed by
`Monica Cooper for
`NDA 13-174
`Reviewed by
`Josephine Jee for
`NDA #21-991
`Reviewed by Mike
`Adam for NDA
`#21-925
`
`Reviewed by Shulin
`Ding for NDA
`
`1 Action codes for DMF Table