CENTER FOR DRUG EVALUATION AND RESEARCH
`
`APPROVAL PACKAGE FOR:
`
`APPLICATION NUMBER '
`
`NDA 21-574
`
`Chemistry Review(s)
`
`

`

` CHENIISTRY REVIEW
`
`NDA 21-574
`
`FortametTM Extended-Release Tablets
`
`Metformin HCl, USP ER Tablets
`
`Andrx Labs, Inc.
`
`(Andrx)
`
`CMC Review # 2
`
`Xavier Ysern, PhD
`
`HFD-510
`
`

`

`CHEMISTRY REVIEW
`
`Table of Contents
`
`Table of Contents .......................................................................................................................... 2
`
`Chemistry Review Data Sheet...................................................................................................... 3
`
`The Executive Summary
`
`............................................. 6
`
`1. Recommendations ....................................................................................................................... 6
`
`A. Recommendation and Conclusion on Approvability .......................................................... 6
`
`B. Recommendation on Phase 4 (Post-Marketing) Commitments, Agreements, and/or Risk
`Management Steps, if Approvable ...................................................................................... 6
`
`II. Summary of Chemistry Assessments .......... ,...............................................................................6
`
`A. Description ofthe Drug Product(s) and Drug Substance(s)
`
`6
`
`B. Description of How the Drug Product is Intended to be Used ............................................. 7
`
`C. Basis for Approvability or Not—Approval Recommendation .............................................. 8
`
`III. Administrative ........................................ 8
`
`A. Reviewer’s Signature .......................................................................................................... 8
`
`B. Endorsement Block ............................................................................................................. 8
`
`C. CC Block ...........' .................................................................................................................. 8
`
`Chemistry Assessment.............................................. ........................................ 8
`
`

`

`
`
`CHER/IISTRY REVIEW
`
`Chemistry Review Data Sheet
`
`Chemistry Review Data Sheet
`
`1. NDA
`
`'
`
`'
`
`21-574
`
`2. REVIEW #
`
`2
`
`3. REVIEW DATE:
`
`.
`
`01-AUG-2003 (review # 2)
`
`4. REVIEWER:
`
`Xavier Ysem
`
`5. PREVIOUS DOCUMENTS:
`
`Documentgs)
`
`Document Date
`
`6. SUBMISSION(S) BEING REVIEWED:
`
`Submissionfs) Reviewed
`Original
`Amendment
`
`Document Date
`17—DEC—2002
`29-JAN-2003
`l7-MAR—2003
`l5-MAY-2003
`28—JUL-2003
`
`7. NAME & ADDRESS OF APPLICANT:
`
`Name:
`Address:
`
`Representative:
`Telephone:
`
`phone (201) 883-1898
`
`Andrx Labs, Inc.
`401 Hackensack Avenue
`Hackensack, NJ 07601
`Nicholas J. Farina, Vice President Regulatory Affairs
`(610) 428-2417
`Fax:
`(201) 883—1893
`
`8. DRUG PRODUCT NAME/CODE/TYPE:
`
`a) Proprietary Name:
`b) Non—Proprietary Name (USAN):
`0) Code Name:
`d) Chem Type/Submission Priority:
`I
`Chem. Type:
`.
`Submission Priority:
`
`.
`FortametTM ER Tablets
`Metformin HCl Extended-Release Tablets
`—-
`
`Type 4
`S
`
`9. LEGAL BASIS FOR SUBMISSION:
`
`'
`
`-—
`
`10. PHARMACOLOGICAL CATEGORY:
`
`Proposed for the treatment of Type 2 diabetes mellitus as an
`adjunct to diet and exercise
`
`11. DOSAGE FORM:
`
`Tablets
`
`12. STRENGTH/POTENCY:
`
`SOO-mg and IOOO-mg
`
`13. ROUTE OF ADMINISTRATION:
`
`l4. Rx/OTC DISPENSED:
`
`Oral
`
`Rx
`
`15. SPOTS jsPECIAL PRODUCTS ON—LlNE TRACKING SYSTEM}:
`
`Not a SPOTS product
`
`NDA 21-574 CMC Review # l Page 3 of 10
`
`

`

`
`CHEMISTRY REVI 1 w
`
`Chemistry Review Data Sheet
`
`16. CHEMICAL NAME, STRUCTURAL FORMULA, MOLECULAR FORMULA, MOL. WEIGHT:
`
`Metformin Hydrochloride
`
`C4HEEN5 I HCI
`MW: 129.l7+36.46= 165.63
`CAS 657-25—9 (free base) 1115—704 (hydrochloride)
`
`3% E
`. NH
`H C/N
`N
`3
`\ll/ T
`- N“
`N“
`
`N,N-Dimethylimidodicarbonimidic diamine monohydrochloride or NJV—Dimethylbiguanide HCl
`
`17. RELATED/SUPPORTING DOCUMENTS:
`
`A. DMFs:
`
`
`
` DMFE LOA
`
`
`Holder
`Item Referenced
`ECode'E
`Statusz EDate ReVlewE
`Comments
`
`
`#
`date
`Completed
`
`
`
`
`
`
`
`'=Adeq_i_iate E
`.
`l—
`
`
`_ ..._4_._I AdequaLeE::..: I ___”___'._
`j 4
`Adequate
`
`
`
`
`
`
`
` Adeq__ate
`Adequate
`
`
`
`Adequate
`
`
`
` =4
`
`
`E Adequate EPart ofthis
`E
`I
`E
`Ereview
`i
`E
`E
`i
`l
`
`.
`
`E 13Feb200
`E 13.Feb.200
`E27. Dec.200
`
`/
`
`.
`
`l
`I
`E
`i
`
`f
`
`,
`
`e». _.___
`‘_
`
`l
`
`' Action codes for DMF Table:
`l — DMF Reviewed.
`Other codes indicate why the DMF was not reviewed, as follows:
`2 —Type I 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)
`
`NDA 21-574 CMC Review# l Page 4 of 10
`
`

`

`
`CHEMISTRY REVIEW
`
`Chemistry Review Data Sheet
`
`B. Other Documents:
`
`DOCUMENT APPLICATION #
`
`DESCRIPTION
`
`'
`
`ANDA
`IND
`
`75-961
`55,962
`
`Metformin HCl Tablets (approved January 25, 2002)
`Metformin extended-release tablets (Aura Laboratories, Inc, a
`subsidi
`of Andrx Co oration)
`
`18. STATUS:
`
`
`
`CONSULTS/ CMC
` RECOMIVIENDATION
`
`REVIEWER
`i' LATED REVIEWS
`EES
`
`
`Acceptable
` 29-JAN-2003
`Office of Compliance
`
`
`
`
`
`Biopharm
`
`Pending
`Dissolution Specification.
`
`ODS/DMETS LNC
`Tradename FORTAMETrM was not
`
`
`
`
`Thomas G. Phillips,
`RPh HFD-4OO
`recommended, however, DMETS has
`
`
`
`no objection to the use of the
`
`
`
`proprietary name FortametTM
`
`
`
`Methods Validation
`
`
`
`DP Assay and Related Substances
`determinations HPLC analytical
`
`methods will be sent to Agency
`
`laboratories for revalidation
`
`EA
`Part of this review
`
`
`
`Categorical exclusion
`
`Microbiolo
`N/A
`y
`
`
`
`
`
`Appears This Way
`On Original
`
`NDA 21—574 CMC Review # l Page 5 of 10
`
`

`

`
`CHEMISTRY REVIEW
`
`Executive Summary Section
`
`1. Recommendations
`
`A. Recommendation and Conclusion on Approvability
`
`This NDA can be approved.
`
`B. Recommendation on Phase 4 (Post-Marketing) Commitments, Agreements, and/or Risk
`Management Steps, if Approvable
`
`There are no CMC Phase IV Commitments.
`
`II. Summary of Chemistry Assessments
`
`A. Description of the Drug Product(s) and Drug Substance(s)
`
`Drug substance
`
`Metforrnin, the active component, is an antihiperglycemic agent that belongs to the biguanide class. Their
`mode of action is well understood, biguanides act primarily by decreasing endogenous hepatic output of glucose by
`inhibition of gluconeogenesis. Structurally metforrnin, L
`.
`J, is a low molecular biguanide
`(129.17 g/mol) synthesized .C
`.
`3 It is
`synthesized L
`3 Metforrnin hydrochloride is a white to off-white crystalline compound.
`The pKa of metforrnin is 12.4. Metforrnin is a class 3 (high solubility-low permeability) BCS drug. Metforrnin
`hydrochloride, drug substance,
`is very stable compound with a well characterized stability degradation pathway.
`Particle size is part of the specifications, and there is no evidence cf polymorphism. Approved drug products using
`metforrnin hydrochloride as drug substance include immediate release (innovator and generics) formulations, an
`extended release formulation (Glucophage® XR), and recently in combination drug products, either with
`sulfonylureas such as Glyburide and Glipizide (GlucovanceTM and MetaglipTM tablets, respectively) or with the
`thiazolidinedione Rosiglitazone (AvandametTM tablets). Metforrnin HCl drug substance, used by the applicant
`Andrx Pharmaceuticals for the manufacture of the drug product FortametTM tablets, is manufactured and supplied by
`r.
`.
`3 (DMF L
`1
`
`Drug Product
`
`The drug product, FortametTM 500- and lOOO-mg Tablets, is an extended release formulation of metforrnin
`hydrochloride designed for once a day administration of metformin. The tablet formulation was developed to
`provide an extended release of the active ingredient using the Andrx’s proprietary single composition osmotic
`tablet (SCOTTM) technology. The tablet consists of an osmotically active core formulation, which is surrounded by
`a semipermeable membrane and a film coating L
`J \. Two laser drilled exit ports exist in
`the membrane, one on either side of the tablet. The osmotically active core contains the drug substance Metforrnin
`HC1. and the L
`1 excipientst
`3 The Semipermeable membrane L
`J is permeable to water but not to higher molecular weight components. Upon ingestion,
`.
`.
`water is taken up through the membrane (osmosis), which in turn dissolves the drug and excipients in the core
`formulation. The dissolved drug and excipients exit through the laser drilled ports in the membrane. The rate of
`drug delivery is constant and dependent upon the maintenance of a constant osmotic gradient across the membrane
`a situation that exists as long as there is undissolved drug present in the core tablet. For Fortamet tablet this
`occurs when about -—-
`of the drug is released. Following dissolution of the core components, the rate of drug
`delivery slowly decreases until the osmotic gradient across the membrane falls to zero at which time delivery
`ceases. The semipermeable membrane remains basically intact C
`3 during the transit of the dosage fomi through the gastrointestinal tract and is
`excreted in the feces. The Andrx’s SCOT delivery technology operates in a very similar way to Alza‘s OROS® oral
`osmotic delivery technology (single composition versus push-pullTM system, respectively).
`
`NDA21—574 CMC Review # l Page 6 of 10
`
`

`

` CHEMISTRY REVIEW
`
`Executive Summary Section
`
`The manufacture of the osmotically active core (or inner core) is similar to that of conventional
`immediate release tablets I
`3 However, to obtain the desired
`extended release tablets, the seal-coated inner cores are additionally coated with the sustained release (SR)
`coating solution, and subsequently laser drilled, color coated, imprinted and packaged. All of these are within
`defined in—process control stipulations. For’tametTM specifications are very similar to those for Bristol Mayer
`Squibb’s approved Glucophage® XR (Metformin HCl extended release tablets). Biconvex—shaped, white round 500-
`and lOOO—mg tables are distinguished by size and debossing.
`
`FortametTM Tablets are packaged in bottles and in blister packages. The drug product stability has been
`evaluated in containers of 30-, 60—, 100- and lOOO-count HDPE bottles as well as unit dose blister packages. It is
`available to patients in 60 cc (SOO—mg strength) and ‘ ; (lOOO-mg strength) white high-density polyethylene
`bottles containing 60 tablets, secured with child resistant white C
`3 caps. Larger capacity HDPE bottles of
`lOOO—counts are also commercially available to Pharmacies and Health Care Centers. The results of the stability
`studies show the drug product compatibility with the packaging materials and reconfirm the expected stability of
`metformin hydrochloride in solid oral dosage forms. Consistent with the results of the stability study, an expiration
`period of 24 months has been granted for FortametTM tablets packaged in bottles and 12 months in blister packages,
`at the recommended storage condition (USP controlled room temperature). Based on the observed degradation
`trends it is expected that FortametTM tablets will remain within specifications for a significant longer period of time.
`Those expiration dates were limited by the available provided stability data and could be extended with additional
`supportive data from the ongoing stability study.
`
`Currently, Glucophage® XR a Metformin hydrochloride extended release drug product is available in the
`market. At the time of Andrx submission of this NDA, Bristol-Myers Squibb Pharrnaceutical’s Glucophage® XR,
`which was approved on October 2000, was available only in 500-mg tablets L
`3 The Agency considerations for accepting other Metformin HCl extended release
`formulation were mainly clinically based. Andrx’s FortametTM claimed clinical benefits included: (1) clinical studies
`up to ZSOO-mg/day (PI Glucophage® XR states “... the maximum recommended daily dose of Glucophage® XR is
`2000 mg”), (2) Patient compliance, if a patient is prescribed 2000 mg/daily, this would require two Fortamet tablets
`instead of four Glucophage® XR tablets (patient compliance decreases relative to the number of daily doses and
`number of pills), (3) Patient convenience, the SOO—mg tablet of FortametTM is significantly smaller than the same
`dosage of Glucophage® XR, advantageous to patients who have difficulty swallowing (e.g., dysphagia caused by
`diabetic neuropathy) and (4) Effects on triglycerides appear to be less pronounced than those occurring with
`Glucophage® XR (although no claim is sought by Andrx).
`
`-
`
`B. Description of How the Drug Product is Intended to be Used
`
`FortametTM Tablets is intended to be used orally as an adjunct to diet and exercise, to improve glycemic
`control in patients with type 2 diabetes mellitus whose hyperglycemia cannot be satisfactorily managed with diet
`and exercise. The drug product can be used either as monotherapy or in combination with a sulfonylurea or insulin.
`Dosage is based on effectiveness and tolerability, and should not exceed the maximum recommended daily dose of
`2500 mg once daily with the evening meal. The usual starting dose is lOOO—mg once daily, although SOD-mg may be
`utilized when clinically appropriate. Dosages increases should be made in increments of SOO—mg weekly (to reduce
`gastrointestinal side effects and to permit identification of the minimum dose required), up to a maximum of 2500-
`mg once daily with the evening meal. As any other metforrnin containing drug product, in the warning section of the
`package insert there is a black box cautioning for potential complications due to development of lactic acidosis.
`Lactic acidosis -characterized by elevated blood lactate levels (> 5 mmol/L), decreased blood pH, electrolyte
`unbalance with an increased anion gap- is a rare, but serious (fatal in 50 ”/0 of the cases) metabolic complication that
`can occur due to metforrnin accumulation (plasma levels > 5 ug/mL) during treatment with the drug product.
`FortametTM tablets should be stored at controlled room temperature. Excessive heat and humidity should be avoided.
`
`NDA 21-574 CMC Revicwfi l Page 7 of 10
`
`

`

`
`
`Executive Summary Section
`
`C. Basis for Approvability or Not-Approval Recommendation
`
`The minor CMC deficiencies, acceptable ESE-free certificate or BSE risk statement for magnesium
`stearate and acceptable packaging labeling, have been adequately addressed by the applicant. All manufacturing
`facilities are acceptable: Based on the information provided in the submission this application can be approved
`from the Chemistry, Manufacturing and Controls (CMC) standpoint.
`
`III. Administrative
`
`A. Reviewer’s Signature
`
`B. Endorsement Block
`
`ChemistName/Date: Same date as draft review
`
`Xavier Ysem
`
`ChemistryTeamLeaderName/Date
`ProjectManagerName/Date
`
`' Stephen Moore
`Jena Weber
`
`C. CC Block
`
`NDA 21-574 CMC Review #1 Page 8 of 10
`
`

`

`£99 Page(s) Withheld
`
`__}__(§ 552(b)(4) Trade Secret / Confidential
`
`§ 552(b)(5) Deliberative Process
`
`§ 552(b)(5) Draft Labeling
`
`

`

`This is a representation of an electronic record that was signed electronically and
`this page is the manifestation of the electronic signature.
`
`Xavier Ysern
`8/1/03 02:13:29 PM
`CHEMIST
`
`Stephen Moore
`8/1/03 02:50:56 PM
`CHEMIST
`
`

`

`CE MISTRY REVIEW
`
`NDA 21-574
`
`FortametTM Extended-Release Tablets
`
`Metformin HCl, USP ER Tablets
`
`Andrx Labs, Inc.
`
`(Andrx)
`
`Xavier Ysern, PhD
`
`HFD-510
`
`

`

` CHEMISTRY REVIEW '
`”
`
`Table of Contents
`
`Table of Contents .......................................................................................................................... 2
`
`Chemistry Review Data Sheet ...................................................................................................... 3
`
`The Executive Summary............................................................................................................... 6
`
`1. Recommendations ..................................................................................................................... 6
`
`A. Recommendation and Conclusion on Approvability .......................................................... 6
`
`B. Recommendation on Phase 4 (Post—Marketing) Commitments, Agreements, and/or Risk
`Management Steps, if Approvable .............. ......................................................................... 6
`
`H. Summary of Chemistry Assessments ........................................................................................ 6
`
`A. Description of the Drug Product(s) and Drug Substance(s) ................................................ 6
`
`B. Description of How the Drug Product is Intended to be Used ......
`
`....................... 7
`
`C. Basis for Approvability or Not—Approval Recommendation .............................................. 8
`
`III. Administrative .......................................................................................................................... 8
`
`A. Reviewer’s Signature..........................f ............................................................................... 8
`
`B. Endorsement Block .............................................................................................................. 8
`
`C. CC Block ............................................................................................................................. 8
`
`Chemistry Assessment ...................................................................................... 8
`
`Appears This Way
`
`

`

`
`CHEMISTRY REVIEW
`
`Chemistry Review Data Sheet
`
`Chemistry Review Data Sheet
`
`1. NBA
`
`2. REVIEW #
`
`21-574
`
`1
`
`3. REVIEW DATE:
`
`12-MAY-2003
`
`4. REVIEWER:
`
`Xavier Yscrn
`
`5.
`
`PREVIOUS DOCUMENTS:
`
`Documentgs)
`
`Document Date
`
`6. SUBMISSION(S) BEING REVIEWED:
`
`Submissiongs) Reviewed
`Original
`Amendment
`
`Document Date
`17-DEC—2002
`29-JAN-2003
`
`7. NAME & ADDRESS OF APPLICANT:
`
`Name:
`Address:
`
`Representative:
`Telephone:
`
`phone (201) 883-1898
`
`Andrx Labs, Inc.
`401 Hackensack Avenue
`Hackensack, NJ 07601
`Nicholas J. Farina, Vice President Regulatory Affairs
`(610) 428—2417 Fax:
`(201) 883—1893
`
`8. DRUG PRODUCT NAME/CODE/TYPE:
`
`a) Proprietary Name:
`b) Non-Proprietary Name (USAN):
`c) Code Name:
`d) Chem. Type/Submission Priority:
`'
`Chem. Type:
`‘
`I
`Submission Priority:
`
`FortametTM ER Tablets
`Metformin HCl Extended—Release Tablets
`--
`
`.
`
`Type 4
`S
`
`9. LEGAL BASIS FOR SUBMISSION:
`
`——
`
`10. PHARMACOLOGICAL CATEGORY:
`
`Proposed for the treatment of Type 2 diabetes mellitus as an
`adjunct to diet and exercise
`
`11. DOSAGE FORM:
`
`Tablets
`
`12. STRENGTH/POTENCY:
`
`SOO-mg and 1000—mg
`
`13. ROUTE OF ADMINISTRATION:
`
`14. Rx/OTC DISPENSED:
`
`Oral
`
`Rx
`
`15. SPOTS (SPECIAL PRODUCTS ON-LINE TRACKING SYSTEMglNote27I:
`
`Not a SPOTS product
`
`NDA 21—574 CMC Review# 1 Page 3 of 42
`
`

`

`
`CHEMISTRY REVIEW
`
`Chemistry Review Data Sheet
`
`16. CHEMICAL NAME, STRUCTURAL FORMULA, MOLECULAR FORMULA, MOL. WEIGHT:
`
`Metformin Hydrochloride
`
`C4HHN5 HCl
`MW=129.17+36.46=165.63
`CAS 657-25-9 (fi'ee base) 1115-70—4 (hydrochloride)
`
`.
`
`?“3
`H C/N
`3
`
`E
`N
`\ll/\ll/
`N“
`N“
`
`NH
`
`N,N-Dimethylimidodicarbonimidic diamine monohydrochloride or N,N—Dimethylbiguanide HCl
`
`17. RELATED/SUPPORTING DOCUMENTS:
`
`A. DMFs:
`
`LOA
`DMFE
`.E
`2 EDate ReviewE
`
`
`
`
`
`
`
`Holder
`Item Referenced
`ECOdeE
`Status
`Com leted
`#
`date
`
`
`
`
`._ch_11__..__._a_;-
`,
`'
`_
`,
`AEdeeguate E23 --.lAN2002E ANDA 75961
`
`.
`EMetformin l_{__C_l ([_)__L"_
`E
`35Nov._2_001E____
`
`'l'vne III
`
`
`
` -EAdecLuate
`.......
`lAdequate E
`l
`
`
`
`" EAdeguate;E01-APR—1999E
`
`
`__E__AdequateE
`
`EAdequate
`
`
` __EAdeguate
`4E. Adeguate :
`
`
`
`E.13 Feb. 2001?
`
`
`4 EAdequate ‘Partof this
`‘
`'-
`
`;13Feb.200;
`Ereview
`i
`27.1)ee.2ooag
`
`
`
`' Action codes for DMF Table:
`l — DMF Reviewed.
`Other codes indicate why the DMF wasvnot 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")
`
`1 Adequate, Inadequate, or N/A (There is enough data in the application, therefore the DMF did not need to be reviewed)
`
`NDA 21—574 CMC Review# I Page 4 of 42
`
`

`

`
`
`C E'TMISTRY REVIEW
`
`Chemistry Review Data Sheet
`
`B. Other Documents:
`
`
`
`
`DOCUMENT APPLICATION #
`DESCRIPTION
`Metformin HCl Tablets (approved January 25, 2002)
`75—961
`Metformin extended—release tablets (Aura Laboratories, Inc., a
`'
`55,962
`subsidiary of Andrx Corporation)
`
`
`
`
`18. STATUS:
`
`RECOMMENDATION
`
`Acceptable
`
`DATE
`
`REVIEWER
`
`Pending
`
`Thomas G. Phillips,_
`RPh HFD—400
`
`
`
`
`
`
`CONSULTS/ CMC
`
`
`LATED REVIEWS
`EES
`
`
`
`29-JAN-2003
`
`Office of Compliance
`
`
`
`Biopharm
`
`Dissolution Specification.
`ODS/DMETS LNC
`Tradename FORTAMETTM was not
`
`
`recommended, however, DMETS has
`
`no objection to the use of the
`
`re nrieta
`name FortametTM
`
`Methods Validation
`
`
`DP Assay and Related Substances
`determinations HPLC analytical
`methods will be sent to Agency
`laboratories for revalidation
`EA
`
`Categorical exclusion
`Part of this review
`N/A
`Microbiology
`
`
`
`
`
`
`
`Appears This Way
`On Original
`
`NDA21—574 CMC Review # l Page 5 of 42
`
`

`

` C . MISTRY REVIEW
`
`1. Recommendations
`
`Executive Summary Section
`
`A. Recommendation and Conclusion on Approvability
`
`This NDA is can be approved pending acceptable BSE-free certificate or BSE risk statement for the
`excipient magnesium stearate, and acceptable carton and immediate container labels for all dosage forms. The
`requested expiration period of 24 months is granted for dosage forms packaged in HDPE bottles. However, due to
`the limited stability data provided on blister packaging, a 12 month expiration period is granted for the blister
`presentations.
`
`B. Recommendation on Phase 4 (Post-Marketing) Commitments, Agreements, and/or Risk
`Management Steps, if Approvable
`
`There are no CMC Phase IV Commitments.
`
`II. Summary of Chemistry Assessments
`
`A Description of the Drug Product(s) and Drug Substance(s)
`
`Drug substance
`
`Metformin, the active component, is an antihiperglycemic agent that belongs to the biguanide class. Their
`mode of action is well understood, biguanides act primarily by decreasing endogenous hepatic output of glucose by
`inhibition of gluconeogenesis. Structurallv metformin. C
`lis a low molecular biguanide
`(129.17 g/mon svnthesized E
`_
`1
`1 It is
`synthesized L
`I . Metformin hydrochloride is a white to off-white crystalline compound.
`The pKa of metformin is 12.4. Metformin is a class 3 (high solubility—low permeability) BCS drug. Metformin
`hydrochloride, drug substance,
`is very stable compound with a well characterized stability degradation pathway.
`Particle size is part of the specifications, and there is no evidence of polymorphism. Approved drug products using
`metformin hydrochloride as drug substance include immediate release (innovator and generics) formulations, an
`extended release formulation (Glucophage® XR), and recently in combination drug products, either with
`sulfonylureas such as Glyburide and Glipizide (GlucovanceTM and MetaglipTM tablets, respectively) or with the
`thiazolidinedione Rosiglitazone (AvandametTM tablets). Metformin HCl drug substance, used by the applicant
`Andrx Pharmaceuticals for the manufacture of the drug product FortametTM tablets, is manufactured and supplied by
`L
`J (DMF 'C
`'1
`
`Drug Product
`
`The drug product, FortametTM 500- and lOOO-mg Tablets, is an extended release formulation of metforrnin
`hydrochloride designed for once a day administration of metformin. The tablet formulation was developed to
`provide an extended release of the' active ingredient using the Andrx’s proprietary single composition osmotic
`tablet (SCOTTM) technology. The tablet consists of an osmoticallv active core formulation, which is surrounded by
`a semipermeable membrane and a film coating L
`'
`1 Two laser drilled exit ports exist in
`_ the membrane, one on either side of the tablet. The osmotically active core contains the drug substance Metformin
`HCl, and the C
`1 excipients L
`J The semipermeable membrane L
`J is permeable to water but not to higher molecular weight components. Upon ingestion,
`water is taken up through the membrane (osmosis), which in turn dissolves the drug and excipients in the core
`formulation. The dissolved drug and excipients exit through the laser drilled ports in the membrane. The rate of
`drug delivery is constant and dependent upon the maintenance of a constant osmotic gradient across the membrane
`a situation that exists as long as there is undissolved drug present in the core tablet. For Fortamet tablet this
`occurs when about
`\— of the drug is released. Following dissolution of the core components, the rate of drug
`delivery slowly decreases until
`the osmotic gradient across the membrane falls to zero at which time delivery
`
`NDA 21—574 CMC Review# 1 Page 6 of 42
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`CHEMISTRY REVIEW
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`Executive Summary Section
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`ceases. The semipermeable membrane remains basically intact L
`I ~ during the transit of the dosage form through the gastrointestinal tract and is
`excreted in the feces. The Andrx’s SCOT delivery technology operates in a very similar way to Alza‘s OROS® oral
`osmotic delivery technology (single composition versus push-pullTM system, respectively).
`
`The manufacture of the osmotically active core (or inner core) is similar to that of conventional
`immediate release tablets L
`.
`3 However, to obtain the desired
`extended release tablets, the seal-coated inner cores are additionally coated with the sustained release (SR)
`coating solution, and subsequently laser drilled, color coated, imprinted and packaged. All of these are within
`defined in-process control stipulations. FortametTM specifications are very similar to those for Bristol Mayer
`Squibb’s approved Glucophage® XR (Metformin HCl extended release tablets). Biconvex-shaped, white round 500-
`and lOOO-mg tables are distinguished by size and debossing.
`
`FortametTM Tablets are packaged in bottles and in blister packages. The drug product stability has been
`evaluated in containers of 30-, 60-, 100— and lOOO—count HDPE bottles as well as unit dose blister packages. It is
`available to patients in 60 cc (500—mg strength) and L
`1 (lOOO—mg strength) white high—density polyethylene
`bottles containing 60 tablets, secured with child resistant white . L
`3 caps. Larger capacity HDPE bottles of
`1000-counts are also cormnercially available to Pharmacies and Health Care Centers. The results of the stability
`studies show the drug product compatibility with the packaging materials and reconfirm the expected stability of
`metforrnin hydrochloride in solid oral dosage forms. Consistent with the results of the stability study, an expiration
`period of 24 months has been granted for FortametTM tablets packaged in bottles and 12 months in blister packages,
`at the recommended storage condition (USP controlled room temperature). Based on the observed degradation
`trends it is expected that FortametTM tablets will remain within specifications for a significant longer period of time.
`Those expiration dates were limited by the available provided stability data and could be extended with additional
`supportive data from the ongoing stability study.
`
`Currently, Glucophage® XR a Metformin hydrochloride extended release drug product is available in the
`market. At the time of Andrx submission of this NDA, Bristol-Myers Squibb Pharmaceutical’s Glucophage® XR,
`which was approved on October 2000, was available only in SOO—mg tablets L
`,
`_
`J The Agency considerations for accepting other Metformin HCl extended release
`formulation were mainly clinically based. Andrx’s FortametTM claimed clinical benefits included: (I) clinical studies
`up to 2500—mg/day (PI Glucophage® XR states
`the maximum .recommended daily dose of Glucophage® XR is
`2000 mg”), (2) Patient compliance, if a patient is prescribed 2000 mgdaily, this would require two Fortamet tablets
`instead of four Glucophage® XR tablets (patient compliance decreases relative to the number of daily doses and
`number of pills), (3) Patient convenience, the SOO—mg tablet of FortametTM is significantly smaller than the same
`dosage of Glucophage® XR, advantageous to patients who have difficulty swallowing (e.g., dysphagia caused by
`diabetic neuropathy) and (4) Effects on triglycerides appear to be less pronounced than those occurring with
`Glucophage® XR (although no claim is sought by Andrx).
`
`B. Description of How the Drug Product is Intended to be Used
`
`FortametTM Tablets is intended to be used orally as an adjunct to diet and exercise, to improve glycemic
`control in patients with type 2 diabetes mellitus whose hyperglycemia cannot be satisfactorily managed with diet
`and exercise. The drug product can be used either as monotherapy or in combination with a sulfonylurea or insulin.
`Dosage is based on effectiveness and tolerability, and should not exceed the maximum recommended daily dose of
`2500 mg once daily with the evening meal. The usual starting dose is lOOO-mg once daily, although SOD-mg may be
`utilized when clinically appropriate. Dosages increases should be made in increments of SOO—mg weekly (to reduce
`gastrointestinal side effects and to permit identification of the minimum dose required), up to a maximum of 2500-
`mg once daily with the evening meal. As any other metforrnin containing drug product, in the warning section of the
`package insert there is a black box cautioning for potential complications due to development of lactic acidosis.
`Lactic acidosis —characterized by elevated blood lactate levels (> 5 mmol/L), decreased blood pH, electrolyte
`unbalance with an increased anion gap— is a rare, but serious (fatal in 50 % ofthe cases) metabolic complication that
`
`NDA 21—574 CMC Reviewfil l Page 7 of 42
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`
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`Executive Summary Section
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`can occur due to metformin accumulation (plasma levels > 5 ug/mL) during treatment with the drug product.
`FortametTM tablets should be stored at controlled room temperature. Excessive heat and humidity should be avoided.
`
`C. Basis for Approvability or Not-Approval Recommendation
`
`There are minor CMC deficiencies. All manufacturing facilities are acceptable. Based on the information
`provided in the submission this application can be approved from the Chemistry, Manufacturing and Controls
`(CMC) standpoint, pending acceptable BSE-free certificate or BSE risk statement for magnesium stearate, and
`acceptable packaging labeling is provided.
`
`III. Administrative
`
`A. Reviewer’s Signature
`
`B. Endorsement Block
`
`ChemistName/Date: Same date as draft review
`
`Xavier Ysern
`
`ChemistryTeamLeaderName/Date
`ProjectManagerName/Date
`
`Stephen Moore
`Jena Weber
`
`C. CC Block
`
`NDA 21—574 CMC Review# 1 Page 8 of 42
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`fl Page(s) Withheld
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`- \/§ 552(b)(4) Trade Secret / Confidential
`
`§ 552(b)(5) Deliberative Process
`
`_'_ § 552(b)(5) Draft Labeling
`
`

`

`This is a representation of an electronic record that was signed electronically and
`this page is the manifestation of the electronic signature.
`
`Xavier Ysern
`
`6/23/03 02:15:08 PM
`CHEMIST
`
`Stephen Moore
`6/23/03 05:27:45 PM
`CHEMIST
`
`