CENTER FOR DRUG EVALUATION AND
`
`RESEARCH
`
`APPLICA TION NUMBER:
`
`22-192
`
`CHEMISTRY REVIEW! S!
`
`

`

`M E M O R A N D U M
`
`DEPARTMENT OF HEALTH AND HUMAN SERVICES
`PUBLIC HEALTH SERVICE
`FOOD AND DRUG ADMINISTRATION
`CENTER FOR DRUG EVALUATION AND RESEARCH
`
`DATE:
`
`9 January 2009
`
`FROM:
`
`Donghao (Robert) Lu, Ph.D.
`Division of Pre-Marketing Assessment - I
`Office of New Drug Quality Assessment
`
`TO:
`
`File NDA 22-192
`
`SUBJECT: Amendments to Pending Application (Nov. 5 and Nov. 19, 2008)
`
`RECONINIENDATION: The drug product Iloperidone immediate-release tablets, l, 2, 4, 6, 8,
`10, and 12 mg, is recommended as APPROVAL from a CMC perspective.
`
`ACTION: These two CMC comments have been sent to the sponsor:
`
`(1) The text “Protect from light and moisture” should be displayed on the draft bottle labels,
`carton labels, blister card labels and blister card carton labels.
`
`(2)
`
`In the labeling text (package insert), the statement awe-“MN"
`
`m-wwww—~e—-~w 7
`m.~....w~W-w—- —~ «A ' should be
`changed to "Each round, uncoated tablet contains 1 mg, 2 mg, 4 mg, 6 mg, 8 mg, 10 mg, or
`12 mg of iloperidone".
`
`13(4)
`
`REVIEW NOTE:
`
`Vanda submitted a Complete Response on November 5, 2008 to the Agency's action letter (July
`25, 2008) and a request for reconsideration of proprietary name for iloperidone on November 19,
`2008. For the original NDA 22-192, the drug product Iloperidone immediate-release tablets, 1, 2,
`4, 6, 8, 10, and 12 mg, was recommended as APPROVAL from a CMC perspective. The
`amendments provided additional information on labeling, which has some modifications and is
`reviewed as shown below.
`'
`
`

`

`_‘/_ Page(s) Withheld
`
`Trade Secret / Confidential (b4)
`
`3‘ Draft Labeling (b4)
`
`X. Draft Labeling (b5)
`
`——.—_
`
`Deliberative Process (b5)
`
`

`

`This is a representation of an electronic record that was signed electronically and
`this page is the manifestation of the electronic signature.
`
`Donghao Lu
`1/12/2009 03:27:42 PM
`CHEMIST
`
`Ramesh Sood
`1/12/2009 03:39:44 PM
`CHEMIST
`
`

`

`lof4
`
`FanaptaTM
`(iloperidone)
`Tablets
`
`NDA 22—192
`
`Division Director Review
`
`Chemistry, Manufacturing, and Controls
`
`Applicant:
`
`Vanda Pharmaceuticals, Inc.
`9605 Medical Center Drive, Suite 300
`Rockville, MD 20850
`
`Indication:
`
`Treatment of schizophrenia
`
`Presentation: Immediate release, white, round, uncoated tablets are available in seven strengths
`(1 mg, 2 mg, 4 mg, 6 mg, 8 mg, 10 mg, and 12 mg) debossed with Vanda logo on
`one side and tablet strength on the other side.
`
`Tablets of all strengths are packaged in 60 count, child-resistant, E-—~—~‘ bottles,
`
`wit}
`, and in 2 count aluminum foil blisters on
`mmmmmmmm.—
`for' dose titration. Except for 1 mg and 2 mg strengths, tablets are provided in «w ..
`Wm; .M —
`
`M4)
`
`-
`
`EER Status:
`
`Consults:
`
`Acceptable
`
`11—JAN—2008
`
`EA — Categorical exclusion granted under 21 CFR §25.3l(a)
`Methods Validation —— Revalidation by Agency not requested.
`
`Original Submission:
`
`27-SEP-2007
`
`Post-Approval Agreements:
`
`None
`
`Drug Substance:
`
`Iloperidone is a psychotropic agent belonging to the chemical class of piperidinylbenzisoxazole
`derivatives. The drug substance, iloperidone , is a small, synthetic, New Molecular Entity (NME)
`with an empirical formula of C24H27N204F and a molecular weight of 426.5. Known chemically
`as 1-[4-[3—[4-(6-fluoro-1,2-benzisoxazol-3- yl)-1-piperidinyl]propoxy]-3—methoxyphenyl]
`ethanone, it forms white to off-white, crystals with a melting range of 120.0-125.0°C.
`Iloperidone is practically insoluble in water (0.012 mg/mL), sparingly soluble in basic aqueous
`solutions, slightly soluble in acidic aqueous solutions, and freely soluble in chloroform, ethanol,
`
`

`

`20f4
`
`methanol, and acetonitrile. The drug substance displays a
`M _.___.._____ . ___._————————-=-‘
`
`
`
`M4)
`
`b(1'1)
`
`M4)
`
`M4)
`
`_
`
`The bulk drug substance is manufactured by r—«rmW- “ - -~ ‘ - »- .--.W-
`
`
`
`
`
`-.,,._-......,..»>_W.....-...,..._t.,..,WWWWW
`’ W...
` \m‘m
`fa..- —-
`
`WWW Comprehensive
`information for all the impurities at the starting material level, at the intermediate level and at the
`final - -~ : level was presented.
`
`
`
`The structure of iloperidone was elucidated using several analytical and spectrophotometric
`
`m...—
`techniques. including r WW...“
`‘
`
`NW .. vulva—Mm-mw.w.
`
`N“ "no...”
`.unm'W
`
`..,o , :v,9“.mv-NMWNn
`
`The proposed release specification for iloperidone includes ,
`
`_wwm
`
`i
`
`.
`.
`The proposed regulatory methods are either
`their intended purpose. The primary reference standard for drug substance, manufactured by
`
`.
`has been characterized by the proposed regulatory methods as well as
`additional methods. The impurity and degradation profiles have been investigated. Reference
`standards for known impurities and in—process intermediates have been synthesized and fully
`characterized.
`
`_,I
`
`retest period for the bulk!
`The stability data for 1w commercial batches support a L
`
`drug substance stored inside WWW WW .M‘HM‘W‘
`
`WW... at controlled room temperature, 25°C /60%RH, W-
`
`
`
`[3(4)
`
`Conclusion: Drug substance is acceptable.
`
`Drug Product:
`
`Fanapta (iloperidone) tablets are uncoated, immediate release tablets, available in seven strengths
`(1 mg, 2 mg, 4 mg, 6 mg, 8 mg, 10 mg, 12 mg). Tablets for all strengths are white, round, flat,
`beveled-edge tablets with the tablet strength debossed on the one side and the Vanda company
`logo debossed on the other side. The tablet diameters are different for each strength, except for
`the 2 and 4 mg strengths which have the same diameter. Iloperidone tablets are packed in mm-
`
`M4)
`..
`
`WWW-WM
`
`

`

`3of4
`
`The drug product1s manufactured beginning rm W ~»————_.____..
`W Adequate information on the
`drug product manufacture has been provided
`
`23(4)
`
`11(4)
`
`11(4)
`
`The composition of the 1 mg strength, round tablet is iloperidone (1.00 mg), lactose
`
`
`monohydrate NF (.
`, microcrystalline cellulose NF
`-. hypromellose USP
`MW crospovidone NF ( a...» 3, colloidal silicon dioxide NF
`_.._.-..
`nagnesium
`stearate NF ( n...”w to give a tablet weight of. -- 3 and diameter of. W Four ‘ —
`
`(1 mg; 2 mg; 4 or 8 mg; 6, 10, or 12 mg) use the same excipients to give
`tablets from 2 mg strength (; WW :1 diameter) to 12 mg strength (. .
`diameter).
`
`The release specification for drug product includes:
`
`
`
`1m
`
`1 1
`
`Mt
`
`The stability data support expiration dating of 36 months for all strengths of drug product stored
`at controlled room temperature conditions [25" C (77° F); excursion permitted to 15-30° C (59-
`86° F)], and packaged in -~ cottles and in blister packages, protected from light and
`moisture.
`
`M4)
`
`Conclusion: Drug product is acceptable.
`
`Additional Items:
`
`I The applicant agreed to continue the primary stability studies on them»--
`commercial scale lots of each strength to firmly establish the proposed
`shelf life.
`
`I The sponsor agreed to placing at least ~— commercial production \-
`the drug product,
`for each ”,2...” _.
`in each package
`configuration, per year following the approved stability protocol.
`
`3(4)
`
`I All associated Drug Master Files (DMFs) are acceptable or the pertinent
`information has been adequately provided in the application.
`
`I- The applicant submitted a methods validation package containing all
`relevant documentation (tests, methods, and acceptance criteria) for the
`control of the drug substance and the drug product.
`
`

`

`4of4
`
`Overall Conclusion:
`
`From a CMC perspective, the application is recommended for Approval,
`pending agreement on product labeling.
`
`Blair A. Fraser, Ph.D.
`Director
`
`DPA I/ONDQA
`
`

`

`This is a representation of an electronic record that was signed electronically and
`this page is the manifestation of the electronic signature.
`
`Blair Fraser
`6/24/2008 05:38:38 AM
`CHEMIST
`
`

`

`
`
`NDA 22—192
`
`(Review #2)
`
`Iloperidone Tablets
`_1, 2, 4, 6, 8, 10 and 12 mg
`
`Vanda Pharmaceuticals Inc.
`
`Division of Psychiatry Drug Products
`
`Donghao (Robert) Lu, Ph.D.
`.
`Division I 'of Pre-Marketing Assessment
`Office of New Drug Quality Assessment
`
`

`

`
`
`Table of Contents
`
`Table of Contents2
`
`Chemistry Review DataSheet3
`
`The Executive Summary7
`
`I. Recommendations ......................................................................................................................7
`
`A. Recommendation and Conclusion on Approvability ....................................................................... 7
`
`B. Recommendation on Phase 4 (Post-Marketing) Commitments, Agreements, and/or Risk
`Management Steps, 1prprovable ....... 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.......................................................... 8
`
`C. Basis for Approvability or Not-Approval Recommendation ............................................................ 8
`
`III. Administrative...........................................................................................................................9
`
`A. Reviewer’s Signature........................................................................................................................ 9
`
`B. Endorsement Block ........................................................................................................................... 9
`
`C. CCBlock ................................................................................................ 9
`
`ChemistryAssessment 10
`
`Review Of Additional CMC Information From Applicant...................................................... 10—16
`
`

`

`
`
`Chemistry Assessment Section
`
`Chemistry Review Data Sheet
`
` Donghao (Robert) Lu, Ph.D.
`
`5. PREVIOUS DOCUMENTS:
`
`
`
`NDA 22-192
`
`27-SEPT-07
`
`NDA 22-192 (Amendment 005, stability)
`
`'
`
`NDA 22-192 (Amendment 006, labeling)
`
`17-MAR-07
`
`l8-APR-07
`
`NDA 22-192 (Amendment 007, CMC response)
`
`25-APR—07
`
`6. SUBMISSION(S) BEING REVIEWED:
`
`
`
`NDA 22-192 (Amendment 009, CMC response)
`
`16-MAY-08
`
`NDA 22-192 (Amendment 010, CMC' response)
`
`13-JUNE—08
`
`NDA 22-192 (Amendment 0011, CMC response)
`
`lS—JUNE-08
`
`7. NAME '& ADDRESS OF APPLICANT:
`
`Vanda Pharmaceuticals Inc.
`
`Paolo Baroldi, M.D., Ph.D., Chief Medical Officer 240-599-4500
`
`9605 Medical Center Drive, Suite 300 ‘
`Rockville, MD 20850
`
`

`

`
`
`Chemistry Assessment Section
`
`8. DRUG PRODUCT NAME/CODE/TYPE:
`
`
`
`
`DMETS did not approve the names
`
`Iloperidone
`
`HP 873 (Hoechst—Roussel), P88 8736
`it; (Hoechst—Roussel), 1L0522 (Novartis)
`IL0522-NXA (Novartis), VYV-683
`(Vanda), "xv
`IS
`
`l1(4)
`
`LEGAL BASIS FOR SUBMISSION:
`
`505(b)l
`
`10.
`
`PHARMACOL. CATEGORY:
`
`Antagonist at selected
`dopaminergic, serotoninergic, and
`adrenergic receptors
`
`ll.
`
`12.
`
`I3.
`
`DOSAGE FORM:
`
`Tablet
`
`STRENGTH/POTENCY:
`
`1, 2, 4, 6, 8, 10 and 12 rng
`
`ROUTE OF ADMINISTRATION:
`
`Oral
`
`14.
`
`Rx/OTC DISPENSED: '
`
`'
`
`
`x Rx
`
`OTC
`
`15.
`
`16.
`
`SPOTS gsPECIAL PRODUCTS ON-LINE TRACKING SYSTEM}:
`
`SPOTS product — Form Completed
`x Not a SPOTS product
`
`CHEMICAL NAME, STRUCTURAL FORMULA, MOLECULAR
`FORMULA, MOLECULAR WEIGHT:
`
`Name (USAN, INN): Iloperidone
`Name (CAS):
`1-[4—[3-[4—(6-fluoro-l,2-benzisoxazol—3 -y1)-l-
`piperidinyl]propoxy]—3 —methoxyphenyl]ethanone
`1-[4-[3-[4-(6-fluorobenzo[d]isoxazol-3 -yl)-l-
`Other Name:
`piperidinyl]propoxy]-3-methoxyphenyl]ethanone
`.
`-
`(CAS) Registry Num: 133454-47—4
`Structural Formula:
`
`m I,
`
`MOI. Formula:
`M01. Wt.:
`
`C24H27N204F
`426.5
`
`\
`/"
`
`H:
`
`o
`
`

`

`
`
`Chemistry Assessment Section
`
`17. RELATED/SUPPORTING DOCUMENTS:
`
`A. DMFs:
`
`
`
`
`
`aw"...
`Note: DMFs of ;
`
`
`
`
`l
`
`-——--—-—--—--—--———-————\
`
`—- see CMC Review MaPP.
`
`‘ 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.
`
`B. Other Documents:
`
`
`
`
`
`11(4)
`
`11(4)
`
`

`

`a: Mismy REVI
`
`
`
` Shaw-Into Adams
`Methods Validation
`
`N0 validation request 25-FEB—'08
`Donghao Lu, Ph.D.
`
`
`
`
`
`5-JUNE-08
`Letter fi'om T. Laughren _
`]
`ODS DMETS
`Not acceptable
`
`
`
`
`
`
`
`
`Acceptable
`11-FEB-08
`__—
`
`
`
`
`Donghao Lu, Ph.D.
`
`APPEARS THIS WAY ON ORIGINAL
`
`

`

`
`
`Chemistry Assessment Section I
`
`The Chemistry Review for NBA 22-192
`
`The Executive Summafl
`
`1.
`
`Recommendations
`
`A. Recommendation and Conclusion on Approvability
`
`The drug product Iloperidone immediate—release tablets, l, 2, 4, 6, 8, 10, and 12 mg,
`is recommended as APPROVAL from a CMC perspective.
`
`B. Recommendation on Phase 4 (Post-Marketing) Commitments, Agreements,
`and/or Risk Management Steps, if Approvable
`
`II.
`
`Summary of Chemistry Assessments
`
`A. Description of the Drug Substance and Drug Product
`
`1. Drug Substance
`
`The drug substance is iloperidone. The chemical name is l-[4—[3-[4-(6-fluoro-l,2-
`benzisoxazol-3 —yl)-l-piperidiny1]propoxy]-3—methoxyphenyl]ethanone. It has a
`molecular formula of C24H27N204F and its molecular weight is 426.5.
`
`Data fiom the studies of elemental analysis, UV, IR, NMR and MS demonstrated that
`the structure was adequately defined.W
`appear adequate for the manufacturing of the iloperidone drug substance.
`
`
`development of the drug substance
`The impurities detected during the
`were evaluated. Analytical methods were developed for the control of the impurities
`listed in the submission. Comprehensive information for all the impurities at the
`
`starting material level, at the intermediate level and at the final
`level were
`' adequately presented.
`
`Iloperidone was subjected to heat, heat and moisture, light, and chemical stresses.
`The drug substance was physically and chemically stable based on evaluation of the
`
`testing data. The drug substance has a retest period of
`
`M4)
`
`11(4)
`
`[1(4)
`
`

`

`
`
`Chemistry Assessment Section
`
`2. Drug Product
`
`The drug product is Iloperidone immediate-release tablets, 1, 2, 4, 6, 8, 10, and 12
`mg. It is intended for oral administration.
`'
`
`The tablets contain 1, 2, 4, 6, 8, 10, and 12 mg iloperidone, respectively. All strengths
`are white, round, flat, beveled—edge tablets with the tablet strength debossed on the
`upper face (e.g., “8” for the 8 mg strength) and the Vanda (Vanda Pharmaceuticals
`Inc.) company logo debossed on the lower face. The tablet diameters are different for
`each strength except for the r“- g strengths. Iloperidone tablets are packed in
`
`WW
`
`.Mm
`
`placed inside dose titration/maintenance cards.
`
`Inactive ingredients consist of lactose monohydrate, microcrystalline cellulose,
`hydroxypropyl methylcellulose, crospovidone, magnesium stearate, colloidal silicon
`
`dioxide. The manufacturing process for iloperidone tablets consists of w
`
`
`W“
`
`Wt)
`
`13(4)
`
`It is noted that DMETS did not recommend the approval of Fiapta or Fanapta as the
`drug product name (per NDA Letter of June 5, 2008).
`
`B. Description of How the Drug Product is Intended to be Used
`
`Iloperidone tablet drug products contain antagonist at selected dopaminergic,
`serotoninergic, and adrenergic receptors and are indicated for the treatment of
`schizophrenia.
`
`The recommended target dosage of iloperidone tablets is 12 mg/day administered
`BID during the acute phase. The recommended titration schedule to target dose is l,
`2, 4, and 6 mg BID on days 1, 2, 3, and 4 respectively. After reaching the target 12
`mg/day dose, titration to the maximum daily dose of 12 mg BID should occur over a '
`3-day period. During the maintenance phase, iloperidone can be administered at a
`
`target dose of
`~———————--—~
`Iloperidone can be
`administered without regard to meals. The products should be stored at controlled
`room temperature, 25°C (77°F); excursions permitted to 15°-30°C (59°- 86°F). The
`products should be protected from light and moisture. The products have an
`expiration period (shelf life) of 36 months.
`
`M4)
`
`C. Basis for Approvability or Not-Approval Recommendation
`
`From a CMC perspective, Vanda has submitted sufficient and appropriate
`information to support the approval of the drug product.
`
`

`

`
`
`Chemistry Assessment Section
`
`III. Administrative
`
`A.
`
`. Reviewer’s Signature
`
`\s\
`
`Donghao (Robert) Lu, Ph.D.
`
`B.
`
`Endorsement Block
`
`\s\
`
`Ramesh Sood, Ph.D.
`
`C. CC Block
`
`7 pages of CCl/TS (b4) was withheld after this page.
`
`CMC_#2_7 pgs.pdf
`
`

`

`7 Page(s) Withheld
`
`X
`
`Trade Secret / Confidential (b4)
`
`.—_
`
`Draft Labeling (b4)
`
`———__ Draft Labeling (b5)
`
`—_
`
`Deliberative Process (b5)
`
`

`

`This'Is a representation of an electronic record that was signed electronically and
`this page is the manifestation of the electronic signature.
`---------------------------------------------------------------------------------------------------------------------
`
`Donghao Lu
`6/23/2008 10:38:15 AM
`CHEMIST
`
`Ramesh Sood
`6/23/2008 10:49:06 AM
`CHEMIST
`
`

`

`
`
`NDA 22-192
`
`FANAPTA (Iloperidone)
`.
`Tablets
`
`1, 2, 4, 6, 8, 10 and 12 mg
`
`Vanda Pharmaceuticals Inc.
`
`Division of Psychiatry Drug Products
`
`Donghao (Robert) Lu, Ph._D‘.
`Division I of Pre—Marketing Assessment
`Office of New Drug Quality Assessment
`
`

`

`
`
`Table of Contents
`
`Table of Contents2
`
`Chemistry Review DataSheet3
`
`The Executive Summary
`
`.......7
`
`1. 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.......................................................... 8
`C. Basis for Approvability or Not-Approval Recommendation............................................................ 8
`
`III. Adm1n1strat1ve .......................................................... 9
`
`A. Reviewer’s Signature ........................................................................................................................ 9
`
`B. EndorsementBlock ...... ......................... ........................................................... 9
`(3. CC Block ..................I........................................................................................................................ 9
`
`ChemistryAssessment 10
`
`1. Review Of Common Technical Document-Quality (Ctd-Q) Module 3.2: Body 'OfData ....... 10
`s. DRUG SUBSTANCE.................................................................................................................... 10
`
`P. DRUG PRODUCT ................'........................................................................................................ 48
`
`A. APPENDICES ............................................................................................................................... 87
`
`R. REGIONAL INFORMATION ..................................V.................................................................... 87
`
`II. Review Of Common Technical Document-Quality (Ctd-Q) Module 1 ..................................90
`
`A. Labeling & Package Insert ............................................................................................................ 90
`
`B. Environmental Assessment Or Claim Of Categorical Exclusion ................................................... 94
`
`III. Establishment Evaluation Report.............................................................................................94
`
`IV. List Of Deficiencies And Responses .......................................................................................97
`
`

`

` HEMISTRY REVIE
`
`Chemistry Assessment Section
`
`Chemistry Review Data Sheet
`
`1.
`
`2.
`
`3.
`
`4.
`
`
`
`
`29 FEBRUARY 2008
`
`Donghao (Robert) Lu, Ph.D.
`
`5. PREVIOUS DOCUMENTS:
`
`
`
`6. SUBMISSION(S) BEING REVIEWED:
`
`
`
`NDA 22-192
`
`NDA 22-192 (Amendment 005, stability)
`
`NDA 22-192 (Amendment 006, labeling)
`
`27-SEPT—07
`
`17-MAR—07
`
`18—APR-07
`
`NDA 22—192 (Amendment 007, CMC response)
`
`25-APR-07
`
`7. NAME & ADDRESS OF APPLICANT:
`
`Vanda Pharmaceuticals Inc.
`
`9605 Medical Center Drive, Suite 300
`Rockville, MD 20850
`
`240-599-4500
`
`Paolo Baroldi, M.D., Ph.D., Chief Medical Officer
`
`

`

`
`Chemistry Assessment Section _
`
`8. DRUG PRODUCT NAME/CODE/TYPE:
`
`
`
`FANAPTA (Iloperidone)
`
`Iloperidone
`
`HP 873 (Hoechst—Roussel), P88 8736
`(Hoechst—Roussel), IL0522 (Novartis)
`IL0522-NXA (Novartis), VYV-683
`(Vanda), -w
`18
`
`13(4)
`
`9. LEGAL BASIS FOR SUBMISSION:
`
`505(b)1
`
`10. PHARMACOL. CATEGORY:
`
`Antagonist at selected
`dopaminergic, serotoninergic, and
`adrenergic receptors
`
`11. DOSAGE FORM:
`
`Tablet
`
`12. STRENGTH/POTENCY:
`
`1, 2, 4, 6, 8, 10 and 12 mg
`
`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:
`
`Name (USAN, INN): Iloperidone
`Name (CAS):
`1-[4-[3—[4-(6-fluoro-l,2—benzisoxazol-3-yl)-l-
`piperidinyl] propoxy]—3 -methoxyphenyl]ethanone
`1-[4-[3-[4-(6-fluorobenzo[d]isoxazol-3-yl)-1-
`piperidinyl]propoxy]-3~methoxyphenyl]ethanone
`(CAS) Registry Num: 133454-47-4
`'
`Structural Formula:
`
`Other Name:
`
`"m /C"‘:
`
`M01. Formula:
`M01. Wt:
`
`C24H27N204F
`426.5
`
`\
`/"
`
`H:
`
`o
`
`

`

`
`
`Chemistry Assessment Section
`
`17. RELATED/SUPPORTING DOCUMENTS:
`
`
`
`9(4)
`
`
`
`Note: DMFs m.“
`
`
`
`system is used for solid oral drug products — see CMC Review MaPP.
`
`' 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 inforrnation 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.
`
`B. Other Documents:
`
`
`
`
`
`

`

`
`
`Chemistry Assessment Section
`
`
`
`G
`x
`
`5:.
`- .
`{£3
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`,.~
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`
`
`-—;——
`———
`
`
`
`
`APPEARS THIS WAY ON ORIGINAL
`
`

`

`
`
`Chemistry Assessment Section
`
`The Chemistry Review for NBA 22—192
`
`. The Executive Summafl
`
`1.
`
`Recommendations
`
`A. Recommendation and Conclusion on Approvability
`
`The drug product FANAPTA (iloperidone) immediate-release tablets, l, 2, 4, 6, 8, 10,
`and 12 mg, is recommended as APPROVAL from a CMC perspective, pending
`DMETS’s recommendation.
`
`B. Recommendation on Phase 4 (Post-Marketing) Commitments, Agreements,
`and/or Risk Management Steps, if Approvable
`
`II.
`
`Summary of Chemistry Assessments
`
`A. Description of the Drug Substance and Drug Product
`
`1. Drug Substance
`
`The drug substance is iloperidone. The chemical name is 1-[4-[3-[4-(6-fluoro-l,2-
`benzisoxazol—3-yl)-l -piperidinyl]propoxy]~3-methoxyphenyl]ethanone. It has a
`molecular formula of C24H27N204F and its molecular weight is 426.5.
`
`Data from the studies of elemental analysis, UV, IR, NMR and MS demonstrated that
`the structure was adequately defined. TheM
`appear adequate for the manufacturing of the iloperidone drug substance.
`
`[3(4)
`
`The impurities detected during the «9—: and development ofthe drug substance
`were evaluated. Analytical methods were developed for the control of the impurities
`listed in the submission. Comprehensive information for all the impurities at the
`starting material level, at the intermediate level and at the final / level were
`adequately presented.
`
`Iloperidone was subjected to heat, heat and moisture, light, and chemical stresses.
`The drug substance was physically and chemically stable based on evaluation of the
`testing data. The drug substance has a retest period of __,..—--~
`
`13(4)
`
`

`

` HEMISTRY REVIE.
`
`Chemistry Assessment Section
`
`2. Drug Product
`
`The drug product is Fanapta (iloperidone) immediate-release tablets, 1, 2, 4, 6, 8, 10,
`and 12 mg. It is intended for oral administration.
`
`The tablets contain 1, 2, 4, 6, 8, 10, and 12 mg iloperidone, respectively. All strengths
`are white, round, flat, beveled-edge tablets with the tablet strength debossed on the
`upper face (e.g., “8” for the 8 mg strength) and the Vanda (Vanda Pharmaceuticals
`Inc.) company logo debossed on the lower face. The tablet diameters are different for
`
`each strength except for the .
`' strengths. Iloperidone tablets are packed in
`NMM 11(4)
`”at.”
`2%
`
`placed inside dose titration/maintenance cards.
`
`Inactive ingredients consist of lactose monohydrate, microcrystalline cellulose,
`4
`hydroxypropyl methylcellulose, crospovidone, magnesium stearate, colloidal silicon
`dioxide. The manufacturing process for iloperidone tablets consists of :M I“ )
`mans-WWW
`
`B. Description of How the Drug Product is Intended to be Used
`
`Iloperidone tablet drug products contain antagonist at selected dopaminergic,
`serotoninergic, and adrenergic receptors and are indicated for the treatment of
`schizophrenia.
`
`The recommended target dosage of iloperidone tablets is 12 mg/day administered
`BID during the acute phase. The recommended titration schedule to target dose is 1,
`2, 4, and 6 mg BID on days 1, 2, 3, and 4 respectively. After reaching the target 12
`mg/day dose, titration to the maximum daily dose of 12 mg BID should occur over a
`3-day period. During the maintenance phase, iloperidone can be administered at a
`
`’—
`target dose of
`.
`iloperidone can be
`administered without regard to meals. The products should be stored at controlled
`room temperature, 25°C (77°F); excursions permitted to «15°—30°C (59°- 86°F). The
`products should be protected from light and moisture. The products have an
`expiration period (shelf life) of 36 menths.
`
`hm)
`
`C. Basis for Approvability or Not-Approval Recommendation
`
`From a CMC perspective, Vanda has submitted sufficient and appropriate
`information to support the approval of the drug product. There were several CMC
`concerns that were sent to the sponsor on April 2, 2008. Vanda has adequately
`addressed these CMC comments. Their responses and the CMC evaluations for these
`responses are described at the end of this document.
`
`

`

` HEMISTRY REVIE
`
`Chemistry Assessment Section
`
`III. Administrative
`
`A. Reviewer’s Signature
`
`\s\
`
`Donghao (Robert) Lu, Ph.D.
`
`B.
`
`Endorsement Block
`
`. \s\
`
`Ramesh Sood, Ph.D.
`
`C.
`
`CC Block
`
`93 pages of CCl/TS (b4) was withheld after this page.
`
`CMC_#1_93 pgs.pdf
`
`

`

`*
`
`73
`
`Page(s) Withheld
`
`g.
`
`Trade Secret / Confidential (b4)
`
`Draft Labeling (b4)
`
`Draft Labeling (b5)
`
`Deliberative Process (b5)
`
`

`

`This is a representation of an electronic record that wassigned electronically and
`this page is the manifestation of the electronic signature.
`
`Donghao Lu
`5/1/2008 11:46:02 AM
`CHEMIST
`
`Ramesh Sood
`5/1/2008 04:42:41 PM
`CHEMIST
`
`

`

`~(sOP~&k4S+&17.27c66F
`
`O6-APR—2009
`
`Page 1 of 3
`
`FDA CDER EES
`
`ESTABLISHMENT EVALUATION REQUEST
`
`SUMMARY REPORT
`
`Application
`
`NDA
`
`22192/000
`
`Sponsor:
`
`VANDA
`
`201
`
`Org Code
`‘
`
`130
`
`9620 MEDICAL CENTER DR STE
`
`Priority
`
`ROCKVILLE, MD
`
`20850
`
`Stamp Date
`
`27-SEP-2007
`
`Brand Name
`
`ILOPERIDONE
`
`PDUFA Date
`
`O6-MAY-2009
`
`Estab. Name:
`
`Action Goal
`
`Generic Name:
`
`ILOPERIDONE
`
`District Goal:
`
`28—MAY—2008
`
`Dosage Form:
`
`(TABLET)
`
`MG
`
`Strength
`
`l,2,4,6,8,10, AND 12
`
`FDA Contacts:
`—796—1924
`
`K. KIEDROW
`
`Project Manager
`
`—796-l710
`
`-796-1728
`
`S. MCLAMORE
`
`Review Chemist
`
`T. OLIVER
`
`Team Leader
`
`301
`
`301
`
`301
`
`Overall Recommendation:
`
`2) 301—796-
`
`ACCEPTABLE on ll-JAN-ZOOBby S. FERGUSON(HFD-32
`
`FEI
`
`: w-.."
`
`.m-u—~
`
`

`

`DMF No:
`
`AADA:
`
`11(4)
`
`Responsibilities:
`
`”wwww~_____l_____.um._wlmimmm_
`
`Profile
`
`:
`
`CTL
`
`OAI Status:
`
`NONE
`
`Last Milestone:
`
`OC RECOMMENDATION
`
`Milestone Date:
`
`24-OCT-07
`
`Decision
`
`Reason
`
`:
`
`:
`
`ACCEPTABLE
`
`BASED ON PROFILE
`
`Establishment
`
`:
`r.”
`
`I
`
`DMF No:
`
`CFN :
`
`__Mn———
`
`,
`
`FEI
`
`: ——m~mwmm—
`
`I
`__J
`AADA:
`
`.
`
`‘14)
`(
`
`Responsibilities:
`
`;~m-~v~—-~—~——~——-———
`
`Profile
`
`:
`
`CTL
`
`OAI Status:
`
`NONE
`
`Last Milestone:
`
`OC RECOMMENDATION
`
`Milestone Date:
`
`. 09-Nov—07
`
`Decision
`
`Reason
`
`:
`
`:
`
`ACCEPTABLE
`
`DISTRICT RECOMMENDATION
`
`Establishment
`
`:
`
`CFN :
`
`-—-*‘
`
`FEI
`
`: _,www~._.
`
`

`

`DMF No:
`
`AADA:
`
`Responsibilities:
`
`APPEARS THIS WAY ON ORIGINAL
`
`

`

`06—APR—2009
`Page 2 of 3
`
`'
`
`_
`
`FDA CDER EES
`
`ESTABLISHMENT EVALUATION REQUEST
`
`SUMMARY REPORT
`
`Profile
`
`:
`
`CTL
`
`OAI Status:
`
`NONE
`
`Last Milestone:
`
`OC RECOMMENDATION
`
`Milestone Date:
`
`24—OCT-07
`
`Decision
`
`Reason
`
`:
`
`':
`
`ACCEPTABLE
`
`BASED ON PROFILE
`
`Establishment
`
`:
`
`CFN :
`
`~mwwm~ww
`
`FEI
`
`:
`
`.uuwmwmmu.
`
`[5—
`
`DMF NO:
`
`AADA:
`
`by“
`
`Responsibilities:
`
`~,—»mw_~——~—-———————¥——
`
`Profile
`
`:
`
`CRU
`
`OAI Status:
`
`NONE
`
`Last Milestonez'
`
`.
`
`OC RECOMMENDATION
`
`Milestone Date:
`
`’
`
`21—Nov—07
`
`Decision
`
`Reason
`
`'
`
`:
`
`:
`
`ACCEPTABLE
`
`DISTRICT RECOMMENDATION
`
`Establishment
`
`:
`
`CFN :
`
`'-—-———
`
`FEI
`
`; *,l~_______
`
`11(4)
`
`

`

`DMF No:
`
`AADA:
`
`Responsibilities:
`
`M4)
`
`Profile
`
`CTL
`
`OAI Status:
`
`NONE
`
`Last Milestone:
`
`OC RECOMMENDATION
`
`Milestone Date:
`
`lO—JAN-08
`
`Decision
`
`Reason
`
`ACCEPTABLE
`
`DISTRICT RECOMMENDATION
`
`Establishment
`
`CFN
`
`.»ww*":
`
`FEI
`
`
`
`PATHEON INC.
`
`— BURLINGTON CENTURY OPERATIONS
`
`977 CENTURY DRIVE
`
`BURLINGTON, ONTARIO, CA
`
`DMF No:
`
`AADA:
`
`[1(4)
`
`Responsibilities:
`
`Profile
`
`:
`
`CTL
`
`OAI Status:
`
`NONE
`
`Last Milestone:
`
`OC RECOMMENDATION
`
`Milestone Date:
`
`24—OCT—07
`
`Decision
`
`ACCEPTABLE
`
`Reason
`
`BASED ON PROFILE
`
`Establishment
`
`CFN
`
`‘,memm-
`
`FEI
`
`*-*-—~*-_WW
`
`PATHEON INC; - TORONTO REGION OPERATIONS
`
`2100 SYNTEX COURT
`
`

`

`MISSISSAUGA, ONTARIO, CA
`
`DMF No:
`
`.
`
`AADA:
`
`APPEARS THIS WAY ON ORIGINAL
`
`

`

`O6~APR—2009
`
`Page 3 of 3
`
`FDA CDER EES
`
`ESTABLISHMENT EVALUATION REQUEST
`
`SUMMARY REPORT
`
`Responsibilities:
`
`FINISHED DOSAGE MANUFACTURER
`
`Profile
`
`TCM
`
`OAI Status:
`
`NONE
`
`Last Milestone:
`
`OC RECOMMENDATION
`
`Milestone Date:
`
`21-NOV-07
`
`Decision
`
`:
`
`ACCEPTABLE
`
`DISTRICT RECOMMENDATION
`
`___________________.__..____.______._.__._____.____.______._________.___.___.__._..____________ __
`
`Establishment
`
`' DMF NO:
`
`AADA:
`
`M4)
`
`Responsibilities:
`
`Profile
`
`. CTL
`
`OAI Status:
`
`NONE
`
`Last Milestone:
`
`OC RECOMMENDATION
`
`Milestone Date:
`
`ll—JAN-O8
`
`Decision
`
`Reason
`
`ACCEPTABLE
`
`DISTRICT RECOMMENDATION
`
`Establishment
`
`

`

`DMF No:
`
`'
`
`'
`
`AADA:
`
`Responsibilities:
`
`{—
`
`11(4)
`
`13(4)
`
`.J
`
`Profile
`
`:
`
`fla—
`
`OAI Status:
`
`NONE
`
`Last Milestone:
`
`OC RECOMMENDATION
`
`Milestone Date:
`
`21—Nov—07
`
`Decision
`
`Reason
`
`:
`
`:
`
`ACCEPTABLE
`
`DISTRICT RECOMMENDATION
`
`Establishment
`
`:
`
`CFN : M
`
`FEI
`
`:
`
`~«-~~—..._....._
`
`DMF No:
`
`AADA:
`
`[1(4)
`
`Responsibilities:
`
`1-—————————————-f—-‘-*-A=~~w~
`
`Profile
`
`I:
`
`~m»
`
`OAI Status:
`
`NONE
`
`Last Milestone:
`
`OC RECOMMENDATION
`
`Milestone Date:
`
`24—OCT—07
`
`Decision
`
`:
`
`ACCEPTABLE
`
`

`

`Reason
`
`:
`
`BASED ON FILE REVIEW
`
`APPEARS THIS WAY ON ORIGINAL
`
`