CENTER FOR DRUG EVALUATION AND
`
`RESEARCH
`
`APPLICA TION NUMBER:
`
`21-880
`
`CHEMISTRY REVIEwgS)
`
`

`

`NDA 21—880
`
`RevlimidTM
`
`(Lenalidomide)
`
`Celgene Corporation
`
`Haripada Sarker, Ph.D.
`HFD-150 Division of Oncology
`
`

`

`CHEMISTRY REVIEW
`
`N21-880 CR#l
`
`Table of Contents
`
`..................................................................... 2
`
`Chemistry Review Data Sheet.................................................................................3
`
`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.
`
`7
`Summary of Chemistry Assessments
`A. Description of the Drug Product(s) and Drug Substance(s) .............................. L .............................. 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
`
`8
`
`A. Reviewer’s Signature ........................................................................................................................ 8
`
`B. EndorsementBlock..................._...............: ...................................................................................... 8
`
`C. CC Block .......................................................................................................................................... 8
`
`Chemistry Assessment ........................................................................ '.....................9
`
`

`

`
`
`N21—880 CR#I
`
`Executive Summary Section
`
`Chemistry Review Data Sheet
`
`1. NDA 21—880
`
`2. REVIEW #1:
`
`3. REVIEW DATE: 12—05—2005
`
`4. REVIEWER: Haripada Sarker, Ph.D.
`
`6. PREVIOUS DOCUMENTS:
`
`Previous Documents
`
`IND 60,100
`n—§
`
`,
`
`Document Date
`
`March 31, 2000
`—/
`_’
`;
`
`1. SUBMISSION(S) BEING REVIEWED:
`
`Submission 5 Reviewed
`
`Original (RRZ—OO l) —rolling
`Amendment (N—000) — Labeling
`Amendment (N—000—BC) — DP stability and spec. update
`Amendment (N-000—BC) — DP dissolution update
`Amendment (N—000—BC) — DS and DP Stability
`Amendment (N—000)C ~ DP Labeling
`
`Document Date
`
`December 22, 2004
`
`Apn'l 7, 2005
`May 17, 2005
`August 25, 2005
`September 30, 2005
`October 27, 2005
`
`7. NAME & ADDRESS OF APPLICANT:
`
`Name:
`
`Address:
`
`Representative:
`
`Celgene Corporation
`
`86 Morris Avenue
`
`Summit, NJ 07901
`
`_ Gretchen Toolan
`
`

`

`
`
`N21 —880 CR#1
`
`Executive Summary Section
`
`Telephone:
`
`908—673—9551
`
`8. DRUG PRODUCT NAME/CODE/TYPE:
`
`a) Proprietary Name: RevlimidTM
`b) Non-Proprietary Name: Lenalidomide
`c) Code Name/#: CC—5013, CDC—501, Revlimid
`d) Chem. Type/Submission Priority (ONDC only):
`
`0 Chem. Type:
`
`1
`
`0 Submission Priority: P
`
`e) ProposedvTrade Name: RevlimidT'M
`
`9. LEGAL BASIS FOR SUBMISSION: N/A
`
`10. PHARMACOL. CATEGORY: Transfusion—Dependent Anemia Due to Low— or
`Intennediate—l—Risk Myelodysplastic Syndroms Associated with a Deletion Sq Cytogenetic
`Abnormality.
`
`ll. DOSAGE FORM:
`
`Capsule
`
`12. STRENGTH/POTENCY:
`
`5 mg and 10 mg
`
`13. ROUTE OF ADMINISTRATION: Oral
`
`14. Rx/OTC DISPENSED:
`
`X Rx
`
`OTC
`
`15. SPOTS gSPEClAL PRODUCTS ON-LINE TRACKING SYSTEM}:
`
`SPOTS product — Form Completed
`
`
`X Not a SPOTS product
`
`16. CHEMICAL NAME, STRUCTURAL FORMULA, MOLECULAR FORMULA,
`MOLECULAR WEIGHT:
`
`Structure:
`
`

`

`
`
`N2 1 -880 CR#1
`
`Executive Summary Section
`
`HN
`
`. O
`
`fire
`
`NH2
`
`Name (drug substance)
`Chemical Name (CAS)
`
`CAS number
`
`Molecular Weight
`Molecular Formula
`Structural formula
`
`Lenalidomide (USAN Name)
`3—(4’—amino— l ,3-dihydro— l -oxo—2H-isoindol—2—yl)—2,6—
`piperidinedione
`»
`191732—72-6
`
`259.25
`C13HI3N303
`As above
`
`17. RELATED/SUPPORTIN G DOCUMENTS:
`
`A. DMFS:
`
`
`
`
`ITEM
`
`STATUS
`DMF #
`TYPE
`HOLDER
`REFERENCED
`CODE
`
`
`1
`
`2
`
`DATE
`
`REVIEW
`COM—
`PLETED
`
`
`
`N/A
`
`4
`
`4
`
`/
`,
`
`'
`
`//
`
`/
`
`/
`
`III
`
`
`III
`
`III
`
`w
`
`:
`.
`
`1
`
`|
`
`l
`
`|
`
`/
`
`/
`
`/
`
`/
`
`.
`
`l
`
`l
`
`I l 1
`
`N/A
`
`
`N/A
`
`COMMENTS
`
`Not reviewed
`
`Not reviewed
`
`
`Not reviewed
`N/A
`
`
`
`I/
`
`4
`
`I
`
`
`
`Not reviewed
`
`1 Action codes for DMF Table:
`l — DMF Reviewed.
`
`Other codes indicate why the DMF was not reviewed, as follows:
`2 ~Type l 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") I
`
`

`

`
`
`N2 l -880 CR#l
`2 Adequate, Inadequate, or N/A (There is enough data in the application, therefore the DMF did not
`need to be'reviewed)
`
`Executive Summary Section
`
`B. Other Documents: None
`
`18. STATUS:
`
`ONDC: To be filled later
`CONSULTS/ CMC
`RELATED REVIEWS
`RECOMMENDATION
`DATE
`REVIEWER
`
`
`EES
`Acceptable
`l—AUG-OS
`J. D. Ambrogio V
`
`
`Pharm/Tox
`Acceptable with comment
`~
`5-Oct-05
`Anwar Goheer
`
`Biophann
`Acceptable
`9—SEPT-05
`Gene William
`
`
`DMETS
`Acceptable with comment
`2—June-05
`Kimberly Culley
`
`Methods Validation
`May be requestedpostflpproval
`Ha_ripada Sarker
`EA (Categorical
`acceptable
`3-Nov-05
`Haripada Sarker
`Exclusion)
`
`
`Microbiology N/A N/A
`
`
`

`

`
`
`Executive Summary Section
`
`N2l-880 CR#l
`
`The Chemistry Review for NBA 21-649
`
`The Executive Summary
`
`I. Recommendations
`
`A. Recommendation and Conclusion on Approvability
`
`This application is recommended for APPROVAL from a chemistry, manufacturing and
`controls standpoint because:
`
`The applicant addressed all the deficiencies satisfactorily. The applicant has validated the
`analytical methods for specified impurities and degradants. The office of compliance has
`provided an overall acceptable recommendation (see attached). The following comments
`regarding retest for the drug substance and shelf—life for the drug product should be included in
`the action letter:
`
`for the drug substance and a shelf—life'of twenty four
`-—
`“A retest period of
`months for the drug product will be granted based On stability data provided”
`
`B. Recommendation on Phase 4 (Post-Marketing) Commitments, Agreements, and/or
`Risk Management Steps, if Approvable.
`N/A
`
`II. Summary of Chemistry Assessments
`
`A. Description of the Drug Product(s) and Drug Substance(s)
`
`Revlimid® (lenalidomide) is formulated as capsules and is supplied in 5 mg and 10 mg
`strengths. Lenalidomide is the active ingredient. Inactive ingredients include lactose
`anhydrous, microcrystalline cellulose, croscarmellose sodium, and magnesium stearate. The 5
`mg capsule shell contains gelatin, titanium dioxide and black ink. The 10 mg capsule shell
`contains gelatin, yellow iron oxide, titanium oxide and black ink. The drug product is stored at
`25 °C (77 °F); excursions permitted to 15-30 °C (59-86 °F). [See USP Controlled Room
`Temperature]. The applicant proposed 24 months of shelf—life for the drug product. Based on
`primary and supportive stability data, an expiration dating period of 24 months may be granted.
`
`The chemical name for lenalidomide is 3—(4—amino—I,3-dihydro—l~oxo—2H—isoindol—2—yl)~2,6—
`piperidinedione. The molecular formula of lenalidomide is C13H13N3O3 with a molecular
`weight of 259.25. Lenalidomide possess piper-idindione and indoline moieties. It has an
`asymmetric center and is manufactured as racematic mixtures. Lenalidomide bears an amino
`function on its aromatic ring system which contributes to its lower lipid solubility. — 7‘
`.._.—
`
`’f
`
`. Two different HPLC methods are utilized for better
`
`

`

`
`
`N21-880 CR#1
`
`Executive Summary Section
`
`separation of the impurities and degradants in drug substance. Validations reports are provided
`for both the methods. Impurities in drug product are mostly carried over from the drug
`substance. Celgene provided real time stability test data on two drug substance batches over the
`period of " and photostability data on one batch over / Celgene has proposed
`a retest period of »
`for the drug substance. Based on provided real time stability data a
`retest period of
`/
`may be granted.
`
`B. Description of How the Drug Product is Intended to be Used
`
`REVLIMID® is supplied as white opaque capsules imprinted “REV” on one half and “5 mg”
`on the other‘half in black ink.. For 10 mg capsules, blue/green and pale yellow opaque capsules
`imprinted “REV” on one half and “10 mg” on the other half in black ink. Both 5 mg and 10 mg
`capsules are packaged in bottles of 30 and 100 counts.
`
`C. Basis for Approvability Recommendation
`
`This application is recommended for APPROVAL from the stand point of chemistry,
`manufacturing and controls because all the deficiencies have been satisfactorily addressed and
`the office of compliance has provided an overall acceptable recommendation (see attached).
`The following comments regarding retest for the drug substance and shelf—life for the drug
`product should be included1n the action letter.
`
`for the drug substance and a shelf—life of twenty four
`-/
`“A retest period of ’
`months for the drug product will be granted based on stability data provided”.
`
`Administrative
`
`A. Reviewer’s Signature
`
`B. Endorsement Block
`
`ChemistName/Datef Haripada Sarker, Ph.D.
`ChemistryTeamLeaderName/Date: Nallaperumal Chidambaram, PhD.
`ProjectManagerName/Date: Carl Huntley
`
`C. CC Block
`
`

`

`11 Page(s) Withheld
`
`___/§552(b)(4). Trade SeCret / Confidential
`
`_ § 552(b)(5) Deliberative Process
`
`‘
`
`_.-_ V§ 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.
`'
`
`Haripada Sarker
`12/5/2005 03:30:12 PM
`CHEMIST
`
`Nallaperumal Chidambaram
`12/5/2005 04:56:53 PM
`CHEMIST
`
`'
`
`