CENTER FOR DRUG EVALUATION AND
`
`RESEARCH
`
`APPLICA TION NUMBER:
`
`2 1 - 1 9 6
`
`CHEMISTRY REVIEWg S)
`
`

`

`DIVISION OF NEUROPHARMACOLOGICAL DRUG PRODUCTS, HFD-120
`REVIEW OF CHEMISTRY, MANUFACTURING, AND CONTROLS
`
`NDA 21-196
`
`CHEM. REVIEW #5
`
`REVIEW DATE 03-JUN-02
`
`SUBMISSION TYPE
`AMENDMENT
`
`DOCUMENT DATE
`16-MAY-02
`
`CDER DATE
`17-MAY-02
`
`ASSIGNED DATE
`21-MAY—02
`
`NAME AND ADDRESS OF APPLICANT
`
`DRUG PRODUCT NAME
`
`Orphan Medical, Inc.
`13911 Ridgedale Drive, Suite 250
`Minnetonka, MN 55305
`
`Proprietary:
`Nonproprietary/USAN [1966]:
`Code Name/Number:
`
`Xyrem® oral solution
`sodium oxybate
`
`Chem. Type/Ther. Class:
`
`1P
`
`PHARMACOLOGICAL CATEGORY/INDICATION
`
`DOSAGE FORM
`
`STRENGTHS
`ROUTE OF ADMINISTRATION
`
`DISPENSED
`SPECIAL PRODUCTS
`
`Reduce the incidence of cataplexy and to improve the
`symptom of daytime sleepiness in patients with
`narcolepsy
`Oral Solution
`
`500 mg/mL
`Oral
`
`___OTC
`2(_X_2(_ RX
`__ Yes & NO
`
`CHEMICAL NAME, STRUCTURAL FORMULA, MOLECULAR FORMULA
`Sodium 4-hydroxybutyrate
`4-Hydroxybutanoic acid monosodium salt
`
`Sodium gamma hydroxybutyrate
`C4H7Na03
`Mol. Wt. 126.09
`CAS Registry #: 502—85-2
`
`0
`
`+ _ /”\/\/OH
`Na 0
`sodium oxybate
`
`SUPPORTING DOCUMENTS: IND --—— IND '— (Treatment IND) and 12 packaging DMF’s
`RELATED DOCUMENTS: None
`CONSULTS: None
`
`REMARKS/COMMENTS: The sponsor has requested a 36-month expiry. The sponsor has submitted updated
`drug product stability from 6 drug product batches manufactured at r--’_'“
`and 4 drug product batches
`produced at
`\———.
`. All batches were easily within specification. The impurity levels do not increase upon
`storage at 25°C: \— .
`
`CONCLUSIONS 8: RECOMMENDATIONS: The reguested tentative expiry of 36 months is acceptable.
`
`cc: Orig. NDA 21-196
`HFD-120
`HFD-1 20/TOliver
`HFD-120lPM/AMHomonnay
`HFD-120/MGuzewska
`
`R/D lnit by: MEG
`
`
`
`__________
`Thomas F. Oliver, Ph.D., Chemist
`
`Filename: n21196.05
`
`

`

` 2 page(s) have been
`removed because it
`
`contains trade secret
`
`and/or confidential
`
`information that is not
`
`disclosable.
`
`

`

`This is a representation of an electronic record that was signed electronically and
`this page is the manifestation of the electronic signature.
`
`/S/
`
`Thomas Oliver
`
`6/3/02 01:44:43 PM
`CHEMIST
`
`Maryla Guzewska
`6/3/02 01:49:00 PM
`CHEMIST
`
`

`

`CHEMISTRY REVIEW
`
`NDA 21-196
`
`Xyrem® (sodium oxybate) oral solution
`
`Orphan Medical, Inc.
`
`Chemistry Review
`
`Thomas F. Oliver, Ph.D.
`
`HFD-120
`
`

`

`CHEMISTRY REVIEW
`
`Table of Contents
`
`Table of Contents ............................................................................................................................2
`
`Chemistry Review Data Sheet ...........................................................................................................3
`
`ew~‘*"“‘““"“—~$M~
`
`
`
`Page 2
`
`

`

` CHEMISTRY REVIEW
`
`CHEMISTRY NDA REVIEW DATA SHEET
`
`0
`+')'\/\/OH
`NaO
`sodium oxybate
`
`wewwé
`
`NDA 21-196 (Xyrem®, sodium oxybate)
`CHEM. REVIEW #4
`REVIEW DATE: 21-MAR-2002
`REVIEWER:
`Thomas F. Oliver, Ph.D
`
`PREVIOUS DOCUMENTS
`Previous Documents
`
`Original
`Telecon (t01)
`Amendment
`Review #1
`
`Telecon (t02)
`Telecon (103)
`Amendment
`Amendment
`
`Telecon (104)
`Amendment
`
`Telecon (t05)
`Amendment
`Amendment
`Amendment
`
`Telecon (t06)
`Review #2
`Amendment
`Amendment
`Amendment
`
`Telecon (t07)
`Amendment
`Review #3
`
`Telecon (108)
`
`Document Date
`30—SEP-2000
`05-DEC-2000
`O7-DEC-2000
`09-FEB-2001
`08—JAN—2001
`10-JAN-2001
`12-JAN-2001
`19-JAN-2001
`25—JAN-2001
`26-JAN-2001
`O1-FEB-2001
`06—FEB-2001
`08-FEB-2001
`15-FEB—2001
`OZ-MAR—2001
`19-MAR—2001
`16—MAR—2001
`12-APR-2001
`16—MAY-2001
`08—JUN-01/ 13-JUN-2001
`18-JUN-2001
`21-JUN-2001
`15—OCT-2001
`
`SUBMISSION BEING REVIEWED:
`Submission Reviewed
`Amendment
`
`Document Date
`07-Nov-2001
`
`NAME AND ADDRESS OF APPLICANT
`
`DRUG PRODUCT NAME
`
`Proprietary:
`NonproprietarleSAN [1966]:
`Code Name/Number:
`
`Chem. Type/Ther. Class:
`
`LEGAL BASIS FOR SUBMISSION
`
`Orphan Medical, lnc.
`13911 Ridgedale Drive, Suite 250
`Minnetonka, MN 55305
`Dr. Dayton Reardan
`(952) 513—6969
`
`Xyrem® oral solution
`sodium oxybate
`
`1P
`
`N/A
`
`10.
`
`PHARMACOLOGICAL CATEGORY/INDICATION
`
`Reduce the incidence of cataplexy and to
`improve the symptom of daytime sleepiness in
`patients with narcolepsy
`
`Page 3
`
`

`

`
`
`CHEMISTRY REVIEW
`
`11.
`12
`13.
`14.
`15.
`
`16.
`
`DOSAGE FORM
`STRENGTHS
`ROUTE OF ADMINISTRATION
`DISPENSED
`
`SPOTS (SPECIAL PRODUCTS ON-LINE TRACKING SYSTEM)
`
`Oral Solution
`
`500 mg/mL
`Oral
`
`w RX
`__ Yes
`
`~__OTC
`)_Q<_)$ NO
`
`CHEMICAL NAME, STRUCTURAL FORMULA, MOLECULAR FORMULA
`Sodium 4-hydroxybutyrate
`C4H7N303
`Mol. Wt. 126.09
`CAS Registry #: 502-85-2
`
`RELATED/ SUPPORTING DOCUMENTS:
`A. DMF’s:
`
`0
`
`+'/U\/VOH
`
`NaO
`
`sodium oxybate
`
`
`
`Page 4
`
`

`

`CHEMISTRY REVIEW
`
`1Action codes for DMF Table:'
`1v—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”)
`
`2Adequate. Inadequate
`
`B. Other Documents
`
`‘D‘agujifiefita:
`
`Treatment lND Orhan Medical, Inc
`
`e{sct
`‘5‘»
`9
`Applicatiéfiéit
`W Commercnal lN Or han Medical, Inc
`
`18.
`
`STATUS
`
`Consults] CMC Related Revrews
`
`
`
`Recom'iiiefifdation’?” '
`
`'
`
`:
`
`'
`
`
`
`
`
`
`
`
`
`
`
`
`——_——
`
`Pharm/Tox
`
`
`
`
`Categorical exemption:
`
`
`<1ppb in aquatic
`environment
`
`
`
`Acceptable
`
`02-FEB—01
`
`
`
`Dr. Barr Rosloff
`
`
`
`
`

`

`Page 5
`
`APPEARS {HES WAY
`
`0%! 0313mm.
`
`APPEARS THIS WAY
`0N GRIGINAL
`
`APPEARS WES WAY
`0N GRMEWAL
`
`

`

`i page(s) have been
`removed because it
`
`contains trade secret
`
`and/or confidential
`
`information that is not
`
`disclosable.
`
`

`

`DIVISION OF NEUROPHARMACOLOGICAL DRUG PRODUCTS, HFD—120
`REVIEW OF CHEMISTRY, MANUFACTURING, AND CONTROLS
`
`SUMMARY REVIEW
`
`NDA 21-196
`
`CHEM. REVIEW # 4
`
`REVIEW DATE 22-MAR-02
`
`SUBMISSION TYPE
`AMENDMENT
`
`DOCUMENT DATE
`07-NOV-01
`
`CDER DATE
`08-Nov-01
`
`ASSIGNED DATE
`08-Nov-01
`
`NAME AND ADDRESS OF APPLICANT
`
`DRUG PRODUCT NAME
`
`Orphan Medical, Inc.
`13911 Ridgedale Drive, Suite 250
`Minnetonka, MN 55305
`
`Proprietary:
`Nonproprietary/USAN [1966]:
`Code Name/Number:
`
`Xyrem® oral solution
`sodium oxybate
`
`Chem. Type/Ther. Class:
`
`1P
`
`PHARMACOLOGICAL CATEGORY/INDICATION
`
`DOSAGE FORM
`
`STRENGTHS
`ROUTE OF ADMINISTRATION
`
`DISPENSED
`
`SPECIAL PRODUCTS
`
`Reduce the incidence of cataplexy and to Improve the
`symptom of daytime sleepiness in patients with nacrolepsy
`Oral Solution
`
`500 mg/mL
`Oral
`
`KM RX
`
`___OTC
`
`Yes
`
`‘ m NO
`
`CHEMICAL NAME, STRUCTURAL FORMULA, MOLECULAR FORMULA
`Sodium 4-hydroxybutyrate
`4-Hydroxybutanoic acid monosodium salt
`
`Sodium gamma hydroxybutyrate
`C4H7Na03
`MO'. Wt.12609
`CAS Registry #: 502—85-2
`
`0
`
`+ _ /U\/VOH
`Na 0
`sodium oxybate
`
`SUPPORTING DOCUMENTS: IND v" , IND - (Treatment IND) and 12 packaging DMF’s
`RELATED DOCUMENTS: None
`"
`
`CONSULTS: The proposed trademark “Xyrem” was found acceptable by the Office of Post-Marketing Drug Risk
`Assessment (OPDRA) on 27-JAN-00. Compliance gave an overall recommendation of acceptable on 06—Nov-
`01. Microbiology found the NDA acceptable (see microbiology review #2, Dr. Neal Sweeney). The MV package is
`being prepared.
`
`REMARKS/COMMENTS: The only CMC issue left unresolved from review #3 was the need for a successful re-
`Inspection of the drug product manufacturing site, -. ~—-———/
`site (only drug product manufacturer).
`Compliance found the site acceptable and gave an overall recommendation of acceptable on 06-Nov-01 (see
`attached EER report). The sponsor’s reguested 30 month expiry has been granted.
`
`CONCLUSIONS & RECOMMENDATIONS: Recommend NDA 21—196 be approved.
`
`cc: Orig. NDA 21-196
`HF D-1 20
`HFD-120/TOliver
`HFD-120/PM/AMHomonnay
`HFD-120/MGuzewska
`
`R/D lnit by: MEG
`
`___________________________
`Thomas F. Oliver, Ph.D., Chemist
`
`Filename: n21196.04.NDA.chemistrytemplate
`
`

`

`__(L page(s) have been
`removed because it
`
`contains trade secret
`
`and/or confidential
`
`information that is not
`
`disclosable.
`
`

`

`NDA 21-196
`27—MAR—2002
`
`, Xyrem (sodium oxybate)
`FDA CDER EES
`ESTABLISHMENT EVALUATION REQUEST
`SUMMARY REPORT
`
`Orphan Medical.
`
`,
`
`16
`Page 1 of 2
`
`Application
`Org Code
`Priority
`
`: NDA
`120
`1P
`
`21196/00
`'
`
`VSponsor:
`
`VORPHAN MEDCL
`13911 RIDGEWAY DR STE 250
`MINNETONKA, MN
`55305
`
`"Stamp Date
`PDUFA Date
`
`02-OCT-2000
`09-APR-2002
`
`Action Goal
`District Goal: Ol-FEB-ZOOI
`
`iBrand Name
`
`:
`
`‘XYREM (SODIUM OXYBATE)
`SOOMG/ML ORAL SOL
`
`Estab. Name:
`Generic Name:
`Dosage Form:
`Strength
`:
`
`‘
`
`SODIUM OXYBATE
`(SOLUTION)
`500 MG/ML
`
`FDA Contacts:
`
`A. HOMONNAY WEIKEL
`T. OLIVER
`M GUZEWSKA
`
`Project Manager
`Review Chemist
`Team Leader
`
`(RFD-120)
`(RFD-810)
`(HFD‘120)
`
`301-594-5535
`301-594—2570
`301-594—5571
`
`Overall Recommendation:
`
`ACCEPTABLE on 06-NOV-2001by J. D AMBROGIO(HFD-324) 301-827-
`0062
`
`WITHHOLD
`
`on 22-MAR-2001by P. LBFLER(HFD-324) 301-827-0062
`
`Establishment :'
`
`VDMF NO: W
`
`Responsibilities:
`
`r—_—~‘
`
`7 Profile
`Last Milestone:
`Milestone Date:
`Decision
`Reason
`
`Establishment
`
`:
`
`A————
`OC RECOMMENDATION
`13-OCT-00
`ACCEPTABLE
`BASED ON PROFILE
`
`OAI Status:
`
`'DMF No:
`
`’AADA
`
`'Responsibilities:
`
`RE
`'-'”“‘_"_-——_—___———“‘—--A
`
`AProfile
`Last Milestone:
`Milestone Date:
`Decision
`Reason
`
`
`
`0C RECOMMENDATION
`06-Nov-01
`ACCEPTABLE
`DISTRICT RECOMMENDATION
`
`'OAI Status:
`
`

`

`M 0
`
`C RECOMMENDATION
`06-NOV‘01
`ACCEPTABLE
`DISTRICT RECOMMENDATION
`
`NDA 21-196
`27-MAR-2002
`
`Profile
`Last Milestone:
`Milestone Date:
`Decision
`Reason
`
`:
`
`Establishment
`
`:
`
`iXyrem (sodium oxybale)
`FDA CDER EES
`ESTABLISHMENT EVALUATION REQUEST
`SUMMARY REPORT
`
`Orphan Medical.
`
`7
`
`17
`Page 2 of 2
`
`OAI Status:
`
`OAI Status:
`
`ANONE
`
`DMF NO:
`
`'AADA:
`
`VResponsibilities:
`
`:
`Profile
`Last Milestone:
`Milestone Date:
`Decision
`Reason
`
`:
`
`Establishment
`
`M
`
`f.“
`
`0C RECOMMENDATION
`19—MAR-01
`ACCEPTABLE
`DISTRICT RECOMMENDATION
`
`VDMF No:
`
`'AADA:
`
`VResponsibilities:
`
`___—-__________________.
`
`Profile
`Last Milestone:
`Milestone Date:
`Decision
`Reason
`
`V
`
`0c RECOMMENDATION
`
`28—Nov-00
`ACCEPTABLE
`DISTRICT RECOMMENDATION
`
`’OAI Status:
`
`

`

`This is a representation of an electronic record that was signed electronically and
`this page is the manifestation of the electronic signature.
`-——--------—-----—--—----——-----——-—-—------—-----------------—-----———-------_--_-------------_----_--..............
`
`Thomas Oliver
`
`3/29/02 10:48:52 AM
`CHEMIST
`
`Hasmukh Patel
`
`3/29/02 10:54:37 AM
`CHEMIST
`
`

`

`DIVISION OF NEUROPHARMACOLOGICAL DRUG PRODUCTS, HFD-120
`REVIEW OF CHEMISTRY, MANUFACTURING, AND CONTROLS
`
`NDA 21-196
`
`CHEM. REVIEW #3
`
`REVIEW DATE 21-JUN-01
`
`SUBMISSION TYPE
`AMENDMENT
`AMENDMENT
`AMENDMENT
`AMENDMENT
`
`DOCUMENT DATE
`16—MAR-01
`12-APR-01
`16-MAY-01
`18-JUN-01
`
`CDER DATE
`20-MAR—01
`13-APR-01
`17-MAY—01
`19-JUN—O1
`
`ASSIGNED DATE
`20—MAR-O1
`13—APR—01
`22-MAY-01
`19—JUN-O1
`
`NAME AND ADDRESS OF APPLICANT
`
`DRUG PRODUCT NAME
`
`Orphan Medical, Inc.
`13911 Ridgedale Drive, Suite 250
`Minnetonka, MN 55305
`
`Proprietary:
`Nonproprietary/USAN [1966]:
`Code Name/Number:
`Chem. Type/Ther. Class:
`
`-
`
`Xyrem® oral solution
`sodium oxybate
`
`1P
`
`PHARMACOLOGICAL CATEGORY/INDICATION
`
`DOSAGE FORM
`STRENGTHS
`ROUTE OF ADMINISTRATION
`DISPENSED
`SPECIAL PRODUCTS
`
`.
`
`Reduce the incidence of cataplexy and to improve the
`symptom of daytime sleepiness in patients with narcolepsy
`Oral Solution
`500 mg/mL
`Oral
`& RX
`. _OTC
`Yes w NO
`
`CHEMICAL NAME, STRUCTURAL FORMULA, MOLECULAR FORMULA
`Sodium 4-hydroxybutyrate
`4-Hydroxybutanoic acid monosodium salt
`Sodium gamma hydroxybutyrate
`Mol. Wt. 126.09
`C4H7Na03
`CAS Registry #: 502-85-2
`
`O
`+ _ /u\/\/OH
`Na 0
`sodium oxybate
`
`SUPPORTING DOCUMENTS: IND v IND —’ (Treatment IND) and 12 packaging DMF's
`RELATED DOCUMENTS: None
`
`CONSULTS: The proposed trademark “Xyrem” was found acceptable by the Office Of Post-Marketing Drug Risk
`Assessment (OPDRA) on 27-JAN-OO. The EER was reduested on 02—OCT-00 and the overall recommendation
`is withhold (copy attached). A microbiology consult was requested 19-JAN-01 and Dr. Neal Sweeney found
`microbiology acceptable (see review dated 23-MAY—01). The MV package is being prepared.
`
`
`(drug product manufacturer) received a warning letter
`—
`REMARKS/COMMENTS:
`24JAN-01, which detailed numerous CGMP deviations \__., will remain unacceptable until a re-inspection
`can verify the firm'5 corrective actions.
`/———- anticipates being ready for inspectionIn late July 2001.
`The sponsor has provided only two batches with 9 months and one batch with 12 months of long term stability
`data for drug product produced at the i #1 site. The sponsor proposed a 36 month expiry but the data
`supports a tentative expiry of~ months. Amendment dated 12-APR-01 provided responses to Microbiology’3
`deficiencies and was found acceptable by Dr Neal Sweeney (see microbiology review dated 23-M-AY—01).As a
`result, microbial testing has been added to the drug product release protocol (see p. 2 Of this review for final drug
`product Specifications) and the stability protocol has been updated (see pp. 8—9 of this review).
`It Should be noted
`the dosing cup does not have a line to fill to, which could be confusing to a patient. The issue has been brought to
`the attention Of Dr. Ranjit Mani (clinical reviewer).
`
`CONCLUSIONS & RECOMMENDATIONS: Not approvable based on the EER overall withhold recommendation.
`
`cc: Orig. NDA21-196
`HFD-120
`HFD- 120r1'OlIver
`HFDIzo/PM/AMHomol
`HFD-120/MGuzewslr/(w1 ‘
`RID lnit by: MEG
`
`0\
`
`/
`8/.
`
`Thomas F. Oliver, Ph.D., Chemist
`
`Filename: n21196.03
`
`

`

`‘ i page(s) have been
`removed because it
`
`contains trade secret
`
`and/or confidential
`
`information that is not "
`
`disclosable.
`
`

`

`NDA 21—196 ,
`21-Jun-2001
`
`Xyrem (sodium oxybate)
`FDA CDER EES
`ESTABLISHMENT EVALUATION REQUEST
`SUMMARY REPORT
`
`Orphan Medical.
`
`Page
`
`11
`of
`
`,
`NDA 211961000
`Application:
`Stamp: 02-OCT-2000 Regulatory Due: 02-JUL-2001
`Applicant:
`ORPHAN MEDCL
`
`Priority: 1?
`Action Goal:
`Brand Name:
`
`Org Code: 120
`District Goat 111-333.2001
`XYREM (SODIUM OXYBATE)
`SOOMGIML ORAL SOL
`Established Name:
`
`Genetic Name: SODIUM OXYBATE
`
`Dosage Four:
`Strength:
`
`SOL (SOLUTION)
`500 MG/ML
`
`FDA Comets:
`
`A. HOMONNAY WEIKEL (111mm)
`T. OLIVER
`(RFD-810)
`
`
`
`
`M. GUZEWSKA
`
`(RFD-120)
`
`301-594-5535 , Project Manager
`2501-5944570 , Review Chemist
`
`301-594-5571
`
`, Team Leader
`
`Overall Recommendation:
`
`EITHHOLD on 22-MAR—2001bv P. ALCOCK(RFD-329301-8210062
`
`Establishmnt: VW DMF No:
`‘
`AADA No:
`
`M
`
`0A1 Status: NONE
`Profile: /——-
`a
`‘
`Last Milestone: 0C RECOMMENDATION
`
`Milestone Date: 13-0CT-2000
`Decision:
`ACCEPTABLE
`Reason:
`BASED ON PROFILE
`
`Responsflailities:
`
`w\
`
`WA
`,-—————————\
`
`
`Establishment:
`
`DMF No:
`-
`O
`N I AADA No:
`
`\
`
`Profile: f“ 0A1 Status: 0A1 ALERT
`Responsibilities:
`Last Milestone: 0C RECOMMENDATION A
`Milestone Date: 13-OCT-zooo
`Decision:
`ACCEPTABLE
`
`Reason:
`Profile:
`
`BASED ON PROFILE w z
`0A1 Status: 0A1 ALERT
`
`.-—"
`
`Last Milestone: 0C RECOMMENDATION
`Milestone Date: 22-MAR—2001
`
`Decision:
`‘
`Reason:
`
`WITHHOLD
`
`DISTRICT RECOMMENDATION
`
`WARNING LETTER ISSUED
`
`
`Establishment
`
`DMF No
`
`w
`
`

`

`NDA 21-196
`
`Xyrem (sodium oxybate)
`
`_
`
`Orphan Medical.
`
`12
`
`21-JUN—2001
`
`‘
`
`FDA CDER EES
`
`'Page
`
`'2 of
`
`ESTABLISHMENT EVALUATION REQUEST
`SUMMARY REPORT
`
`
`
`OAI Status: NONE
`‘Profilc:
`Last Milestone: OC RECOMMENDATION
`
`Milestone Date: 19-MAR—2001
`Decision:
`ACCEPTABLE
`
`‘
`
`Reason:
`
`DISTRICT RECOMNIENDATION
`
`'ReSponsibilitiesw
`
`Establishment:
`
`,———————-‘.
`A
`
`HA
`
`-DMF No:
`AADA No:
`
`
`
`0A1 Status: NONE
`Profile:
`Last Milestone: 0C RECOMMENDATION
`
`Milestone Date: 28—Nov-2000
`Decision:
`ACCEPTABLE
`
`Reason:
`
`DISTRICT RECOMMENDATION
`
`_RCSPonsibi1itics= fl
`
`, ”
`
`

`

`DIVISION OF NEUROPHARMACOLOGICAL DRUG PRODUCTS. HFD-‘IZO
`REVIEW OF CHEMISTRY, MANUFACTURING, AND CONTROLS
`
`NDA 21 -196
`
`CHEM. REVIEW #2
`
`REVIEW DATE 19-MAR—O1
`
`SUBMISSION TYPE
`AMENDMENT
`AMENDMENT
`AMENDMENT
`AMENDMENT
`AMENDMENT
`AMENDMENT
`
`DOCUMENT DATE
`12-JAN-01
`IQ—JAN-01
`26-JAN-01
`06—FEB-O1
`08-FEB-01
`15—FEB-01
`
`CDER DATE
`16-JAN-01
`22—JAN-O1
`29-JAN-O1
`O7-FEB-01
`09-FEB—O1
`20-FEB—01
`
`ASSIGNED DATE
`16-JAN-01
`22-JAN-01
`29-JAN-01
`07-FEB-01
`12-FEB-O1
`21-FEB-01
`
`NAME AND ADDRESS OF APPLICANT
`
`DRUG PRODUCT NAME
`
`Orphan Medical, Inc.
`13911 Ridgedale Drive, Suite 250
`Minnetonka, MN 55305
`
`Proprietary:
`Nonproprietary/USAN [1966]:
`Code Name/Number:
`
`‘
`
`Xyrem® oral solution
`sodium oxybate »
`
`'
`
`Chem. Type/Ther. Class:
`
`1P
`
`PHARMACOLOGICAL CATEGORY/INDICATION
`
`DOSAGE FORM
`
`STRENGTHS
`ROUTE OF ADMINISTRATION
`
`DISPENSED
`SPECIAL PRODUCTS
`
`Reduce the incidence of cataplexy and to improve the
`symptom of daytime sleepiness in patients with narcolepsy
`Oral Solution
`
`500 mg/mL
`Oral
`
`__OTC
`529$ RX
`Yes w NO
`
`CHEMICAL NAME, STRUCTURAL FORMULA, MOLECULAR FORMULA
`Sodium 4-hydroxybutyrate
`4-Hydroxybutanoic acid monosodium salt
`
`Sodium gamma hydroxybutyrate
`C4H7N303
`MOI. Wt. 126.09
`CAS Registry #: 502-85‘2
`
`0
`+ - /U\/\/OH
`
`N3 0
`
`sodium oxybate
`
`SUPPORTING DOCUMENTS: IND —— IND —-—4
`RELATED DOCUMENTS: None
`
`(Treatment IND) and 12 packaging DMF’s
`
`CONSULTS: The proposed trademark “Xyrem” was found acceptable by the Office of Post-Marketing Drug Risk
`Assessment (OPDRA) on 27—JAN-00. The EER was requested on 02—OCT—OO (copy attached). A microbiology consult was
`requested 19-JAN—01 and Dr. Neal Sweeney found two deficiencies (see micro review dated 01-MAR-O1). The MV package
`is being prepared.
`
`was withdrawn as an alternate drug product manufacturer,
`.____._.__.——-—-——-"‘
`REMARKS/COMMENTS:
`
`which leavesW Impurity
`has been
`
`identified to be
`The impurity profiles for the toxicology and clinical batches appear
`similar, with the two most Significant imnnrities being I h -— is known to be rapidly converted to GHB in vivo.
`
`The potential site specific degradant at
`-— was not detected in any of the three —-
`hatches durino the latest time
`point analysis, which lends credence to the sponsor's claim that the peak is an artifact of .
`Only 9
`months (two batches) and 12 months (one batch) of long term stability data were provided from the
`«~— site (24 months
`
`of long term data was provided from r‘ . The sponsor has requested a
`expiry, but this is
`unacceptable at this time. The pH of the drug product Increases after insertion of the PIBA (30 and 60 day stability study).
`The pH of the drug product also increases during storage in the bottle. The sponsor has not adequately addressed the
`possible additive effect Of these events and how it would affect the impurity profile. A complete list of deficiencies and
`comments can be found on pp. 1142 of this review.
`
`CONCLUSIONS & RECOMMENDATIONS: Not approvable at this time.
`
`cc: Orig. NDA 21—196
`HFD—120
`HFD—IZOfTOIiver
`HFD—IZO/PM/AMHomonnay
`HFD-120/MGuzew
`
`R/D lnit by: ME0 I
`
`\l
`
`I ”(0‘
`
`/8/
`7V
`Thomas F. Oliver, PhiD; Chemist
`
`Filename: n21196.02
`
`

`

`_[O_ page(s) have been
`removed because it
`
`contains trade secret
`
`and/or confidential
`
`information that is not
`
`disclosable.
`
`

`

`NDA 21-196
`l9-MAR-2001
`
`Xyrem (sodium oxybate)
`
`Orphan Medical.
`FDA CDER EES
`
`14
`’Pagc
`
`or
`
`ESTABLISHMENT EVALUATION REQUEST
`
`SUMMARY REPORT
`
`_
`NDA 21196/000
`Application:
`Stamp: 02-OCT-2000 Regulatory Due: 02-APR-2001
`Applicant:
`ORPHAN MEDCL
`
`' Priority: 1P
`Action GOal:
`Brand Name:
`
`Org Code: 120
`District Goal: 01-FEB.2001
`XYREM (SODIUM OXYBATE)
`500MG/ML ORAL SOL
`
`Established Name:
`Generic Name: SODIUM OXYBATE
`
`Dosage Form‘
`Strength:
`
`SOL (SOLUTION)
`500 MG/ML
`
`_FDA Contactst A. HOMONNAY WEIKEL (HFD—120)
`
`301-594-5535 , Project Manager
`
`T. OLIVER
`
`(RFD—810)
`
`301-594-2570 , Review Chemist
`
`M. GUZEWSKA
`
`
`(HFD-120)
`301-594-5571
`, Team Leader
`
`Overall Recommendation:
`7
`A
`7
`
`
`Establishment:
`
`.
`
`DMF No:
`
`
`
`OAI Status: NONE
`'Profiie:
`Last Milestone: 0C RECOMMENDATION
`Milestone Date:
`l3-OCT-2000 /
`Decision:
`ACCEPTABLE f
`_Reason:
`BASED ON PROFILE
`
`Responsibilities: ///-‘
`
`Establishment: m DMF N03
`“a AADA No:
`
`OAI Status: OAI ALERT
`‘Profile: it:
`Last Milestone: 0C RECOMMENDATION
`Milestone Date: 13~OCT-2000
`Decision:
`ACCEPTABLE
`Reason-
`BASED ON PROFILE
`
`‘Responsibilifics=
`
`(“ii——
`
`/’/'__\
`
`OAI Status: 0A1 ALERT
`Profile: _,
`Last Milestone: DO RECOMMENDATION
`Milestone Date: 28-FEB-2001
`.
`Decnsxon:
`WITHHOLD
`
`‘
`
`g___________/
`
` .
`
`_ Reason: _
`
`_
`
`>
`
`’
`
`PEND REG ACTION - WARNING LT.
`
`‘
`
`Establishment:
`
`A
`
`———’————__\
`
`DMF No:
`AADA No:
`
`

`

`NDA 21—1 95
`
`Xyrem (sodium oxybate)
`
`Orphan Medical.
`
`15
`
`OMEN;
`
`‘.
`FDA .CDER EES
`n
`ESTABLISHMENT EVALUATION REQUEST
`SUMMARY REPORT
`
`Page
`
`2 or
`
`0A1 Status: NONE
`--\
`Profile:
`Last Milestone: D0 RECOMMENDATION
`
`Milestonc Date:
`Decision:
`
`16—MAR~200£
`ACCEPTABLE
`
`Reason:
`
`INSPECTION
`
`Responsibilities: W
`
`Establishment: fl DMF N03
`
`m AADA No:
`
`//
`
`M
`
`0A1 Status: NONE
`Profile: V ,
`Last Milestone: 0C RECOMMENDATION
`Milestone Dam: 28-Nov-2060
`
`Decision:
`Reason:
`
`.
`ACCEPTABLE
`DISTRICT RECOMMENDATION
`
`Responsfoilitiw
`
`M
`
`fl
`
`fl
`
`

`

`DIVISION OF NEUROPHARMACOLOGICAL DRUG PRODUCTS, HFD~120
`REVIEW OF CHEMISTRY, MANUFACTURING, AND CONTROLS
`
`NDA 21-196
`
`CHEM. REVIEW #1
`
`REVIEW DATE 09-FEB—01
`
`SUBMISSION TYPE
`ORIGINAL
`AMENDMENT
`
`DOCUMENT DATE
`30-SEP—00
`07-DEC-OO
`
`CDER DATE
`02-OCT-00
`08-DEC-00
`
`ASSIGNED DATE
`05-OCT-00
`13~D EC—OO
`
`NAME AND ADDRESS OF APPLICANT
`
`DRUG PRODUCT NAME
`Proprietary:
`Nonproprietary/USAN [1966]:
`Code Name/Number:
`
`Orphan Medical, Inc.
`13911 Ridgedale Drive, Suite 250
`Minnetonka, MN 55305
`
`Xyrem® oral solution
`sodium oxybate
`
`Chem. TypefTher. Class:
`
`1P
`
`PHARMACOLOGICAL CATEGORY/INDICATION
`
`DOSAGE FORM
`
`'
`
`STRENGTHS .
`ROUTE OF ADMINISTRATION
`
`DISPENSED
`SPECIAL PRODUCTS
`
`Reduce the incidence of cataplexy and to improve the
`symptom of daytime sleepiness in patients with narcolepsy
`Oral Solution
`
`500 mg/mL
`Oral
`
`__OTC
`& RX
`Yes w NO
`
`CHEMICAL NAME, STRUCTURAL FORMULA, MOLECULAR FORMULA
`Sodium 4-hydroxybutyrate
`4-Hydroxybutanoic acid monosodium salt
`
`Sodium gamma hydroxybutyrate
`C4H7N303
`Mol. Wt. 126.09
`CAS Registry #: 502-85-2
`
`0
`
`+ _ MOP!
`N8 0
`sodium oxybate
`
`SUPPORTING DOCUMENTS: IND -— . IND T." (Treatment IND) and 12 packaging DMF’s
`RELATED DOCUMENTS: None
`
`CONSULTS: The proposed trademark "Xyrem" was found acceptable by the Office of Post—Marketing Drug Risk
`Assessment (OPDRA) on 27-JAN-OO. The EER was requested on OZ—OCT-OO (copy attached). A microbiology consult was
`requested 19—JAN-01. The MV package is being prepared.
`
`REMARKS/COMMENTS: The drug substance will be manufactured bv . M The drug product
`
`will be produced byW Impurity
`has an inadequate specification of NMT-
`Since impurity A has not be identified the upper limit should be
`NMT -— (see ICH Q3A “ImpuritiesIn New Drug Substances"; >20 per day) A degradant at —-
`appeared during
`
`stability testing of all three drug product batches manufactured at I ~ This degradant was not observed from stability
`testing 0ft \— drug product. Only 9 months of long term stability data was provided from the
`site (24
`months of long term data was provided from ~ ” site). The sponsor has requested a 36-month expiration date, but
`this is unacceptable at mis time. The pH of the drug product'Increases after insertion of the PIBA (30 and 60 day stability
`
`study). The pH of the drug product alsoIncreases during storage in the bottle. The sponsor provided no data evaluatino the
`possible additive effect of these two events and how it would affect the impurity profile.
`were requested for all drug substance batches to evaluate the impurity profiles of the clinical and toxicology batcheS. A
`complete list of questions and comments, which were communicated to the sponsor, are found at the end of this review
`
`CONCLUSIONS & RECOMMENDATIONS: Not approvabie at this time.
`
`cc: Orig. NDA 21-196
`
`HFD-120
`HFD-120/TOIiver
`HFD-120/PM/AMHD
`
`HFD-120/MGuzevJ:
`R/D lnit by: MF" 1 \
`
`n ay
`
`I , -\
`[LII/J
`
`IS/
`
`_,.._.__~
`a, ___-__
`,,,,,,
`Thomas F Oliver, Ph. D ,Chemist
`
`
`
`Filename:n21196.01
`
`

`

`_f/I_ page(s) have been
`removed because it
`
`contains trade secret
`
`and/or confidential
`
`information that is not
`
`disclosable.
`
`

`

`NDA 21-196
`06—FEB-2001
`
`7
`
`Xyrem (sodium oxybate)
`FDA CDER EES
`
`Orphan Medical.
`
`‘Page
`
`44
`‘1 of
`
`ESTABLISHMENT EVALUATION REQUEST
`SUMMARY REPORT
`
`,
`NDA 21196/000
`Application:
`Stamp: 02-OCT-2000 Regulatory Due: 02-APR—2001
`Applicant:
`ORPHAN MEDCL
`
`_Priority: 1P
`Action Goal:
`Brand Name:
`
`Org Code: 120
`District Goal: 014153.200]
`XYREM (SODIUM OXYBATE)
`500MG/ML ORAL SOL
`
`Established Name:
`Generic Name: SODIUM OXYBATE
`
`Dosage Form:
`Strength:
`
`SOL (SOLUTION)
`500 MGIML
`
`TFDA Contacts:
`
`A. HOMONNAY WEIKEL (HFD-120)
`T. OLIVER ~
`_ (RFD-810) _
`
`301-594-5535 , Project Manager
`~
`301-594-2570 , Review Chemist
`
`M. GUZEWSKA - (RFD-120)
`301-594—5571
`, Team Leader
`
`.MW
`
`Overall Recommendation:
`
`
`
`Establishment:
`
`DMF No:
`
`W AADA N
`
`w
`
`OAI Status: NONE
`AProfile: _’\'
`Last Milestone: 0C RECOMMENDATION
`
`ResponsfloilitiCSI
`,
`
`Milestone Date: 13-OCT-2000
`
`, F
`
`Decision:
`ACCEPTABLE
`f
`
`Reason:
` BASED ON PROFILE
`
`‘
`
`‘
`Establishment:
`
`_ m .
`.
`DMF No.
`t
`AADA No:
`
`m
`
`m'\
`
`l (
`
`OAI Status: 0A1 ALERT .
`;;’_ ‘
`'Profile:
`v
`I
`Last Milestone: 0C RECOMMENDATION
`
`VRespomibflifi“:
`
`K/‘fi
`
`Milestone Date: 13-OCT-2000
`Decision:
`ACCEPTABLE W
`
`Reason:
`
`BASED ON PROFILE
`
`OAI Status: OAI ALERT b
`.._,—
`Profile:
`Last Milestone: ASSIGNED INSPECTION T0 113
`
`Milestone Date: 16-OCT-2000
`
`“fl
`
`
`
`Establishment:
`
`,
`'
`
`«————-—-—-\
`
`‘DMF No:
`AADA N0:
`
`

`

`NDA 21-196
`06-FEB-2001
`
`_
`
`Xyrem (sodium oxybate)
`FDA CDER EES
`
`Orphan Medical.
`
`APage
`
`_ 45
`2 0f
`
`ESTABLISHMENT EVALUATION REQUEST
`SUMMARY REPORT
`
`0A1 Status: NONE.
`‘
`-—-r
`-Profile:
`Last Milestone: ASSIGNED INSPECTION TO 13
`Milestone Date: 16-Oct-2000
`
`Ilesponsibilitics: fix
`
`
`
`A
`
`Establishment:
`
`KM _
`
`‘
`
`/’"’—‘\
`
`m
`
`DMF No:
`
`AADA No:
`
`0A1 Status: NONE
`_Profile: ' _....
`Last Milestone: ASSIGNED INSPECTION T0 IB
`
`Milestone Date: 22-JAN-2001
`
`wResponsibilities: \w
`
`Establishment: fl ‘DMF N01
`fl AADA No:
`
`
`
`,— OAI Status: NONE
`iProfile:
`Last Milestone: OC RECOMMENDATION
`
`Milestone Date: 28.Nov-2ooo
`Decision:
`ACCEPTABLE
`
`Reason:
`
`DISTRICT RECOMMENDATION
`
`Respommilifies: A
`
`“A
`
`

`

`
`
`5L page(s) have been
`removed because it
`
`contains trade secret
`
`,
`
`and/or confidential
`
`information that is not
`
`disclosable.
`
`T
`
`

`

`21-JUN-2001
`
`FDA CDER EES
`
`Page
`
`1 of
`
`ESTABLISHMENT EVALUATION REQUEST
`SUMMARY REPORT
`
`Application:
`
`NDA 21196/000
`
`Priority: 1P
`
`Org Code: 120
`
`Stamp: 02-OCT-2000 Regulatory Due: 02—JUL-2001
`
`Action Goal:
`
`District Goal:
`
`01—FEB-2001
`
`Applicant:
`
`ORPHAN MEDCL
`
`Brand Name:
`
`XYREM (SODIUM OXYBATE)
`500MG/ML ORAL SOL
`
`Established Name:
`
`Generic Name: SODIUM OXYBATE
`
`Dosage Form:
`Strength:
`
`SOL (SOLUTION)
`500 MG/ML
`
`FDA Contacts:
`
`A. HOMONNAY WEIKEL (HEB-120)
`
`301—594-5535
`
`, Project Manager
`
`T. OLIVER
`
`(HFD—810)
`
`301-594-2570
`
`, Review Chemist
`
`, Team Leader
`301-594-5571
`(HFD-120)
`M. GUZEWSKA
`
`Overall Recommendation:
`
`WITHHOLD 0n 22-MAR-2001 by P. ALCOCK(HFD—324) 301—827-0062
`
`Establishment: ‘\~\‘ DMF No:
`fl, AADA N0:
`
`W:
`
`OAI Status: NONE
`.f—fi
`Profile:
`Last Milestone: OC RECOMMENDATION
`
`Milestone Date:
`Decision:
`
`13—OCT—2000
`ACCEPTABLE
`
`Reason:
`
`BASED ON PROFILE
`
`R65p0nsibilitiesr /\
`
`W
`
`___._.———-————\
`
`
`Establishment; A DMF No:
`
`VA : AADA No:
`Q
`
`OAI Status: OAI ALERT
`Profile: v»
`Last Milestone: 0C RECOMMENDATION
`Milestone Date: 13-0CT—2000
`Decision:
`ACCEPTABLE
`Reason:
`BASED ON PROFILE
`
`Responsibilitiesz
`
`fl
`
`”Tm
`
`OAI Status: OAI ALERT M:
`————
`Profile:
`Last Milestone: 0C RECOMMENDATION
`
`Milestone Date: 22-MAR—2001
`Decision:
`WITHHOLD
`Reason:
`DISTRICT RECOMMENDATION
`
`.
`
`WARNING LETTER ISSUED
`
`Establishment:
`DMF No:
`
`,_,_____________
`
`AADA No:
`
`

`

`Zl-IUN—ZOOI
`
`FDA CDER EES
`
`Page
`
`2 of
`
`ESTABLISHMENT EVALUATION REQUEST
`SUMMARY REPORT
`
`.-
`'
`
`OAI Status: NONE
`Profile: ~
`Last Milestone: 0C RECOMMENDATION
`Milestone Date:
`19-MAR—2001
`'
`
`Decision:
`
`ACCEPTABLE
`
`Responsibilities: /\
`
`
`Reason:
`DISTRICT RECOMMENDATION
`
`Establishment: K“ DMF No:
`
`f AADA No:
`
`
`
`OAI Status: NONE
`.—
`Profile:
`_
`Last Milestone: 0C RECOMMENDATION
`
`Milestone Date: 28-Nov-2000
`Decision:
`ACCEPTABLE
`
`
`
`Reason: DISTRICT RECOMMENDATION
`
`Responsibilities:
`
`m
`
`fl
`
`fl
`
`