CENTER FOR DRUG EVALUATION AND
`
`RESEARCH
`
`APPLICA TION NUMBER:
`
`21-196
`
`CORRESPONDENCE
`
`

`

`July 1, 2002
`
`Russell Katz, MD, Director
`Division of Neurophamiacological Drug Products [HFD-120]
`Food and Drug Administration
`Center for Drug Evaluation and Research
`1451 Rockville Pike, Room 4025
`Rockville, MD 20852
`Phone: 301-594-2850
`
`SUBJECT:
`
`Xyrem® (sodium oxybate) oral solution
`NDA #21 -196 Post-NDA Submission No. 99
`
`USER FEE NUMBER 3,814, ORPHAN DESIGNATION NUMBER 94-858
`
`Commitment to Timing of Anticipated Post-Approval Clinical Trials
`
`Dear Dr. Katz:
`
`Orphan Medical has previously indicated that we commit to conducting two additional
`clinical trials as post-approval commitments following FDA marketing authorization of
`this pending priority NDA.
`In a recent phone call, Ms. Anna Marie Homonnay—Weikel,
`requested that we document our anticipated timing for completion of those two clinical
`trials. We were asked to indicate three approximate dates that include the anticipated
`date of protocol submission to our IND, the date the study would be initiated; and the
`anticipated date of final report submission to FDA. We commit to the following timing on
`these two clinical trials with this letter.
`
`Trial 1: Drug Interaction Study:
`
`Description: Evaluation of the pharmacokinetics of oxybate when administered
`concomitantly with a proton pump inhibitor in normal human volunteers.
`
`Protocol Submission: A protocol will be submitted to Ni: V” within three months
`of market authorization of Xyrem NDA 21-196.
`
`Protocol Initiation This trIal WIll be InItIated t” rst patient,Ifrst VISIt within three
`months of FDA approval of the protocol.
`
`Final Report: A final report on this trial will be submitted to FDA NDA 21-196 within
`6 months of study initiation.
`
`r.\ghb\postnda\submissions\xyrem nda—99 commiflettenoover letter 99.doc
`
`1 D
`
`edicated to Patients with Uncommon Diseases”
`
`I 39] I Ridgedo/e Drive, Suite 250 0 Minneionka, Minnesota 55305
`
`9525136900 0 Fax: 952-54 7-9209 ' wvvw.orphon.com
`
`

`

`CONFIDENTIAL
`
`_
`Orphan Medical, Inc.
`XyremO (sodium oxybate) oral solution
`
`Trial 2: Xyrem Study in Respiratory Compromised Subjects
`
`Protocol Submission: Orphan Medical anticipates making a written request for
`discussion of study design with the Division of Neuropharmacology within three
`months of FDA marketing authorization of Xyrem NDA 21-196. We then commit to
`submission of a protocol for FDA review within 3 months of a meeting with FDA to
`present the final trial design of this study.
`
`Protocol Initiation: We commit to initiate the trial (first patient. first visit) within three
`months of FDA approval of the protocol.
`
`Final Report: This trial is anticipated to take 12 months from initiation, with a final
`report 3 months following completion of the study (last patient, last visit).
`
`Sincerely yours,
`
`
`
`Dayton . Reardan, Ph.D., RAC
`Vice President of Regulatory Affairs
`Phone: 952-513-6969
`
`E-mail: dreardan@orghan.com
`
`cc:
`
`Anna Marie Homonnay—Weikel RPh [Cover Letter - E—mail]
`
`r:\ghb\posmda\submissions\xyrem nda-99 oommiflettencover letter 99.doc
`
`

`

`January 8, 2002
`
`Russell Katz, M.D., Director
`Division of Neuropharmacological Drug Products [RFD—120]
`Food and Drug Administration
`Center for Drug Evaluation and Research
`1451 Rockville Pike, Room 4025
`Rockville, MD
`20852
`Phone:
`301—594-2850
`
`SUBJECT:
`
`Xyrem? (sodium oxybate) oral solution
`NDA #21—196 Post-NDA Submission No. 80
`
`USER FEE NUMBER 3,814, ORPHAN DESIGNATION NUMBER 94-858
`
`Product Label revision to comply with Medication Guide
`Regulation (21 CFR 208.24)
`
`Dear Dr. Katz:
`
`Thank you for the letter of notice provided in December regarding
`the requirement to amend our proposed product labeling for Xyrem
`in relation to the medication guide.
`A copy of that letter is
`included with this submission. Your letter was electronically
`signed on December 13, 2001.
`
`The Medication Guide regulations promulgated in part 208 of Title
`21,
`in particular 208.24(d) require that:
`“The label of each
`container or package, where the container label is too small, of
`drug product for which a Medication Guide is required under this
`part shall instruct the authorized dispenser to provide a
`Medication Guide to each patient to whom the drug product is
`. dispensed, and shall state how the Medication Guide is provided.”
`
`Orphan Medical proposed in our class 2 response dated October 5,
`2001 to include a copy of the approved Medication Guide in each
`box of Xyrem. Each box is proposed to contain a 180 mL bottle of
`Xyrem, a PIBA, an oral syringe,
`two child resistant dosing cups,
`a professional insert with a Medication Guide attached via a tear
`off perforation. Therefore each box of Xyrem will contain a
`Medication Guide. Since the central pharmacy and each dispenser
`will be required to provide the full box of Xyrem each time Xyrem
`is dispensed, Orphan Medical proposes that only the carton (box)
`of Xyrem include language requiring dispensing of the Medication
`Guide.
`
`&\GHB\PostNDA\Submissions\Xyrem NBA-80 MedGuidePkgLabelemm NDA—80.doc
`
`— l -
`
`
`
`Dedicated to Patients with Uncommon Diseases‘
`
`1391 I Ridgedale Drive, Suite 250 O Minnefonko, Minnesota 55305
`
`95251315900 0 Fax: 952-541-9209 ° www.0rphan.com
`
`

`

`The regulation as restated above, allows for the container OR the
`package to instruct the authorized dispenser regarding the
`Medication Guide.
`In addition, since virtually all Xyrem will be
`dispensed by a central pharmacy,
`training and instruction can be
`assured so that each patient will receive the Medication Guide
`each time Xyrem is dispensed.
`Since all cartons (boxes, kits) of
`Xyrem must be dispensed to ensure that each patient receives all
`components, it is certainly justified to include the instructions
`to the pharmacist prominently on the outer carton.
`
`This item has a production lead—time of about 5—6 weeks, and in
`fact was already printed at substantial cost to the company in
`order to be prepared for distribution upon FDA approval.
`Feedback was obtained from the chemistry review group at FDA in
`about February or March of last year that the bottle label and
`The
`carton label appeared to meet all requirements at that time.
`original proposal of a patient package insert was modified when
`FDA requested a Medication Guide in place of our proposed patient
`package insert last August 2001. Orphan Medical will therefore
`have to reprint this component with the proposed change in
`advance to ensure timely supply of Xyrem upon FDA approval. We
`would like to request feedback that what we have proposed is
`acceptable to FDA at this time. We recognize that FDA reserves
`the right to make changes up to and after approval, however, we
`request some assurance that what we have proposed is acceptable
`at this time.
`
`Please find attached the following documents:
`
`1.
`
`The letter from Dr. Katz requiring medication guide
`instructions on the product label.
`2. Our proposed language for the Xyrem carton to meet this
`requirement.
`A copy of the current proposed bottle label which remains
`unchanged.
`
`3.
`
`R:\GHB\PostNDA\Submissions\Xyrem NBA-80 MedGuidePngAbCRXyrem NDA-80.doc
`
`- 2 —
`
`

`

`If you have any suggestions or modifications, please communicate
`those to us at your earliest opportunity. We remain, as always,
`available to answer any questions you may have regarding this
`submission.
`
`Sincerely your ,
`
`9%
`
`Dayton T. Reardan, Ph.D., RAC
`Vice President of Regulatory Affairs
`Phone: 952—513—6969
`
`E-mail: DReardan@Orphan.com
`
`cc:
`
`Anna Marie Homonnay—Weikel RPh [E-mail]
`
`R:\GHB\PostNDA\Submissions\Xymm NDA-80 MedGuidePkgLabcflXyrem NDA—SO.doc
`
`- 3 -
`
`

`

`[RV]
`
`(“a
`
`r“ s
`
`}*
`
`‘6 DEPARTMENTOFHEALTH& HUMANSERVICES
`
`3
`
`Food and Drug Administration
`Rockville MD 20857
`
`Orphan Medical
`Attention: Dayton Reardan, Ph.D., RAC
`
`Vice President of Regulatory Affairs
`1391 1 Ridgedale Drive
`Suite 250
`
`Minnetonka, MN 55305
`
`Dear Dr. Reardan:
`
`Please refer to your September 30, 2000, new drug application (NDA) submitted under section 505(b)
`of the Federal Food, Drug, and Cosmetic Act for Xyrem® (sodium oxybate) Oral Solution.
`
`On March 26, 2001, we received your March 23, 2001, major amendment to this application. The
`receipt date is within three months of the user fee goal date. Therefore, we are extending the goal date
`by three months to provide time for a full review of the submission. The extended user fee goal date is
`July 2, 2001.
`
`If you should have any questions, please call Ms. Anna Marie Homonnay, R.Ph ,Regulatory Health
`Project Manager, at (30]) 594- 5535
`
`Sincerely,
`
`{See appended electronic signature page}
`
`Russell Katz, MD.
`Director
`
`Division of Neuropharmacological Drug Products
`Office of Drug Evaluation I
`Center for Drug Evaluation and Research
`
`

`

`Russell Katz
`
`3/30/01 09:43:24 AM
`
`

`

`W151
`
`“a.
`
`DEPARTMENT OF HEALTH & HUMAN SERVICES
`
`Public Health Service
`
`Food and Drug Administration
`Rockville, MD 20857
`
`NDA 21~196
`
`Orphan Medical Inc-
`Attention: Dayton Reardan, PhD.
`Vice President, Regulatory Affairs
`13911 Ridgedale Drive, Suite 250
`Minnetonka, MN 55305
`
`Dear Dr. Reardan:
`
`Please refer to your new drug application (NDA) dated September 30, 2000, received October 2, 2000,
`submitted under section 505(b) of the Federal Food, Drug, and Cosmetic Act for Xyrem® (sodium
`oxybate) Oral Solution.
`
`FDA is notifying Orphan Medical Inc. that we have determined that Xyrem® Oral Solution poses a
`serious and significant public health concern requiring distribution of a Medication Guide pursuant to
`21 CFR Part 208. Distribution of a Medication Guide would be necessary to help prevent serious
`adverse effects [21 CFR 208 (c) (1)].
`
`Therefore, in accordance with 21 CFR 208, you are responsible for ensuring that a Medication Guide
`for Xyrem® is available for every patient who is dispensed a prescription for Xyrem®. In addition,
`you are responsible for ensuring that the label of each container of Xyrem® includes a prominent and
`conspicuous instruction to authorized dispensers to provide a Medication Guide to each patient to
`whom the drug is dispensed, and states how the Medication Guide is to be provided.
`
`If you would like to discuss this issue with the division, please call MsAnna Marie Homonnay, R.Ph.,
`Regulatory Health Project Manager, at (301) 594—5535.
`
`Sincerely,
`
`{See appended electronic signature page}
`
`Russell Katz, MD.
`Director
`
`Division of Neuropharmacological Drug Products
`Office of Drug Evaluation I
`Center for Drug Evaluation and Research
`
`

`

`m-mflmm~mmmm~mn-Mlfi
`
`
`
`This is a representation of an electronic record that was signed electronically and -
` —mm--mm-_
`this page is the manifestation of the electronic signature.
`
`Russell Katz
`12/13/01 01:03:31 PM
`
`

`

`
`
`3 page(s) of
`revised draft labeling
`has been redacted
`
`frOm this portion of
`the review.
`
`