CENTER FOR DRUG EVALUATION AND
`
`RESEARCH
`
`APPLICA TION NUMBER:
`
`2 1 - 1 9 6
`
`APPROVAL LETTER
`
`

`

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`
`DEPARTMENT OF HEALTH & HUMAN SERVICES
`
`Public Health Service
`
`Food and Drug Administration
`Rockville MD 20857
`
`NDA 21-196
`
`Orphan Medical
`
`Attention: Dayton Reardan, Ph.D.
`
`Vice President, Regulatory Affairs
`
`1391 l 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.
`
`We acknowledge receipt of your submissions dated May 8 and 28; June 6; July 1, 12 and 15, 2002. Your
`submission of May 16, 2002 constituted a complete response to our April 9, 2002 action letter.
`
`This new drug application provides for the use of Xyrem® Oral Solution for the treatment of cataplexy
`associated with narcolepsy.
`'
`
`We also refer to your March 12, 2002, correspondence requesting review of Xyrem® Oral Solution under
`the provisions of Subpart H for restricted distribution. Therefore, as previously agreed, we have reviewed this
`application under the restricted distribution regulations contained in 21 CFR 314.500 (Subpart H) to assure
`safe use of the product.
`
`Finally, we refer to the July 17, 2002, teleconference between representatives of Orphan Medical Inc. and this
`division during which the final language of the labeling text was agreed upon.
`
`We have completed the review of this application, including the Xyrem® Risk Management Program, as
`amended, and have concluded that adequate information has been presented to approve Xyrem® (sodium
`oxybate) Oral Solution under 21 CFR 314 Subpart H. Accordingly, the application is approved under the
`provisions of 21 CFR 314, Subpart H. Approval is effective on the date ofthis letter. Marketing of this drug
`product and related activities are to be in accordance with the substance and procedures of all FDA
`regulations and the specific restrictions on distribution and use described below.
`
`

`

`Xyrem® Risk Management Program
`
`We remind you that Xyrem is being approved with a Risk Management Program (RMP) that must include
`each of the following components:
`
`1)
`2)
`
`Implementation of a restricted distribution program for Xyrem.
`Implementation of a program to educate physicians and patients about the risks and benefits of Xyrem,
`including critical information necessary for the safe use and handling of the drug.
`3) Filling ofthe initial prescription only after the prescriber and patient have received and read the educational
`materials.
`
`4) Maintenance of a registry of all patients and a record of all prescribers.
`
`The RMP, as described in the attached documents, adequately addresses each of these requirements. Any
`proposed change in the RMP must be discussed with FDA prior to its institution. FDA will determine
`whether the proposed change is subject to FDA approval before implementation. We expect your continued
`cooperation to resolve any problems regarding the RMP that may be identified following approval of this
`NDA.
`
`Medication Guide
`
`As previously communicated to you in our December 13, 2001 , letter, we have determined that Xyrem®
`poses a serious and significant public health concern requiring distribution of a Medication Guide. This
`Medication Guide is necessary to help prevent serious adverse effects due to Xyrem® pursuant to 21 CFR
`Part 208.1 (c)(1).
`
`In accordance with 21 CFR Part 208, Orphan Medical is responsible for ensuring that:
`
`0 A Medication Guide for Xyrem® is available for every patient who is dispensed a prescription for
`Xyrem®.
`o The label of each carton container of Xyrem® include a prominent and conspicuous instruction to
`authorized dispensers to provide a Medication Guide to each patient to whom Xyrem® is dispensed.
`o The label of each container includes a statement about how the Medication Guide is dispensed.
`
`Post Marketing Commitments
`
`You have made a commitment to conduct the following post marketing studies, as specified in your submission
`dated July 1, 2002, and our telephone conversation of July 12, 2002:
`
`1. Description: conduct a drug interaction study to evaluate the pharmacokinetics of Xyrem® when
`administered concomitantly with a proton pump inhibitor in normal human volunteers.
`
`Protocol Submission: within three months of FDA approval of the NDA
`
`Study Start: within three months of FDA approval of the protocol
`
`Final Report: within six months of study initiation
`
`

`

`NDA 21-196
`
`Page 3
`
`2. Description: conduct a clinical study in subjects with respiratory compromise.
`
`Protocol Submission: within three months of FDA approval of the NDA
`
`Study Start: within three months of FDA approval of the protocol
`
`Final Report: completion of the study within 12 months of initiation with the final report three months
`
`following completion of the study.
`
`3. Description: assess the post marketing safety of Xyrem in a prospective cohort of one thousand (1,000)
`patients prescribed Xylem by evaluating physician-filed adverse event data sheets; each patient will be
`assessed for at least 6 months.
`
`Submission ofPlans: within one month of approval
`
`Start Date: immediately upon treatment of any patient
`
`Reports to FDA: every three months fiom time of approval
`
`Clinical protocols should be submitted to your IND for this product and all study final reports to this NDA. In
`addition, under 21 CFR 314.8l(b)(2)(vii) and 314.8l(b)(2)(viii), you should include a summary of the status
`of each commitment in your annual report to this NDA. The summary should include expected study
`completion and final report submission dates, any changes in plans since the last annual report, and, for clinical
`studies. The number ofpatients entered into each study. All submissions, including supplements, relating to
`these postmarketing study commitments must be prominently labeled 'Postmarketing Study Protocol",
`"Postmarketing Study Final Report", or 'Postmarketing Study Correspondence."
`
`The final printed labeling (FPL) must be identical to the enclosed agreed upon labeling text for the Product
`Information Insert and Medication Guide. The immediate container and carton labels must be identical to those
`
`submitted on January 8, 2002. Marketing the product with FPL text that is not identical to the agreed upon
`approved labeling text may render the product misbranded and an unapproved new drug.
`
`Please submit the copies of final printed labeling (FPL) electronically according to the guidance for industry
`titled Providing Regulatory Submissions in Electronic Format — NDA (January 1999). Alternatively, you
`may submit 20 paper copies of the FPL as soon as it is available but no more than 30 days afier it is printed.
`Please individually mormt ten of the copies on heavy-weight paper or similar material. For administrative
`purposes, this submission should be designated "FPL for approved NDA 21-196." Approval of this
`submission by FDA is not required before the labeling is used.
`
`We also remind you that, under 21 CFR 314.550, after the initial 120 day period following this approval, you
`must directly submit all promotional materials, including promotional labeling as well as advertisements, at least
`
`30 days prior to the intended time of initial dissemination of the labeling or initial publication of the
`
`advertisement to the Division of Drug Marketing, Advertising and Communications. Please submit all
`
`

`

`NDA 21-196
`
`Page 4
`
`proposed materials in draft or mock up form, not final print and send one copy to the Division of
`Neuropharmacological Drug Products. We acknowledge your agreement to submit the reprint with the citation
`Sleep 2002; 25:42—49, under 21 U.S.C. § 360aaa.
`
`We have approved an expiration date of 36 months for this drug product.
`
`Validation of the regulatory methods has not been completed. At the present time, it is the policy of the
`Center not to withhold approval because the methods are being validated. Nevertheless, we expect your
`continued cooperation to resolve any problems that may be identified.
`
`We remind you that you must comply with the requirements for an approved NDA set forth under 21 CFR
`314.80, 314.81, 314.520, 314.550 and 314.560.
`
`Sincerely,
`
`{See appended electronic signature page}
`
`Robert Temple, MD.
`Director
`
`Office of Drug Evaluation I
`
`Center for Drug Evaluation and Research
`
`Enclosures:
`
`Professional Labeling
`Patient Medication Guide
`
`Risk Management Plan
`
`Post Marketing Evaluation Program
`
`Physician and Patient Educational Programs
`
`

`

`This is a representation of an electronic record that was signed electronically and
`this page is the manifestation of the electronic signature.
`
`/S/
`
`Robert Temple
`7/17/02 04:57:49 PM
`
`

`

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

`

`5:“VICE: .
`
`‘x
`a?v
`Q")
`S
`
`“D/(C NDA 21—196
`
`Orphan Medical
`Attention: Dayton Reardan, Ph.D.
`Vice President, Regulatory Affairs
`1391 l 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) ofthe Federal Food, Drug, and Cosmetic Act for Xyrem® (sodium
`oxybate) Oral Solution.
`
`We acknowledge receipt of your submissions dated October 30, 2000; November 1, l6, l7 (2), 2000;
`December 1, 5, 6(2), 7 (3), ll, 15, 16 and 18, 2000; January 1 l, l5, l9 and 31, 2001; February 1, 5, 6,
`12, 13(2), 15 and 23, 200]; March 16 and 23, 2001; April 10, ll, 12 and 19, 2001; May 4, and
`June 18, 200].
`
`We also refer to the meeting of the Peripheral and Central Nervous Systems Drugs Advisory
`Committee of June 6, 2001, at which your NDA was discussed.
`
`We have completed the review ofthis application, as amended, and it is approvable. Before this
`application may be approved; however, it will be necessary for you to address the following:
`
`Clinical Issues
`
`1.
`
`As recommended by the Advisory Committee, the approval ofyour application will be contingent
`upon your adoption of an adequate Risk Management Program (RMP). You have proposed an
`extensive program, described in the attachment to this letter (the description attached is based on
`several of your submissions to the NDA and represents our understanding of the key elements of
`your proposal). We consider the proposed program a condition of approval with the following
`modifications:
`
`3) Prescribers must state, in writing, that a patient has narcolepsy with cataplexy before drug will
`be released to the patient.
`b) Prescribers must state, in writing, that they have read the educational materials provided to
`them before educational materials will be sent to the patient.
`c) Patients must state, in writing, that they have read the educational materials provided to them
`before their first prescription is filled.
`d) A single prescription must be limited to a maximum of} months supply of drug, and the
`maximum dose prescribed must be no more than 9 gms/day, given in 2 equally divided doses.
`Prescriptions for a dose greater than 9 gms/day, or for more than 3 months supply, must not be
`filled by the pharmacist.
`e) Patients must be seen and evaluated by the prescriber with the issuance of each new
`prescription (every 3 months), at which time a detailed account of the patient’s experience on
`treatment must be provided. Prescribers must submit reports of all serious adverse reactions to
`
`

`

`Cz/wpfiles/NDA/Xyrem/Zl l96AELTR03doc
`
`3. The status ofthe l l patients who were enrolled in the Scharf study and had not entered the
`treatment IND study #OMC-SXB—7 as of 5/31/99, needs to be described to the extent possible.
`These patients are listed below by ID# and initials:
`
`01-004/
`
`01—027/
`
`01-054/
`
`01—065/
`
`01—228/
`
`01-240/
`
`01-262/
`
`01—269/
`01-283/
`
`01-268/
`
`01-256/
`
`4. An analysis should be provided of all patients in the entire safety database listed as having
`“sleepwalking” as an adverse event. Such an analysis should include detailed clinical descriptions
`ofthe episodes, whenever they can be obtained from source documents, and the following
`additional elements: demographics, relationship to dose, frequency, seriousness, reason for
`discontinuation, further evaluations (e.g., EEGs and polysomnograms) and outcome.
`
`5. As a CNS depressant, sodium oxybate is capable of producing respiratory depression. However,
`your application contains no formal assessment of this potential. Such assessments are routinely
`required in the evaluation of sedative-hypnotic drug products. For this reason, you should perform
`such a study. The study should examine the effects of the recommended dosing regimen (2 doses
`nightly, including the highest recommended dose-9 gms divided), with both doses given in the
`fasted state. The study should include patients who are and who are not receiving concomitant
`stimulant treatment, a positive control, and patients with concomitant illnesses that might increase
`their risk of respiratory depression (e.g., patients with COPD, sleep apnea, etc.). In addition,
`plasma level data should be obtained at appropriate times. We would be happy to discuss the
`design of such a study with you. We believe there is sufficient suggestion of occasional respiratory
`depression in the clinical studies to ask that these data be collected prior to marketing.
`
`6. While there do not appear to be any important effects of sodium oxybate on the major CYP 450
`metabolizing enzymes, the levels of sodium oxybate used in your studies were far below those
`expected to be seen clinically. Please assess the effects of sodium oxybate on these enzymes at
`clinically relevant exposures.
`
`Labeling Issues
`
`Accompanying this letter as an attachment is our proposal for the labeling of Xyrem® Oral Solution.
`In some places, we have extensively revised the text that you proposed; we request that you adopt the
`language we have proposed verbatim.
`In several places in labeling, we have embedded bolded requests
`for you to draft appropriate language. We would be happy to discuss these proposed changes in more
`detail through a teleconference if you wish.
`
`

`

`C:/wpfiles/NDA/Xyrem/21 l96AELTR03.doc
`you every 3 months initially, with the longer term reporting requirements to be further
`negotiated with the Agency. The patient registry that is an intrinsic part of this program must
`also be used to actively monitor for evidence of abuse, misuse, and diversion. You will need to
`incorporate these elements into your RMP documents.
`
`0 The educational materials you have prepared must note prominently that Xyrem® is gamma
`hydroxybutyrate, or GHB, and that this is the same compound that is used illicitly.
`g) The individual dosing cups must be labeled with the dose and name of the drug.
`
`These provisions are required because, given the safety data available in the NDA, and the potential
`risks of sodium oxybate, we believe that the drug can be used safely only with the restrictions
`imposed by the RMP. Use beyond the population-for whom the drug will be indicated poses an
`unreasonable risk, and, therefore, all reasonable efforts should be made to restrict its use to the
`
`appropriate population, and to avoid, to the extent possible, accidental use by members ofthe
`patient’s household, as well as to restrict, extra-label, recreational use. Further, because of the
`small database in the NDA, we believe that the registry should be maximally utilized to obtain
`additional data on serious adverse events as quickly as possible after approval.
`
`We will provide you with a detailed review ofthe Physician and Patient Success Programs once the
`product labeling is written and the entire RMP is defined.
`
`We believe that adoption ofthis RMP is critical to the safe use of Xyrem®. Therefore, before this
`product can be approved, restrictions under 21 CFR 314.520 will need to be carefully defined.
`
`2. A safety update for the ongoing studies, OMC-SXB—7 and — should be provided (the
`latter study is intended to assess the efficacy of Xyrem® in. treating excessive daytime sleepiness).
`Even though the data for Study " may still be blinded, safety data may still be submitted.
`We would be happy to discuss with you appropriate ways in which this might be accomplished.
`
`APPEARS rms WAY
`0N ORIGINAL
`
`

`

`C :/wpfiles/NDA/Xyrem/2 l l96AELTR03.doc
`
`While we have made extensive changes to your proposed labeling, there are two important changes that
`we wish to draw your attention to:
`
`l.
`
`2.
`
`‘Jndicalions ‘: we have proposed that Xyrem be indicated for patients with cataplexy who are being
`treated with concomitant CNS stimulants. We have proposed this restriction because almost all of
`the clinical experience in your NDA was accrued in such patients, and we believe that it is possible
`that the use of stimulants may be protective of some of the CNS/respiratory depressant effects of
`Xyrem, especially at the higher doses.
`In the absence of evidence that Xyrem is devoid of
`important depressant effects when given alone, we believe it is appropriate to restrict its use to
`patients also receiving stimulants.
`
`‘Contraindications’: we have contraindicated the use of Xyrem with sedative—hypnotic drugs. We
`recognize that you have performed a pharmacokinetic study with zolpidem and determined no
`important kinetic interaction, but we believe the combination of Xyrem with potent CNS
`depressants is ill—advised, and should be avoided, absent data to the contrary.
`
`Chemistry and Manufacturing Issues
`
`the manufacturer of your drug product, recently received a Warning
`f—‘
`Letter from the Agency which cited numerous cGMP violations. The application cannot be approved
`until the Agency has re-inspected that site, and has determined that the deficiencies cited in that letter
`
`have been corrected. As ofthis time,
`'
`is not prepared for a re—inspection.
`
`Postmarketing Issues
`
`While the following issues need not be resolved prior to approval, the following will be required after
`marketing:
`
`l. Because sodium oxybate is ionized in the GI tract, we would like you to perform drug interaction
`studies with drugs that alter gastric pH, such as antacids, proton-pump inhibitors, and H2 blockers,
`all of which may alter the absorption of sodium oxybate.
`
`2. Please submit the results of the rat carcinogenicity study when available.
`
`If additional information relating to the safety or effectiveness ofthis drug becomes available, revision
`ofthe labeling may be required.
`
`Under 2] CFR 314.50(d)(5)(vi)(b), we request that you update your NDA by submitting all safety
`information you now have regarding your new drug. The safety update should include data from all
`nonclinical and clinical studies ofthe drug under consideration regardless ofindication, dosage form,
`or dose level.
`
`

`

`NDA 21-196
`
`Page 5
`
`In addition, please submit three copies ofthe introductory promotional materials that you propose to
`use for this product. All proposed materials should be submitted in draft or mock—up form, not final
`print. Please send one copy to the Division of Neuropharmacological Drug Products and two copies of
`both the promotional materials and the package insert directly to:
`
`Division of Drug Marketing, Advertising, and Communications, HFD—42
`Food and Drug Administration
`5600 Fishers Lane
`
`Rockville, Maryland 20857
`
`Within 10 days after the date ofthis letter, you are required to amend the application, notify us ofyour
`intent to file an amendment, or follow one of your other options under 21 CFR 314.] 10.
`In the absence
`of any such action FDA may proceed to withdraw the application. Any amendment should respond to
`all the deficiencies listed. We will not process a partial reply as a major amendment nor will the
`review clock be reactivated until all deficiencies have been addressed.
`
`The drug product may not be legally marketed until you have been notified in writing that the
`application is approved.
`
`If you should have any questions, please call Ms. Anna Marie Homonnay, R.Ph., Regulatory Health
`Project Manager, at (301) 594-5535.
`
`Sincerely,
`
`{See appended electronic signature page}
`
`Robert Temple, MD.
`Director
`
`Office of Drug Evaluation 1
`Center for Drug Evaluation and Research
`
`Attachments (2)
`
`C:\wpfiles\NDA\Xyrem\21l96AELTR04.doc
`
`

`

`This is a representation of an electronic record that was signed electronically and
`this page is the manifestation of the electronic signature.
`
`Robert Temple
`7/2/01 05:58:12 PM
`
`

`

`/: DEPARTMENTOFHEALTH & HUMAN SERVICES
`
`Public Health Service
`
`Food and Drug Administration
`Rockville, MD 20857
`
`NDA21-196
`
`Orphan Medical
`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.
`
`We acknowledge receipt of your amendments dated October 5 and 23, November 7 and 27, December
`13, 2001; and January 9, February 27, and March 8, 2002.
`
`Your October 5, 2001, amendment constituted a complete response to our July 2, 2001, approvable
`letter.
`
`We also acknowledge receipt of your submission dated April 3, 2002, containing the results of the
`completed rat carcinogenicity study.
`
`We also refer to the April 2, 2002, meeting between you and FDA.
`
`We have reviewed this application under the restricted distribution regulations contained in
`21 CFR 314.520 of Subpart H.
`
`We have completed the review of this application, as amended, and it is approvable. The remaining
`issues that you will need to address before this application may be approved are outlined below.
`
`Assessment of Xyrem’s Potential to Induce Respiratory Depression
`
`In our July 2, 2001 Approvable Letter we asked you to perform a formal assessment of the respiratory
`effects of Xyrem prior to marketing. Such assessments are routinely required in the evaluation of
`sedative-hypnotic drug products. Subsequently, we agreed to review the results of SXB-20, an
`uncontrolled polysomnographic study previously performed to evaluate the effect of Xyrem on
`different sleep stages. You believed the results of the respiratory monitoring in SXB-20 provided
`enough reassurance to allow approval while formal, controlled studies could be performed post-
`approval.
`
`We have reviewed the results of SXB~20 and are concerned that Xyrem may produce clinically
`important deleterious effects on respiratory function during sleep, especially in patients with sleep
`
`

`

`NDA 21—196
`
`Page 2
`
`apnea. While there was marked variability in the data collected, 2 of the 4 patients with moderate—
`severe sleep apnea had marked elevations over baseline in the RBI (respiratory distress index) while
`on treatment. Absent a control group, it is impossible to distinguish between variability and a drug
`effect as the cause of these elevations. As discussed in our meeting of April 2, 2002, we believe that
`these changes may represent a clinically significant worsening of respiratory function at night related
`to treatment with Xyrem in at least one, and perhaps in both, patients. We acknowledge that you
`believe that none of the patients experienced a clinically relevant decline in respiratory function. We
`agreed that you may submit a comprehensive response to our stated concerns in lieu of a definitive
`assessment of Xyrem’s effect on respiratory function in response to this letter. While it is possible that
`we may find your arguments convincing (if we do, you would still need to perform an adequately
`designed trial to definitively address this question in Phase 4), it is also possible that we will remain
`concerned that Xyrem may cause an important deterioration of nighttime respiratory function. If this is
`the outcome, you will be required to perform an adequate study addressing this issue prior to approval.
`
`Adequacy of the Safety Database
`
`As you know, the size of the safety database in your application is, and remains, with the Safety
`Update, small by the usual standard. The number of patients who reached the highest daily dose,
`9gms/day, did not change appreciably with the Safety Update and is only 141, 74 of whom were
`treated for at least 6 months.
`
`Given this small experience, we are particularly concerned about the results of a recent site audit,
`which have raised questions about the acceptablity of the data generated at this site. As a result of this
`audit, we now believe that one or more additional site audits will be needed prior to approval. The
`next site audit is planned within a month.
`
`Once the above issues are adequately addressed, we are prepared to approve Xyrem for the treatment
`of cataplexy in narcolepsy under Subpart H as requested in your March 12, 2002 letter. Upon initial
`marketing under Subpart H, the distribution of Xyrem will be regulated as described in 21 CFR
`314.520. Attached to this letter are proposed labeling and an outline of a proposed risk management
`program that is acceptable to us. The primary component of the risk management program is a central
`pharmacy.
`
`Also attached to this letter are marked up versions of the documents you plan to send to doctors and
`patients as part of your Physician and Patient Success Programs, including draft product labeling and a
`draft Medication Guide for distribution with Xyrem. All of these documents, and the specific details
`of the risk management program, are subject to change pending your response to this Approvable
`Letter, and therefore should be considered provisional at this time.
`
`1.5::
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`

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

`

`NDA 2l—l9o
`
`Page 4
`
`Within 10 days after the date of this letter, you are required to amend the application, notify us of your
`intent to file an amendment, or follow one of your other options under 21 CFR 314.110.
`In the
`absence of any such action FDA may proceed to withdraw the application. Any amendment should
`respond to all the deficiencies listed. We will not process a partial reply as a major amendment nor
`will the review clock be reactivated until all deficiencies have been addressed.
`
`The drug product may not be legally marketed until you have been notified in writing that the
`application is approved.
`
`If you should have any questions, please call Ms. Anna Marie Homonnay, R.Ph., Regulatory Health
`Project Manager, at (301) 594-5535.
`
`Sincerely,
`
`{See appended electronic signature page}
`
`Robert Temple, MD.
`Director
`
`Office of Drug Evaluation I
`Center for Drug Evaluation and Research
`
`Enclosures:
`
`Labeling
`Medguide
`Risk Management Program
`
`