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
`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(cid:226)
`(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 of this 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) Implementation of a restricted distribution program for Xyrem.
`2) 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 of the 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:
`
`• A Medication Guide for Xyrem® is available for every patient who is dispensed a prescription for
`Xyrem®.
`• 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.
`• 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 Xyrem by evaluating physician-filed adverse event data sheets; each patient will be
`assessed for at least 6 months.
`
`Submission of Plans: within one month of approval
`Start Date: immediately upon treatment of any patient
` Reports to FDA: every three months from 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 314.81(b)(2)(vii) and 314.81(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 of patients 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 after it is printed.
`Please individually mount 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, M.D.
`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
`
`