May 3. 2001
`
`Advisors and Consultants Staff
`Center for Drug Evaluation and Research, ORM
`Food and Drug Administration
`HFD-2‘l, Room 1093
`5630 Fishers Lane
`
`Rockviile, MD 20852
`Peripheral and Central Nervous System Drugs Advisory Committee,
`cio Dr. Sandra Titus; 301-827-7001
`
`Subject:
`
`Xyrem® (sodium oxybate) oral solution, NDA #21-196
`USER FEE NUMBER 3.314, ORPHAN DESIGNATION NUMBER 94-853
`
`Peripheral and Central Nervous System Drugs Advisory Committee
`Briefing Booklet for June 6, 2001 Presentation
`
`7 Dear Advisory Committee Member.
`
`This briefing booklet presents data for the use of Xyrem for treatment in narcolepsy, a
`seriously debilitating disease. The disease is lifelong after onset, which usually occurs
`in the second and third decade of life. Historically, diagnosis takes an average of ten
`years clue 'to low physician awareness. These factors and disease symptomatology
`negatively affect patients' education, employment potential and interpersonal
`relationships for the rest of their lives. Current treatments are unsatisfactory, and
`although approved therapies for daytime sleepiness exist, no therapies are approved for
`the aUxiliary REM-related symptoms of 'cataplexy, hypnagogic hallucinations, and sleep
`paralysis. For these reasons Xyrem represents an important new therapeutic advance
`to meet an unmet medical need.
`
`Narcolepsy affects an estimated 125,000 individuals in the United States, an incidence
`that qualifies for orphan drug designation. Excessive daytime sleepiness is diagnostic
`of this disease, while the REM-related symptoms affect 60-90% of patients. About
`25,000 individuals have cataplexy of severity requiring pharmacologic intervention.
`
`Limited patient availability has influenced the size of the database. Xyrem safety,
`efficacy, pharmacokinetics, abuse pharmacology, scheduling and risk management are
`summarized in this booklet from over 250 volumes of electronic and paper information '
`which has been submitted to FDA for review.
`
`This NDA was designated a priority by the FDA shortly after submission in recognition of
`the fact that narcolepsy is serious and debilitating with inadequate therapeutic options,
`particulariy for oataplexy. The compelling medical need of narcoleptic patients for
`additional therapeutic options is summarized in section 2.
`
`thGHEitPostNDAtAdvisory Meetingu'une 6-2001 Meetinngriefing BookstCover Letter.ch
`
`1
`
`Dedicated to Patients with Uncommon Diseases”
`
`1391 i Ridgedol'e Drive, Suite 250 ' Minneronko, Minnesota 55305
`
`9525136900 I Fax: 952-541-9209 ' morphoncom
`
`_ AMNLOQS
`_
`,
`.
`........ _
`IPR of US. Patent No. 7,765,106
`
`
`._
`
`AMN1005
`IPR of U.S. Patent No. 7,765,106
`
`

`

`
`
`Orphan Medical, inc.o
`NDA #21-196 Xyremo (sodium oxybate) oral solution
`Peripheral and Central Nervous System Drugs Advisory Committee Briefing Booklet
`
`The premise for approval for efficacy is based upon four double—blind controlled clinical
`trials. two of which were sponsored by the company and two of which were conducted
`by academics. one in the US and 'one in the Netherlands. Efficacy is summarized in
`section 3 of this booklet.
`
`The company has collected data from over 400 patients during the course of its two
`lNDs including a treatment IND approved by FDA in 1998 (section 4).
`In addition, an
`investigator"In this country has been treating a small group of patients (N=—143) for up to
`18 years under his IND The company has collected information from his database that
`reflects over 900 patient years of clinical safety data.
`Information from such a database
`is not usually available for a new chemical entity. Questions related to this database led
`to the cancellation of the initial advisory committee review scheduled for March 15‘“.
`The company has now addressed these questions and our response is under review by
`FDA. Overall the safety data set, while not large (604 patients and subjects), supports
`the safe use of Xyrem for the proposed indication.
`
`The phannaookinetics and abuse pharmacology are included for completeness in
`sections 5 and 6 respectively. Also included are sections dealing with scheduling and
`risk management.
`
`Public health issues related to GHB have been well recognized for over 10 years. FDA
`took action to remove GHB from the market in 1990 due to public health risks of abuse
`and its illegal promotion as a ‘dietary supplement’. FDA subsequently approached
`Orphan Medical to develop this compound in narcolepsy in 1994. FDA again took
`additional action when analogues began to surface over the last 5 years. The
`scheduling of Xyrem was completed in 2000 following extensive public debate in
`Congress with advice from FDA, DEA and other stakeholders. A federal law was
`enacted in 2000 to create a bifurcated schedule for GHB with all illicit use falling under
`schedule 1 and medical use placed into schedule 3. This law. along with the 2000
`World Health Organization expert working committee recommendation for schedule 4,
`and the HHS recommendation to Congress is included in section 7. Regrettably, these
`laws do not adequately address promotion of precursor chemicals as abuse alternatives
`to GHB.
`-
`
`The advisory committee has also been asked to review and discuss the risk
`management of Xyrem. Risk management refers to minimization of public health issues
`associated with a pharmaceutical product. There is no evidence that Xyrem has been
`diverted or used for any purpose but to evaluate its safety and efficacy in treating
`narcolepsy. We believe that the precautions included in the Company's post-marketing
`program will constrain in every way possible the risks associated with this medicine
`while allowing its use by patients to meet their medical needs. These precautions
`include mechanisms to educate physicians and patients about the proper use of Xyrem,
`the unique implications of the bifurcated schedule, as well as closed-loop prescription
`and distribution systems to restrict the opportunity for diversion or misuse.
`Included with
`this package of information from Orphan Medical is a short 8-minute video on the
`prescription process. along with patient and physician education materials (the two
`binders). The risk of diversion and abuse of Xyrem is further reduced when these post-
`
`(
`
`R:\GHB\PostNDA\Adviscry MeetingUune 6-2001 MeetingiBriefing BooksiCover Letter.doc
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`IPR of US. Patent No. 7,765,106
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`
`AMN1005
`IPR of U.S. Patent No. 7,765,106
`
`

`

`Orphan Medical, Inc.
`NDA #21-196 Xyrem” (sodium oxybate) oral solution
`Peripheral and Central Nervous System Drugs Advisory Committee Briefing Booklet
`
`marketing processes to which the Company has committed are combined with the
`It
`scheduling restrictions recommended by FDA and imposed by Public Law 106-172.
`should be noted that narcolepsy patients and their physicians are already very familiar
`with the responsible use of controlled substances since they typically manage symptoms
`with-schedule 2 amphetamine related medications and other medications in schedule 4.
`
`it is an unfortunate fact that illicit GHB substances, not Xyrer‘n, represent a risk to the
`public health. This risk will neither be increased by approval of Xyrem, nor decreased
`by denial of approval due to the easy availability of analogues of GHB. While Orphan
`Medical has no legal responsibility for the illicit use of GHB or its precursor chemicals,
`we have made a moral and practical commitment to assist the FDA, DEA and other law
`enforcement and abuse specialists in their efforts to minimize the public health risk of
`illicit GHB substances.
`
`Sodium oxybate, or gamma hydroxybutyrate, is defined as a new chemical entity since it
`has never been approved for human use in the United States. Products containing
`oxybate have been approved in Europe,as an anesthetic since the 19605, and in Italy
`for use in treatment of alcoholism since 1994. We believe the data presented herein
`establish the medical need, efficacy and safety of Xyrem, and provide the basis for our
`request for approval of the following proposed indication:
`
`Xyrem® (sodium oxybate) orai solution is indicated to reduce the
`incidence of catapiexy and to improve the symptom of daytime
`sieepiness in patients with narcoiepsy.
`
`Should you have any questions not addressed in this briefing booklet, please let us
`know through Dr. Sandra Titus. the Committee‘s Executive Secretary.
`
`Sincerely yours,
`
`Dayton T. Reardan. Ph.D., RAC
`Vice President of Regulatory Affairs
`Phone:
`(952) 513-6969
`FAX:
`(952) 541—9209
`E-mail: DReardan@0rphan.com
`
`cc:
`
`Russell Katz MD for NBA #21-196
`
`R:\GHB\Postl~lDA\Advisory MeetinglJune 6-2001 Meetingmrlefing Books\Cover Letterdoc
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`3
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`.AMN1.005_...E,
`.
`.
`.
`IPR of US. Patent No. 7,765,106
`
`
`AMN1005
`IPR of U.S. Patent No. 7,765,106
`
`

`

`Orphan Medical, Inc.
`NDA #21-196 Xyrem® (sodium oxybate) oral solution
`Peripheral and Central Nervous System Drugs Advisory Committee Briefing Booklet
`
`Xyrem® (sodium oxybate) oral solution
`
`NDA #21 -1 96
`
`Briefing Booklet for the
`Peripheral and Central Nervous
`System Drugs Advisory Committee Meeting
`
`June 6, 2001
`
`AVAILABLE FOR PUBLIC DISCLOSURE WITHOUT REDACTION
`
`RzlGHBlPoslNDMAdvisory MeetinglJune 6-2001 Meeting\Briefing Booksl‘l’ltle Page.doc
`
`1
`
`IPR of US. Patent No. 7,765,106
`
`
`AMNlOOS
`
`AMN1005
`IPR of U.S. Patent No. 7,765,106
`
`

`

`
`
`Orphan Medical, Inc.
`NDA #21-196 Xyrom® (sodium oxybate) oral solution
`Peripheral and Central Nervous System Drugs Advisory Committee Briefing Booklet
`
`SECTION 1
`
`TABLE OF CONTENTS,
`LIST OF ABBREVIATIONS,
`AND
`
`DEFINITION OF TERMS
`
`
`
`R:\GHB\PostNDA\Advisory Meetinngriefing Booleable of Contenlsdoc
`
`IPR of US. Patent No. 7,765,106
`
`
`AMNlOOS
`
`AMN1005
`IPR of U.S. Patent No. 7,765,106
`
`

`

`Orphan Medical, Inc.
`NDA #21-196 Xyrem® {sodium oxybate) oral solution
`Peripheral and Central Nervous System Drugs Advisory Committee Briefing Booklet
`
`1.0
`
`TABLE OF CONTENTS
`
`COVER LETTER
`
`TITLE PAGE
`
`Page
`
`1.0
`
`TABLE OF CONTENTS ........................................................................................ 1
`
`LIST OF TABLES................................................................................................ 12
`
`LIST OF FIGURES .............................................................................................. 17
`LIST OF ABBREVIATIONS................................................................................. 19
`
`DEFINITION OF TERMS ..................................................................................... 23
`
`2.0 MEDICAL NEED ................................................................................................. 25
`
`2.1 Disease and Pathogenesis ...................................................................... 26
`
`2.2 History....................................................................................................... 27
`
`2.3 Epidemiology ............................................................................................ 28
`
`2.4 Clinical Picture ......................................................................................... 29
`
`2.4.1
`2.4.2
`2.4.3
`2.4.4
`2.4.5
`
`EXCESSIVE DAYTIME SLEEPINESS (EDS) ............................... 29
`CATAPLEXY ................................................................................ 29
`SLEEP PARALYSIS ..................................................................... 30
`HYPNAGOGIC HALLUCINATIONS ............................................. 30
`OTHER SYMPTOMS ................................................................... 30
`
`2.5 Evolution of Narcolepsy .......................................................................... 30
`
`2.6 Psychosocial Impact of Narcolepsy........................................................ 31
`
`3.0
`
`EFFICACY .......................................................................................................... 34
`
`3.1 Controlled Studies ................................................................................... 35
`
`3.1.1
`
`OMC-GHB-Z ................................................................................. 35
`
`31 1 1 Study Objectives ............................................................. 36
`3 1 1 2
`Investigational Plan ........................................................ 36
`3.1.1.3 Discussion of Study Design ............................................ 37
`3.1.1.4 Assignment of Patients to Treatment Groups ................. 39
`31 15 Selection and Timing ofDose 39
`3 1
`1 6 Concomitant Medications ............................................... 39
`
`R:\GHB\PostNDA\Advisory Meetinngn‘efing BooktTable of Contentsdoc
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`2
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`:
`
`.
`I
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`IPR of US. Patent No. 7,765,106
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`
`AMNlOOS
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`AMN1005
`IPR of U.S. Patent No. 7,765,106
`
`

`

`
`
`Orphan Medical, Inc.
`NDA #21-196 )(yrem® {sodium oxybate) oral solution
`Peripheral and Central Nervous System Drugs Advisory Committee Briefing Booklet
`
`-
`
`TABLE OF CONTENTS (continued)
`
`£295
`
`3.1.1.7 Primary Efficacy Variable ................................................ 39
`3.1.1.8 Statistical and Analytical Plans ....................................... 39
`3.1. 1. 9 Determination ofSample Size ........................................ 41
`3.1 1.10 Disposition of Patients .................................................... 41
`3.1. 1.11 Data Sets Analyzed ........................................................ 42
`3.1.1.12 Demographic and Other Baseline Characteristics .......... 42
`3.1.1.13 Excessive Daytime Sieepine55...
`45
`3.1 1 14 Clinical Global Impression of Seventy (CGI-S)m............... 46
`3.1 1. 15 Analysis of Efficacy ......................................................... 47
`3.1.1.151
`Primary Efficacy Variable ........................... 47
`3.1.1.152
`Secondary Efficacy Variables ..................... 55
`3.1.1.153 Other Secondary Efficacy Measures .......... 60
`3.1.1.154 Abrupt Cessation of Double-Blind
`Medication .................................................. 62
`
`3.1.1.16 Efficacy Conclusions ...................................................... 63
`
`3.1.2
`
`SCRIMA TRIAL ............................................................................ 64
`
`3.1.2.1 Design ............................................................................ 64
`3.1.2.2 Objectives ....................................................................... 65
`3.1.2.3 Statistical Analysis .......................................................... 65
`3.1.2.4 Efficacy Results .............................................................. 66
`3.1.2.5 Conclusions .................................................................... 69
`
`3.1.3
`
`OMC—SXB—21 ............................................................................... 70
`
`3.1.3.1 Rationale for OMC-SXB—21 ............................................ 70
`
`3.1.3.2 Trial Objectives and Design ............................................ 70
`3.1.3.2.1
`Efficacy Objective ....................................... 70
`3.1.3.2.2
`Trial Design ................................................ 71
`3.1.3.2.3
`Patient Selection Criteria ............................ 71
`3.1 .3.2.4
`Treatments ................................................. 72
`
`Randomization and Blinding ....................... 72
`3.1.3.2.5
`Efficacy Measurements .............................. 72
`3.1.3.2.6
`Statistical Analysis ...................................... 72
`3.1.3.2.7
`3.1.3.3 Patient Disposition and Demographics........................... 73
`3.1.3.3.1
`Patient Disposition ...................................... 73
`3.1.3.3.2
`Patient Demographics ................................ 74
`3.1.3.4 Efficacy Evaluation ......................................................... 77
`31.3.4.1
`Treatment Compliance ............................... 77
`3.1.3.4.2
`Efficacy Results .......................................... 77
`3.1.3.4.3
`Efficacy Conclusions .................................. 84
`
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`AMN1005
`IPR of U.S. Patent No. 7,765,106
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`

`

`
`
`Orphan Medical, Inc.
`NDA #21-196 Xyrem® (sodium oxyba te) oral solution
`Peripheral and Central Nervous System Drugs Advisory Committee Briefing Booklet
`
`TABLE OF CONTENTS (continued)
`
`Page
`
`3.1.4
`
`LAMMERS TRIAL ......................................................................... 84
`
`3.1.4.1 Design ............................................................................ 84
`3.1.4.2 Objectives ....................................................................... 85
`3.1.4.3 Statistical Analysis .......................................................... 86
`3.1.4.4 Efficacy Results .............................................................. 86
`3.1.4.5 Conclusions .................................................................... 88
`
`3.2 Uncontrolled Studies ............................................................................... 88
`
`3.2.1
`
`OMC—GHB—3 ................................................................................. 88
`
`3.2.1.1 Trial Objectives and Design ............................................ 88
`32.1.1.1
`Objectives .................................................. 88
`3.2.1.1.2
`Trial Design ................................................ 88
`3.2.1 .13
`Patient Selection Criteria ............................ 89
`3.2.1 .1.4
`Treatments ................................................. 89
`
`Efficacy Measurements and Analysis ......... 90
`32.1.1.5
`Statistical and Analytical Plans ................... 90
`32.1.1.6
`3.2.1.2 Patient Disposition and Demographics ........................... 91
`3.2.1.2.1
`Patient Disposition ...................................... 91
`3.2.1.2.2
`Patient Demographics ................................ 94
`3.2.1.3 Efficacy Evaluation ......................................................... 95
`3.2.1.3.1
`Treatment Compliance ............................... 95
`3.2.1.3.2
`Efficacy Results .......................................... 95
`3.2.1.4 Conclusions .................................................................. 107
`
`3.2.2
`
`OMC-SXB-20 ............................................................................. 108
`
`3.2.2.1 Rationale ...................................................................... 108
`
`3.2.2.2 Trial Objectiveleesign ................................................. 109
`3.2.2.2.1
`Primary Measures .................................... 110
`3.2.2.2.2
`Secondary Measures................................ 111
`3.2.2.3 Patient Demographics .................................................. 112
`3.2.2.4 Efficacy Evaluation ....................................................... 113
`3.2.2.4.1
`Primary Variables ..................................... 113
`3.2.2.4.2
`Secondary Variables ................................ 118
`3.2.2.5 Conclusions and Discussion ......................................... 124
`3.2.2.5.1
`Conclusions.............................................. 124
`3.2.2.5.2
`Discussion ................................................ 125
`
`3.3 Efficacy Summary .................................................................................. 127
`
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`AMN1005
`IPR of U.S. Patent No. 7,765,106
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`
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`
`
`Orphan Medical, Inc.
`NDA #21-196 Xyrem” (sodium oxybate) oral solution
`Peripheral and Central Nervous System Drugs Advisory Committee Briefing Booklet
`
`TABLE OF CONTENTS (continued)
`
`Page
`
`4.0
`
`SAFETY ............................................................................................................ 129
`
`4.1 Overview of Sodium Oxybate Trials ..................................................... 130
`
`4.2 Drug Exposure ....................................................................................... 132
`
`4.3 Updated Integrated Clinical Trials ........................................................ 134
`
`4.3.1
`4.3.2
`4.3.3
`
`4.3.4
`4.3.5
`
`4.3.6
`4.3.7
`
`INCIDENCE OF ADVERSE EVENTS ......................................... 135
`SERIOUS ADVERSE EVENTS ................................................... 141
`DISCONTINUATIONS AND OTHER SIGNIFICANT ADVERSE
`EVENTS ..................................................................................... 142
`DEATHS ..................................................................................... 147
`LABORATORY RESULTS .......................................................... 147
`
`4.3.5.1 Blood Chemistry ........................................................... 147
`4.3.5.2 Hematology .................................................................. 147
`4.3.5.3 Urinalysis ...................................................................... 147
`VITAL SIGNS AND ECG ............................................................. 148
`SAFETY SUMMARY - UPDATED INTEGRATED CLINICAL
`
`TRIALS ....................................................................................... 148
`
`4.4 Lammers Trial ......................................................................................... 148
`
`4.5 Scharf Trial ............................................................................................. 149
`
`4.5.1
`
`4.5.2
`4.5.3
`
`4.5.4
`
`INCIDENCE OF ADVERSE EVENTS -— SCHARF TRIAL............ 150
`4.5.1.1 Adverse Events Over the First 6 Months ...................... 151
`SERIOUS ADVERSE EVENTS — SCHARF TRIAL ..................... 152
`DISCONTINUATIONS AND OTHER SIGNIFICANT ADVERSE
`EVENTS ..................................................................................... 154
`DEATHS — SCHARF TRIAL ....................................................... 155
`
`4.6 OMC-SXB-21 Trial .................................................................................. 155
`
`4.7 Safety Summary of the Pharmacokinetic Trials ................................... 156
`
`4.8 Adverse Events of Special Interest ....................................................... 158
`
`4.8.1
`
`ADVERSE EVENTS CODED AS CONFUSION .......................... 159
`
`4.8.1.1 Updated Integrated Clinical Trial Database .................. 159
`4.8.1.2 Analysis of Trial OMC—GHB—2 ....................................... 161
`4.8.1.3 Scharf Trial ................................................................... 161
`
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`IPR of U.S. Patent No. 7,765,106
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`

`

`Orphan Medical, Inc.
`NDA #21-196 Xyremé’ (sodium oxybate) oral solution
`Peripheral and Central Nervous System Drugs Advisory Committee Briefing Booklet
`
`TABLE OF CONTENTS (continued)
`
`Egg
`
`4.8.2
`
`ADVERSE EVENTS CODED AS CONVULSION ........................ 163
`
`163
`4.8.2.1 Updated Integrated ClinicaITrial Database
`4.8.2.2 Scharf Trial ................................................................... 165
`
`4.8.3
`
`NEUROPSYCHIATRIC ADVERSE EVENTS .............................. 167
`
`168
`4.8.3.1 Updated Integrated ClinicaITriaI Database
`4.8.3.2 Scharf Trial ................................................................... 170
`
`4.8.3.3 Depression ................................................................... 171
`4.8.3.3.1
`Updated Integrated Clinical Trial
`Database .................................................. 171
`
`Scharf Trial ............................................... 172
`4.8.3.3.2
`4.8.3.4 Hallucinations ............................................................... 173
`
`4.8.3.4.1
`
`4.8.3.4.2
`
`Updated Integrated Clinical Trial
`Database .................................................. 173
`Scharf Trial ............................................... 173
`
`4.8.3.5 Stupor ........................................................................... 173
`4.8.3.5.1
`Updated Integrated Clinical Trial
`Database .................................................. 173
`
`4.8.3.5.2
`
`Scharf Trial ............................................... 174
`
`4.8.3.6 Suicide Attempt, Overdose. Intentional Overdose ........ 174
`4.8.3.6.1
`Updated Integrated Clinical Trial
`Database .................................................. 174
`Scharf Trial ............................................... 175
`4.8.3.6.2
`4.8.3.7 Paranoid Reaction ........................................................ 175
`
`4.8.3.7.1
`
`Updated Integrated Clinical Trial
`Database .................................................. 175
`Scharf Trial ............................................... 176
`4.8.3.7.2
`4.8.3.8 Coma ............................................................................ 176
`
`4.8.3.8.1
`
`4.8.38.2
`
`Updated Integrated Clinical Trial
`Database .................................................. 176
`Scharf Trial ............................................... 176
`
`4.8.3.9 Psychosis ..................................................................... 177
`4.8.3.10 Manic Depressive Reaction .......................................... 177
`4.8.3.11 Personality Disorder ..................................................... 178
`4.8.3.12 Emotional Lability ......................................................... 178
`4.8.3.13 Thinking Abnormal ........................................................ 178
`4.8.3.14 Depersonalization ......................................................... 178
`4.8.3.15 Hostility .......................................................... . .............. 179
`4.8.3.16 Neurosis ....................................................................... 179
`
`4.8.4
`
`BLOOD GLUCOSE ..................................................................... 179
`
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`AMN1005
`IPR of U.S. Patent No. 7,765,106
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`

`Orphan Medical, Inc.
`NDA #21-196 Xyrem® {sodium oxybate) oral solution
`Peripheral and Central Nervous System Drugs Advisory Committee Briefing Booklet
`
`TABLE OF CONTENTS (continued)
`
`Page
`
`4.8.5
`
`DETAILED ANALYSIS OF ELEVATED ANTI-NUCLEAR
`ANTIBODY AND STUDY DRUG-RELATED LUPUS .................. 181
`4.8.5.1 Scharf Trial ................................................................... 181
`
`4.8.5.2 Updated Integrated Clinical Trial Database .................. 182
`
`4.8.6
`
`DETAILED ANALYSIS OF INCONTINENCE AEs AND
`
`RELATIONSHIP TO SEIZUROGENESIS ................................... 183
`
`4.8.6.1 Updated Integrated Clinical Trial Database .................. 183
`4.8.6.2 Scharf Trial ................................................................... 184
`
`4.8.7
`
`SUMMARY OF DISCONTINUED PATIENTS — SCHARF
`TRIAL ......................................................................................... 186
`
`4.8.8
`
`EVALUATION OF "REACTION UNEVALUABLE"
`PATIENTS - SCHARF TRIAL ..................................................... 192
`
`4.8.9 ADVERSE EVENTS: COMPARISON OF SODIUM
`OXYBATE AND PLACEBO IN CONTROLLED TRIALS .............. 193
`
`4.9 Other Safety Information ....................................................................... 195
`
`4.9.1
`
`ANALYSIS OF ADVERSE EVENT DOSE-RESPONSE
`INFORMATION ........................................................................... 195
`
`4.9.1.1 Dosage Justification ..................................................... 195
`4.9.1.1.1
`Historical Clinical Experience ................... 195
`4.9.1.1.2
`Dosage Justification ................................. 195
`4.9.1.2 Adverse Event Dose-Response Analysis ...................... 196
`LONG-TERM ADVERSE EVENTS ............................................. 197
`4.9.2
`4.9.3 WITHDRAWAL EFFECTS .......................................................... 197
`
`4.10 Safety Summary ..................................................................................... 198
`
`4.11 Overall Conclusion ................................................................................. 200
`
`5.0 PHARMACOKINETICS, DRUG INTERACTIONS, AND
`PHARMCODYNAMICS ...................................................................................... 201
`
`5.1 Human Pharmacokinetics and Drug Interactions Summary ..................... 202
`
`5.1.1
`
`NARRATIVE SUMMARIES FOR XYREM (SODIUM OXYBATE)
`ORAL SOLUTION BIOPHARMACEUTIC STUDIES ................... 202
`
`
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`IPR ofU.S. Patent No. 7,765,106
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`AMN 1005
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`AMN1005
`IPR of U.S. Patent No. 7,765,106
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`

`

`Orphan Medical, Inc.
`NDA #21-196 )(yrema (sodium oxybate) oral solution
`Peripheral and Central Nervous System Drugs Advisory Committee Briefing Booklet
`
`TABLE OF CONTENTS (continued)
`
`Page
`
`5.1.1.1 Pharmacokinetics of Sodium Oxybate in Oxybate—
`Experienced Narcoleptic Patients (OMC—GHB-4) ......... 203
`5.1.1.2 Pharmacokinetics of Sodium Oxybate After Single
`and Chronic(8-week) Dosing in Oxybate-na'ive
`Narcoleptic Patients) (OMC-SXB-i O) ........................... 204
`5.1.1.3 Pharmacokinetics of Sodium Oxybate in Healthy
`Male and Female Volunteers (OMC-SXB-S)................. 204
`5.1.1.4 Dose Proportionality of Sodium Oxybate
`(OMC-SXB-Q) ............................................................... 205
`5.1.1.5 Effect of Food on Pharmacokinetics of Sodium
`
`Oxybate (OMC—SXB—1 1) ............................................... 206
`5.1.1.6 Hypnotic Drug Interaction: Sodium Oxybate and
`Zolpidem (OMC-SXB-12) .............................................. 208
`5.1.1.7 Antidepressant Drug Interaction: Sodium Oxybate
`and Protriptyline (OMC-SXB-14) ................................... 208
`5.1.1.8 Stimulant Drug Interaction: Sodium Oxybate and
`Modafinil (OMGSXB-17) .............................................. 209
`5.1.1.9 Potential for Drug interaction Through Inhibition
`of Cytochrome P450 lsozymes (Covance Study
`No. 6627-129) .............................................................. 210
`PHARMACOKINETICS OF SODIUM OXYBATE ........................ 211
`
`5.1.2.1 Absorption .................................................................... 214
`5.1.2.2 Distribution ................................................................... 214
`5.1.2.3 Metabolism ................................................................... 215
`5.1.2.4 Elimination .................................................................... 218
`5.1.2.5 Other Pharmacokinetic Considerations ........................ 219
`5125.1
`Non-linear Pharmacokinetics .................... 219
`51.252
`Chronic Pharmacokinetics ........................ 219
`
`Drug Interactions ...................................... 219
`5.1253
`5.1.2.6 Pharmacokinetics in Special Populations ..................... 219
`512.61
`Sex—related Differences ............................ 219
`
`51.262
`5.1.2.6.3
`5.1.2.6.4
`
`Hepatic Dysfunction ................................. 219
`Alcohol-Dependent Patients ..................... 220
`Pediatric Patients ..................................... 220
`
`5.1.2
`
`5.1.3
`
`Patients with Renal Dysfunction ............... 220
`5.1.2.6.5
`OVERALL CONCLUSIONS ........................................................ 220
`
`6.0 ABUSE LIABILITY AND OVERDOSAGE .......................................................... 222
`
`6.1 Abuse Liability ........................................................................................ 223
`
`6.1.1
`
`INTRODUCTION ........................................................................ 223
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`R:\GHEI\P05INDA\Advisory MeetingIBriefing Book\TabIe of Contentsdoc
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`8
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`AMN1005
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`
`IPR of US. Patent No. 7,765,106
`
`
`AMN1005
`IPR of U.S. Patent No. 7,765,106
`
`

`

`
`
`Orphan Medical, Inc.
`NDA #21-196 )(yrem® (sodium oxybate) oral solution
`Peripheral and Central Nervous System Drugs Advisory Committee Briefing Booklet
`
`TABLE OF CONTENTS (continued)
`
`Page
`
`6.1.2
`6.1.3
`6.1.4
`
`GHB MISUSE AND ABUSE ........................................................ 223
`EXTENT OF THE PROBLEM OF GHB ABUSE .......................... 224
`PRECLINICAL STUDIES RELEVANT TO ASSESSMENT
`OF ABUSE POTENTIAL OF GHB
`
`227
`
`6.1.4.1 Drug Discrimination ...................................................... 227
`6.1.4.2 Tolerance and Dependence ......................................... 228
`6.1.4.3 Drug Self-Administration and Related Studies .............. 228
`6.1.4.4 College on Problems of Drug Dependence
`Testing Program ........................................................... 230
`6.1.4.5 Conclusions .................................................................. 232
`TABULAR SUMMARIES OF PRECLINICAL STUDIES
`RELEVANT TO ABUSE POTENTIAL ASSESSMENT ................ 233
`
`6.1.5
`
`6.2 Overdosage ............................................................................................ 237
`
`7.0
`
`SCHEDULING ................................................................................................... 239
`
`7.1
`
`Introduction ............................................................................................ 240
`
`7.2
`
`The Scheduling of GHB ......................................................................... 241
`
`7.3
`
`The HHS — FDA — NIDA Recommendation
`
`242
`
`7.4
`
`Public Law 106-172 ................................................................................ 244
`
`7.5