jllI~
`II
`IIORPHAN II
`~III' M E D I ( A L
`
`May 3,2001
`
`Advisors and Consultants Staff
`Center for Drug Evaluation and Research, ORM
`Food and Drug Administration
`HFD-21, Room 1093
`5630 Fishers Lane
`Rockville, MD 20852
`Peripheral and Central Nervous System Drugs Advisory Committee,
`c/o Dr. Sandra Titus; 301-827-7001
`
`Subject:
`
`Xyrem® (sodium oxybate) oral solution, NDA #21-196
`USER FEE NUMBER 3,814, ORPHAN DESIGNATION NUMBER 94-858
`
`Peripheral and Central Nervous System Drugs Advisory Committee
`Briefing Booklet for June 6, 2001 Presentation
`
`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 due 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,
`particularly for cataplexy. The compelling medical need of narcoleptic patients for
`additional therapeutic options is summarized in section 2.
`
`R:\GHB\PostNDA\Advisory Meeting\June 6-2001 Meeting\Briefing Books\Cover Letter.doc
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`Dedicated to Patients with Uncommon Disease~
`/39/ / Ridgedale Drive, Suite 250 • Minnetonka, Minnesota 55305
`952-5/3-6900 • Fax: 952-54/-9209 • wvvvv.orphan.com
`
`PAR1005
`IPR of U.S. Patent No. 8,731,963
`Page 1 of 353
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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
`
`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
`INDs, 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 15th
`•
`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 pharmacokinetics 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-
`
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`PAR1005
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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
`
`marketing processes to which the Company has committed are combined with the
`scheduling restrictions recommended by FDA and imposed by Public Law 106-172. It
`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 Xyrem, 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 1960s, 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) oral solution is indicated to reduce the
`incidence of cataplexy and to improve the symptom of daytime
`sleepiness in patients with narcolepsy.
`
`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@Orphan.com
`
`cc:
`
`Russell Katz MD for NDA#21-196
`
`R:\GHB\PostNDA\Advisory Meeting\June 6-2001 Meeting\Briefing Books\Cover Letter.doc
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`PAR1005
`IPR of U.S. Patent No. 8,731,963
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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
`
`
`Xyrem® (sodium oxybate) oral solution
`
`NDA #21-196
`
`
`
`Briefing Booklet for the
`Peripheral and Central Nervous
`System Drugs Advisory Committee Meeting
`
`
`
`
`
`June 6, 2001
`
`AVAILABLE FOR PUBLIC DISCLOSURE WITHOUT REDACTION
`
`R:\GHB\PostNDA\Advisory Meeting\June 6-2001 Meeting\Briefing Books\Title Page.doc
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`PAR1005
`IPR of U.S. Patent No. 8,731,963
`Page 4 of 353
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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
`
`
`SECTION 1
`TABLE OF CONTENTS,
`LIST OF ABBREVIATIONS,
`AND
`DEFINITION OF TERMS
`
`
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`Page
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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
`
`1.0
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`TABLE OF CONTENTS
`
`
`
`COVER LETTER
`
`TITLE PAGE
`
`1.0 TABLE OF CONTENTS ........................................................................................ 1
`
`LIST OF TABLES................................................................................................ 12
`LIST OF FIGURES.............................................................................................. 17
`LIST OF ABBREVIATIONS................................................................................. 19
`DEFINITION OF TERMS..................................................................................... 23
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`2.0 MEDICAL NEED ................................................................................................. 25
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`3.0 EFFICACY .......................................................................................................... 34
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`3.1 Controlled Studies ................................................................................... 35
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`3.1.1 OMC-GHB-2................................................................................. 35
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`3.1.1.1 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
`3.1.1.5 Selection and Timing of Dose......................................... 39
`3.1.1.6 Concomitant Medications ............................................... 39
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`2.1 Disease and Pathogenesis ...................................................................... 26
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`2.2 History....................................................................................................... 27
`
`2.3 Epidemiology............................................................................................ 28
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`2.4 Clinical Picture ......................................................................................... 29
`
`2.4.1
`EXCESSIVE DAYTIME SLEEPINESS (EDS)............................... 29
`
`2.4.2 CATAPLEXY ................................................................................ 29
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`2.4.3
`SLEEP PARALYSIS..................................................................... 30
`
`2.4.4 HYPNAGOGIC HALLUCINATIONS ............................................. 30
`
`2.4.5 OTHER SYMPTOMS ................................................................... 30
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`2.5 Evolution of Narcolepsy .......................................................................... 30
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`2.6 Psychosocial Impact of Narcolepsy........................................................ 31
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`PAR1005
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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)
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`3.1.1.7 Primary Efficacy Variable................................................ 39
`3.1.1.8 Statistical and Analytical Plans ....................................... 39
`3.1.1.9 Determination of Sample 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 Sleepiness ....................................... 45
`3.1.1.14 Clinical Global Impression of Severity (CGI-S) ............... 46
`3.1.1.15 Analysis of Efficacy......................................................... 47
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`3.1.1.15.1 Primary Efficacy Variable ........................... 47
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`3.1.1.15.2 Secondary Efficacy Variables..................... 55
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`3.1.1.15.3 Other Secondary Efficacy Measures .......... 60
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`3.1.1.15.4 Abrupt Cessation of Double-Blind
`Medication.................................................. 62
`3.1.1.16 Efficacy Conclusions ...................................................... 63
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`3.1.2
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`SCRIMA TRIAL ............................................................................ 64
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`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
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`3.1.3 OMC-SXB-21 ............................................................................... 70
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`3.1.3.1 Rationale for OMC-SXB-21 ............................................ 70
`3.1.3.2 Trial Objectives and Design............................................ 70
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`3.1.3.2.1
`Efficacy Objective....................................... 70
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`3.1.3.2.2
`Trial Design................................................ 71
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`3.1.3.2.3
`Patient Selection Criteria............................ 71
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`3.1.3.2.4
`Treatments................................................. 72
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`3.1.3.2.5
`Randomization and Blinding....................... 72
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`3.1.3.2.6
`Efficacy Measurements .............................. 72
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`3.1.3.2.7
`Statistical Analysis...................................... 72
`3.1.3.3 Patient Disposition and Demographics ........................... 73
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`3.1.3.3.1
`Patient Disposition...................................... 73
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`3.1.3.3.2
`Patient Demographics ................................ 74
`3.1.3.4 Efficacy Evaluation ......................................................... 77
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`3.1.3.4.1
`Treatment Compliance ............................... 77
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`3.1.3.4.2
`Efficacy Results.......................................... 77
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`3.1.3.4.3
`Efficacy Conclusions .................................. 84
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`PAR1005
`IPR of U.S. Patent No. 8,731,963
`Page 7 of 353
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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)
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`LAMMERS TRIAL......................................................................... 84
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`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
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`3.2 Uncontrolled Studies ............................................................................... 88
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`3.2.1 OMC-GHB-3................................................................................. 88
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`3.2.1.1 Trial Objectives and Design............................................ 88
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`3.2.1.1.1 Objectives .................................................. 88
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`3.2.1.1.2
`Trial Design................................................ 88
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`3.2.1.1.3
`Patient Selection Criteria............................ 89
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`3.2.1.1.4
`Treatments................................................. 89
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`3.2.1.1.5
`Efficacy Measurements and Analysis ......... 90
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`3.2.1.1.6
`Statistical and Analytical Plans ................... 90
`3.2.1.2 Patient Disposition and Demographics ........................... 91
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`3.2.1.2.1
`Patient Disposition...................................... 91
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`3.2.1.2.2
`Patient Demographics ................................ 94
`3.2.1.3 Efficacy Evaluation ......................................................... 95
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`3.2.1.3.1
`Treatment Compliance ............................... 95
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`3.2.1.3.2
`Efficacy Results.......................................... 95
`3.2.1.4 Conclusions.................................................................. 107
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`3.2.2 OMC-SXB-20 ............................................................................. 108
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`3.2.2.1 Rationale ...................................................................... 108
`3.2.2.2 Trial Objectives/Design................................................. 109
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`3.2.2.2.1
`Primary Measures .................................... 110
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`3.2.2.2.2
`Secondary Measures................................ 111
`3.2.2.3 Patient Demographics .................................................. 112
`3.2.2.4 Efficacy Evaluation ....................................................... 113
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`3.2.2.4.1
`Primary Variables ..................................... 113
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`3.2.2.4.2
`Secondary Variables ................................ 118
`3.2.2.5 Conclusions and Discussion......................................... 124
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`3.2.2.5.1
`Conclusions.............................................. 124
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`3.2.2.5.2
`Discussion................................................ 125
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`3.3 Efficacy Summary .................................................................................. 127
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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
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`4.0 SAFETY ............................................................................................................ 129
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`4.1 Overview of Sodium Oxybate Trials ..................................................... 130
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`4.2 Drug Exposure ....................................................................................... 132
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`4.3 Updated Integrated Clinical Trials ........................................................ 134
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`INCIDENCE OF ADVERSE EVENTS ......................................... 135
`4.3.1
`4.3.2 SERIOUS ADVERSE EVENTS................................................... 141
`4.3.3 DISCONTINUATIONS AND OTHER SIGNIFICANT ADVERSE
`EVENTS ..................................................................................... 142
`4.3.4 DEATHS..................................................................................... 147
`4.3.5
`LABORATORY RESULTS .......................................................... 147
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`4.3.5.1 Blood Chemistry ........................................................... 147
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`4.3.5.2 Hematology .................................................................. 147
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`4.3.5.3 Urinalysis...................................................................... 147
`4.3.6 VITAL SIGNS AND ECG............................................................. 148
`4.3.7 SAFETY SUMMARY – UPDATED INTEGRATED CLINICAL
`TRIALS ....................................................................................... 148
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`4.4 Lammers Trial......................................................................................... 148
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`4.5 Scharf Trial ............................................................................................. 149
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`INCIDENCE OF ADVERSE EVENTS – SCHARF TRIAL............ 150
`4.5.1
`4.5.1.1 Adverse Events Over the First 6 Months ...................... 151
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`4.5.2 SERIOUS ADVERSE EVENTS – SCHARF TRIAL ..................... 152
`4.5.3 DISCONTINUATIONS AND OTHER SIGNIFICANT ADVERSE
`EVENTS ..................................................................................... 154
`4.5.4 DEATHS – SCHARF TRIAL ....................................................... 155
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`4.6 OMC-SXB-21 Trial .................................................................................. 155
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`4.7 Safety Summary of the Pharmacokinetic Trials................................... 156
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`4.8 Adverse Events of Special Interest....................................................... 158
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`4.8.1 ADVERSE EVENTS CODED AS CONFUSION.......................... 159
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`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. 8,731,963
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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)
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`4.8.2 ADVERSE EVENTS CODED AS CONVULSION........................ 163
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`4.8.2.1 Updated Integrated Clinical Trial Database .................. 163
`4.8.2.2 Scharf Trial................................................................... 165
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`4.8.3 NEUROPSYCHIATRIC ADVERSE EVENTS .............................. 167
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`4.8.3.1 Updated Integrated Clinical Trial Database .................. 168
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`4.8.3.2 Scharf Trial................................................................... 170
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`4.8.3.3 Depression ................................................................... 171
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`4.8.3.3.1
`Updated Integrated Clinical Trial
`Database.................................................. 171
`Scharf Trial............................................... 172
`4.8.3.3.2
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`4.8.3.4 Hallucinations ............................................................... 173
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`4.8.3.4.1
`Updated Integrated Clinical Trial
`Database.................................................. 173
`Scharf Trial............................................... 173
`4.8.3.4.2
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`4.8.3.5 Stupor........................................................................... 173
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`4.8.3.5.1
`Updated Integrated Clinical Trial
`Database.................................................. 173
`Scharf Trial............................................... 174
`4.8.3.5.2
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`4.8.3.6 Suicide Attempt, Overdose, Intentional Overdose ........ 174
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`4.8.3.6.1
`Updated Integrated Clinical Trial
`Database.................................................. 174
`Scharf Trial............................................... 175
`4.8.3.6.2
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`4.8.3.7 Paranoid Reaction ........................................................ 175
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`4.8.3.7.1
`Updated Integrated Clinical Trial
`Database.................................................. 175
`Scharf Trial............................................... 176
`4.8.3.7.2
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`4.8.3.8 Coma............................................................................ 176
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`4.8.3.8.1
`Updated Integrated Clinical Trial
`Database.................................................. 176
`Scharf Trial............................................... 176
`4.8.3.8.2
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`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
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`4.8.4 BLOOD GLUCOSE..................................................................... 179
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`NDA #21-196 Xyrem® (sodium oxybate) oral solution
`Peripheral and Central Nervous System Drugs Advisory Committee Briefing Booklet
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`TABLE OF CONTENTS (continued)
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`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
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`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
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`4.8.7 SUMMARY OF DISCONTINUED PATIENTS – SCHARF
`TRIAL ......................................................................................... 186
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`4.8.8 EVALUATION OF “REACTION UNEVALUABLE”
`PATIENTS - SCHARF TRIAL ..................................................... 192
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`4.8.9 ADVERSE EVENTS: COMPARISON OF SODIUM
`OXYBATE AND PLACEBO IN CONTROLLED TRIALS.............. 193
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`4.9 Other Safety Information ....................................................................... 195
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`4.9.1 ANALYSIS OF ADVERSE EVENT DOSE-RESPONSE
`INFORMATION........................................................................... 195
`4.9.1.1 Dosage Justification ..................................................... 195
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`4.9.1.1.1
`Historical Clinical Experience ................... 195
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`4.9.1.1.2
`Dosage Justification ................................. 195
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`4.9.1.2 Adverse Event Dose-Response Analysis...................... 196
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`LONG-TERM ADVERSE EVENTS ............................................. 197
`4.9.2
`4.9.3 WITHDRAWAL EFFECTS.......................................................... 197
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`4.10 Safety Summary ..................................................................................... 198
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`4.11 Overall Conclusion................................................................................. 200
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`5.1 Human Pharmacokinetics and Drug Interactions Summary ..................... 202
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`5.1.1 NARRATIVE SUMMARIES FOR XYREM (SODIUM OXYBATE)
`ORAL SOLUTION BIOPHARMACEUTIC STUDIES ................... 202
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`5.0 PHARMACOKINETICS, DRUG INTERACTIONS, AND
`PHARMCODYNAMICS...................................................................................... 201
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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
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`TABLE OF CONTENTS (continued)
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`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-naïve
`Narcoleptic Patients) (OMC-SXB-10) ........................... 204
`5.1.1.3 Pharmacokinetics of Sodium Oxybate in Healthy
`Male and Female Volunteers (OMC-SXB-8)................. 204
`5.1.1.4 Dose Proportionality of Sodium Oxybate
`(OMC-SXB-9) ............................................................... 205
`5.1.1.5 Effect of Food on Pharmacokinetics of Sodium
`Oxybate (OMC-SXB-11)............................................... 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 (OMC-SXB-17) .............................................. 209
`5.1.1.9 Potential for Drug Interaction Through Inhibition
`of Cytochrome P450 Isozymes (Covance Study
`No. 6627-129) .............................................................. 210
`5.1.2 PHARMACOKINETICS OF SODIUM OXYBATE ........................ 211
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`5.1.2.1 Absorption .................................................................... 214
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`5.1.2.2 Distribution ................................................................... 214
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`5.1.2.3 Metabolism ................................................................... 215
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`5.1.2.4 Elimination.................................................................... 218
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`5.1.2.5 Other Pharmacokinetic Considerations ........................ 219
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`5.1.2.5.1
`Non-linear Pharmacokinetics.................... 219
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`5.1.2.5.2
`Chronic Pharmacokinetics........................ 219
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`5.1.2.5.3
`Drug Interactions...................................... 219
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`5.1.2.6 Pharmacokinetics in Special Populations ..................... 219
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`5.1.2.6.1
`Sex-related Differences............................ 219
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`5.1.2.6.2
`Hepatic Dysfunction ................................. 219
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`5.1.2.6.3
`Alcohol-Dependent Patients ..................... 220
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`5.1.2.6.4
`Pediatric Patients ..................................... 220
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`5.1.2.6.5
`Patients with Renal Dysfunction ............... 220
`5.1.3 OVERALL CONCLUSIONS ........................................................ 220
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`6.0 ABUSE LIABILITY AND OVERDOSAGE.......................................................... 222
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`6.1 Abuse Liability........................................................................................ 223
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`6.1.1
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`INTRODUCTION ........................................................................ 223
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