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,
`clo Dr. Sandra Titus; 301-827-T001
`
`Subject:
`
`Xyremfi’ (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
`
`T 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, pharmaookinetics, 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 Meetinguune 6-2001 Meetinglflriefing Bookslcover Letter.doc
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`.Dedr'cafed to Patients vvilth Uncommon Diseases”
`
`i391 i Ridgedoie Drive, Suite 250 ' Minneronka, Minnesota 55305
`
`952-5 i'3<§9OO ' Fax: 952-541-9209 0 wvvw_orphcm.com
`
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`Orphan Medical, inc.
`NBA #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-
`
`i
`
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`Orphan Medical, Inc.
`NDA #21-196 Xyrerna’ (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 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
`iilicit 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
`sieepiness in patients with narcofepsy.
`
`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 NDA #21-196
`
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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 -1 96
`
`Briefing Booklet for the
`Peripheral and Central Nervous
`System Drugs Advisory Committee Meeting
`
`June 6, 2001
`
`AVAILABLE FOR PUBLIC DISCLOSURE WITHOUT REDACTION
`
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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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`Orphan Medical, Inc.
`NDA #21-196 Xyrems {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-2 ............................................................................... .. 35
`
`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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`Orphan Medical, Inc.
`NDA #21-196 Xyrema {sodium oxybate) oral solution
`Peripheral and Central Nervous System Drugs Advisory Committee Briefing Booklet
`
`-
`
`TABLE OF CONTENTS (continued)
`
`E292
`
`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
`3.1.1.15.1
`Primary Efficacy Variable ......................... .. 47
`3.1.1.152
`Secondary Efficacy Variables ................... .. 55
`3.1.1.15.3 Other Secondary Efficacy Measures ........ .. 60
`3.1.1 .15.4 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
`
`OIVIC-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
`3.1.32.5
`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
`3.1.3.4-.1
`Treatment Compliance ............................. .. 77
`3.1.3.4.2
`Efficacy Results ........................................ .. 77
`3.13.4.3
`Efficacy Conclusions ................................ .. 84
`
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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 .1.3
`Patient Selection Criteria .......................... .. 89
`3.2.1.1.4
`Treatments ............................................... .. 89
`
`Efficacy Measurements and Analysis ....... .. 90
`3.2.1.1.5
`Statistical and Analytical Plans ................. .. 90
`3.2.1.1.6
`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 0bjectivesIDesign ............................................... .. 109
`32.2.2.1
`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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`NDA #21 -1 96 Xyremfi’ (sodium oxybate) oral solution
`Peripheral and Central Nervous System Drugs Advisory Committee Briefing Booklet
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`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 TR|AL............ 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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`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)
`
`392
`
`4.8.2
`
`ADVERSE EVENTS CODED AS CONVULSION ...................... .. 163
`
`163
`4.8.2.1 Updated Integrated CIInicalTria| Database
`4.8.2.2 Scharf Trial ................................................................. .. 165
`
`4.8.3
`
`NEUROPSYCHIATRIC ADVERSE EVENTS ............................ .. 167
`
`168
`4.8.3.1 Updated Integrated C|inicalTrial 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
`
`48.3.4.1
`
`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
`
`4.8.37.1
`
`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
`
`4.83.8.2
`
`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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`Orphan Medical, In c.
`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 CIinica|Tria| 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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`Orphan Medical, Inc.
`NDA #21-196 Xyrems (sodium oxybate) oral solution
`Peripheral and Central Nervous System Drugs Advisory Committee Briefing Booklet
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`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-naive
`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 (OMOSXB-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
`5.1.2.5.1
`Non—linear Pharmacokinetics .................. .. 219
`5.1.2.5.2
`Chronic Pharmacokinetics ...................... .. 219
`
`Drug Interactions .................................... .. 219
`5.1.2.5.3
`5.1.2.6 Pharmacokinetics in Special Populations ................... .. 219
`5.1.2.6.1
`Sex—related Differences .......................... .. 219
`
`5.1.2.6.2
`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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`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)
`
`3%
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`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 WHO Recommendation ....................................................................... .. 244
`
`7.6 Conclusion ............................................................................................ .. 244
`
`ATTACHMENT 1: David Satcher, MD, PhD (DHHS) Letter (May 19, 1999),
`Gamma Hydroxybutyrate: Eight Factor Analysis
`(September 1997),