DIVISION OF NEUROPHARMACOLOGICAL DRUG PRODUCTS
`
`PRELIMINARY CLINICAL SAFETY REVIEW OF NDA
`
`Brand Name:
`
`Xyrem
`
`Generic Name:
`
`Sodium Oxybate
`
`Sponsor:
`
`Orphan Medical, Inc.
`
`Indication:
`
`Narcolepsy
`
`NDA Number:
`
`21196
`
`Original Receipt Date:
`
`10/3/00
`
`Clinical Reviewer:
`
`Ranjit B. Mani, M.D.
`
`Review Author:
`
`Ranjit B. Mani, M.D.
`
`Review Completed:
`
`5/3/01
`
`PAR1004
`IPR of U.S. Patent No. 8,731,963
`Page 1 of 122
`
`

`
`Ranjit B. Mani, MD, HFD-120 Medical Review
`NDA 21196, Xyrem, Orphan Medical, Inc.
`
`Page 2 of 122
`5/3/01
`
`Table of Contents
`
`1.
`
`2.
`
`3.
`
`4.
`
`5.
`
`6.
`
`7.
`
`8.
`
`REVIEW SOURCES .......................................................................................................................... 7
`1.1 MATERIALS FROM NDA.................................................................................................................... 7
`1.2 RELATED REVIEWS, CONSULTS......................................................................................................... 7
`1.3 OTHER REVIEWS ............................................................................................................................... 7
`BACKGROUND.................................................................................................................................. 8
`2.1
`INDICATION....................................................................................................................................... 8
`IMPORTANT INFORMATION FROM PHARMACOLOGICALLY RELATED AGENTS..................................... 8
`2.2
`2.3 ADMINISTRATIVE HISTORY ............................................................................................................... 8
`PROPOSED LABELING ........................................................................................................................ 8
`2.4
`FOREIGN MARKETING ....................................................................................................................... 8
`2.5
`2.6 MISCELLANEOUS BACKGROUND INFORMATION................................................................................ 9
`CHEMISTRY, MANUFACTURING AND CONTROLS............................................................... 9
`
`TOXICOLOGY................................................................................................................................. 10
`
`CLINICAL DATA SOURCES......................................................................................................... 10
`5.1
`SOURCES OF ALL DATA IN INTEGRATED SUMMARY OF SAFETY..................................................... 10
`5.1.1
`Study Type............................................................................................................................. 10
`5.1.2
`Number Of Unique Narcoleptic Patients And Healthy Subjects In Integrated Summary Of
`Safety
`11
`5.1.3
`Demographics....................................................................................................................... 12
`5.1.4
`Extent of Exposures............................................................................................................... 13
`5.2 CUT-OFF DATE FOR DATA IN INTEGRATED SUMMARY OF SAFETY................................................ 14
`PRIMARY DATA SOURCES ............................................................................................................... 14
`5.3
`5.3.1
`Efficacy And Long-Term Safety Studies................................................................................ 14
`5.3.2
`Pharmacokinetic Studies....................................................................................................... 15
`SECONDARY DATA SOURCES .......................................................................................................... 15
`5.4
`5.5 OTHER DATA SOURCES................................................................................................................... 15
`5.6 ADEQUACY OF HUMAN EXPERIENCE............................................................................................... 16
`5.7 DATA QUALITY AND COMPLETENESS.............................................................................................. 16
`HUMAN PHARMACOKINETICS ................................................................................................. 16
`
`TABULAR SUMMARY OF KEY EFFICACY STUDIES............................................................ 17
`7.1
`STUDY OMC-GHB-2 ...................................................................................................................... 17
`SCRIMA STUDY................................................................................................................................ 17
`7.2
`7.3 LAMMERS STUDY............................................................................................................................ 18
`STUDY OMC-SXB-21..................................................................................................................... 18
`7.4
`INTEGRATED REVIEW OF SAFETY ......................................................................................... 18
`8.1 BACKGROUND AND METHODOLOGY ............................................................................................... 18
`8.2 DEATHS........................................................................................................................................... 19
`8.2.1
`Tabular Summary Of Deaths ................................................................................................ 19
`8.2.2
`Conclusions Regarding Deaths............................................................................................. 19
`SERIOUS ADVERSE EVENTS............................................................................................................. 19
`8.3
`8.3.1
`Serious Adverse Events In Integrated Clinical Trials ........................................................... 20
`8.3.2
`Serious Adverse Events In Scharf Study................................................................................ 23
`8.4 DROPOUTS AND “OTHER SIGNIFICANT ADVERSE EVENTS”............................................................. 25
`8.4.1
`Adverse Event Discontinuations In Integrated Clinical Trials ............................................. 26
`8.4.2
`Adverse Event Discontinuations In Scharf Trial................................................................... 31
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`IPR of U.S. Patent No. 8,731,963
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`

`
`Ranjit B. Mani, MD, HFD-120 Medical Review
`NDA 21196, Xyrem, Orphan Medical, Inc.
`
`Page 3 of 122
`5/3/01
`
`Adverse Event Discontinuations In Integrated Pharmacokinetic Trials ............................... 35
`8.4.3
`8.5 ADVERSE EVENTS INCIDENCE TABLES............................................................................................ 35
`8.5.1
`Approach to Eliciting Adverse Events................................................................................... 35
`8.5.2
`Adverse Events Categorization and Preferred Terms........................................................... 36
`8.5.3
`Key Adverse Events Tables ................................................................................................... 36
`8.5.4
`Common and Drug-Related Side Effects............................................................................... 41
`8.5.5
`Additional Analyses and Explorations.................................................................................. 42
`8.6 LABORATORY FINDINGS.................................................................................................................. 56
`8.6.1
`Extent of Laboratory Testing During Development.............................................................. 56
`8.6.2
`Selection of Studies for Overall Drug-Control Comparisons And Other Analyses............... 57
`8.6.3
`Standard Analyses and Explorations of Laboratory Data .................................................... 57
`8.7 VITAL SIGNS ................................................................................................................................... 64
`8.7.1
`Extent of Vital Sign Testing During Development ................................................................ 64
`8.7.2
`Selection of Studies for Overall Drug-Control Comparisons And Other Analyses............... 65
`8.7.3
`Standard Analyses and Explorations of Vital Sign Data ...................................................... 65
`8.8 ECG................................................................................................................................................ 67
`8.8.1
`Extent of Electrocardiogram Testing During Development.................................................. 67
`8.8.2
`Selection of Studies for Overall Drug-Control Comparisons And Other Analyses............... 67
`8.8.3
`Standard Analyses and Explorations of Electrocardiogram Data........................................ 67
`8.9 WITHDRAWAL PHENOMENON AND ABUSE POTENTIAL ................................................................... 70
`8.9.1
`Background........................................................................................................................... 70
`8.9.2
`Purposes For Which GHB Is Misused Or Abused ................................................................ 70
`8.9.3
`Clinical Psychological And Physical Dependence In Humans............................................. 70
`8.9.4
`Rebound Symptoms With GHB Withdrawal.......................................................................... 71
`8.9.5
`Extent Of GHB Abuse In The United States.......................................................................... 72
`8.9.6
`Pre-Clinical Studies Of Drug Abuse Potential ..................................................................... 72
`HUMAN REPRODUCTION DATA................................................................................................... 72
`8.10
`OVERDOSE.................................................................................................................................. 73
`8.11
`8.11.1 Background........................................................................................................................... 73
`8.11.2 Clinical Presentation ............................................................................................................ 73
`8.11.3 Treatment .............................................................................................................................. 74
`STUDY OMC-SXB-20 ...................................................................................................................... 74
`9.1 OBJECTIVES..................................................................................................................................... 74
`9.1.1
`Primary ................................................................................................................................. 74
`9.1.2
`Secondary.............................................................................................................................. 74
`9.2 DESIGN/SUMMARY OF INVESTIGATIONAL PLAN.............................................................................. 75
`9.2.1
`Phase I .................................................................................................................................. 75
`9.2.2
`Phase II................................................................................................................................. 75
`9.3 DURATION....................................................................................................................................... 75
`SAMPLE SIZE ................................................................................................................................... 75
`9.4
`9.5 KEY INCLUSION CRITERIA............................................................................................................... 75
`9.6 KEY EXCLUSION CRITERIA.............................................................................................................. 76
`9.7 DOSAGE .......................................................................................................................................... 76
`9.8 OUTCOME MEASURES ..................................................................................................................... 76
`9.8.1
`Primary Efficacy Measures................................................................................................... 76
`9.8.2
`Secondary Efficacy Measures ............................................................................................... 77
`9.8.3
`Safety Measures .................................................................................................................... 77
`9.9 ANALYSIS PLAN .............................................................................................................................. 77
`RESULTS..................................................................................................................................... 78
`9.10
`9.10.1 Patient Disposition................................................................................................................ 78
`9.10.2 Baseline And Demographic Characteristics ......................................................................... 78
`9.10.3 Tricyclic Antidepressants, Selective Serotonin Re-Uptake Inhibitors And Hypnotics At
`Baseline 78
`9.10.4 Protocol Deviations .............................................................................................................. 78
`9.10.5 Treatment Compliance.......................................................................................................... 79
`
`9.
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`IPR of U.S. Patent No. 8,731,963
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`

`
`Ranjit B. Mani, MD, HFD-120 Medical Review
`NDA 21196, Xyrem, Orphan Medical, Inc.
`
`Page 4 of 122
`5/3/01
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`9.10.6 Extent Of Exposure ............................................................................................................... 79
`9.10.7 Efficacy Results..................................................................................................................... 79
`9.10.8
`Safety Results ........................................................................................................................ 79
`REVIEWER’S COMMENTS............................................................................................................ 81
`9.11
`10.
`SAFETY DATA FROM STUDY OMC-SXB-21 ............................................................................ 81
`10.1
`BRIEF SUMMARY OF STUDY PROTOCOL..................................................................................... 81
`10.1.1 Objective ............................................................................................................................... 81
`10.1.2 Design ................................................................................................................................... 81
`10.1.3 Duration................................................................................................................................ 82
`10.1.4
`Sample Size ........................................................................................................................... 82
`10.1.5 Key Inclusion Criteria........................................................................................................... 82
`10.1.6 Key Exclusion Criteria.......................................................................................................... 83
`10.1.7 Concomitant Medications ..................................................................................................... 83
`10.1.8 Dosage .................................................................................................................................. 83
`10.1.9
`Schedule................................................................................................................................ 83
`10.1.10
`Outcome Measures........................................................................................................... 84
`10.1.11
`Analysis Plan.................................................................................................................... 84
`PROTOCOL AMENDMENTS .......................................................................................................... 85
`10.2
`ACTUAL ANALYSES PERFORMED ............................................................................................... 85
`10.3
`EFFICACY RESULTS .................................................................................................................... 85
`10.4
`10.4.1 Patient Disposition................................................................................................................ 85
`10.4.2 Protocol Deviations .............................................................................................................. 86
`10.4.3 Medication Compliance ........................................................................................................ 86
`10.4.4 Baseline And Other Demographic Characteristics............................................................... 87
`10.4.5 Primary Efficacy Analysis..................................................................................................... 87
`10.4.6 Analysis Of Secondary Efficacy Measures............................................................................ 89
`SAFETY RESULTS........................................................................................................................ 89
`10.5
`10.5.1 Exposure ............................................................................................................................... 89
`10.5.2 Deaths, Serious Adverse Events And Adverse Event Discontinuations................................. 90
`10.5.3 Other Adverse Events............................................................................................................ 90
`10.5.4 Laboratory Data ................................................................................................................... 92
`10.5.5 Vital Signs............................................................................................................................. 93
`SPONSOR’S CONCLUSIONS REGARDING SAFETY......................................................................... 93
`10.6
`REVIEWER’S COMMENTS............................................................................................................ 93
`10.7
`11. KEY INFORMATION FROM INTEGRATED SUMMARY OF SAFETY AND OMC-SXB-21
`SAFETY DATA .......................................................................................................................................... 94
`ALL ADVERSE EVENTS............................................................................................................... 94
`11.1
`DEATHS ...................................................................................................................................... 94
`11.2
`SERIOUS ADVERSE EVENTS........................................................................................................ 94
`11.3
`ADVERSE EVENT DISCONTINUATIONS........................................................................................ 95
`11.4
`LABORATORY DATA................................................................................................................... 95
`11.5
`ELECTROCARDIOGRAMS............................................................................................................. 96
`11.6
`VITAL SIGNS............................................................................................................................... 96
`11.7
`11.8 WITHDRAWAL PHENOMENA....................................................................................................... 96
`12. LITERATURE REVIEW................................................................................................................. 96
`12.1
`PUBLISHED STUDIES CONDUCTED IN HEALTHY INDIVIDUALS.................................................... 96
`PUBLISHED STUDIES CONDUCTED FOR SPECIFIC MEDICAL INDICATIONS .................................. 97
`12.2
`13.
`120-DAY SAFETY UPDATE........................................................................................................... 98
`13.1
`CONTENTS .................................................................................................................................. 98
`OUTLINE OF PROTOCOL FOR OMC-SXB-7................................................................................ 99
`13.2
`13.2.1 Objectives.............................................................................................................................. 99
`13.2.2 Design ................................................................................................................................... 99
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`

`
`Ranjit B. Mani, MD, HFD-120 Medical Review
`NDA 21196, Xyrem, Orphan Medical, Inc.
`
`Page 5 of 122
`5/3/01
`
`Inclusion Criteria.................................................................................................................. 99
`13.2.3
`13.2.4 Exclusion Criteria............................................................................................................... 100
`13.2.5
`Sample Size ......................................................................................................................... 100
`13.2.6 Duration.............................................................................................................................. 100
`13.2.7 Dosage ................................................................................................................................ 100
`13.2.8 Concomitant Medication..................................................................................................... 100
`13.2.9
`Schedule.............................................................................................................................. 101
`13.2.10
`Statistical Considerations............................................................................................... 101
`13.2.11
`Safety Monitoring........................................................................................................... 101
`PROTOCOL AMENDMENTS ........................................................................................................ 101
`13.3
`PATIENT DISPOSITION............................................................................................................... 101
`13.4
`DEMOGRAPHICS........................................................................................................................ 101
`13.5
`DOSAGE.................................................................................................................................... 102
`13.6
`PATIENT EXPOSURE.................................................................................................................. 102
`13.7
`SAFETY RESULTS...................................................................................................................... 103
`13.8
`13.8.1 All Adverse Events .............................................................................................................. 103
`13.8.2 Adverse Event Tables.......................................................................................................... 103
`DEATHS .................................................................................................................................... 104
`13.9
`SERIOUS ADVERSE EVENTS...................................................................................................... 105
`13.10
`13.10.1
`Patient # 0214 ................................................................................................................ 105
`13.10.2
`Patient # 0232 ................................................................................................................ 106
`13.10.3
`Patient # 0931 ................................................................................................................ 106
`13.10.4
`Patient # 1131 ................................................................................................................ 106
`13.10.5
`Patient # 14043 .............................................................................................................. 106
`13.10.6
`Patient # 2030 ................................................................................................................ 107
`13.11 ADVERSE EVENT DISCONTINUATIONS...................................................................................... 107
`13.11.1
`Patient 1305 ................................................................................................................... 107
`REVIEWER’S COMMENTS.......................................................................................................... 108
`13.12
`14. RISK MANAGEMENT PROGRAM ............................................................................................ 108
`14.1
`STRUCTURE .............................................................................................................................. 108
`14.1.1 Closed-Loop Distribution System ....................................................................................... 108
`14.1.2 Drug Product Kit ................................................................................................................ 110
`14.1.3 Xyrem® Physician Success Program.................................................................................. 111
`14.1.4 Xyrem® Patient Success Program...................................................................................... 113
`OPDRA COMMENTS ................................................................................................................ 114
`14.2
`COMMENTS OF CONTROLLED SUBSTANCES STAFF .................................................................. 115
`14.3
`ADDITIONAL RISK MANAGEMENT RECOMMENDATIONS .......................................................... 115
`14.4
`15. LABELING REVIEW .................................................................................................................... 115
`
`16. OVERALL COMMENTS .............................................................................................................. 115
`16.1
`CLINICAL SAFETY..................................................................................................................... 115
`CLINICAL EFFICACY ................................................................................................................. 116
`16.2
`16.3 WITHDRAWAL PHENOMENA AND ABUSE POTENTIAL .............................................................. 116
`RISK MANAGEMENT PROGRAM ................................................................................................ 117
`16.4
`ADDITIONAL COMMENTS.......................................................................................................... 117
`16.5
`17.
`STUDY SITE INSPECTIONS ....................................................................................................... 117
`
`18. FINANCIAL DISCLOSURE CERTIFICATION........................................................................ 118
`18.1
`COMPONENTS OF CERTIFICATION ............................................................................................ 118
`18.1.1 Certification Pertinent To Dr Lawrence Scrima................................................................. 118
`18.1.2 Certification Pertinent To Other Investigators ................................................................... 118
`REVIEWER’S COMMENT............................................................................................................ 119
`18.2
`
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`

`
`Ranjit B. Mani, MD, HFD-120 Medical Review
`NDA 21196, Xyrem, Orphan Medical, Inc.
`
`Page 6 of 122
`5/3/01
`
`19. MAJOR AMENDMENT ................................................................................................................ 119
`
`20. ADDITIONAL COMMENTS BASED ON REVIEW OF MAJOR AMENDMENT ............... 119
`
`21. CONCLUSIONS.............................................................................................................................. 121
`
`22. RECOMMENDATIONS ................................................................................................................ 121
`
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`

`
`Ranjit B. Mani, MD, HFD-120 Medical Review
`NDA 21196, Xyrem, Orphan Medical, Inc.
`
`Page 7 of 122
`5/3/01
`
`1. Review Sources
`This submission contains an original New Drug Application for Xyrem® (sodium
`oxybate; γ-hydroxybutyrate) oral solution. The application is dated 9/30/2000 and
`was received by the Center for Drug Evaluation and Research of this Agency on
`10/3/00.
`
`In this review the words/phrases “γ-hydroxybutyrate (GHB)”, “sodium oxybate”,
`and “Xyrem®” have been used interchangeably.
`
`Xyrem® has been developed by Orphan Medical, Inc. for the treatment of
`narcolepsy under IND # 49641 and Treatment IND # 57271. Data obtained from
`individual sponsor-investigator INDs #s 21654 (M. Scharf) and 19911 (L. Scrima)
`have also been used in support of this application.
`
`Note that this is a preliminary, and not final review. Further editing of this review
`is possible.
`1.1 Materials from NDA
`In reviewing this application I have read the following volumes of the NDA
`submission of 9/30/00. These volumes have been read almost entirely in
`electronic format.
`Volumes 1, 5, 25-34, 36-63, 100-104 and 114-122
`
`I have also reviewed the following:
`•
`A separate submission dated 12/16/00 containing the final reports for several clinical trials: OMC-SXB-
`16, OMC-SXB-20 and OMC-SXB-21
`•
`The sponsor’s responses to a number of requests for information from this reviewer
`•
`A 120-Day Safety Update
`• Risk management materials, comprising physician and patient information materials, supplied by the
`sponsor
`1.2 Related Reviews, Consults
`I have utilized the many reviews that I have done, since 1997, of submissions
`under IND # 49641 and Treatment IND # 57271 for details about this drug.
`
`Consults that were obtained from other Divisions within the Agency and have
`been reviewed by me include reports from
`•
`The Controlled Substances Staff
`•
`The Office of Post-Marketing Drug Risk Assessment
`1.3 Other Reviews
`I have reviewed publications submitted by the sponsor as part of the NDA and
`the following recently published article:
`Zvosec DL et al. Adverse Events, Including Death, Associated With The Use Of 1,4-Butanediol. N Engl J Med
`2001;344:87-94
`
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`IPR of U.S. Patent No. 8,731,963
`Page 7 of 122
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`

`
`Ranjit B. Mani, MD, HFD-120 Medical Review
`NDA 21196, Xyrem, Orphan Medical, Inc.
`
`Page 8 of 122
`5/3/01
`
`2. Background
`2.1 Indication
`The sponsor wishes to pursue the following claim:
`
`“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.”
`
`Narcolepsy is a chronic neurological disorder characterized by excessive daytime
`sleepiness, disturbed nocturnal sleep, cataplexy, sleep paralysis and hypnagogic
`hallucinations. The prevalence of this condition in the United States, as per a
`publication cited by the sponsor, is between 0.02% and 0.07%. According to the
`sponsor, current treatments for this condition are limited in effectiveness and
`have frequent undesirable adverse events.
`2.2 Important Information from pharmacologically related agents
`None.
`2.3 Administrative History
`This drug has been developed by Orphan Medical, Inc. for the treatment of
`narcolepsy under IND # 49641 and Treatment IND # 57271. Data obtained from
`individual sponsor-investigator INDs #s 21654 (M. Scharf) and 19911 (L. Scrima)
`have also been used in support of this application.
`
`This drug product has been the subject of numerous meeting and items of
`correspondence involving the following: the current sponsor; this Division; the
`Controlled Substances Staff; the Division of Anesthetic, Critical Care and
`Addiction Drug Products; the Division of Orphan Drug Products; and other
`bodies. These contacts are too numerous to summarize in this review
`2.4 Proposed Labeling
`The proposed labeling for this drug is reviewed separately
`2.5 Foreign Marketing
`Currently, this drug product has not been marketed in any country. However,
`according to the sponsor
`• Gamma-OH® an injectable oxybate preparation is marketed as an adjuvant anesthetic and
`sedative in France
`• Somsanit® an injectable oxybate preparation is marketed as a sedative in Germany
`• Alcover® an oxybate contai