Ranjit B. Mani, MD, HFD-120 Medical Review
`NBA 21196, Xyrem, Orphan Medical, Inc.
`
`Page 57 of 93
`5/14/01
`
`,4“
`
`. Medical conditions that the sponsor felt be relevant to the adverse event of
`“confusion” were present in 7/30 patients: these included multiple sclerosis,
`hypothyroidism, sleep apnea, and previous head injury.
`20/30 (66.7%) were over 50 years of age
`26 such adverse events occurred during the first 60 days of treatment
`All such adverse events eventually resolved
`
`.
`.
`.
`
`14.5 “Confusion” In Study 0MC—GHB-2
`
`In this randomized, double-blind, placebo—controlled trial of 4 weeks’ duration 10
`patients receiving GHB and 1 patient receiving placebo experienced confusion
`
`The distribution of this adverse event by dose group, based on the sponsor’s
`table described in Section 14.4 was as follows
`
`Dose Group
`
`Total Number Number of Patients with
`Randomized
`Confusion
`
`
`
`Percentage of Patients with
`Confusion
`
`Number (%) Permanently
`
`Discontinuing Treatment On
`Account Of Confusion
`
`
`
`
`
`
`
`
`
`
`
`m—__ 1 3.0%
`m—_
`
`The sponsor has drawn attention to the following:
`. The highest incidence of confusion was at the 9 g/day dose
`.
`6/10 GHB-treated patients (4/6 patients treated with 9 g/day) developed confusion
`during the first week of drug exposure
`7/ 10 GHB—treated patients with confusion were > 50 years of age
`
`0
`
`The sponsor attributes the high incidence of confusion in this short trial to the
`assignment of patients to fixed doses of GHB without titration.
`
`14.6 Narratives For Patients With Confusion As A Serious Adverse Event
`
`I have read the sponsor's narratives and supplemented them with Case Report
`Forms when needed.
`~
`
`14.6.1 Patient 0207 (Initials ~_
`
`This 53 year old woman participating in OMC-GHB-Z had a past medical history of narcolepsy with
`cataplexy, and fibromyalgia. Several close family members had died shortly prior to her entering the Scharf
`trial. The patient’s father was reportedly a manic-depressive. Concomitant medications included imipramine,
`estrogen and testosterone, progestin, methylphenidate and a laxative.
`
`She received Xyrem® 6 g daily. On Day 4 of treatment she developed nausea. Beginning Day 5 she .
`became very talkative with pressured speech, and the next day was noted to be disoriented, agitated and to
`sleep poorly. She was seen at an emergency room where neurological examination was remarkable'for
`hyperreflexia. Xyrem® was discontinued, the patient was treated with haloperidol and by the next day her
`confusion had resolved. An EEG was normal and a CT scan of the head showed minor temporal lobe
`asymmetry. The study drug was permanently discontinued.
`
`14.6.2 Patient 0231 (Initials .~--
`
`This patient’s narrative is also reproduced in Section 18.2
`
`

`

`Ranjit B. Mani, MD, HFD-120 Medical Review
`NBA 21196, Xyrem, Orphan Medical, Inc.
`
`Page 58 of 93
`6/14/01
`
`This 67 year old man was enrolled in Study OMC-SXB-B. His past medical history was remarkable for a
`stomach ulcer, gastroesophageal reflux disease, and a cholecystectomy. Concomitant medications at study
`entry included clomipramine, methylphenidate, paroxetine, imipramine and modafinil.
`
`He took Xyrem® in a dose of 4.5 g/day for 12 days and 9 g/day for 106 days. After having been on a stable
`dose of 9 g/day for 106 days he awoke about 1 hour after his second nightly dose feeling dizzy and
`confused On getting out of bed he felt nauseated and vomited after reaching the bathroom. He felt a .
`sensation of "shut down" and difficulty breathing, crawled from the bathroom to lie down in the hallway until
`he felt well enough to return to bed about 1 ‘/2 hours after the episode began. Frequent cataplexy attacks
`apparently accompanied the episode. After returning to bed he slept soundly and awoke the next morning
`feeling well. The same, day he contacted the Principal investigator and withdrew from the study. He was
`never hospitalized or seen in an emergency room.
`
`At the time the episode occurred his concomitant medications included a multivitamin, DGL (a herbal
`preparation), an unspecified medication for gastroesophageal reflux and methylphenidate.
`
`The episode occurred on 7/27/99. A follow-up phone call from the study coordinator on 3/19/01 indicated
`that no further such episodes had occurred.
`
`14. 7 Narratives For Patients With Confusion As An Adverse Event
`
`Warranting Permanent Discontinuation Of GHB
`
`l have read the sponsor's narratives supplemented by Case Report Forms when
`needed
`‘
`
`14. 7.1 Patient 0207 (Initials -\_
`See Section 14.6.1
`
`14.7.2 Patient 0231 (Initials -- 1
`
`See Section 14.6.2
`
`14.7.3 Patient # 0702 (Initials . «—
`This 59 year old woman participated in Study OMC-GHB-2. She had a past history of narcolepsy with '
`cataplexy, cirrhosis and a left facial palsy. Concomitant medications included ipratropium bromide and
`albuterol.
`
`She received OMC-GHB-Z in a dose of 9 g/day. 20 days later she began experiencing confusion,
`hallucinations and forgetfulness followed in the next 2 days by nausea and paranoia. Study medication was
`discontinued when these symptoms began and her symptoms resolved 5 days later.
`
`14.8 Reviewer’s Comments
`
`‘
`0 As records for contemporaneous formal mental status examinations for‘
`patients with “confusion" are unavailable it is unclear if all patients coded as
`having this adverse event were really confused, as the term is conventionally
`understood. investigator terms suggest that at least some patients may not
`have been confused
`'
`
`o Nevertheless, the information available does suggest that GHB is capable, at
`therapeutic doses, of causing a confusional state which may be accompanied
`by psychotic symptoms. The incidence and seriousness of such adverse
`events may be slightly more pronounced at higher doses, and especially if
`higher doses are administered without titration. However a confusional state
`also appears to be capable of occurring at lower and even sub-therapeutic
`
`

`

`Ranjil B. Mani, MD, HFD-120 Medical Review
`NBA 21196, Xyrem, Orphan Medical, inc.
`
`Page 59 of 93
`6/14/01
`
`(e.g., 3 g/day) doses of GHB, and after maintenance treatment for several
`months.
`
`0 The presence of true confusion in patients taking GHB could lead to their
`taking GHB in a manner other than as prescribed.
`o The symptoms that have been subsumed under the COSTART term
`“confusion” are not surprising for a sedative drug.
`
`15. Neuropsychiatric Adverse Events In Integrated Clinical Trials
`
`15.1 Background
`
`At the Division's request neuropsychiatric adverse events in the updated
`Integrated Clinical Trials database (including the-120-Day Safety Update) were
`characterized further by the sponsor. The cut-off date for the 120-Day Safety
`Update was 9/30/00.
`
`The sponsor’s methods were as follows:
`. Adverse events coded under the following preferred terms were selected from the
`above: overdose, coma, death, depression, hallucinations, intentional overdose,
`manic depressive reaction, overdose, paranoid reaction, personality disorder,
`psychosis, stupor, suicide, and suicide attempt.
`. Source documents, Case Report Forms and data listings were reviewed for the
`above patients
`. Tabular and narrative summaries of events were then constructed. Narratives were
`
`prepared for deaths, serious adverse events and adverse event discontinuations.
`. A review of the literature relevant to the incidence of neuropsychiatric adverse events
`in narcolepsy was completed
`. The dosage at onset of each adverse event was determined and the start and stop
`dates for the adverse events recorded.
`
`15.2 Overall Summary
`
`50/402 (12.4%) GHB-treated patients had at least one adverse event coded '
`under one or more of the neuropsychiatric adverse event terms outlined in
`Section 15.1. Their distribution by dose and severity is displayed in the following
`table which i have copied from the submission.
`— lyrem Oral Solution Dosage what at Onset
`Eu':1.rc (.1 [21:33:16
`mum. Ramayana“ nu ma mm” mum-mm\ b «.
`r
`x
`Pnizexits 1mm 2 3 AF.
`Panama Hzth $35.23
`its with zelaced A53
`its $15}: seveze Mrs
`:Ls mete-nunus-d due to his
`.r. deaths due to 11::
`‘ P..- :m.: are counted cal); our: in each zeta! calm.
`= Patten-a. ver: a: placebo far a 11730:? zxnc :4. weeks! relatzv: t: the Emmy—19m expcman- cf than neatea‘ v32: szcm.
`' Sm pa:i:n:: were exposed to ante than 3 flan-g: Mung the ::;u3lx:§ . no 11:: can of ”5:27;: exposed t: spa-2:52:
`dcuggs exceed: the toza‘; number of panes“: :z: the :ncegraned dunes} (rs-1:.
`
`
`
`
`
`
`
`As the table above indicates
`
`o
`0
`0
`
`1 death was associated with a neuropsychiatric adverse event
`7/402 (1 7%) patients had a serious neuropsychiatric adverse event
`10/402 (2.5%) patients discontinued treatment on account of a neuropsychiatric
`adverse event
`
`

`

`Ranjit e. Mani, MD, HFD-120 Medical Review
`NBA 21196, Xyrem. Orphan Medical, Inc.
`
`Page 60 of 93
`6/14/01
`
`.
`
`Such adverse events did appear to have their highest incidence at the 9 g/day
`dosage
`
`Note that 2 prominent neuropsychiatric adverse events were not included in the
`above table
`
`.
`
`.
`
`Patient # 14043, participating in Study OMC-SXB-7, who had obsessive compulsive
`disorder survived a suicide attempt. This patient was not included in the table as the
`suicide attempt was, based on an incorrectly entered date in a Case Report Form,
`mistakenly considered to have occurred about 6 weeks after treatment ended. In fact
`she was still a participant in the trial when the suicide attempt was made
`Patient # 0936, participating in Study OMC-SXB-7, who had a previous history of
`depression died from what was believed to be an overdose of multiple drugs. The
`event occurred on 2/24/01, 5 months after the cut-off date for the 120-Day Safety
`Update.
`
`15.3 Distribution Of Individual Neuropsychiatric Adverse Events
`
`The distribution of individual COSTART-coded neuropsychiatric adverse events
`is as illustrated in the following table
`'
`
`Note that patients ma have had adverse events in more than one category
`
`_
`[—
`'
`Paranoid Reaction _
`'
`
`__
`_I_
`
`
`
`
`
`15.4 Specific Neuropsychiatric Adverse Events
`
`15.4. 1 Depression
`
`'
`
`The sponsor has provided a table summarizing all patients coded to have the
`COSTART preferred term “depression."
`
`The table provides the following data: patient ID #, trial #, sex, age, dosage at
`onset of confusion, start and stop date for adverse event, investigator term,
`whether serious or not, action taken, frequency, relationship to study drug,
`severity and relevant medical history.
`
`I have not reproduced the table in this review.
`
`in regard to the table the following are noteworthy
`o Verbatim investigator terms included “depression", “depressed mood”, “situational
`depression”, “down in the dumps”, and “dysphoria”. The sponsor points out that the
`COSTART term “depression” as used in this particular context is not equivalent to a
`psychiatric diagnosis of Major Depressive Disorder using DSM-lV criteria.
`27 patients experienced a total of 30 adverse events coded as depression
`26/27 patients were receiving GHB at the time of this adverse event and 1/27
`placebo
`
`0
`0
`
`,‘u
`
`

`

`Ranjit B. Mani, MD, Hszo Medical Review
`NDA 21196. Xyrem, Orphan Medical, Inc.
`
`Page 61 of 93
`6/14/01
`
`.
`3 patients had a recorded previous history of depression or bipolar disorder
`o
`in none of the instances was depression considered a serious adverse event
`. GHB was permanently discontinued in 2 patients and temporarily stopped in 2
`additional patients
`5 patients received antidepressant medication to control depressive symptoms
`0
`. No patient who attempted to or committed suicide is listed in the table
`
`15.4.2 Hallucinations
`
`The sponsor has provided a table summarizing all patients coded to have the
`COSTART preferred term “hallucinations."
`
`The table provides the following data: patient lD #, trial #, sex, age, dosage at
`onset of confusion, start and stop date for adverse event, investigator term,
`whether serious or not, action taken, frequency, relationship to study drug,
`severity and relevant medical history.
`
`l have not reproduced the table in this review.
`
`o
`o
`
`In regard to the table the following are noteworthy
`o
`9 patients had adverse events that were coded as hallucinations. In all 9 the
`investigator term also indicated that they had hallucinations.
`All 9 patients were receiving GHB at the time this adverse event appeared
`In 4/9 the hallucinations, based on the investigator term used. were hypnagogic
`hallucinations. In a further patient the hallucinations ceased with an increased dose
`of GHB and were therefore presumed to be hypnagogic hallucinations.
`. The hallucinations were characterized in 4 patients (these were not patients with
`hypnagogic hallucinations): the hallucinations were auditory in 3 and visual in 1.
`In only 1 patient were hallucinations a reason for medication discontinuation. This
`patient has already been described (see Section 14.7.3)
`
`o
`
`15.4.3 Stupor
`
`The sponsor has provided a table summarizing all patients who had an adverse
`event coded using the preferred term stupor.
`
`This table is below
`
`APPEARS THlS WAY
`0N ORlGlNAL
`
`

`

`Ranjit B. Mani, MD, HFD—120 Medical Review
`NDA 21196, Xyrem Orphan Medical, Inc.
`Donny.
`a:
`0:11.:
`(g/d)
`
`Box/Ago
`(yr)
`F4125. 4
`K135 5
`
`C12:
`
`OM:-
`as -3
`-
`
`:21.) Day‘
`Start
`Stop
`3‘
`
`era: on:- (3—1»: mecca. binary: no history I“ taxes. 1.: new taco access—3.
`
`1123'. drunk
`atcer first
`
`.
`
`.
`
`GEE-3
`
`1:75
`
`cac-
`GEE - 3
`
`ritsfli
`
`No.’
`temporarily
`:Lopped
`Bay :aL-dve t:- f. :3: .35: of xyre: it first trial 1:: the 21.31:".2: database.
`‘ "marge pas cutie: toward {run In: no»: entry,
`
`/no change
`
`intoxication
`{2:11:29
`rel:
`intoxicated
`
`'
`
`Page 62 of 93
`6/14/01
`
`Serious]
`Iroqumcy/
`{many-tor Much fur-n
`lolndmhfip/
`Ton
`V/Study Drug
`Severity
`rel: 4mm.
`rec/no—hanga 1m:mtcent/
`unknown/mild
`mccxicued —o/ Conzinuous/
`[eel mg
`temporarily
`probably
`scrapped
`related}
`IloderaLe
`con::'.n\:ous /
`probably
`related!
`moderate
`.*
`..
`
`Relevant
`lodical
`litter-y
`fiaxcclepsy.
`cataplexy ‘
`narcolepsy,
`cacaplexy ‘
`
`flax to] e.,. 5y.
`cacaplexy ‘
`
`Narcolepsy.
`cacn;lexy ‘
`Non-specific
`headaches
`flamolepsy,
`caLaplm ‘
`
`Saxrclepsy
`cataplexy‘
`
`'
`
`'
`
`Continuous/
`possibly
`relaced:'mld
`CorLLnuous/
`possibly
`related! mild
`
`Note that
`
`.
`.
`
`.
`
`“Stupor” occurred in 6 patients, all of whom had only 1 episode of this adverse event
`Investigator terms suggested that all 6 patients did not have “stupor” in the sense in
`which the term is conventionally used in the medical literature (i. e., obtunded) -
`In no patient was the adverse event serious or a reason for permanent study drug
`discontinuation
`
`0 As the sponsor has pointed out, such an adverse event is not unexpected given'the
`sedative properties of GHB
`
`15.4.4 Suicide Attempt
`
`A total of 4 GHB-treated patients attempted to commit, or successfully committed
`suicide. These patients are summarized in the following table.
`
`Patient l0 :3
`
`Study
`
`
`
`
`0531
`
`0936
`
`OMC 8X8-7
`
`F/46. 5
`
`Gglday
`
`OMC-SXB-7
`
`F/52
`
`18 months
`
`6 g/day
`
`Pre-Existing
`Investigator
`GHB Dose
`Duration Of
`
`
`
`Psychiatric
`Term And
`At Time Of
`Treatment
`
`
`
`
`History
`With GHB At Adverse
`Details Of
`
`
`Time Of
`Event
`Episode
`
`Adverse
`Event
`394 days
`
`
`
`Bipolar
`suicide
`Disorder
`3?NElicable
`Death from
`None
`Not
`multiple
`recorded at
`applicable
`
`
`
`drug
`time of study
`
`
`overdose
`entry.
`,
`'
`
`(suicide)
`Dun'ng study
`.
`was
`
`
`
`diagnosed
`‘
`
`.
`to have
`.
`‘
`bipolar
`
`
`disorder
`Depression.
`Conscious
`Study drug
`
`
`
`
`previous
`discontinued
`overdose
`
`
`
`
`(suicide
`suicide
`
`
`attem -t
`
`
`
`
`
`
`
`
`
`
`compulsive
`(suicide
`disorder
`attem-t
`
`
`Obsessive-
`
`Overdose
`
`discontinued
`
`Study dmg
`
`1131
`
`OMC-SXB~7
`
`F/46.2
`
`280 days
`
`9 g/day
`
`-4043 OMC—SXB-7
`
`
`
`Fl26
`
`11 years
`
`9 g/day
`
`
`
`
`
`The nature of the overdose in the case of the above patients was as follows
`
`

`

`Ranjit e. Mani, MD, HFD-120 Medical Review
`Page 63 of 93
`NDA 21196, Xyrem, Orphan Medical, lnc.
`6/14/01
`
`
`
`
`
`
`
`
`
`The sponsor points out that neither of the above fatalities was due to an
`overdose of GHB alone
`
`15.4.5 Paranoia
`
`The sponsor has provided a table summarizing all patients coded to have the
`COSTART preferred term “paranoia.”
`
`"Iqulnty/
`lolltlallbipl
`Sovcti :y
`.
`
`, I
`
`ulnar.
`Indie-1
`I: I tory
`
`These patients are summarized in the following table which I have copied from
`the submission
`
`lava-nan"
`
`s-nou-l
`“do: Ink-r.
`
`' ‘sd aiahaua .
`
`As is evident from the above table
`
`0
`
`0
`
`4/402 (1%) of patients experienced paranoia as an adverse event: in each instance
`the COSTART term matched the investigator term
`in only 1 patient was this adverse event serious and sufficient to lead to treatment
`discontinuation
`.
`
`o A previous history of depression and anxiety was present in one patient
`
`15.4.6 Coma
`
`~.
`
`The 2 patients who were coded as having this adverse event are summarized in
`the following table which i have copied from the submission
`
`.v a “W.-.” _
`
`,k.-- »--..—‘--.—..—...- A_...,._.,._. 1—._,._..‘.‘..__.__.A. -fl.‘_. .
`
`

`

`2:11) nay‘
`
`H164. 3
`
`170
`
`:70
`
`nave-agate:
`
`run
`
`non-
`responsive
`
`
`
`Inquuiqil
`lclntlonabip/
`
`6/14/01
`
`Bistcry
`Narcol epsy,
`cauplexy
`
`Page 64 of 93
`Ranjit B. Mani, MD, HFD—120 Medical Review
`
`Donny
`
`o It
`Carson-l
`On”:
`Action Taken
`I/Sru- Dr
`Savors :y
`mu: Study Drug
`
`
`
`Conunw,’
`Yes/
`
`probably
`discontinued
`
`
`related;
`
`
`
`severe
`
`
`
`
`possibly
`M "HI-- “Cindi!
`narcolepsy
`severe -
`related}
`5x2 5
`M‘ -“--i ”Ohm”
`
`
`tLl-z 1v: -o {1 rs: cost: :7.
`)y': (r. 1:;
`
`0239
`
`our
`sxs -é
`
`$15— 6
`
`NDA21196,X-yremOrphanMedical.Inc.
`
`.71“ Box/Lg.
`(9/2)
`.3an Stop
`
`
`,
`
`DepreSsi‘".
`
`in L‘n. a.:e;r.n:o.=1d.1.aux-c
`
`possibly
`related!
`
`
`
`
`
`
`
`
`above
`
`
`
`
`
`
`:11-1 :zxa.
`
`The following additional observations can be made
`. Only one 1 patient was this adverse event seriousand sufficient to lead to GHB
`discontinuation
`Patient # 2830 is described as falling repeatedly due to cataplexy, striking her head
`against an object and losing consciousness
`
`.
`
`The sponsor points out that neither of these adverse events could be considered
`a neuropsychiatric adverse event
`
`15.4.7 Psychosis
`
`The 2 patients for whom the COSTART term “psychosis” was used are
`summarized in the following table which is copied from the submission
`'ublo 5.3.7
`lacuna I'ho zxporloncud roulblo anmnc—lurgm: acutopaychucnc zvunu of can”:
`Preferred Tar- ‘ruychOIu’ - mtogxacod Clinical “It‘d!
`
`Ne: dzsclcled a: sneezing.
`
`Sudan-l
`Action Token
`l/Btudy Drug
`
`dis:onunued
`
`Brie:
`reactive
`psychosis
`
`Stief
`reactive
`psychosis
`
`so/no change
`
`Yes/
`discontinued
`
`Iroquency/
`lolntnnahxp/
`Smrizy
`commuous/
`possbly
`:eLaLed/
`Iodezate
`
`Ruler-11:
`.061ch
`litres-y
`Ixazcalepi‘_.
`cataclexy,
`congen.‘: a1
`axouopia
`Beadlcé‘ms, .
`bizarre
`dream.
`Poor
`concentration
`and
`Intention ‘
`schixophxenta ‘
`Intcmiztent/ Narcolepsy
`definitely
`'
`xelazed,’
`moderate
`continuous] Narcolepsy
`possibly
`related]
`‘QVEYE
`
`its: on»: at Kyla: 1!: fix". :"ia.
`Dang: v-1 cutie: {maxi i... In: Ina-n entry'y.
`5702: 32-6313-3 medics: meter).- :2: :unory III “is. a: r_~::ry 3.2L: mC-GEE—s.
`
`i.a: the unegraufl database.
`
`As the table indicates
`
`o The COSTART term matched the investigator term in each instance
`. Both patients discontinued GHB on account of this adverse event; in one patient the
`adverse event was considered serious
`
`. One patient had a pre-existing history of schizophrenia
`
`15.4.8 Manic Depressive Reaction
`
`The single patient who had this adverse is summarized in the next table
`
`

`

`Ranjit B. Mani, MD. HFD-120 Medical Review
`NBA 21196 Xyrem Orphan Medical, Inc.
`Dosage
`a:
`nu: Dny’
`enact
`(g/d) Stu:
`
`nvuugnzor
`tn:-
`
`nipo-ar
`affective
`disorder
`
`5inu t: 2..
`
`11:
`
`the. imam-anti {azalasn
`
`Page 65 of 93
`6/14/01
`
`Serious]
`bctton Token
`v/s tudy Drug
`Yes/
`diumiinud
`
`Iroquucy/
`nlotxonlhtp/
`Severity
`
`lolovmt
`undies]
`In tax-y
`
`Continuous/
`no: related/
`severe
`
`Karcolepsy
`nig:;ing ‘
`Depresszc-f‘;
`
`*‘
`
`Note that this patient had a prior history of depression
`
`15.4. 9 Personality Disorder
`
`The patient outlined in the next table experienced a prolonged grief reaction
`(coded using the COSTART term of “personality disorder") following the death of
`a relative. The event appears to have resolved without cessation of study
`medication.
`
`Faun:
`so.
`
`trial
`
`Do::ge
`lax/Ago Once: Rh; Day‘
`(old)
`tyx)
`sun.
`Stop
`
`Investigator
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`15.5 Narratives For Deaths Associated With Neuropsychiatric Adverse
`Events, Serious Neuropsychiatric Adverse Events, and Discontinuations
`Due To Neuropsychiatric Adverse Events
`-
`These narratives are below
`
`15.5.1 Patient # 0932 (Initials ‘—
`
`This 24 year old woman who participated in OMC-SXB-6 had a history of depression dating back to 1994.
`Her dose of Xyrem® was increased from 4.5 g daily to 6 g daily. On Day 84 she experienced auditory
`hallucinations for which she was hospitalized and treated with olanzapine. Her dose of Xyrem® was then
`reduced to 4.5 g daily. Her hallucinations resolved and she was discharged after 14 days continuing with
`GHB for the remainder of the trial. Hospital discharge records indicated to her investigator that for the
`previous 5 years she had experienced repeated auditory hallucinations and had 2 psychiatric
`-
`hospitalizations
`
`'
`
`15 5 2 Patient # 0531 (Initials ——
`
`Patient # 0531 was a 47 year old woman who had earlier participatedin the OMC- SXB6 trial and had been
`taking Xyrem® 6 g/day since 6/3/99 Her past medical history that the investigator was aware of at
`‘
`screening was remarkable for a bipolar disorder, a previous head injury with coma and a morphine allergy.
`‘ Concomitant medications included thyroxine, zolpidem, an albuterol inhaler, loratadine, risperidone and '
`temazepam. Subsequently the investigator realized that she had previously made a suicide attempt
`
`in May 2000 she began experiencing worsening insomnia On 6/12/00 she underwent an elective surgical
`procedure for metrorrhagia
`.,-
`
`On 7/4/00 she asked friends to leave a gathering at her home as she felt unwell. After a friend was unable to
`contact her, emergency personnel entered her home and found her dead the following day. A postmortem
`toxicology screen was positive for opiates, acetaminophen and benzodiazepines. Quantitative testing
`showed toxic levels of multiple drugs including hydrocodone, oxycodone, morphine, hydromorphone.
`
`

`

`Ranjit e. Mani, MD.’HFD-120 Medical Review
`NDA 21196, Xyrem, Orphan Medical. Inc.
`
`Page 66 of 93
`6/14/01
`
`nordiazepam and zolpidem. it was presumed that she had committed suicide by taking an overdose of
`multiple drugs. The death certificate listed multiple‘drug toxicity as the cause of her death with
`atherosclerotic cardiovascular disease also being listed as a significant factor.
`
`Post-modem toxicology screening for GHB was not done, but the sponsor believes that this patient did not
`take an overdose of that drug for the following reasons
`0
`At her last trial visit on 5/23/00 the patient received 6 bottles of Xyrem®, each containing 200 mL of the
`drug (each bottle contained 500 mg/mL)
`On 7/11/00 the patient's family returned to the investigator 5 bottles (4 full and 1 empty)
`The f3m bottle containing some drug was retained by the medical examiner but the quantity of drug in
`that bottle is not known
`
`o
`.
`
`0
`
`The sponsor states that the although the patient‘s compliance with the drug could not be precisely
`estimated it was calculated as being between 39 and 78%
`
`15.5.3 Patient#0936 (Initials -—
`
`"
`
`This 52 year old woman participated first in Study OMC-SXB-B, and then in OMC-SXB-T. She has a past
`medical history of narcolepsy with cataplexy, surgery for obesity and depression.
`
`She received Xyrem® for a total of about 18 months. About 3 days before her death she saw a psychiatrist
`who diagnosed a possible bipolar disorder and prescribed lithium and paroxetine.
`
`She was found dead in her home. Based on what remained of her supply of GHB she was believed to have
`consumed about 600 mL over 3 days. Prescription bottles for lithium (which should have contained about 60
`tablets of uncertain strength), paroxetine (which should have contained about 45 tablets of uncertain
`strength) and oxycodone-acetaminophen were found to be empty. A full medical examiners report is
`pending but she was felt by the investigator to have died of an overdose of multiple drugs.
`
`Earlier during the study she had been hospitalized twice on account of kidney stones. Other medications
`prescribed during the study were cephalexin and iron supplements
`‘
`,
`
`15.5.4 Patient # 1 131 (Initials
`
`--‘-‘
`
`This 46 year old man was begun on Xyrem® on 4/30/99. At study entry he did not disclose that he had a
`past history of depression and a previous suicide attempt. Concomitant medications at study entry included
`modafinii 400 mg/day, ibuprofen. an aspirin-acetaminophen-caffeine combination pill, dextroamphetamine
`and bupropion (for smoking cessation).
`-
`
`His regular dose of Xyrem® at the time of the serious adverse event described below was 9 g/day.
`
`'
`He took an overdose of Xyrem® (subsequently estimated at 150 g) on 2/2/00. His wife found him
`unresponsive and incontinent of urine and feces that day. He was initially unresponsive with apneic spells,
`but with normal arterial blood gases He later became combative and finally awoke, at which time he was
`observed to be depressed. He reported multiple major sources of stress He required psychiatric
`hospitalization and did not resume Xyrem®.
`
`15 5. 5 Patient # 14043 (India/s"
`This 26 year old woman had previously participatedin the Scharf trial and had received GHB since 7/5/89.
`She entered the OMC—SXB—7 trial on 8/30/99. Her past medical history was remarkable for obsessive
`compulsive disorder. Concomitant medications during the OMC-SXB-7 trial include fluvoxamine, buspirone
`and methylphenidate.
`
`On 4/2/00 she took her usual dose of Xyrem® (7.5 g/day) and then attempted suicide by taking 56 tablets of
`buspirone 5 mg. She immediately told her father what had happened, was taken to an emergency room
`
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`

`

`Ranjit r3. Mani. MD, HFD—120 Medical Review
`NBA 21196. Xyrem. Orphan Medical. Inc.
`
`Page 67 ~of 93
`6/14/01
`
`where she was treated and released. She reported being increasingly self-critical from January 2000
`onward after beginning methylphenidate. After discontinuing Xyrem® (last dose on 4/4/00) she became
`more negative in outlook and noted an increase in cataplexy and in sleepiness.
`
`15.5.6 Patient # 0232 (Initials ‘—
`This 44 year old woman with no previous history of psychiatric illness began taking Xyrem® on 4/1/99; from
`January 2000 onwards she took a stable dose of 9 g/day.
`
`She entered OMC-SXB-21 from OMC-SXB-Y. Concomitant medications at that time included modafinil,
`verapamil, ranitidine, aspirin and ibuprofen. She completed OMC-SXB-21 on 7/28/00 and re-entered OMC—
`SXB»7 taking 9 g/day again. After the blind for OMC-SXB-21 was broken it was confirmed that she had
`taken Xyrem® 9 g/day throughout that study as well.
`
`On 8/1/00 she was hospitalized in an acutely paranoid state. She discharged herself from the hospital but
`was readmitted on 8/3/00. During her hospitalization she was treated with haloperidol, temazepam and
`clomipramine (clomipramine had been discontinued on 5/9/00). No GHB was administered after 7/30/00 and
`on 8/14/00 she told the investigator that she well. Clomipramine was apparently stopped and then resumed
`on 9/28/00 with a return of paranoia for a limited duration; this drug was however continued as apparently
`was modafinil. By 10/12/00 she had apparently returned to normal.
`
`15.5. 7 Patient # 0238 (Initials t,
`This 65 year old man, participating in OMC—SXB-B, had been taking Xyrem® 4.5 g daily for 5 months. He
`had a background history of hypertension.
`
`Immediately after his wife heard a loud noise around midnight, he was found comatose, flaccid, incontinent,
`bradycardic and hypoventilating. No convulsive movements had been witnessed. He required intubation and
`artificial ventilation. However the same day he awoke, was extubated and returned home. An EEG was
`normal; an echocardiogram showed ventricular hypertrophy with posterolateral wall hypokinesia, but with a
`satisfactory ejection fraction. A 'cardiac event" was proposed as a cause for his symptoms by the hospital
`staff caring for him. However the Principal Investigator, after reviewing his hospital records considered the
`possibility that an inadvertent overdose with GHB was responsible for the episode was responsible for the
`episode. Study medication was permanently discontinued. Further information is not available.
`
`15.5.8 Patient # 2030 (Initials --')
`
`This 18 year old man began taking Xyrem® on 5/28/99 and was maintained on a stable dose of 9 g/day
`thereafter. Concomitant medications included zolpidem, protriptyline, modafinil (200 mglday), fluoxetine 20
`mg/day. methylphenidate 4045 mg/day. He reported no previous psychiatric history.
`
`On 12/15/99 he began experiencing paranoia, confusion and hallucinations. He reported increasing his dose
`of methylphenidate earlier while preparing for examinations. He was hospitalized and treated with multiple
`medications. Xyrem® was stopped on 12/22/99. He improved and his psychosis was attributed to
`‘
`‘
`methylphenidate overuse and to sleep deprivation.
`
`15.5.9 Patient # 0931 (Initials—’7
`
`This 29 year old woman had taken Xyrem® from 7/5/99 until she developed the serious adverse event listed
`in the table above in April 2000. At screening, she did not disclose that she had a past history of depression.
`
`Her dose of Xyrem® at the time of the adverse event was 4.5 g/day. She was also receiving modafinil 600
`mg/day.
`"
`
`On 4/27/00 the study coordinator was informed that the patient had been hallucinating and had lost herjob
`owing to a diminished ability to function at work. On 4/29/00 the patient was found to be unarousable m her
`car by emergency personnel: on being awakened she became violently agitated, but was also slow in'
`
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`

`

`Ranjit e. Mani. MD. HFD—120 Medical Review
`NDA 21196, Xyrem. Orphan Medical, inc.
`
`Page 68 of 93
`6/14/01
`
`responding to questions. She was hospitalizedand treated with multiple medications for agitation. Her urine
`drug screen was positive for benzodiazepines. The patient later reported that on 4/29/00 she pulled off the
`road to sleep at which time she took both nightly doses of Xyrem® together without dilution. She was
`diagnosed to have a bipolar disorder.
`
`She did not take any Xyrem® after 4/29/00 and at a follow-up visit on 6/14/00 appeared mentally well.
`
`15. 5 10 Patient # 0204 (Initials‘—-
`
`This 60 year old woman received GHBin OMC-GHB—3 At the time of her entry into the study, and prior to
`receiving GHB she was irritable, depressed and had difficulty awaking Her only concomitant medication
`included acetaminophen.
`
`During her participation in the trial she reported continued depression and insomnia.'She received GHB
`initially in a dose of 6.0 g/day and later in a dose of 9 g/day. 19 days after first entering the study she
`discontinued participation on account of a lack of efficacy
`
`155.11 Patient # 0213 (Initials W
`This 60 year old man participatedin OMC-GHB-3 prior to which he had received GHB for about 4 months.
`He did not have a past medical history of depression
`
`He entered the OMC-GHB’3 study on a dose of 6 g/day. While in this study his dose was increased to 9
`g/day; it was later reduced to 3 g/day on account of a depressed mood and excessive tiredness. After
`temporary interruptions of treatment to see if he improved . he eventually discontinued taking the drug
`permanently following which these adverse events resolved
`'
`
`15.5.12 Patient # 0702 (Initials -
`
`This 59 year old woman participated in Study OMC-GHB-Z. She had a past history of narcolepsy witli
`cataplexy, cirrhosis and a left facial palsy. Concomitant medications included ipratropium bromide and
`albuterol.
`
`She received OMC-GHB-2m a dose of 9 g/day. 20 dayslater she began experiencing contusion,
`hallucinations and torgetfulness followedin the next 2 days by nausea and paranoia Study medication was
`discontinued when these symptoms began and her symptoms resolved 5 days later.
`
`15.5.13 Patient # 1101 (Initials ~—
`This 39 year old man participatedin Study OMC~GHB~3 At the time of entry into the study he was receiving
`dextroamphetamine and methylphenidate both of which had been taken for about a year.
`
`He received GHB for about 6 months, last in a dose of 4.5 g/day. After 6 months of treatment he developed
`an “acute psychosis" leading to discontinuation of all stimulant drugs. About 2 months prior to that,
`methylphenidate had been discontinued and amph