Ranjit a. Mani, MD, HFD-120 Medical Review
`NDA 21196 (N-BZ), Xyrem, Orphan Medical Inc.
`
`Page 56 of 127
`3/4/02
`
`7.3 Methods OfAnalysis
`
`The sponsor describes the methods of analysis as follows
`. The analysis was performed separately on the 2 safety databases that were
`looked
`
`integrated Clinical Trials
`0
`Scharf Open-Label Study
`.
`. Each database was searched for adverse events that could indicate
`
`sleepwalking. The following were the verbatim adverse event terms looked
`for: “sleepwalking," “somnambulism,” and “wanders in sleep.”
`. For each adverse event dosage at onset and start and stop trial days were
`calculated.
`
`0 For each of the 2 databases analyzed, summary tables were prepared
`grouping adverse events that could suggest sleepwalking by dosage at onset
`0 Tables were also prepared for each sleepwalking-related adverse event for
`each patient with such an event: in addition to relevant medical history and
`concomitant medications for each patient, the following were recorded in the
`table for each event: start and stop dates, dosage of GHB at onset, verbatim
`(investigator) term, seriousness/severity, action taken, outcome, frequency,
`and relationship to drug. Tables were prepared from integrated listings for the
`2 databases and listings for the individual trials
`
`The analysis performed by the sponsor also looked at concurrent adverse
`events, which were included in the table for individual sleepwalking adverse
`events. Concurrent adverse events were defined as
`
`. Any accidental injury occurring at the time of the sleepwalking adverse event
`(: 1 day from trial day of onset of sleepwalking adverse event; or between the
`start and stop trial days for sleepwalking adverse event) with no other causal
`explanation
`. Any other sleep disorder occurring at the time of the sleepwalking adverse
`event
`
`0 Any other accidental injury that may have indicated an additional
`sleepwalking event
`. Any other adverse event that may have indicated non—compliance with the
`dosing regime
`
`The results of the analysis are described separately for the Integrated Clinical
`Trials and Scharf Trials databases. The following description utilizes summary
`data, as well as the more detailed tabulations of individual events supplied by the
`sponson
`
`7.4 Integrated Clinical Trials
`
`7. 4. 1 Overall Summary
`
`Of the 402 patients in this grouping, 28 patients (7%) had one or more episodes
`of sleepwalking (they had a total of 45 such adverse events) through the cut-off
`date of September 30, 2001. One of these 28 patients also had a separate
`
`

`

`Ranjit B. Mani, MD, HFD—120 Medical Review
`NBA 21196 (N—BZ), Xyrem, Orphan Medical Inc.
`
`Page 57 of 127
`3/4/02
`
`adverse event for which the investigator term "sleepwalking — fell” was used; the
`sponsor has not listed this adverse event as an instance of sleepwalking; if this
`event is counted as an instance of sleepwalking, the 28 patients had 46
`instances of sleepwalking. Only one of these patients was receiving placebo at
`the time the adverse event occurred; the rest were receiving Xyrem®.
`
`None of the instances of sleepwalking were considered serious adverse events
`or lead to a patient’s death.
`
`2 patients discontinued Xyrem® on account of sleepwalking.
`
`These data are summarized along with the adverse event distribution by dose in
`the following table which I have copied from the submission.
`
`xylem oral SoluLicn Dosage (g/di at on“:
`3.0
`roul‘ mam—m-I--m-
`{1005.)
`not“
`(1003)
`(1'30“
`{100%}
`(1003}
`(1005)
`(100%)
`2'} PH}
`'.
`IE 1‘33,
`:
`121‘-
`1-1,:
`F- 13":
`11‘
`:3'5‘
`5 an
`‘5
`(5,2;
`:7
`f‘.
`C
`5
`fl
`2
`'2
`‘_j‘ "
`..5‘
`M'r
`
`:
`
`-
`
`.i‘-.,
`
`‘
`
`k
`
`szeepvamnm an new
`,“v “re: A.:'
`,
`'s
`
`L
`
`'.
`
`=
`
`
`
`:he Lets) column.
`gamed 321'; case -_r.
`mass were EX}*’.‘§='§ to were that: 1 :jaeagi- damn} it») {nails}, 3:: the anti 0: patienka exposed 1c epecztlc
`ir-xages excess; Lke Lana} number a: pallaate .u’: the integzatee cluncal tnais.
`
`The table above does not indicate a dose-response in the incidence of this
`adverse event.
`
`The actual investigator (verbatim) terms used for the 28 patients with
`sleepwalking were
`.
`“Sleepwalking” or “sleepwalked” in 25 patients
`0
`“Somnambulism” in 2 patients
`0
`‘Wanders in sleep" in 1 patient
`
`All instances of sleepwalking were coded using the COSTART term “sleep
`disorder”. A total of 47 patients in the Integrated Clinical Trials grouping had
`"sleep disorder" (COSTART). Of the 19 patients with "sleep disorder"
`(COSTART) who did not have sleepwalking the distribution of investigator terms
`was as follows
`
`. Sleep paralysis in 10 patients
`0
`increased awakenings/arousals at night in 5 patients (one of whom also had
`sleep paralysis)
`. Disruptive nocturnal sleep in 1 patient
`. Micro-sleeps in 1 patient
`. Somniloquy in 1 patient
`0 Motor activity in sleep in 1 patient
`. Difficulty awakening in the morning in 1 patient
`
`9a;..41.338
`
`
`W03318%
`
`

`

`Ranjit a. Mani, MD, HFD-120 Medical Review
`NBA 21196 (N-BZ), Xyrem, Orphan Medical Inc.
`
`Page 58 of 127
`3/4/02
`
`7 of the 28 patients with sleepwalking also had other conditions classified under
`the COSTART term “sleep disorder.” The investigator terms for these patients
`were as follows (4 of these patients had 2 of these terms each):
`2 patients with sleep paralysis
`4 patients with sleep talking
`2 patients with involuntary limb movements of sleep
`1 patient with poor sleep maintenance
`1 patient with fragmented sleep
`1 patient with screaming during sleep
`
`7.4.2 Demographics Of Patients With Sleepwalking
`
`.
`
`54% of patients were women (versus 57% for the entire cohort participating in
`the integrated Clinical Trials)
`o The mean age of the 28 patients with sleepwalking was 45.7 years (range:
`15.2 to 74.2 years) versus 46.1 years for the entire cohort of 402 patients in
`the Integrated Clinical Trials
`
`7.4.3 Distribution Of Sleepwalking By Clinical Trial
`
`The 28 patients with sleepwalking were distributed as follows across the
`individual trials in the Integrated Clinical Trials grouping; note that some patients
`had episodes in more than one trial
`
`Clinical Trial
`OMC-GHB-Z
`OMC-GHB-3
`OMC-SXB-G
`OMC-SXB-7
`Scrima
`
`Number of Patients
`2
`6
`13
`9
`1
`
`7.4.4 Frequency Of Sleepwalking Adverse Events
`
`individual sleepwalking adverse events did not necessarily correspond to
`individual episodes of sleepwalking. For example, multiple sleepwalking episodes
`were at times subsumed under a single sleepwalking adverse event.
`
`The numerical distribution of sleepwalking adverse events for the 28 patients with
`sleepwalking were as follows
`
`Number of Patients
`18
`7
`
`1 1 1
`
`Number of Sleegwalking Adverse Events
`
`VO‘OOM—K
`
`7.4.5 Onset Of Sleepwalking
`
`The onset of sleepwalking during treatment with GHB did not relate to the
`duration of treatment within the first 90 days of treatment as indicated by the
`following table. Sleepwalking episodes were however more likely to have their
`onset during the first 90 days rather than subsequently.
`
`

`

`Ranjit B. Mani, MD. HFD-120 Medical Review
`NBA 21196 (N-BZ), Xyrem, Orphan Medical Inc.
`
`Page 59 of 127
`3/4/02
`
`Time of Onset of Sleepwalking
`
`
`(Trial Days)
`1 throuoh 3O
`31 thouh 60
`61 throu-h 90
`91 throuh 120
`121 throuoh 150
`151 throu-h 180
`181 throuh 270
`211 throuh 240
`271 throu-h 300
`331 through 360
`361 throuh 390
`
`
`
`
`
`
`
`
`
`
`Number of Patients with Onset of Sleepwalking
`
`I—
`
`[—
`
`
`
`
`
`7.4.6 Duration Of Individual Adverse Events
`
`For 36 sleepwalking adverse events in 23 patients the duration of individual
`adverse events was available (i.e., start and stop dates were provided in the
`Case Report Forms). The duration of individual episodes of sleepwalking is not
`available
`
`The distribution of the durations of individual sleepwalking adverse events is in
`the followin table.
`
`
`
`
`
`
`
`-—l—
`__
`
`
`
`
`——_
`
`
`l-
`1
`—
`
`
`
`All sleepwalking adverse events 2 5 days (and 1 of the adverse events that
`lasted 1 day) in duration were listed as being intermittent.
`
`9 sleepwalking adverse events in 8 patients had no stop date and were assumed
`to be unresolvedx7 of those events were listed as being intermittent; the 2
`remaining events were described as being isolated
`
`7.4. 7 Falls and Injuries From SIeepwa/king Adverse Events
`
`4 of 46 sleepwalking adverse events were associated with falls, with or without
`injuries. that could be attributed to the sleepwalking events themselves: 3 were
`instances of falls during sleepwalking without any injuries being listed in the
`sponsor’s tables; in a fourth instance the patient was described as having
`sustained “cut fingers/multiple bruises during sleepwalking episode/fall."
`
`ln 4 patients with sleepwalking adverse events there were 5 instances of injuries
`that were not clearly related to events of sleepwalking. The investigator terms
`used were as follows: “cut on foot;” “contusion due to head due to fall and hitting
`head on cabinet;" “abrasion to head resulting from fal|;” bruise on forehead;" and
`“bruised hip.” As the sponsor points out such injuries could also have resulted
`from attacks of cataplexy.
`
`

`

`Ranjit e. Mani, MD, HFD-120 Medical Review
`NDA 21196 (N-BZ). Xyrem, Orphan Medical Inc.
`
`Page 60 of 127
`3/4/02
`
`7.4.8 Timing Of Sleepwalking Adverse Events Relative To The Two Nighttime
`Doses
`
`1"“
`
`Such information is available for only 4 adverse events in 2 patients
`
`o
`0
`
`in one patient both events occurred after the first dose
`In the second patient one event occurred after the first dose and one event
`after the second dose
`
`7.4.9 Factors Contributing To Episodes Of Sleepwalking
`
`The sponsor has proposed that a number of additional factors may have
`contributed to the episodes of sleepwalking seen in the integrated Clinical Trials
`grouping. These factors have been grouped into-3 categories by the sponsor
`
`7.4. 9.1 Relevant Medical History
`
`Relevant (according to the sponsor) medical history predating Xyrem® exposure
`include the following
`
`Medical History Predating Xyrem® Use
`Sleepwalking
`Dizziness/dysequiiibrium
`Sleep apnea
`Insomnia
`
`Nightmares
`
`Number Of Patients
`2
`
`2
`1
`2
`
`1
`
`7. 4. 9. 2 Concomitant Medications
`
`Concomitant medications that the sponsor believes could have contributed to the
`episodes of sleepwalking are listed below
`
`Medication
`Methylphenidate, pemoline, or amphetamines
`Modafinil or zolpidem
`Tricyclic antidepressants, selective serotonin re-uptake inhibitors or other antidepressants
`Antihistamines of decongestants
`Cardiovascular medications
`
`Codeine or fentanyl
`
`Number Of Patients
`16
`11
`
`woooooo
`
`7.4.9.3 Concurrent Adverse Events
`
`Concurrent adverse events (other than falls) that the sponsor believes could
`have been contributory to the episodes of sleepwalking are listed below
`
`Concurrent Adverse Events
`involuntary limb movements, night tremors or leg cramps
`Sleep-talking
`Insomnia
`
`Number Of Patients
`3
`3
`3
`
`Fragmented sleep, poor sleep maintenance or prolonged sleep paralysis
`Loss of balance or unsteady gait
`
`3
`2
`
`7.4.10 Discontinuations Due To SIeepwa/king In Integrated Clinical Trials
`
`2 patients discontinued Xyrem® on account of sleepwalking. Brief narratives for
`these patients are provided below
`
`

`

`Ranjit B. Mani, MD, HFD-120 Medical Review
`NBA 21196 (N-BZ), Xyrem, Orphan Medical Inc,
`
`Page 61 of 127
`3/4/02
`
`7.4.10.1 Patient #1631
`
`This 69 year old man participated in Study OMC-SXB-6. He had a history of narcolepsy with
`cataplexy; his concomitant medications included methylphenidate, clomipramine, atorvastatin and
`methamphetamine.
`
`On Day 23 of participation in the study, and while taking a Xyrem® dose of 6 g/day he began
`having intermittent episodes of sleepwalking. Later he developed fragmented sleep and involuntary
`limb movements of sleep. On Day 59, on account of all 3 of the above adverse events continuing to
`occur, Xyrem® was withdrawn. All 3 adverse events resolved after Xyrem® was stopped.
`
`7.4.10.2 Patient # 2532
`
`This 35 year old woman participated in Study OMC-SXB-G. She has a past history of occasional
`dysequilibrium. She had a past history of narcolepsy; concomitant medications included modafinil
`and cetirizine.
`
`On Day 16 of participation in the study whe began having intermittent episodes of sleepwalking. At
`the same time she began experiencing dizziness and later in the study noted numbness in her
`arms and legs. On account of the dizziness and sleepwalking she was withdrawn from the study on
`Day 43. All her adverse events resolved after Xyrem® was discontinued.
`
`7.4.11 Sleepwalking In Control/ed Clinical Trials
`
`0 The database for the Integrated Clinical Trials grouping includes both
`controlled and uncontrolled clinical trials
`
`. The controlled clinical trials in the grouping are listed in the following table
`
`OMC-GHB-2
`
`Randomized,double-blind,
`
`
`Treatment
`4weeks
`
`
`
`Enrolled
`136
`
`Scrima
`
`Lammers
`
`OMC-SXB-21
`
`oarallel-arm
`Randomized,double-blind,
`placebo-controlled, cross-
`over
`
`Randomized, double-blind,
`placebo-controlled, cross-
`over
`
`
`
`Randomized.double-blind.
`placebo~controlled.
`withdrawal
`
`4weeks
`
`4weeks
`
`2weeks
`
`20
`
`25
`
`55
`
`
`
`
`
`
`
`
`
`
`
`
`
`. The incidence of sleepwalking in the drug and placebo groups in each of the
`above trials is shown in the next table which I have COpied from the
`submission
`
`Number of Patients
`
`Placebo
`
`Sodium Oxybata
`
`Lat-rune I S 1
`
`CINC- SXS' 2 l
`
`’
`
`sleepwalkin
`
`sleepwalking
`
`Total
`102
`
`2 B
`
`(0.9%)
`
`2
`
`(1.2%)
`
`

`

`Ranjit B. Mani, MD, HFD—120 Medical Review
`NDA 21196 (N-B2), Xyrem, Orphan Medical Inc.
`
`Page 62 of 127
`3/4/02
`
`. Overall, as the above table indicates, the incidence of sleepwalking was 1.2%
`in GHB-treated patients and 0.9% in placebo—treated patients
`
`7.5 Scharf Trial
`
`7. 5. 1 Overall Summary
`
`Of the 143 patients participating in the Scharf trial, 45 patients (32%) had a total
`of 235 adverse events of sleepwalking through the data cut—off point of May 31,
`1999. The 45 patients had the verbatim term “sleepwalking" used to designate
`their adverse event (which was coded using the COSTART term “sleep
`disorder"). There were no adverse events other than sleepwalking coded under
`this COSTART term “sleep disorder."
`
`None of the episodes of sleepwalking led to a patient's death or were considered
`serious. One patient discontinued treatment on account of episodes of
`sleepwalking.
`
`These data are summarized along with the adverse event distribution by dose in
`the following table which I have copied from the submission.
`
`Sleepwalkiusz m mm
`Number 0: patients
`LeaaL J n:
`PuLJvr‘s nll“ IL
`Patients with SASS
`Pa:ianas with :elacefi RES
`Patient discontinuaticxs due
`
`not: Commonly Tnkon nyon oral Solution Dosago (g/d)
`Tom “nu—m-
`143 (100%) m
`45 €31.5‘.
`
`LO 35 A; Fazien: deaths
`
`As the above table indicates the incidence of this adverse event did not appear to
`increase with increasing dose.
`
`7.5.2 Demographics Of Patients With Sleepwalking
`
`.
`
`53% of patients were men (versus 56% for the entire cohort participating in
`the Scharftrial)
`. The mean age of the 45 patients with sleepwalking was 46.0 years (range:
`14.9 to 66.5 years) versus 45.3 years for the entire cohort of 143 patients in
`the Scharf Trial
`
`7.5.3 Frequency Of Sleepwalking Adverse Events
`
`Individual sleepwalking adverse events did not necessarily correspond to
`individual episodes of sleepwalking. For example, multiple sleepwalking episodes
`were at times subsumed under a single sleepwalking adverse event.
`
`Recording of the frequency of adverse events was not a requirement in the
`Scharf trial.
`
`However
`
`

`

`Ranjit B. Mani. MD, HFD-120 Medical Review
`NDA 21196 (N-BZ), Xyrem, Orphan Medical lnc.
`
`Page 63 of 127
`3/4/02
`
`.
`
`.
`
`.
`
`11 sleepwalking adverse events in 9 patients in this trial were characterized
`as intermittent or ongoing.
`For the 6/11 sleepwalking adverse events with stop dates the duration was as
`follows: 10, 15, 49, 53, 389 and 1736 days.
`5/11 intermittent or ongoing sleepwalking adverse events were characterized
`by multiple episodes as follows: 15, 16, 19, 128 and 346 episodes,
`respectively.
`
`7.5.4 Onset Of Sleepwalking
`
`The trial date of onset for the first sleepwalking adverse event experienced by
`patients in this trial ranged from Day 4 to Day 3520. 51.1% of patients had their
`first episode after 1 year on sodium oxybate.
`
`The table below has been copied from the submission and shows the day of
`onset of sleepwalking adverse events in this trial
`
`First
`
`All sleepwalking AEs
`No. of Patients
`No. of AEa
`45 (100%)
`235 (100%)
`m
`LI
`Lh ‘JB
`
`5 {12.2%}
`{8.9%}
`
`Day of Onset
`
`fix
`
`v
`
`i \tb-
`
`'Of‘J .x)
`
`i[F
`
`IAI
`la) UM
`
`Sleepwalking At
`No. of Patients
`
`45 (100%)
`5
`(11.1%}
`2
`(4.4%)
`
`2
`3
`1
`1
`1
`3
`
`1
`2
`5.:
`
`9
`2
`
`(4.4%3
`(6.7%)
`(2.2%)
`(2.2%}
`(2.2%)
`(6.7%)
`
`(2.2%)
`{4.4%}
`
`[2 2%i
`(20.0%)
`i4,4%i
`
`(6.7%)
`3
`4 (8.9%)
`
`5.-
`
`FJ[J
`
`h)h)0?w -..
`
`7.5.5 Duration Of Individual SIeepwa/king Adverse Events
`
`Note again that individual sleepwalking adverse events did not necessarily
`correspond to individual episodes of sleepwalking. For example, multiple
`sleepwalking episodes were at times subsumed under a single sleepwalking
`adverse event.
`
`The duration of individual episodes of sleepwalking is not available.
`
`

`

`Page 64 of 127
`Ranjit B. Mani, MD, HFD—120 Medical Review
`
`NBA 21196 (N—BZ), Xyrem, Orphan Medical Inc. 3/4/02
`
`The distribution of the durations of individual sleepwalking adverse events is in
`the followino table.
`
`
`
`
`
`
`
`553 da s _
`
`“Unresolved
`'i.e., occurred on 1 day only
`
`7.5.6 Timing Of Sleepwalking Adverse Events Relative To The Two Nighttime
`Doses
`
`This information is not available except in 1 patient who reported “sleepwalking”
`during the day; the sponsor suggests that may have been an episode of
`automatic behavior due to narcolepsy.
`
`7.5. 7 Falls, Injuries, Accidents And Overdoses From SIeepwa/king Adverse
`Events
`
`A total of 7 sleepwalking adverse events in 5 patients appear to have had further
`adverse consequences that resulted from sleepwalking.
`
`These events are summarized in the followino table
`
`Number Of Sleepwalking Adverse Events Associated With
`Additional Adverse Conse-uences
`2
`
`
`
`
`
`
`
`
`‘This 48 year old woman is reported to have had 19 individual episodes of sleepwalking between Days 148 and 536 while
`receiving GHB in a dose of 6.8 g/day. She is reported to have fallen during one such episodes and injured her arm and
`back
`
`A further patient (#01—031) reported having a total of 136 episodes of sleepwalking in her diaries. She
`sustained a cut to her left index finger although it is clear if that occurred during an episode of sleepwalking.
`
`Narratives for several patients in the above table are below. The narratives use
`material from earlier submissions.
`
`7. 5. 7. 1 Patient 01—206 (Initials . we
`
`See Section 7.5.9.1
`
`7.5.7.2 Patient 01—215 (Initials 'T'.
`
`This 46 year old woman with narcolepsy, who sustained a skull fracture 5 years prior to study entry, took
`GHB in a variable dose of 4.5 to 10.5 g/day in 2 or 3 divided doses despite being prescribed 7.5 g/day (this
`is not consistent with what has been entered in the medication logs in the Case Report Form. About 4
`months after entering the study she reported symptoms of nausea, a tipsy feeling, blurred vision, and a
`swollen face and hands. These symptoms persisted for 14 days, no action was taken, and her doses
`subsequently were variable and as high as 10.5 g/day. She continued in the study for a further4 years when
`she was discontinued on account of non-compliance which involved not submitting daily sleep log diaries
`and modifying dosing schedules without prior consultation with Dr Scharf.
`
`
`
`
`
`
`
`
`

`

`Ranjit B. Mani, MD. HFD-120 Medical Review
`NDA 21196 (N-BZ), Xyrem, Orphan Medical lnc.
`
`Page 65 of 127
`3/4/02
`
`A number of unexplained fits of laughter (termed “hysterical" in one instance, and “uncontrollable” at other
`times), and episodes of “sleepwalking” (during one of which she tried to drink nail polish remover).
`Episodes of headache, nausea, dizziness, blurred vision, enuresis, “fogginess”, “stumbling around-unsure of
`self on feet after gamma , drugged effect, vision blurred, unsteady on feet”, “drunken stupor; rage”, other
`similar events, and sleeplessness, were also noted during the study.
`
`A telephone contact with the patient 12 1/2 years after she discontinued from the study indicated that her
`neurological adverse events, with the exception of blurred vision, had resolved once GHB was discontinued.
`
`7.5. 7.3 Patient 01-017 (Initials \y
`
`This 63 year old man had a history of narcolepsy and sleep apnea. as well as hypertension. Initial physical
`examination is reported to have shown a “mildeto-moderate degree of oropharyngeal compromise."
`
`He began taking GHB in a dose of 4.5 g daily. About 11 months after enrolling, in an incident attributed
`to possible sleepwalking he ingested an additional estimated 9 g of GHB in addition to his first
`nightly 3 g dose of the drug. He drove himself to an emergency room, where he was administered
`ipecac and slept for 2 hours
`
`Approximately 1 1/2 years after enrolling in the study he was hospitalized after an overdose of GHB 18 9,
`again attributed to sleepwalking. At the time of hospitalization he was comatose and unresponsive. He
`needed intubation and artificial ventilation, and awoke 6 hours later. He continued in the study.
`
`.
`
`.
`
`Other significant items of information regarding this patient are as follows
`0
`He had many episodes of sleep walking and multiple episodes of urinary incontinence.
`o
`In 2 instances episodes of sleep walking and urinary incontinence are listed in the Case Report Form as
`occurring on the same day although there is no evidence presented that they occurred at the same time.
`0n the days when both incontinence and sleep walking are listed as having occurred, the patient’s
`prescribed dose was 7.5 glday
`As noted above this had multiple episodes of sleep walking that did not occur on the same days as his
`episodes of incontinence.
`.
`He also reported muscle jerks over the front of his trunk over a period of several years while taking GHB. These
`were stated to be most prominent when lying in bed in the morning as the last dose of GHB was wearing off; they
`could be controlled voluntarily and would disappear with ambulation, returning when at rest.
`He developed congestive heart failure during the study and died about 5 years after study entry. While
`participating in the study he underwent a thoracotomy for a right lung nodule that was confirmed to be a
`squamous cell carcinoma.
`
`.
`
`0
`
`7.5.7.4 Patient 01-267 (Initials “1
`
`This 65 year old woman had a history of obesity, sleep apnea on treatment, and narcolepsy. She began
`taking GHB in a dose of4.5 g daily.
`
`About 4 ‘/2 years after study entry she was reported to have taken an overdose of GHB, consuming
`a third nightly dose instead of merely two doses. The patient’s daughter reported that the patient
`was shortly afterward incontinent of urine, awoke and (for unclear reasons) was covered with
`spaghetti sauce. She also appeared dazed and confused. Her diaries are unavailable for that period
`and it is therefore unclear what her regular dose of GHB was at the time. She was taken to an
`emergency room but had recovered by that time. She was reported to have continued GHB after that
`episode but ceased returning any daily diaries at all beginning about 5 V. years after study entry and was
`therefore recorded as having left the study on account of non-compliance. Repeated letters to the patient
`from the study center were reportedly unanswered. Further information about this patient is unavailable.
`
`

`

`Ranjit B. Mani, MD, HFD-120 Medical Review
`NBA 21196 (N—BZ), Xyrem, Orphan Medical Inc.
`
`Page 66 of 127
`3/4/02
`
`During her participation in the study she was also recorded to have multiple episodes of
`sleepwalking and multiple additional episodes of urinary incontinence, not apparently occurring
`contemporaneously. She was also seen at an emergency room for an episode of somnolence which was
`felt to be related to her sleep apnea. She reported swollen ankles and wrists, and pain, numbness and
`tingling in her feet.
`
`(It is not clear from the above or from the Case Report Form whether the overdose occurred during an
`episode that would have been considered to represent “sleepwalking”)
`
`7.5.8 Factors Contributing To Episodes Of Sleepwalking
`
`The sponsor has proposed that a number of additional factors may have
`contributed to the episodes of sleepwalking seen in the Scharf study. These
`factors have been grouped into 3 categories byéhe sponsor.
`
`7.5.8.1 Relevant Medical History
`
`Relevant (according to the sponsor) medical history predating Xyrem® exposure
`include the following
`
`Relevant Medical History
`Sleep apnea
`Severe headaches or head trauma
`
`Number Of Patients
`13
`6
`
`7. 5. 8. 2 Concomitant Medications
`
`Concomitant medications that the sponsor believes could have contributed to the
`episodes of sleepwalking are listed below
`
`Medication
`Methylphenidate, pemoline, or amphetamines
`Tricyclic antidepressants, selective serotonin re-uptake inhibitors or other antidepressants
`Cardiovascular medications
`Benzodiazepines
`Caffeine
`
`Number Of Patients
`29
`26
`10
`2
`1
`
`7. 5. 8.3 Concurrent Adverse Events
`
`Concurrent adverse events (other than falls) that the sponsor believes could
`have been contributory to the episodes of sleepwalking are listed below
`.
`Extra doses of GHB in 2 patients; none of these extra doses were taken around the time that
`the sleepwalking episodes occurred
`A grand mal seizure in 1 patient: this patient had intermittent sleepwalking between Days 91
`and 1028 of the trial and the grand mal seizure occurred on Day 311.
`
`-
`
`7.5.9 Discontinuations Due To Sleepwalking In Scharf Trial
`
`A single patient discontinued Xyrem® on account of sleepwalking in the Scharf
`trial. The following narrative is based largely on earlier submissions under this
`application
`
`7.5.9.1 Patient 01-206 (Initials ~—-——_l
`
`This 62 year old woman had a history of narcolepsy, hypertension and heavy smoking. She began taking
`GHB in a dose of 3 g/day. Concomitant medications included spironolactone-hydrochlorthiazide, caffeine
`and atenolol.
`
`

`

`Ranjit B. Mani, MD, HFD-120 Medical Review
`NBA 21196 (N-BZ), Xyrem, Orphan Medical Inc.
`
`Page 67 of 127
`3/4/02
`
`While participating in the trial she had 7 episodes of sleep walking, beginning on Day 93. 2 episodes which
`occurred, separated by a 2-day interval, 7 V2 months after she entered the study, led to her discontinuing
`GHB. During each of these episodes she was found by her husband with a burning cigar or cigarette in her
`hand, apparently not aware of having been smoking. On one of these occasions she was found in a room
`other than their bedroom asleep with a cigar in her hand. On the second occasion the cigarette was found to
`be burning her nightgown; her husband threatened at that point to end their marriage unless she stopped
`taking GHB. The patient's entries in her daily sleep log indicate that she was unaware of her actions during
`these episodes and had no personal recollection of them subsequently . Prior to the above 2 episodes she
`fell off a toilet and struck her head on the floor during another sleepwalking episode.
`
`All her episodes of sleepwalking occurred while taking a Xyrem® dose of 6 glday. After Xyrem® was
`stopped, the episodes ceased.
`
`7.6 Sponsor’s Conclusions
`
`. A review of the 63 patients reported to have sleepwalking in the Integrated
`Clinical and Scharf trials revealed no dose, gender, ortime-on-treatment
`trends for such events
`
`0
`
`in the placebo-controlled clinical trials a slightly greater proportion (1.2%) of
`GHB—treated patients developed sleepwalking as compared with placebo-
`treated patients (0.9%)
`. The first sleepwalking adverse event occurred primarily during the first 90
`days in the Integrated Clinical Trials and after more than 1 year in the Scharf
`trial
`
`0
`
`.
`
`.
`
`. The explanation for the higher incidence of sleepwalking adverse events in
`the Scharf trial may be as follows
`0
`In this study patient diaries contained a specific line item for each day asking
`whether the patient had experienced sleep walking
`By specifically soliciting information regarding sleepwalking the incidence may
`have been higher than seen in other clinical trials
`In both the Integrated Clinical and Scharf trials the majority of patients (64%
`in the Integrated Clinical Trials, and 88% in the Scharf trial) with sleepwalking
`adverse events had isolated non-recurring events. In most instances
`sleepwalking adverse events are of short duration and of little consequence to
`patients
`0 Sleepwalking-related injuries were uncommon in GHB-trials. The risk of injury
`may be reduced with preventive measures (see below)
`“Pro-active” preventive approaches are effective for sleepwalking episodes.
`An example is that of a male patient (#01-042) who participated in the Scharf
`trial began having episodes of sleepwalking after taking GHB for 6.1 years; he
`reported a total of 346 adverse events of sleepwalking. He lived alone in a
`trailer and became aware of the episodes after awaking in areas of the trailer
`other than the bedroom. Dr Scharf suggested that he attach a bell to the
`bedroom door and obtain a dog. Since then, although his sleepwalking
`episodes are continuing he is awakened whenever he attempts to leave his
`bedroom.
`
`0 The differential diagnosis of sleepwalking episodes is discussed by the
`sponsor (see Section 7.2). The sponsor believes that the 2 most likely
`explanations for such episodes in Xyrem®-treated patients are as follows
`
`

`

`Ranjit B. Mani, MD. HFD-120 Medical Review
`NDA 21196 (N-BZ), Xyrem, Orphan Medical Inc.
`
`Page 68 of 127
`3/4/02
`
`. NREM parasomnias: these are associated with slow-wave sleep and it is
`possible that GHB-induced slow-wave sleep may predispose susceptible patients
`to sleepwalking; also, the fragmented sleep and sleep deprivation seen in
`patients with narcolepsy may predispose patients to NREM parasomnias
`0 REM Behavior Disorder: this condition is common in narcoleptics, older patients
`and in men, and a number of patients with sleepwalking adverse events had
`such predisposing factors; sleepwalking-like behavior has been described in
`REM Behavior Disorder
`
`7.7 Reviewer’s Comments
`
`In most instances of sleepwalking in GHB clinical trials, a detailed description
`of patient behavior during that adverse event is not available; in the absence
`of adequate clinical descriptions, in most instances it is unclear what the
`investigator term “sleepwalking” represents as a clinical entity, or whether it
`refers to single or multiple entities. The basis of these episodes has not been
`further elucidated by the current analysis.
`Regardless of what the term “sleepwalking” means in the context of this NDA,
`it is clear that such episodes are common; almost one-third of patients
`participating in the long-term Scharf safety study did have one or more such
`occurrences, and a single patient is recorded as having as many as 346
`episodes.
`The few clinical descriptions of this adverse event that are available in this
`NDA suggest that during at least a few such episodes patients may be
`confused and may act in a manner that could be seriously prejudicial to their
`own safety and to that of others.
`It is possible that sleepwalking as seen in the context of this application, was
`causally related to GHB use
`.
`Similar adverse events appear to be uncommon in narcoleptic patients who have
`not been treated with GHB.
`
`. Although the incidence of this adverse event was only slightly higher than that of
`placebo in controlled clinical trials of GHB, these were of short duration (2 1
`month). The highest incidence was seen in the long-term Scharf study
`The sponsor has not supplied any evidence other than a single anecdote
`which suggests that preventive measures are of value in reducing the
`adverse consequences of such episodes
`
`8. Respiratory Data In Study OMC-SXB-ZO
`
`8.1 Background
`
`This was an open-label study that was intended to evaluate the effects of 4
`doses of Xyrem® on sleep architecture.
`
`The final study report for OMC-SXB-ZO was submitted on 12/16/00, i.e., after the
`original NDA submission, and was reviewed by me along with that submission.
`The effects of Xyrem® on sleep architecture as derived from this study are
`described in my Efficacy Review of the original NDA. Safety data from this study
`are described in my Safety Review of the original NDA.
`
`

`

`Ranjit B. Mani. MD. HFD-120 Medical Review
`NDA 21196 (N-BZ), Xyrem, Orphan Medical Inc.
`
`Page 69 of 127
`3/4/02
`
`Arterial oxygen saturation data from all-night recordings, and data on the
`frequency and severity of specific respiratory-event-related measures were
`collected as part of the polysomnogram recordings in this study but were not
`included in the original clinical trial report.
`
`In the Approvable letter that was issued on 7/2/01 it was noted that although
`GHB was a central nervous system depressant and therefore capable of
`producing respiratory depression, no formal assessment of its effects on
`respiration had been performe