Ranjit e. Mani, MD, HFD-120 Medical Review
`NDA 21196, Xyrem, Orphan Medical, Inc.
`
`Page 22 of 135
`6/15/01
`
`study she complained of knee pain and on Day 31 reported generalized joint pain. At
`that point Xyrem® was stopped temporarily (it is uncertain for how long) but was then
`resumed in a dose of 6 g/day. On Day 68 on account of continued generalized joint pain,
`she was referred to a rheumatologist (details of this consultation are unavailable);
`treatment with diclofenac 100 mg/day was begun. On Day 131 the patient was stated to
`have patellovfemorai syndrome (presumably she had knee pain at that point). Study
`medication was then stopped for 3 days, resumed and continued until Day 185. Her
`generalized arthralgia and knee pain were apparently continuing at her last visit.
`
`8.3.1.5 Patient I735 (Initials. -— ,)
`
`This 26 year old woman participating in OMC-SXB-6 initially took Xyrem® 4.5 g/day for
`13 days, followed by 6 g/day for 52 days. On Day 66 she was discontinued from the
`study on account of her becoming pregnant, a protocol violation. She had a miscarriage
`on Day 108.
`
`8.3.].6 Patient 0214 (Initials --’i
`
`This 42 year old man participating in OMC-SXB-7, was noted to have abnormal liver
`function tests at the Month 6 (Day 196) visit; he was taking 9 g/day of Xyrem® at that
`time. At that time he had a tremor and diaphoresis. His concomitant medications at that
`time included ascorbic acid, multivitamins, methylphenidate, acetaminophen and '
`pseudoephedrine; earlier he had also taken a butalbital-aspirin combination, zolpidem,
`tramadol, alprazolam, fluoxetine and paroxetine for unknown periods of time, and
`modafinil for about 5 months. At that time (Day 196) his liver function studies were as
`follows: total protein 7.3 g/dl; albumin 4.2 g/dl; total bilirubin 0.6 mg/dl; alkaline
`phosphatase 135 U/L AST 189 lU/L; ALT 362 lU/L. A further 9 days later (Day 205) his
`liver functions were: total protein 7.0 g/dl; albumin 4.1 g/dl; total bilirubin 0.4 mg/dl;
`.
`alkaline phosphatase 112 U/L; AST 141 lU/L; ALT 271 lU/L.
`_
`
`His past medical history was remarkable for migraine, hay fever, a right nephrectomy
`and known hepatitis C infection.
`
`At the time of his entry into the OMC-SXB-7 study his serum liver function tests were as
`follows: total protein 7.2 g/dl; albumin 4.2 g/dl; total bilirubin 0.4 mg/dl; alkaline
`phosphatase 63 U/L AST 27 IU/L; ALT 41 lU/L (all well within normal limits)
`
`On Study Day 205 Xyrem® was permanently discontinued. Results of follow-up liver
`functions, if any, are not available. It is unclear based on the Case Report Form, if his
`abnormal liver functions were associated with any symptoms.
`
`8.3.1.7 Patient 0231 (Initials \— ,‘
`
`This 67 year old man participating in Study OMC-SXB-6 took Xyrem® in a dose'of 4.5
`g/day for 12 days and 9 g/day for 106 days. He was reported to experience nausea,
`vomiting, dizziness, confusion and generalized weakness. His past medical history was
`remarkable for a stomach ulcer, gastroesophageal reflux disease, and a
`cholecystectomy. Concomitant medications included clomipramine, methylphenidate,
`paroxetine, imipramine and modafinil.
`
`Xyrem® was permanently discontinued. Within 24 hours the adverse event had
`resolved.
`
`

`

`Ranjit B. Mani, MD, HFD-120 Medical Review
`NBA 21196, Xyrem, Orphan Medical, lnc.
`
`.
`
`Page 23 of 135
`6/15/01
`
`8.3.1.8 Patient I305 (Initials L:
`
`This 73 year old woman participating in Study OMC-GHB-3 became agitated, frightened
`and restless after taking GHB for 670 days. Her dose of Xyrem® at that time was not
`recorded; her last recorded dose was 9 g/day and this dose was carried forward.
`Xyrem® was temporarily stopped, and she was treated at an emergency room with
`diphenhydramine and Iorazepam injections. She was discharged home having
`apparently recovered, and was able to complete the study (study medication was
`resumed but it is unclear for how long and in what dose it was administered).
`
`8.3.2 Serious Adverse Events In Scharl Study
`
`54 patients had serious adverse events in the Scharf study. 51 of these patients
`had serious adverse events that occurred after they started to receive study drug:
`these adverse events are tabulated below.
`— Number or Patients
`Total Number With Serious Adverse Events
`1
`Asthenia
`Cellulltrs
`
`Percentaoe of Patients Partici-oatin In Stud
`
`.5
`
`
`
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`
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`
`

`

`Ranjit B. Mani, MD, HFD-120 Medical Review
`NDA 21196, Xyrern, Orphan Medical, inc.
`
`Page 2”}01 1 35
`6/15/01
`
`
`
`
`
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`I have read through the narratives, and Case Report Forms where needed, for
`the above patients. Serious adverse events that warrant further description are
`listed below.
`'
`
`8.3.2.1 Patient 012 (Initials “—9 i
`
`This man was 74 years old at the time of study entry. He had a past history of
`cardiomyopathy, left bundle branch block and sleep apnea. About 2 years after
`.
`beginning GHB and while taking a dose of 7.5 g daily he had an episode of
`disorientation, stupor and weakness that necessitated hospitalization and a reduction in
`dose of GHB to 6 g daily for one day. The episode resolved and did not recur despite the
`patient continuing to take 7.5 g daily.
`‘
`
`_
`
`8.3.2.2 Patient 017 (Initials \v ,l
`
`_
`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 “mild-to-moderate
`degree of oropharyngeal compromise.”
`-
`-
`
`He began taking GHB in a dose of 4.5 g daily. About 11 months after enrolling in'Jn
`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
`
`

`

`Ranjit e. Mani, MD, HFD-12O Medical Review
`NBA 21196. Xyrem, Orphan Medical, Inc.
`
`Page 250i 135
`6/15/01
`
`. He had many episodes of sleep walking and multiple episodes of urinary incontinence.
`.
`ln 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.
`
`o On the days when both incontinence and sleep walking are listed as having occurred, the
`patient’s prescribed dose was 7.5 g/day
`. 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 mornirtj 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.
`
`8.3.2.3 Patient 019 (Initials 3-“ I)
`
`This 41 year old man with a past history of depression and suicidal ideation was begun
`on treatment with GHB in a dose of 5.3 g/day. 6 months later he was hospitalized for
`treatment of depression at a time when he was taking GHB in a dose of 6 g/day; that
`medication was interrupted for a day and then resumed at 9 g/day. About 2 years after
`first beginning the drug he was hospitalized after a suicide attempt that consisted of
`taking an overdose of GHB. At that time he was dropped from the study
`
`8.3.2.4 Patient 257 (Initials _- )
`
`This 32 year old man with a past history of a whiplash injury with numbness and
`paresthesia in his hands was begun on treatment with GHB 4.5 g daily while
`concomitantly taking protryptiline. About 3 months later he was seen at a hospital
`emergency room on account of complaints of chills, sweating, blurred vision, memory
`loss, and shaking as well as vibrating sensations. A further 6 months later shaking and
`vibrating sensations occurred again at which time he was also recorded as having
`attacks of cataplexy at least one of which resulted in a fall. 2 further years later he was
`hospitalized overnight after an unspecified adverse reaction that was attributed to
`ingesting too much GHB.
`
`After an additional 2 years on GHB the patient fell on a long butcher knife, and
`perforated his colon. During the pen—operative period GHB was stopped for 10 days.
`About 2 months after surgery he was hospitalized on account of hypoxemia and required
`intubation and mechanical ventilation. Further details are unavailable. GHB was ..
`apparently not stopped at the time.
`
`8.4 Dropouts and “Other Significant Adverse Events ”
`A total of 63 GHB-treated patients permanently discontinued treatment on 1
`account of adverse events. Their distribution by study grouping, according to the
`sonsor, is as follows.
`Study Grouping
`
`
`
`Total number of patients/subjects in
`grouping
`
`P
`l
`Number (%) of atients/sub'ects with
`adverse events leading to
`discontinuation
`
`
`
`
`
`
`
`__
`”IE—
`‘Note that the sponsor has counted 7 deaths as discontinuations due to adverse events. The actual adverse event
`discontinuation rate is 12/143 or 8.4%.
`'
`
`
`
`
`

`

`Page 26 of 135
`Ranjit B. Mani, MD, HFD~120 Medical Review
`
`NBA 21196, Xyrem, Orphan Medical, Inc. 6/15/01
`
`A single placebo-treated patient (# 0818; initials ——‘-'-'I participating in OMC-
`GHB-2 discontinued treatment 1 month after study entry on account of insomnia
`(see Section 8.4.1)
`
`These adverse event discontinuations are further discussed under the 3 study
`groupings in which they occurred.
`
`8.4.1 Adverse Event Discontinuations In Integrated Clinical Trials
`
`44 patients discontinued treatment on account of adverse events in this grouping
`
`
`
`
`
`
`
`
`
`
`Of the 44 patients who discontinued treatment in the Integrated Clinical Trials Grouping, 10 discontinued
`treatment in the 3 controlled clinical trials; all 10 participated in OMC-GHB-Z. The adverse events that led to
`treatment discontinuation in OMC-GHB-2 (n = 136) were as follows
`Nausea 2.9%
`Somnolence 2.2%
`Confusion 1.5%
`
`Amnesia, asthenia, chest pain, dizziness, dyspnea, hyperkinesia, fecal incontinence, insomnia, paranoid reaction, thinking
`abnormal. vertigo, and vomiting each 0.7%.
`
`
`
`
`
`A listing of patients who discontinued treatment in OMC-GHB-2 is as follows; as the table indicates these
`
`adverse events were dose-related. Also note, however, that individual doses were not titrated in this study.
`
`
`Patient
`
`Number
`Preferred term {investigator term}
`Placebo
`
` 818 Insomnia [érmmnia]
`
`
` 39 GHB
` 901
`Nausea {nausea}. Widener; {lethargy}. pain chest [chest pressure}
` Gg GHB
`
` 207 Confusion [acme conlugonat state]
`
`
`
`509
`Hype‘kinesia [realises leg increased]. Madame [Madame]
`
`221
`
`Sommtence [irraeased sleepiness}. dizziness {fizzy}. nausea Inmseated}, and
`astlrerséa [weakness (had deficulty standing};
`
` 99 6H8
`
`
`
`
`605
`
`Sommlerce [daytime sedation feeling: ’dmgged taelrngl thinking abnormat
`[pom concentration}
`
`
`
`702
`Cadusion {emulsion}. helium {haHuanat‘xms}. amnesia iforgettdness}.
`
`nausea [nausa-a}, paranoid reaction [paranoia
`
`Dyspnea {dithcmty breathing}
` lr‘mntinenc‘e least [patient test boweé contact white esteem
` Nausea (nausea). vertigo {vertigo}. vomit [vomiting]
`
`
`
`
`The following table, supplied by the sponsor, provides a summary for 38 out of
`44 patients who discontinued treatment on account of an adverse event in the
`entire Integrated Clinical Trials grouping. In these 38 patients discontinuation was
`considered to be treatment-related by the investigator.
`
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`

`Ranjn B. Mani, MD, HFD~120 Medical Review
`NDA 21196, Xyrem, Orphan MedicaL Inc.
`
`Page 27 bf 135
`6/15/01
`
`APPEARS THIS WAY
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`

`Ranjit B. Mani, MD, HFD»120 Medical Review
`NDA 21196. Xyrem, Orphan Medical, Inc.
`
`Page 28 of 135
`5/15/01
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`Ranjit B. Mani. MD, HFD~120 Medical Review
`NBA 21196, Xyrem, Orphan Medical, Inc.
`
`Page 29 of 135
`6/15/01
`
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`

`Ranjit B. Mani, MD, HFD-120 Medical Review
`NBA 21196, Xyrem, Orphan Medical, lnc.
`
`Page 30 of 135
`‘ 6/15/01
`
`Of the patients listed in the table above, short narratives have already been
`provided under the discussion of Serious Adverse Events above for the following:
`#5 0207, 0231, 0238 and 1735. Brief narratives are provided for the following
`additional patients. Narratives for more patients do not appear to be needed
`based on a review of the data provided by the sponsor.
`
`8.4.1.1 Patient 0221 (Initials “‘— )
`
`This 57 year old woman was enrolled in the OMC-GHB-2 trial and was begun on GHB in
`a dose of 9 g/day. 12 days later she complained of increased sleepiness along with
`dizziness, nausea and weakness (with difficulty maintaining an upright posture). GHB
`was discontinued and her symptoms resolved. She was next enrolled in OMC-GHB-3
`during which her most common dose of GHB was 6 g/day; while taking a dose of 3
`g/day, her initial dose, she reported excessive somnolence from the first day in the trial
`onward. After about 1.5 months of participation in OMC-GHB-S, the study drug was
`stopped permanently with resolution of this adverse event
`
`8.4.1.2 Patient 3831 (Initials ——-—il
`
`This 31 year old woman with a previous history of eczema was enrolled in OMC-SXB-G.
`She took Xyrem® 4.5 g/day for 10 days followed by 3 g/day for 2 days; she then ,
`,
`experienced itching and swelling of her extremities leading to discontinuation of GHB on
`Day 13. By Day 24 both itching and extremity swelling had resolved.
`
`The 6 remaining patients who discontinued study drug permanently on account
`of adverse events and are not listed above are summarized in the table below. in
`
`these patients the adverse events that lead to treatment discontinuation were not
`
`considered to be dru-related
`
`Patient 1D
`Gender
`GHB Dose
`Study Day
`
`
`
`When
`Initials
`Age (years)
`At Onset Of
`
`
`
`
`
`Adverse
`Study if
`Adverse
`
`
`
`
`Event Ended
`Event
`
`
`
`
`
`
`Study Day
`
`When
`
`Adverse
`
`Event Began
`
`
`
`None
`
`Unintended
`pregnancy
`
`Outcome After
`
`
`Study Drug
`
`Discontinuation
`
`
`
`“”Unresolved
`
`-
`
`
`
`'
`
`‘
`
`Twitching
`
`Resolved
`
`2-8
`
`77
`
`None
`
`Abnormal liver
`function tests
`
`Unresolved
`
`[2634
`OMC-SXB-6
`. 3“”
`
`
`
`51.2
`
`.
`
`None
`
`None
`
`
`
`Sinusitis
`Generalized
`edema
`Apnea
`(sleep apnea)
`
`Unresolved
`
`Unresolved
`
`5MZ.6
`OMC-SXB—6
`
`
`
`A narrative for Patient # 0214 has already been provided under the discussion of
`Serious Adverse Events. Narratives are provided below for 2 additional patients
`
`
`
`8.4.1.3 Patient 0504 (Initials . —-'—'t
`This 45 year old woman participated first in OMC-GHB-2 and then in OMC-GHB~$ for a
`total period in these trials of 10 months. While taking Xyrem® in a dose of 6 g/day in
`
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`

`Ranjit e. Mani, MD, HFD—120 Medical Review
`NBA 21196. Xyrem, Orphan Medical, Inc.
`
`I
`
`Page 31 of 135
`6/15/01
`
`OMC-GHB-B she was reported to have lapses of memory each afternoon. Xyrem® was
`stopped and this adverse event resolved.
`
`8.4.1.4 Patient 3533 (Initials 3—4)
`
`This 52 year old man participating in OMC-SXB-B had no significant past medical
`history. At entry into the study he was begun on GHB in a dose of 4.5 g/day. This dose
`was gradually increased in steps to 9 g/day. After 4 days on the last dose and after 86
`days of treatment with GHB he was noted to have sleep apnea which was judged to be
`severe and lead to Xyrem® being stopped. The adverse event did not resolve after the
`study drug was stopped
`
`8.4.2 Adverse Event Discontinuations In Scha Trial
`
`According to the sponsor, 19 patients withdrew from this study because of
`adverse events. They are listed in the following table which I have copied from
`the submission. Note that of the 19 patients listed, 7 patients were “withdrawn"
`because of death; ordinarily such patients would not be considered as having
`withdrawn due to adverse events. An eighth patient (# 064; Initials m; ‘t is
`incorrectly listed in this table as having died
`
`APPEARS THIS WAY
`
`0N ORiGlNAL
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`

`

`Page 32 of 135
`Ranjit B. Mani, MD. HFD~12O Medical Review
`
`NBA 21196, Xyrern, Orphan Medical, Inc. 6/15/01
`
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`

`Ranjit B. Mani, MD, HFD-120 Medical Review
`NDA 21196, Xyrem, Orphan Medical, |nc.
`
`Page 33 of 135
`6/15/01
`
`After reading through the sponsor-supplied narratives, and Case Report Forms
`(when needed) for the above patients further details are provided for the
`following patients. Patient # 019 has already been described in the discussion of
`Serious Adverse Events.
`
`8.4.2.] Patient 005 (Initials «~— i
`
`This 53 year old woman was reported to have developed anger, hostility and
`suspiciousness, while taking dextroamphetamine and other stimulants, prior to study
`entry. She was begun on GHB in a dose of 5.3 g/day; concomitant medications include
`clomipramine as well as caffeine tablets. After taking GHB for 4.7 years that drug was
`discontinued when the patient had difficulty sleeping and “psychiatric problems” that
`were considered similar to those that occurred when she was taking stimulants. She
`required a psychiatric hospitalization, the outcome of which and her subsequent course
`are unknown.
`
`8.4.2.2 Patient 064 (Initials ‘— ,‘
`
`This 15 year old girl had a previous history of a left frontal lobe lesion, previous burr hole
`placement after a “concussion" and headaches. Concomitant medications at study entry
`included protriptyline and methylphenidate. She received treatment with GHB for 1.8
`years at a mean dose of 6 g/day. While on treatment she was reported to have
`“increased seizure activity” (no details of the seizures are provided; it is not clearly stated
`that she had seizures prior to study entry), increased urinary frequency, headache,
`vomiting, dyslexia, an increased appetite and shortness of breath. The increased .
`seizures reportedly led to hospitalization and to discontinuation from the study, although
`the last date of medication administration is listed as being unknown. No further details
`are provided.
`
`8.4.2.3 Patient 066 (Initials ——-— _
`
`This 50 year old woman had a past medical history of hypertension, occasional cnest
`pain, a dry skin rash, penicillin allergy, a hysterectomy and weight gain of 45 kg over 9
`years. Concomitant medications at study entry included triamterene-hydrochlorthiazide,
`clorazepate and methylphenidate. She took GHB for a total of about 6 years, most
`commonly in a dose of 7.5 g/day. After a little less than 6 years of treatment she was
`noted to have an anti-nuclear antibody titer of 1:640 (this test was not performed earlier
`in the study). Over the next 3 months successive antinuclear antibody titers were 1:1280
`and >1:2560, respectively. GHB was stopped; over the next 11 months follow-up
`antinuclear antibody titers were always > 1:160 (in a range of 1:160 to 111280). A
`diagnosis of drug-induced lupus was apparently considered. Antihistone antibody testing
`was not done.
`
`The above summary is based on information obtained from the Case Report Form and
`sponsor narrative. However the sponsor has also supplied the following documents
`. An abstract published by Dr Scharf in 1993 indicated that the same patient (Whose
`identity was confirmed separately by Dr Scharf) developed‘‘clinical symptoms
`suggestive of arthritis” after having received GHB for 68 months
`A letter to the sponsor from Dr Scharf dated 7/24/98, had been on GHB for 72
`months at which time she was diagnosed to have rheumatoid arthritis was diagnosed
`This diagnosis appears to have been made a few months before her first, positive
`antinuclear antibody test. Further clinical details are unavailable.
`
`.
`
`”\
`
`

`

`Page 35 of 135
`Ranjit B. Mani, MD, HFD-120 Medical Review
`
`NBA 21196, Xyrem, Orphan Medical, Inc. 6/15/01
`
`g/day. A further 8 days later the dose was reduced to 0.8 g/day. As her symptoms had
`not resolved a month later the drug was stopped. No additional information is available;
`it is unclear if her symptoms eventually resolved.
`
`8.4.3 Adverse Event Discontinuations In Inte rated Pharmacokz'netic Trials
`
`
`2 subjects discontinued study participation on account of adverse events. They
`are summarized in the table below:
`
`
`
`
`Subject lD
`GHB Dose
`Study Day
`Study Day
`Adverse Event
`Outcome After Study
`
`At Onset Of When
`When
`Drug Discontinuation
`Initials
`
`
`Study #
`Adverse
`Adverse
`Adverse
`'
`
`
`
`Event
`Event
`
`
`Ended
`
`In is n19
`
`
`Headache nausea and
`Adverse events
`Unclear
`
`
`diarrhea
`resolved
`MC-SXB-Q
`
`
`lD # 003
`..__-2
`5 hours
`After initial
`Dizziness, nausea
`Adverse events
`
`after onset
`dose
`vomiting, apneic
`resolved
`OMU-SXB-H
`
`
`episodes and fecal
`
`
`incontinence'“
`
`
`
`'Administered'In 2 divided doses of 2.25 g each, 4 hours apart
`“Administered in a single dose of 4.5 9
`
`After initial
`dose
`
`
`
`4.5'
`
`4.5"
`
`‘ O
`
`“‘2 hours after her initial and only dose of GHB this subject began experiencing dizziness, nausea and vomiting. At the
`same time or shortly afterward the patient also experienced a single 2-minute period of apnea, a generally depressed
`depth of respiration and fecal incontinence. She was treated by rolling her over on her side, and administering oxygen by
`mask for several minutes on 2 occasions. All adverse events resolved over a period of about 5 hours after they first
`began. This summary is based on a review of the sponsor-supplied narrative and Case Report Form
`
`
`In a further communication dated 2/23/01 the sponsor had, at my request, submitted further information about subject #
`003 (initials
`, participating in Study # OMC~SXB~11. The information is as follows:
`.
`This patient weighed 137 lbs (62.3 kg) and was 63 inches in height
`.
`She received a single 4.5 g dose of GHB after a 10 hour fast
`.
`30 minutes after dosing she reported dizziness
`.
`One hour after dosing and while asleep in the supine position she had labored, “decreased” respiration with
`inspiratory stridor. She did not improve with repositioning and was then apneic briefly before the episode resolved on
`stimulation and application of an oxygen mask
`After stimulation she awoke and vomited once.
`
`.
`
`.
`
`She then fell asleep again. 1 further hour later, and 2 hours after dosing her she vomited twice and then had a further
`episode of stridor (when lying on her side) and a brief pause in spontaneous respiration that again responded to
`stimulation and the use of an oxygen mask. At the same time she was fecally incontinent, but had her eyes open,
`could respond to verbal commands and was not observed to have any “seizure-like movements"
`2 further hours later she was able to consume most of the offered lunch.
`.
`Pulse and blood pressure remained normal throughout
`.
`The sponsor further stated that this food-effect pharrnacokinetic study confirmed that exposure (based on Cm. and AUC)
`was significantly increased, and tm, delayed, in the fasted state
`
`8.5 Adverse Events Incidence Tables
`
`8.5.] Approach to Eliciting Adverse Events
`Approaches used differed based on the clinical trial grouping, as discussed
`below.
`
`8.5.1.] Integrated Clinical Trials
`
`In this clinical study grouping the following approach was used.
`. Adverse events that occurred during the trial and up to 10 days after the last dose of
`study medication were recordedIn detail on the appropriate page of the Case Report
`Form
`
`. The frequency, severity, seriousness and relationship to study medication was
`recorded. A serious adverse event was defined using standard criteria. Serious
`adverse events were not recorded in the Scrima trial
`
`

`

`Ranjil B. Mani. MD, HFD-120 Medical Review
`NDA 21196, Xyrem, Orphan Medical, Inc.
`
`Page 36 of 135
`6/15/01
`
`. Medication dosage at which the adverse event began was also recorded
`
`8.5.1.2 Lammers Trial
`
`Only the incidence of adverse events was recorded. Serious adverse events were'not
`recorded.
`
`8.5.1.3 Integrated Pharmacokinetic Trials
`
`The frequency, severity, seriousness and relationship to study medication were each
`recorded in a variable number of studies
`
`8.5.1.4 Scharf Trial
`
`The following is stated
`. Adverse events were recorded retrospectively omCase Report Forms from
`information recorded by patients in daily diaries and from investigator-maintained
`medical records.
`c The seriousness, severity and relationship to study medication of these adverse
`events was also recorded.
`
`- A serious adverse event was defined using standard criteria
`
`8.5.2 Adverse Events Categorization and Preferred Terms
`
`Adverse events were initially entered in Case Report Forms using investigator
`terms, but were tabulated in the Integrated Summary of Safety and in the
`majority of study reports using
`8.5.3 Kev Adverse Events Tables
`
`Key adverse event tables are grouped as follows
`
`8.5.3.1 Controlled Clinical Trials
`
`The following table, copied from the Integrated Summary of Safety, presents the
`number of adverse events that occurred in 2 5% of patients in each treatment
`group in the following controlled clinical trials, combined: OMC-GHB-2, Lammers
`and Scrima.
`
`APPEARS THIS WAY
`0N ORIGINAL
`
`

`

`Ranjit B. Mani. MD, HFD-12O Medical Review
`NDA 21196, Xyrem, Orphan Medical, Inc.
`
`Page 37 of 135
`6/15/01
`
`—100%t
`
`S}’S’_€;I‘ u
`
`Byspepsia
`Nausea
`
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`Confusion
`
`Eizziness
`Nervousness
`
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`
`14 {6%}
`28 (12%}
`
`as {35%}
`12 {5%}
`
`{15%}
`
`As the above table indicates
`
`. The proportion of patients with adverse events was higher in those treated
`with GHB than in those treated with placebo
`. The most common adverse events in those treated with GHB were headache,
`nausea and dizziness. All 3 were more common in those treated with GHB
`
`than in those treated with placebo; nausea and dizziness were > 3-fold more
`common in the GHB group
`
`8.5.3.2 Integrated Clinical Trials
`
`The following table, copied from the Integrated Summary of Safety, presents the
`number of adverse events that occurred in 2 5% of patients in each treatment
`group in all studies in the Integrated Clinical Trials grouping. The dose listed is
`that at onset of the adverse event.
`
`BEST POSSIBLE COPY
`
`

`

`Ranjit BI Mani, MD, HFD-120 Medical Review
`NBA 21196, Xyrem. Orphan Medical, Inc.
`
`Page 38. of 1 35
`6/15/01
`
`Body iysLu
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`Tu:
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`The above table confirms that
`
`‘
`
`. The most common adverse events in those treated with GHB were headache,
`
`pain, nausea and dizziness.
`. A dose response could be seen, at leastIn the case of the 9 g dose, in the
`case of nausea.
`
`8. 5.3.3 Lammers Trial
`
`Only a few adverse events were seen in this study as summarized by the
`following table taken from the Lammers study report. Note that
`.
`Only 3 patients had adverse events while taking GHB
`.
`Adverse events seen in this study have also been includedIn the Controlled Clinical Trials grouping
`above
`
`

`

`Page 39 of 135
`Ranjit B. Mani, MD, HFD»120 Medical Review
`
`NBA 21196, Xyrem, Orphan Medical, inc.
`6/15/01
`
`Patent number
`
`Investigator rem
`
`
`
`
`
`
`
`
`
`_—terribledreaming
`
`
`
`
`
`
`
`dry mouth
`paralysis in legs and arms
`anxious
`
`insecure
`
`kidney problems
`
`urination problems
`
`
`
`
`(stranguria)
`
`
` severe perspiration
`influenza (common cold),
`
`
`sore throat
`
`
`headache
`
`frequent micturition
`infection bladder
`sore throat
`
`GHB
`
`
`
`
`
`
`flickering in the eyes
`
`8.5.3.4 Integrated Pharmacokinetic Trials
`
`The following table, copied from the integrated Summary of Safety, presents the
`number of adverse events that occurred in 2 5% of subjects in the integrated
`Pharmacokinetic Trials Grouping
`
`Body System
`COSTAR'I‘ Preferred Term
`1-2321th of Subjects
`
`Sodium Oxybate
`
`144 ll06%
`
`Subjects are caused only craze i:- eat: Category.
`
`As the above table indicates the most common adverse events in this grouping
`as well are headache, nausea, vomiting and dizziness.
`
`8.5.3.5 Scharf Trial
`
`Given the duration of this study, adverse events were common and at least 1
`adverse event was experienced by 95.1% of those participating in this trial.’
`Adverse events that occurred in 2 5 % of patients in the study are in the following
`table
`
`“vhf .- ,
`
`__
`
`

`

`Ranjit B. Mani, MD, HFD-120 Medical Review
`NBA 21196, Xyrern, Orphan Medical, Inc.
`
`Page 40 of 135
`6/15/01
`
`
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`

`

`Ranjit B. Mani, MD, HFD~120 Medical Review
`NBA 21196, Xyrem, Orphan Medical, lnc.
`
`Page 41 of 135
`6/15/01
`
`rings at
`
`.
`
`.
`
`.
`
`I
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`The most common adverse events in this study, at least some of which were due
`to intercurrent illnesses, included (in descending order of frequency) viral
`infection, headache, pain, accidental injury, nausea, flu syndrome, pharyngitis,
`rhinitis, increased cough, sleep disorder, diarrhea, dizziness, fever, abdominal
`pain, sinusitis and dyspepsia.
`
`The most common adverse events considered to be drug-related by the
`investigator, and occurring in the first 6 months (in descending order of
`frequency) of GHB use were sleep walking, dizziness, nausea, pain, dyspepsia,
`abdominal pain, viral infection and headache. The most frequent adverse events
`(whether considered related to GHB or not) during that period were headache,
`viral infection, pain, nausea and dizziness: tables for all adverse events in this
`time period have been provided by the sponsor
`
`The most common adverse events occurring after the first 6 months of treatment
`were viral infection, pain, headache and accidental injury. Tables for all adverse
`events in this time period have been provided by the sponsor.
`
`8.5.4 Common and Drug-Related Side Effects
`
`l have used 2 sets of studies in defining these
`. Controlled clinical trials
`
`. All clinical trials
`
`8.5.4.] Controlled Clinical Trials
`
`in the controlled clinical trials group i have selected those adverse events that
`have been listed as occurring in 2 5% of Xyrem®~exposed patients and at least
`twice as frequently as those exposed to placebo. The following adverse events,
`listed using COSTAFtT terms, fit these criteria:
`
`Infection (5%), pain (8%), nausea (12%), vomiting (4%), confusion (5%), dizziness (16%), sleep
`disorder (7%) and urinary incontinence (4%)
`'
`
`8.5.4.2 All Clinical Trials
`
`The 3 most common adverse events in GHBotreated patients across the 2 main
`clinical trial subsets (integrated Clinical Trials, Integrated Pharmacokinetic Trials
`and Schan‘ Study) were:
`
`Headache, nausea and dizziness.
`
`

`

`Ranjit B. Mani, MD, HFD—120 Medical Review
`NDA 21196. Xyrem. Orphan Medical, Inc.
`
`Page 42 of 135
`6/15/01
`
`The next table indicates their incidence in each of the clinical trial uroupings
`Adverse Event
`Integrated Clinical Trials
`Integrated Pharmacokinetic Trials
`Scharl Trial
`(%
`%)
`(°/°
`
`
`
`
`
`
`
`—_—_
`
`
`
`8.5.5 Additional Analyses and Explorations
`
`Special analyses were performed by the sponsor for the following adverse events
`0 Urinary incontinence (and its rela