Page 26 of 35
`.
`Ranjit B. Mani. MD, HFD-120 Medical Review
`—————————_——_________________
`NDA 21196 (000). Xyrem, Orphan Medical, Inc.
`6/14/01
`
`Body As A Whole
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`
`

`

`Page 27 of 35
`Ranjit B. Mani, MD, HFD-120 Medical Review
`—-——____—._.______—________
`NDA 21196 (000), Xyrem, Orphan Medical, inc.
`6/14/01
`
`Nervous system
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`

`Review and Evaluation of Clinical Data
`
`
`NDA (Serial Number)
`Sponsor:
`Drug:
`Proposed Indication:
`Material Submitted:
`Correspondence Date:
`Date Received I Agency:
`Date Review Completed
`Reviewer:
`
`
`
`I'm;
`
`
`
`21196 (000)
`Orphan Medical, Inc.
`Xyrem
`Narcolepsy
`Labeling Review
`9/30/00
`10/3/00
`6/14/01
`Ranjit B. Mani, M.D.
`
`This submission contains an original New Drug Application for Xyrem® (sodium
`oxybate; y-hydroxybutyrate) oral solution.
`
`This document reviews the sponsor’s proposed labeling as proposed in the
`original application and as modified in a further submission dated 12/16/00.
`
`The safety and efficacy data in this application have each been reviewed by me
`in separate applications.
`
`The sponsor’s draft labeling, as edited by me, is presented below. My editing and
`review of the label have been confined to sections subsumed under my clinical
`reviews
`
`
`
`;_1:_
`
`
`
`Draft Professional Insert (December 15, 2000 Version) Modified to include
`information from Trial OMC-SXB-21 and OMC-SXB-20
`
`Rx only
`
`Clll
`
`Xyrem® (sodium oxybate) oral solution
`
`DESCRIPTION
`
`Xyrem (sodium oxybate) is a neuroactive agent with effects on sleep architecture
`that include increased slow wave sleep, increased delta power, and decreased
`
`

`

`Page 2 of 35
`Ranjit B. Mani, MD. HFD-120 Medical Review
`
`NDA 21196 (000), Xyrem. Orphan Medical, lnc. 6/14/01
`
`nocturnal awakenings. Xyrem is intended for oral administration. The chemical
`name for sodium oxybate is gamma-hydroxybutyric acid (GHB), sodium. The
`molecular formula is NaC4H703 and the molecular weight is 126.1 grams/mole.
`The chemical structure is:
`
`i
`
`Na+'O-C-CH2-CH2-CH2-O-H
`
`Sodium oxybate is a white to off-white, crystalline powder that is very soluble in
`aqueous solutions. Xyrem contains 500 mg of sodium oxybate per milliliter of
`USP purified water, neutralized to pH 7.5 with malic acid.
`
`CLINICAL PHARMACOLOGY
`
`Mechanism of Action
`
`

`

`Page 3 of 35 -
`’
`Ranjit B. Mani, MD, HFD-120 Medical Review
`——-—————_—__*________________
`NDA 21196 (000). Xyrem. Orphan Medical, Inc.
`6/14/01
`
`. .a,
`
`4
`
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`
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`
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`v 9
`
`4.
`
`“flu”, flu; ¢r&&Wfl.wwWM‘mwa“wm:wr‘vur-
`may”
`
`‘
`
`Pharmacokinetics and Metabolism
`
`Absorption
`
`W is M absorbed following oral administration. The average =
`W ‘peak plasma concentration.m
`
`Wm.-WMWMW—wwwmh
`
`
`
`~ ”we. 'after a high fat meal resulted in M average
`Administration of
`Tmax increasing from 0.75 hr to 2.0 hr and a ““
`reductions in peak plasma levels
`(Cmax) of 58% and systemic exposure (AUC) by 37%.
`.-
`
`.
`
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`
`Distribution
`
`

`

`Ranjit B. Mani, MD, HFD’120 Medical Review
`NBA 21196 (000), Xyrem. Orphan Medical, lnc.
`
`Page 5 of 35
`6/14/01
`
`
`
`a )4,:A:'61L‘Lr-’.-un-l'l:
`
`..
`
`._t
`
`Elimination
`
`The clearance of oxybate is almost entirely by biotransformation to carbon.
`dioxide, which is then eliminated by expiration. On average, less than 5% of
`unchanged drug appears in human urine within 6 to 8 hours after dosing. Fecal
`excretion is negligible.
`'
`
`.
`
`Special Populations
`
`Geriatric
`
`The pharmacokinetics of sodium oxybate in patients greater than the age of 85
`years has not been studied.
`
`Pediatric
`
`;
`
`The pharmacokinetics of sodium oxybate in pediatric patients under the age’of
`18 years has not been studied.
`‘
`
`Gender
`
`in a study of 18 female and 18 male healthy adult volunteers, no gender
`differences were detected in the pharmacokinetics of sodium oxybate following a
`single oral dose of4.5 grams.
`-‘
`
`

`

`Page 6 of 35
`Ranjit B, Mani, MD, HFD-120 Medical Review
`————_..__.__._______________
`NDA 21196 (000). Xyrem. Orphan Medical, Inc.
`6/14/01
`
`Renal Disease
`
`Because the kidney does not have a significant role in the excretion of oxybate,
`no pharmacokinetic study in patients with renal dysfunction has been conducted.
`
`Hepatic Disease
`
`-—-~
`Oxybate undergoes srgnifcant presystemic (hepatic first-pass) metabolism.
`
`
` ‘ .
`AUC values were doublein the cirrhotic patients,
`with
`7. wapparent oral clearance from 9.1 in healthy adults to 4. 5 and 4 l
`mL/min/kg W-7-~m4"““M"
`patients, respectively. Elimination half-life
`was sionificantlv lonoer'in ,
`.77-
`
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`
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`

`

`
`
`(0 page(s) of
`revised draft labeling
`has been redacted
`
`'
`
`frOm this portion of
`the review.
`
`

`

`Page 13 of 35
`Ranjit BA Mani. MD, HFD-120 Medical Review
`
`NDA 21196 (000), Xyrem. Orphan Medical. Inc. 6/14/01M
`
`m w»,
`
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`
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`
`INDICATIONS AND USAGE
`
`Xyrem® (sodium oxybate) oral solution is indicated ‘W IfCTt‘he
`treatment of cataplexwaW~*
`9W
`
`

`

`
`
`3 page(s) of
`revised draft labeling
`has been redacted
`
`from this portion of
`the review.
`
`

`

`Ranjit B. Mani. MD, Hszo Medical Review
`NBA 21196 (000), Xyrem, Orphan Medical. lnc.
`
`Page 17Vof 35
`6/14/01
`
`Daily sodium intakeiIn patients taking sodium oxybate ranges from 0. 5 g (for 3 g
`
`Xyrem dose) to 1.6 g (for 9 g Xyrem dose), thereforeeeesideratien—teand the
`implications of—sueh that sodium load must be given—consideredIn hypertensive
`patients or patients with compromised renal function.
`
`Hepatic
`
`Patients with compromised liver function will have increased elimination half-life
`and systemic exposure M -7 (see Pharmacokinetics
`
`
`M
`
`WM‘W _
`
`Renal Insufficiency
`
`
`less than
`_
`No studies have been conducted in renal failure W"; ’
`_'
`
`5% of sodium oxybate is excreted via the kidney
`no dose adjustment
`should be necessary in patients with renal impairment. The sodium load ~—
`associated with administration 01 ,....._._ should be considered in patients with
`renal insufficiency.
`
`v1
`
`.—. , Lawnmu-ngsxpmaaw: made. .7 .
`
`,
`
`

`

`Ranjit B. Mani, MD, HFD-120 Medical Review
`NBA 21196 (000), Xyrem, Orphan Medical, Inc.
`
`Page 18 of 35
`6/14/01
`
`Drug Interactions
`
`A
`
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`~
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`‘
`
`In animal models, oxybate and depressant drug combinations generally WWW
`greater ”WWW depressant effectst ”We either drug alone. Concomitant
`administration of oxybate and benzodiazepines, barbiturates, or ethanol
`increases sleep duration.
`In primates, oxybate blood levels were elevated with
`phenytoin pretreatment and reduced with L-Dopa and ethosuximide, and
`'
`trimethadione.
`
`Carcinogenicity, Mutagenicity, Impairment of Fertility
`
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`
`

`

`Ranjit B. Mani, MD. HFD-120 Medical Review
`NDA 21196 (000). Xyrem. Orphan Medical. Inc.
`
`Page 20 of 35
`5/14/01
`
`\EFWBWv’zw-té—uul‘
`
`.7
`
`
`
`I)"
`
`
`Approximately "
`
`‘ “Wk-3M ( mum.
`
`of patients ( min 3 controlled clinical trials (n= M)
`,
`e W: “WM h»v>:.~1_-_:L‘Ia‘.’n;".'l9v:r¢'32(£A;vazw:mwis~3m.ntkm
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`
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`
`Incidence in Controlled Clinical Trials
`
`Most Commonly Reported Adverse Events in Controlled Clinical Trials
`
`The most commonly reported adverse events associated with the use of sodium
`oxybate and occurring with at lea‘St 5% greater frequency than seen in placeho-
`treated patients were dizziness (23%), headache (20%), nausea (16%), pain
`(12%), sleep disorder (9%), confusion (7%), infection (7%), vomiting (6%), and
`urinary incontinence (5%). These incidences are based on combined data from
`Trial 1 and two smaller randomizedI double-blind, placebo-controlled. cross—over
`trials (n=181)
`.
`
`t
`
`Trial 1, the parallel-group, placebo-controlled trial, M used 3"
`fix d
`doses of sodium ogvbate (30. 60. and 9,c1)l__x In that trial
`,'
`
`._ _,- e
`-- V - summer. m... -.a...~;--..-- ..
`~ ‘ v-v»»-v~-m-»«~w~~w-M»~wr-v-N...
`dizziness, nausea, urinary incontinence, and vomiting were more common at
`
`

`

`Ranjii B. Mani, MD, HFD—120 Medical Review
`NDA 21196 (000). Xyrem, Orphan Medical, Inc.
`
`Page 22 of 35
`6/14/01
`
`Digestive System
`
`Diaryrhea
`Dyspepsia
`Nausea
`Nausea and Vomiting
`Vomiting
`
`2 (6%)
`2 (6%)
`o (0%)
`o (0%)
`2 (6%)
`3 (9%)
`o (0%)
`2(6%)
`2 (6%) W2(3%)WW 5(15%) 12 (34%)
`0 (0%)
`0 (0%)
`2 (6%)
`2 (6%)
`o (0%)
`o (0%)
`2 (6%)
`4 (11%)
`
`\
`\xmmwmm»mwgmmmww~ww mp
`
`
`5.2
`
`~ ”7 WWW".
`
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`
`Musculoskeletal System
`
`I'mw...«Mn—MWWMMMWm-» ‘W\V_,~___j
`
`1(3%)
`
`0(0%)
`
`Myasihenia
`
`0(0%)
`
`2(6%)
`
`Nervous System
`Amnesia
`Anxiety
`'0337550}W W
`Sizziness
`Dream Abnormal
`
`o (0%)
`1 (3%)
`1 (3%)
`2 (6%)
`O (0%)
`
`2 (6%)
`o (0%)
`1 (3%)
`2 (6%)
`o (0%)
`1 (3%)
`5 (14%)
`1 (3%)
`:3(9%)
`8 (24%) 16 (36%) W 12 (34%)
`0 (0%)
`3 (9%)
`1 (3%)
`
`

`

`Ranjit B. Mani, MD, HFD-120 Medical Review
`NDA 21196 (000). Xyrem, Orphan Medical. inc.
`
`Page 23 of 35
`6/14/01
`
`
`
`Hypertension
`Hypesthesia
`
`1 (3%)
`0 (0%)
`
`o (0%)
`2 (6%)
`
`2 (6%)
`0 (0%)
`
`o (0%)
`O (0%)
`
`r-\..M__M_~W_WW
`
`wmm‘M—M‘MWMM
`Sleep Disorder
`1 (3%)
`2 (6%)
`4 (12%)
`5 (14%)
`Somnolence
`4 (12%)
`5 (15%)
`4 (12%)
`5 (14%)
`Thinking Abnormal
`0 (0%)
`1 (3%)
`O (0%)
`2 (6%)
`"‘w—nr.w,w..M.N»MMvmem—mmw, ,
`“WM—bemqfi
`
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`
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`mm)“,
`
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`
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`
`am;
`
`Sweat
`
`'
`
`0(0%')
`
`1(3%)
`
`1(3%)
`
`4(11%)
`
`Special Senses
`
`Amblyopia
`
`1 (3%)
`
`2 (6%)
`
`O (0%)
`
`O (0%)
`
`Tihnit'us
`
`o (0%)
`
`2 (6%)
`
`0 (0%)
`
`o (0%)
`
`Urogenital System
`
`Dysmenorrhea
`Incontinence Urine
`
`1 (3%)
`0 (0%)
`
`1 (3%)
`0 (0%)
`
`0 (0%)
`2 (6%)
`
`2 (6%)
`5 (14%)
`
`

`

` 2 page(s) of
`revised draft labeling
`has been redacted
`
`frOm this portion of
`the review.
`
`

`

`Page 26 of 35
`»
`Raniit B. Mani. MD. HFD-120 Medical Review
`
`NBA 21196 (000). Xyrem, Orphan Medical, inc. 6/14/01
`
`Body As A Whole
`
`
`
`al
`
`Hemic and lymphatic system
`
`Ieukocytosis, "W“
`Anemia, ecchymosis. Meme“
`Iymphadenopathy, Aw‘m—W , polycythemia.
`
`Metabolic and nutritional
`
`.
`~
`Alkaline phosphatase increased,
`
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`
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`
`-..‘
`
`Arthritis, arthrosis,
`
`
`

`

`Page 27 of 35
`Ranjit B. Mani, MD, HFD—120 Medical Review
`
`NBA 21196 (000), Xyrem, Orphan Medical. Inc. 6/14/01
`
`Nervous system
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`
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`.NNNNNNN
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`. 1ng
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`
`5“
`
`

`

`
`
`Page 28 of 35
`BI14IO1
`
`APPEARS nus Pm
`ms “Pu.
`
`APPEARS nus WAY
`on 9mm
`
`APPEARS nus Pm
`on omemAL
`
`

`

`Ranjil B. Mani, MD, HFD-120 Medical Review
`NBA 21196 (000), Xyrem, Orphan Medical, Inc,
`
`Page 29 of 35
`6/14/01
`
`~ -'
`
`v:
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`
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`
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`
`DRUG ABUSE AND DEPENDENCE
`
`Controlled Substance Class
`
`Xyrem is classified as a Schedule III controlled substance by Federal law. Non-
`medical uses of sodium oxybate are classified under Schedule I.
`
`Abuse, Dependence, and Tolerance
`
`Abuse
`
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`Dependence
`
`There have been ~~L~;“'””"“‘“ case reports of dependence after illicit use of ”N
`
`

`

`/
`/
`
`Page 30,0f 35
`Ranjit B. Mani, MD. HFD-120 Medical Review
`
`NBA 21196 (000), Xyrem, Orphan Medical, Inc. 6/14/01
`
`“New at frequent repeated doses (18 to 250 g/d), w in excess of the
`therapeutic dose range.
`In these cases, the signs and symptoms of abrupt
`discontinuation included an abstinence syndrome I ,mwww‘... insomnia,
`restlessness, anxiety, psychosis, lethargy, nausea, tremor, sweating, muscle
`cramps, and tachycardia. These symptoms generally abated in 3 to 14 days.
`
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`
`the treatment of alcohol withdrawal suggest a potential cross—tolerance with
`alcohol. Because illicit use and abuse of «mm-“Mew“
`been reported,
`physicians should carefully evaluate patients for a history of drug abuse and
`follow such patients closely, observing them for signs of misuse or abuse of
`WW (e.g. increase in size or frequency of dosing, drug-seeking
`behavior).
`
`OVERDOSAGE
`
`Human Experience
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`information regarding overdose with sodium oxybate is derived IMWW-nfrom
`
`reports in the medical literature .-
`
`thatde_______s_____cribemWW»+ ,
`symptoms and signs in drug—abusers individuals who have ingested the drug
`illicitly or for medicallyunaggroved pumosesu in those circumstances the co;
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`f.a_nd
`alcohol, is ~mmwm-common, and may influence the presentationand severity
`of clinical manifestations of overdose.
`
`

`

`Ranjit B. Mani, MD, HFD—120 Medical Review
`NDA 21196 (000), Xyrem, Orphan Medical, Inc.
`
`Page 31 of 35
`6/14/01
`
`Signs and Symptoms
`
` ~
`
`-. Emesisieven .....--MW...
`obtund l;, diaphoresis, headache,
`1»; mam impaired psychomotor skills maybe observed w-we-
`and
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`reactivity to lightIs maintained-
`weiBlurred visionhas been reported
`«»m~r;~->-¥~M~=->=»-«»=zwésmw.m;s AnIncreasin de th of ”WWW?“ W
`may be observed with higher doses. Myoclonus and Itonic-clonic seizures have
`been reported. Respiration may be maintained or be compromised in rate
`a_nd_
`depth NewsWWW; Cheyne-Stokes respiration or apnea. Bradycardia and
`hypothermia may accompany unconsciousness, as may muscular hypotonia, but
`tendon reflexes remain intact.
`
`Recommended Treatment of Overdose
`
`General symptomatic and supportive care should be instituted immediately, and
`gastric decontamination may be considered if coingestants are suspected. Wm
`emesis is a frequent symptom in the presence of me“rm-w» obtundation,
`appropriate posture (left lateral recumbent position) Wand__protection of the
`
`airway by intubation
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`As with the management of all overdosage, the possibility of multiple drug
`ingestion should be considered. The physician «Wm—M
`Ne,
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`
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`screening.
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`
`‘
`
`blood samples for routine toxicolégic
`
`

`

`Ranjit s. Mani, MD. HFD—120 Medical Review
`NBA 21196 (000). Xyrem, Orphan Medical. Inc.
`
`Page 32 of 35
`6/14/01
`
`DOSAGE AND ADMINISTRATION
`
`Preparation and Administration Precautions
`
`Bottles of Xyrem are provided with a child resistant cap and child resistant dosing
`cups.
`
`Care should be taken to prevent access to this medication by children:
`
`See W for a complete description.
`
`1%mmxnmwm,sammmw_ . .9 ' “WW,»
`WW?"
`
`_ J, ataSW=flfi&rm-WWW
`
`APPEARS THIS WAY
`0N ORIGINAL
`
`

`

`Ranjit B. Mani, MD. HFD-120 Medical Review
`NDA 21196 (000), Xyrem, Orphan Medical, lnc,
`
`Page 33 of 35
`6/14/01
`
`HOW SUPPLIED
`
`ICSISLdIIl Udp.
`
`
`
`
`
`NDC 62161—008-20: Each tamper evident single unit carton contains one 180 mL
`bottle (500 mg/mL) of Xyrem®, one press-in-bottle-adaptor sm- . one oral
`syringe. and two dosing cups with child resistant cap.
`
`HANDLING AND DISPOSAL
`
`Xyrem is a Schedule ill drug under the Controlled Substances Act. Xyrem
`should be handled according to state and federal regulations.
`It is safe to
`dispose of Xyrem oral solution down the sanitary sewer.
`
`Rx only
`
`Distributed By
`Orphan Medical Inc.
`Minnetonka, Minnesota 55305
`
`'
`
`v
`
`I
`
`For questions of a medical nature or to order Xyrem call the Xyrem Patient
`Success Program at 1-XXX-XXX-XXXX..
`
`US Patents Pending
`
`Rev. 12/15/2000
`Part No.
`
`
`
`The following major changes have been made to specific sections of the
`sponsor’s draft label
`
`

`

`Ranjit B. Mani, MD, HFD—120 Medical Review
`NDA 21196 (000), Xyrem. Orphan Medical, Inc.
`
`Page 34 of 35
`6/14/01
`
`Clinical Trials
`
`. Descriptions of, and all data from, the Scrima and Lammers studies (Trials 2
`and 3 in the sponsor’s version of the label) have been deleted as the
`evidence for efficacy in these studies is marginal or questionable (see NDA
`Efficacy Review for full details)
`. All information about open-label, uncontrolled studies has also been deleted
`from the label as such studies cannot be used to support the efficacy of
`Xyrem®
`. _ Data pertaining to secondary efficacy measures have also been deleted. For
`a number of reasons, described in greater detail in the Efficacy Review, these
`measures cannot be used to support the efficacy of Xyrem®
`
`Indications And Usage
`0 The indication has been limited to the treatment of cataplexy. As further
`described in the NDA Efficacy Review, the evidence that Xyrem® is effective
`in treating daytime sleepiness accompanying narcolepsy is questionable
`
`Warnings
`. The text of this section of the label has been altered so as to be more clearly
`informative.
`
`. A description of the special safety concerns associated with GHB, and the
`risk management program has been added to this section
`. A statement indicating that convulsions have been noted in clinical trials of
`Xyrem® has been added
`
`Precautions
`
`. The text of this section has been made more accurate
`
`Adverse Reactions
`
`. Tables depicting adverse event data from the Lammers and Scrima studies
`have been deleted. These studies were cross-over in design, enrolled a small
`number of patients only, and the adverse events noted did not differ materially
`from those in the larger controlled Trial 1
`. The text of this section has been reorganized
`.
`in the section entitled “Adverse Events in All Clinical Trials”, adverse events
`of unclear meaning (e. 9., “reaction unevaluable’’) have been deleted
`0 The description of positive antinuclear antibody testsIn the Schar‘f study has
`been altered so as to be more consiStent with the actual data
`
`Overdosage
`. The text of this section has been made more compact
`o A recommendation that physostigmine be used for the treatment of
`overdosage with GHB has been deleted as the recommendation is based on
`very limited anecdotal evidence.
`
`

`

`Ranjit a. Mani. MD, HFDo120 Medical Review
`NBA 21196 (000), Xyrem. Orphan Medical. Inc.
`
`.
`
`Page 35'of 35
`6114/01
`
`Dosage And Administration
`. This section has been made consistent with the conclusion that was made in
`
`the NDA Efficacy Review that the most clearly effective dose of GHB was 9
`g/day, but that some evidence of efficacy was also present in the dose range
`6-9 g/day
`
`Ranjit B. Mani, MD.
`Medical Reviewer
`
`J. Feeney, M.D.
`
`rbm 6/14/01
`cc:
`
`HFD-120
`
`‘
`
`NDA 21196 (000)
`Homonnay
`
`

`

`
`
`”Cu-v" uuu bVGlUGlIUII Ul ulllllb’al Udld
`
`NDA (Serial Number)
`Sponsor:
`Drug:
`Proposed Indication:
`Material Submitted:
`Correspondence Date:
`Date Received I Agency:
`Date Review Completed
`Reviewer:
`
`1. Table Of Contents
`
`21196
`Orphan Medical, Inc.
`Xyrem
`Narcolepsy
`Major Amendment
`3/23/01
`3/26/01
`6/14/01
`Ranjit B. Mani, MD.
`
`1.
`
`2.
`
`3.
`
`4.
`
`TABLE OF CONTENTS .................................................................................................................... l
`
`BA CKGROUND ................................................................................................................................. 5
`
`ORGANIZATION OF CLINICAL TRIALS IN INTEGRATED SUMMARY OF SAFETY ..... 6
`
`DEFICIENCIES IN SCHARF STUDY DATA REVEALED AT INITIAL SITE INSPECTION
`7
`
`4.1
`4.2
`4.3
`
`OUTLINE OF SCHARF STUDY ............................................................................................................. 7
`PRELIMINARY RESULTS OF INSPECTION ........................................................................................... 7
`DIVISIONAL RECOMMENDATIONS FOR ADDRESSING DEFICIENCIES IN SCHARF STUDY .................... 8
`
`5.
`
`AGENCY QUESTIONS ABOUT ORPHAN-SPONSORED CLINICAL TRIALS ...................... 8
`
`5.]
`5.2
`5.3
`
`EXPOSURE TABLE ............................................................................................................................. 9
`SERIOUS ADVERSE EVENTS ............................................................................................................... 9
`LABORATORY DATA ......................................................................................................................... 9
`
`Table Of Interest ..................................................................................................................... 9
`5.3.]
`Questions About Table.......................................................................................................... 1]
`5.3.2
`5.4 - ADDITIONAL QUESTIONS ................................................................................................................ 11
`5.5 ADDITIONALREQUEST........ 12
`
`6.
`
`CONTENTS OF SUBMISSION ...................................................................................................... 12
`
`DISPOSITION OF SCHARF STUDY PATIENTS WHO DID NOT ENTER STUDY OMC-
`7.
`SXB-7 ........................................................................................................................................................... 12
`
`7.1
`7.2
`7.3
`7.4
`
`BACKGROUND ................................................................................................................................. 12
`SPONSOR’S METHODS ........................................................................................................... . ........ 13
`DISPOSITION OF SCHARF STUDY PATIENTS WHO DID NOT ENTER OMC-SXB-7 ................'. .......... I3
`DISCONTINUATIONS DUE TO ADVERSE EVENTS
`........ I4
`7.4. 1
`Deaths ................................................................................................................................... 14
`
`Non-Fatal Adverse Events Leading To Discontinuation ...................................................... 15
`7.4.2
`REVIEW OF INDIVIDUAL NARRATIVES AND CASE REPORT FORMS ................................................. 16
`
`7.5
`
`7.5.]
`7.5.2
`7.5.3
`7.5.4
`
`Source OfCase Repon Forms .............................................................................................. 16
`Structure Of Case Report Forms .......................................................................................... 16
`Deficiencies III Structure Of Case Report Forms And Additional Related Concerns ........... 17
`Deaths And Adverse Event Discontinuations........................................................................ 18
`
`Patients Discontinued From ScltarfStudy For Non-Compliance ......................................... 18
`7.5.5
`Discontinuation: 0n Account OfProtocolDeviations ....... 21
`7.5.6
`Discontinuations 0n Account 0fMedication Cost, Medication Cost, Lack OfEflicacy, And
`7.5.7
`Transfer To Another Study .................................................................................................................. 22
`7.5.8
`Patients Continuing In Sellarf Study..................................................................................... 22
`7.5.9
`Patients Subjected To Recent Attempts At Follow- Up .......................................................... 23
`7.5.10 Unresolved Adverse Events 0f Concern ............................................................................... 24
`
`

`

`Page 2 of 93
`RanjiI a. Mani. MD, HFD—120 Medical Review
`
`NDA 21196, Xyrem. Orphan Medical, Inc.
`5/14/01
`7.6
`REVIEWER’S COMMENTS................................................................................................................. 26
`
`8.
`
`NARRATIVE FOR PATIENT 01-064 PARTICIPATING IN SCHARF STUDY ...................... 26
`
`8.1
`8.2
`
`NARRATIVE ..................................................................................................................................... 26
`REVIEWER’S COMMENTS................................................................................................................. 27
`
`9.
`
`“REACTION UNEVALUABLE” ADVERSE EVENTS IN SCHARF TRIAL ........................... 27
`
`BACKGROUND ................................................................................................................................. 27
`9.1
`CATEGORIES OF “UNEVALUABLE” ADVERSE EVENTS .................................................................... 28
`9.2
`SERIOUS “UNEVALUABLE” ADVERSE EVENTS ................................................................................ 28
`9.3
`' 9.4 ALL “UNEVALUABLE” ADVERSE EVENTS ....................................................................................... 28
`9.5
`REVIEWER‘S COMMENTS................................................................................................................. 29
`
`10. ANALYSIS OF URINARY AND FECAL INCONTINENCE IN SCHARF TRIAL .................. 29
`
`BACKGROUND ............................................... 9'. .............................................................. 29
`10.1
`SPONSOR’S METHODS................................................................................................................. 29
`10.2
`TABULAR SUMMARY OF CASES IDENTIFIED BY SPONSOR ......................................................... 30
`10.3
`NARRATIVEs FOR SELECTED PATIENTS IN ABOVE TABLE.......................................................... 30
`10.4
`10.4.1 Patient # 01-048.................................................................................................................... 30
`10.4.2 Patient # 01-247.................................................................................................................... 31
`10.4.3 Patient # 01-255.................................................................................................................... 32
`10.4.4 Patient # 01-257.................................................................................................................... 32
`10.5
`PATIENTS WITH SLEEPWALKING AND INCONTINENCE ............................................................... 33
`10.6
`SPONSOR‘SCONCLUSIONS-........ 33
`
`10.7
`
`REVIEWER’S COMMENTS .......................................................................................................... .. 34
`
`11. ADVERSE EVENTS CODED AS “CONFUSION” IN SCHARF STUDY“..... 35
`1].]
`BACKGROUND AND METHODS .................................................................................................... 35
`11.2
`OVERALL SUMMARY .................................................................................................................. 35
`
`11.3
`11.4
`1 1.5
`
`VERBATIM INVESTIGATOR TERMS .............................................................................................. 36
`TABULAR SUMMARY .................................................................................................................. 36
`NARRATIVE FOR PATIENT WITH CONFUSION As A SERIOUS ADVERSE EVENT.......................... 36
`
`36
`11.5.1 Patient 01-012 (Initials “"
`1 1.6
`NARRATIVES FOR ADDITIONAL PATIENTS WITH CONFUSION .................................................. 37
`
`11.6.1 Patient 01-016 (Initials __, ............................................................................................... 37
`11.6.2 Patient 01-027 (Initials
`............................................................................................... 37
`11.6.3 Patient 01-048(1nitials “I ............................................................................................... 37
`I 1.6.4 Patient 01-215 (Initials / ............................................................................................... 37
`11.6.5 Patient 01—235 (Initials .3.” ............................................................................................... 38
`11.6.6 Patient 01-248 (Initials
`............................................................................................... 38
`11.6. 7 Patient 01-251 (Initials M ................................................................................................ 38
`11.7
`REVIEWER‘SCOMMENTS 38
`
`12. NEUROPSYCHIATRIC ADVERSE EVENTS IN SCHARF STUDY......................................... 38
`
`12.1
`12.2
`12.3
`12.4
`
`BACKGROUND ........