Ranjit B. Mani, MD, HFD—120 Medical Review
`NDA 21196 (N-BZ), Xyrem® . Orphan Medical. Inc.
`
`Page 15 of 33
`2/22/02
`
`Sodium oxybate did not impair fertility in rats at doses up to 1000 mg/kg (approximately
`equal to the maximum recommended human daily dose on a m g/mz basis).
`
`Pregnancy
`
`Pregnancy Category B: Reproduction studies conducted in pregnant rats at doses up to
`1000 mg/kg (approximately equal to the maximum recommended human daily dose on 3
`mg/m2 basis) and in pregnant rabbits at doses up to 1200 mg/kg (approximately 3 times
`the maximum recommended human daily dose on 3 mg/m2 basis) revealed no evidence of
`teratogenicity. In a study in which rats were given sodium oxybate from day 6 of
`gestation through day 21 post-partum, slight decreases in pup and maternal weight gains
`were seen at 1000 mg/kg; there were no drug effects on other developmental parameters.
`There are, however, no adequate and well—controlled studies in pregnant women.
`Because animal reproduction studies are not always predictive of human response, this
`drug should be used during pregnancy only if clearly needed.
`
`Labor and Delivery
`
`In obstetric anesthesia using
`Sodium oxybate has not been studied in labor or delivery.
`an injectable formulation of sodium oxybate newborns had stable cardiovascular and
`respiratory measures but were very sleepy, causing a slight decrease in Apgar scores.
`There was a fall in the rate of uterine contractions 20 minutes after injection. Placental
`transfer is rapid, but umbilical vein levels of sodium oxybate were no more than 25% of
`the maternal concentration. No sodium oxybate was detected in the infant’s blood 30
`minutes after delivery. Elimination curves of sodium oxybate between a 2—day old infant
`and a 15-year old patient were similar. Subsequent effects of sodium oxybate on later
`growth, development and maturation in humans are unknown.
`
`Nursing Mothers
`
`It is not known whether sodium oxybate is excreted in human milk. Because many drugs
`are excreted in human milk, caution should be exercised when sodium oxybate is
`
`administered to a nursing woman.
`
`Pediatric Use
`
`Safety and effectiveness in patients under 16 years of age have not been established.
`
`Race and Gender Effects
`
`

`

`Ranjit a. Mani, MD, HFD»120 Medical Review
`NBA 21196 (N—BZ). Xyrem® , Orphan Medical, Inc.
`
`Page 16 of 33
`2/22/02
`
`effects on safety or efficacy. More than
`_.,
`,
`“NW” ”N "W
`90% of the subjects in clinical trials were Caucasian.
`
`
`W
`The database was 58%Mfemale.
`.. “1.7.: s
`. .‘fccswlwifiamz v —
`r~~'- «Nut—“- u Lav/7“”
`
`_
`
`_ ““"N~w~~---—~~---~~»‘,_;_;,
`,, ,,
`,
`_
`
`The overall percentage of patients with at least one adverse event was slightly higher in
`women (80%) than in men (69%). The incidence of serious adverse events and
`discontinuations due to adverse events were similar in both men and women.
`
`ADVERSE REACTIONS
`
`A total of 448 narcoleptic patients were exposed to sodium oxybate in clinical trials. The
`most commonly observed adverse events associated with the use of sodium oxybate
`were:
`
`Headache 1250/011, nausea 121%), dizziness (,1 7%,), pain g16%), somnolenceg13%),
`pharyngitis 3,11%), infection “0%), viral infection 110%; flu syndrome g9%g, accidental
`injury {9%}, diarrhea {8%}, urinary incontinence g8%), vomiting 33%), rhinitis 18%),
`asthenia 48%), sinusitis 17%), nervousness ;7%), back pain gm), confiision (7%),
`sleepwalking gm), depression g6%), dyspepsia L6%), abdominal pain 95%), abnormal
`dreams 16%), insomnia 15%)
`
`
`
`tlicwse giiiijficaltrials bothmligoggflrdrugogerdosesfi, Both these
`2 @4111; 75299111239;
`u __ J
`deathsresuledfromthemgem iofmutipledrugsIncludingsodiumoubatemone
`
`
`(l)
`
`Approximately 6 % of patients receiving sodium oxybate in 3 controlled clinical trials
`(n=l47) withdrew due to an adverse event, compared to 1% receiving placebo (n=79).
`
`
`
`

`

`Ranjit B. Mani. MD. HFD-120 Medical Review
`NBA 21196 (NvBZ), Xyrem® , Orphan Medical, Inc.
`
`Page 17 of 33
`2/22/02
`
`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 least 5% greater frequency than seen in placebo-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 l and two smaller randomized, double-
`
`blind, placebo-controlled, cross—over trials (n=l 81).
`
`
`used 3 fixed doses of sodium oxybate
`-
`Trial 1,
`;
`» V
`_
`_
`(3g, 6g, and 9g). In that trial dizziness, nausea, urinary incontinence, and vomiting were
`more common at higher doses, with the majority of events occurring in the 6g and 9g
`dose groups.
`
`I
`
`Adverse Events With an Incidence of > 1% in Trial 1
`
`lists the incidence of treatment emergent adverse events in Trial 1. Events have
`Table
`been included for which there are at least 2 episodes in the considered drug group and for
`which the incidence in at least one dosage group is greater on drug than placebo.
`
`The prescriber should be aware that data provided below cannot be used to predict the
`incidence of adverse experiences during the course of usual medical practice where
`patient characteristics and other factors may differ from those occurring during clinical
`trials. Similarly, the cited frequencies cannot be compared with figures obtained from
`other clinical investigations involving different treatments, uses, and investigators.
`However, the cited figures do provide the prescribing physician with some basis for
`
`

`

`Ranjit 8, Mani, MD, HFD-120 Medical Review
`NBA 21196 (N-BZ), Xyrem® , Orphan Medical, Inc.
`
`Page 18 of 33
`2/22/02
`
`taxI,
`
`estimating the relative contribution of drug and non-drug factors to the adverse event
`d.
`incidence rate in the population studie
`
`Table ——-
`
`Incidence (%) of Treatment-Emergent Adverse Events in
`Trial 1
`
`Body System
`Preferred Term
`
`Placebo
`(n=34)
`
`Sodium Oxybate Dose
`3g
`6g
`(n=34)
`(n=33)
`
`9g
`(n=35)
`
`Body as a Whole
`O (0%)
`2 (6%)
`O (0%)
`1 (3%)
`Asthenia
`_W
`
`
`Flu Syndrome
`Headache
`infection
`Infection Viral
`Pain
`
`0 (0%)
`7 (21%)
`1 (3%)
`1 (3%)
`2 (6%)
`
`1 (3%)
`3 (9%)
`3 (9%)
`1 (3%)
`3 (9%)
`
`0 (0%)
`5 (15%)
`5 (15%)
`3 (9%)
`4 (12%)
`
`2 (6%)
`11 (31%)
`0 (0%)
`0 (0%)
`7 (20%)
`
`Digestive System
`0 (0%)
`Diarrhea
`2 (6%)
`Dyspepsia
`2 (6%)
`Nausea
`Nausea and VomitingO (0%)
`Vomiting
`0 (0%)
`
`0 (0%)
`O (0%)
`2 (6%)
`0 (0%)
`O (0%)
`
`2 (6%)
`3 (9%)
`5 (15%)
`2 (6%)
`2 (6%)
`
`2 (6%)
`2 (6%)
`12 (34%)
`2 (6%)
`4 (11%)
`
`Musculoskeletal System
`Myasthenia
`
`Nervous System
`Amnesia
`Anxiety
`Confusion
`Dizziness
`Dream Abnormal
`
`Hypertension
`Hypesthesia
`Sleep Disorder
`
`O (0%)
`
`2 (6%)
`
`1 (3%)
`
`O (0%)
`
`O (0%)
`1 (3%)
`1 (3%)
`2(6%)
`0 (0%)
`
`1 (3%)
`0 (0%)
`1 (3%)
`
`1 (3%)
`1 (3%)
`3 (9%)
`8(24%)
`0 (0%)
`
`
`0 (0%)
`2 (6%)
`2 (6%)
`
`O (0%)
`O (0%)
`1 (3%)
`10(30%)
`3 (9%)
`
`2 (6%)
`2 (6%)
`5(14%)
`12(34%)
`1 (3%)
`
`2 (6%)
`O (0%)
`4 (12%)
`
`0 (0%)
`0 (0%)
`5(14%)
`
`

`

`Ranjit a. Mani. MD, HFD-120 Medical Review
`NBA 21196 (N-BZ), Xyrem® _ Orphan Medical, Inc.
`
`Page 19 of 33
`2/22/02
`
`4 (12%)
`Somnolence
`Thinking Abnormal O (0%)
`
`5 (15%)
`1 (3%)
`
`4 (12%)
`0 (0%)
`
`5(14%)
`2 (6%)
`
`Skin
`
`Increased sweating
`
`O (0%)
`
`l (3%)
`
`1 (3%)
`
`4(1 1%)
`
`Special Senses
`Amblyopia
`Tinnitus
`
`1 (3%)
`O (0%)
`
`2 (6%)
`2 (6%)
`
`O (0%)
`0 (0%)
`
`O (0%)
`0 (0%)
`
`Urogenital System
`Dysmenorrhea
`Incontinence Urine
`
`1 (3%)
`0 (0%)
`
`1 (3%)
`0 (0%)
`
`O (0%)
`2 (6%)
`
`2 (6%)
`5(14%)
`
`Other Adverse Events Observed During All Clinical Trials
`
`fw,rat
`i,
`v
`To establish the rate of adverse events, data from all
`subjects receiving any dose of sodium oxybate were pooled. All adverse events reported
`by at least two people are included except for those already listed elsewherein the
`labeling, terms too general to be informative, or events unlikely to be drug-induced.
`Events are classified by body system and listed under the following definitions: frequent
`adverse events (those occurring in at least l/lOO people); infrequent events (those
`occurring in 143100
`l .’l 000 people). These events are not necessarily related to sodium
`oxybate treatment.
`
`Body As A Whole
`
`
`Infrequent:
`Frequent: Allergic reaction, chills, ->wéwéw==~w~¥~emw~ '
`Abdomen enlarged, we“ hangover effect,
`“We!“mum-WWWWWMWW ,neck
`rigidity.
`
`Cardiovascular system
`
`WM_F w9“ ,1 In freq“ en“metric.tetrt.s.....w.,t.,t-.W .
`
`syncope,
`
`Digestive system
`
`

`

` 0-120 Medical Review
`
`Ranjit B. Mani, MD, HF em® ,Orphan Medical, Inc.
`NDA 21196 (N—BZ). Xyr
`
`Frequent: Anorexia, constipation,
`"
`',
`Infrequent:
`th ulceration, stomatitis.
`
`mou
`
`~ “--
`
`APPEARS THIS WAY
`
`0N ORIGINAL
`
`APPEARS THIS WAY
`
`0N ORIGINAL
`
`APPEARS THIS WAY
`0H ORIGIHAL
`
`

`

`Ranjit B. Mani, MD, HFD—120 Medical Review
`NDA 21196 (N-BZ), Xyrem® , Orphan Medical, Inc.
`
`Page 22 of 33
`2/22/02
`
`gamma hydroxybutyrate (GHB), is listed in the most restrictive schedule of the Controlled
`Substances Act (Schedule 1). Thus, non-medical uses of sodium oxybate (Xyrem® or GHB) are
`classified under Schedule 1.
`
`Abuse, Dependence, and Tolerance
`
`Abuse
`
`See applicable directions for use under HANDLING AND DISPOSAL below.
`
`Although sodium oxybate has not been systematically studied in clinical trials for its
`potential for abuse, illicit use and abuse « ~
`»
`have been reported.
`
`is a psychoactive drug that produces a wide range of pharmacological effects. It is
`e ‘-
`a sedative-hypnotic that produces dose- and concentration-dependent central nervous
`system effects in humans. The onset of effect is rapid, enhancing its potential for abuse
`or misuse.
`
`The rapid onset of sedation, coupled with the amnestic potential of ,.__._ particularly
`when combined with alcohol, has proven to be dangerous for the voluntary and
`involuntary (assault victim) user.
`
`GHB is abused in social settings primarily by young adults m-wm-
`WW“ wM
`mem.—-“.9..WRag-Wm.“
`N GHB has some commonalties with ethanolover a limited dose range and some
`
`cross tolerance with ethanol has been reported.-~—WWW»mashamwmwc -.A
`
`
`
`
`
`MMWMMN»M“ “(mam/cat“ “scream“.(wwN‘W -
`
`s7 ,c .
`
`,
`
`.
`
`

`

`Ranjit B. Mani, MD, HFD-120 Medical Review
`NBA 21196 (N-BZ), Xyrem® , Orphan Medical, Inc.
`
`Page 24 of 33
`2/22/02
`
`depth. Cheyne-Stokes respiration and apnea have been observed. Bradyeardia and
`hypothermia may accompany unconsciousness, as well as 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 co-ingestants are suspected. Because emesis may
`occur in the presence of obtundation, appropriate posture (left lateral recumbent position)
`and protection of the airway by intubation may be warranted. Although the gag reflex
`may be absent in deeply comatose patients, even unconscious patients may become
`combative to intubation, and rapid-sequence inductim (without the use of sedative)
`should be considered. Vital signs and consciousness should be closely monitored. The
`bradycardia reported with l m overdose has been responsive to atropine intravenous
`administration. No reversal of the central depressant effects of sodium oxybate can be
`expected from naloxone or flumazenil administration. The use of hemodialysis and other
`forms of extracorporeal drug removal have not been studied in GHB overdose. However,
`due to the rapid metabolism of sodium oxybate, these measures are not warranted.
`
`Poison Control Center
`
`As with the management of all cases of drug overdose, the possibility of multiple drug
`ingestion should be considered. The physician is encouraged to collect urine and blood
`samples for routine toxicologic screening, and to consultat with a regional poison control
`center (1-800-222-1222) for current treatment recommendations.
`
`DOSAGE AND ADMINISTRATION
`
`Xyrem is required to be taken at bedtime and again 2.5-4 hours later. The recommended
`starting dose W’ is 4.5 g/day divided into 2 equal doses of 2.25 g. The starting
`dosage can then be increased to a maximum of 9 g/day in increments of 1.5 g/d (0.75 g
`per dose). Two weeks are recommended between dosage increases to evaluate clinical
`response and minimize adverse effects. Xyrem is effective at doses of 6-9 g/day. The
`efficacy and safety of Xyrem at doses higher that 9 g/day have not been investigated, and
`doses greater than 9 g/day should ordinarily not be administered.
`
`Prepare both doses of Xyrem prior to bedtime. Each dose of Xyrem must be diluted with
`2 ounces (60mL) of water in the child resistant dosing cups provided prior to ingestion.
`The first dose is to be taken at bedtime and the second taken 2.5-4 hours later while
`
`sitting in bed. Patients may need to set an alarm to awaken for the second dose. The
`second dose must be prepared prior to ingesting the first dose, and should be placed in
`close proximity to the patient’s bed. After ingesting each dose patients should then lie
`down and remain in bed.
`
`Because food significantly reduces the bioavailability of sodium oxybate,
`- «a
`.. (m V“
`,
`, W,M,.tm».~4.u~rv
`”W“
`
`
`
`

`

` Page 25 of 33
`
`2/22/02
`
`APPEARS THlS WAY
`
`0N ORIGINAL
`
`APPEARS THIS WAY
`0N ORIGINAL
`
`‘
`
`

`

`Ranjit a. Mani, MD. HFD—120 Medical Review
`NDA 21196 (N—BZ), Xyrem® . Orphan Medical, Inc.
`
`Page 26 of 33
`2/22/02
`
`Preparation and Administration Precautions
`
`Each bottle of Xyrem® is provided with a child resistant cap and two dosing cups with
`child resistant caps.
`
`Care should be taken to prevent access to this medication by children and
`pets.
`
`See the Medication Guide for a complete description.
`
`HOW SUPPLIED
`
`Xyrem® (sodium oxybate) is a clear to slightly opalescent oral solution. It is supplied in
`kits containing one bottle of Xyrem®, a press-in-bottle-adaptor, a 10 mL oral measuring
`device (plastic syringe), a Medication Guide, a professional insert, and two 90 mL dosing
`cups with child resistant caps. Each amber oval PET bottle contains 180 mL of Xyrem®
`oral solution at a concentration of 500 mg/mL and is sealed with a child resistant cap.
`
`NDC 62161-008-20: Each tamper evident single unit carton contains one 180 mL bottle
`(500 mg/mL) of Xyrem®, one press-in—bottIe—adaptor, one oral syringe, and two dosing
`cups with child resistant cap.
`
`STO RAG E
`
`Store at 25° C (77° F); excursions permitted up to 15° -30° C (59° -86° F) [see USP Controlled
`Room Temperature]. Solutions prepared following dilution should be consumed within 24 hours
`to minimize bacteria growth and contamination.
`
`HANDLING AND DISPOSAL
`
`Xyrem® is a Schedule 111 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.
`
`CAUTION
`
`Rx only
`
`Federal law prohibits the transfer of this drug to any person other than the patient
`for whom it was prescribed.
`
`Distributed By
`Orphan Medical Inc.
`Minnetonka, Minnesota 55305
`For questions of a medical nature or to order Xyrem® call the Xyrem® Patient Success
`Program at
`l-877-67-XYREM (877-679-9736).
`
`

`

`Ranjit B. Mani, MD, HFD—120 Medical Review
`NBA 21196 (N-BZ), Xyrem® , Orphan Medical, lnc.
`
`Page 27 of 33
`2/22/02
`
`US Patents Pending
`Rev. October 2001
`Part No.
`
`Comments
`
`My comments on individual sections of the label are below
`
`Black Box Warning
`
`.-
`
`x:.‘(»"5:.«Y:1)a.;>rh:'szum'A-fi-‘N-n‘mtrN» ,.:,t ;..,r,.»,;.. a . /., m; new" ~
`
`Description
`
`The sponsor’s changes to the label are acceptable
`
`Clinical Pharmacology
`
`Mechanism of Action
`
`I have deleted the sponsor’s description of the proposed mechanism of action of
`GHB as it is unclear that the mechanism of action of this drug in cataplexy is
`clearly understood.
`
`Pharmacokinetics and Metabolism, Absorption and Distribution, Metabolism and
`Elimination
`
`The sponsor’s minor changes to the draft labeling that accompanied the
`Approvable letter of 7/2/01 are acceptable, pending Biopharmaceutics review
`
`Special Populations,
`
`The sponsor’s minor changes to the draft labeling that accompanied the
`Approvable letter of 7/2/01 are acceptable, pending Biopharmaceutics review.
`
`Drug-Drug Interactions
`
`The sponsor has made changes to the draft labeling that accompanied the
`Approvable letter of 7/2/01 based on the results of an in-vitro study of the
`interaction of GHB with human hepatic microsomal CYP450 isoenzymes. These
`changes are acceptable pending Biopharmaceutics review.
`
`

`

`Ranjit B. Mani, MD. HFD~120 Medical Review
`NDA 21196 (N-BZ), Xyrem® , Orphan Medical, Inc.
`
`Page 28 of 33
`2/22/02
`
`Clinical Trials
`
`.
`
`In a table depicting the results of the primary efficacy analysis for OMC-GHB-
`2 trial, the sponsor has changed the p-values for the comparison of the 3
`g/day, 6 g/day, and 9 g/day doses of GHB with placebo to reflect the
`sponsor’s own analysis (an ANCOVA on log-transformed data which was not
`specified a priori in either the original protocol or in protocol amendments). I
`have changed these p-values to those contained in the Approvable letter
`dated 7/2/01 which reflect the protocol-specified analysis (ANOVA on log-
`transformed data) as performed by Dr Sharon Yan, Agency statistician.
`. Statements regarding stimulant drug usage in 2 key efficacy trials have been
`verified and are acceptable
`. Other changes to the labeling made by the sponsor in the current submission
`are minor and acceptable.
`
`Indications And Usage
`
`The changes made by the sponsor to the labeling that accompanied the
`Approvable letter are consistent with previous discussions with the Division
`
`Contraindications
`
`The labeling submitted by the sponsor is acceptable but has been altered
`slightly.
`
`Warnings
`
`Key changes made by the sponsor to the draft labeling accompanying the
`Approvable letter of 7/2/01, or by me to the draft labeling that accompanied this
`submission. are summarized below. Other changes are minor.
`
`Central Nervous System Depression/Respiratory Depression
`
`l have deleted the description of the OMC-SXB-20 trial as the results of that
`study were inconclusive in regard to demonstrating the presence, or absence
`thereof, of depressed respiration.
`
`Con/usion/Neuropsychiatric Adverse Events
`
`. These adverse events were previously evaluated by me in my review of the
`earlier Major Amendment submitted 3/23/01 (review completed 6/14/01;
`please see that review for full details). Based on those data, as updated in the
`current submission, I have made the following changes to the proposed
`labeling that accompanied this submission
`. The incidence of confusion at the 9 g/day dose in the OMC—GHB-2 trial was
`17.1% (6/35) and not 14% (5/35) as stated by the sponsor in the labeling. The
`incidence of 17.1% was based on the sponsor’s own listing as contained in the
`Major Amendment of 3/23/01. I have therefore changed the percentage in
`question to 17%
`. A statement that most events of confusion in the Scharf trial were transient in
`
`nature (single episodes) and of short duration has been deleted. The veracity of
`such data for the Scharf trial is open to question.
`
`

`

`Ranjit B. Mani, MD, HFD-120 Medical Review
`NDA 21196 (N-BZ), Xyrem® . Orphan Medical, Inc.
`
`Page 29 of 33
`2/22/02
`
`.
`
`I have confirmed that, with the exception of the above, the incidence figures
`contained in this section are accurate and updated based on data in the
`current submission.
`
`Depression
`
`.
`
`.
`
`. This adverse event was also previously evaluated by me in my review of the
`earlier Major Amendment submitted 3/23/01. Based on that review and on
`updated information included in the current submission, the incidence figures
`cited in the application are accurate.
`l have however deleted statements about the brevity of episodes of
`depression since they have not been further qualified in regard to duration
`l have also deleted a statement about the incidence of patients with
`depression who were put on treatment, since I did not feel that that was
`clinically useful information
`l have provided a few more details about patients who attempted suicide
`while taking GHB.
`l have also indicated that in patients with a prior history of depression and/or
`suicide attempts careful monitoring is needed for the emergence of symptoms
`of depression while taking Xyrem®
`
`.
`
`o
`
`Precautions
`
`Incontinence
`
`o The incidence rates cited by the sponsor in this section are based on data
`submitted previously with this application and to a lesser extent on data
`included in the current submission. I have confirmed that the data are
`
`accurate
`
`. As data from a fixed~dose parallel-arm study are more clinically meaningful
`(e.g., in indicating whether a dose-response is present) I have included a
`short summary of data from OMC-GHB-2 in place of the information supplied
`by the sponsor
`l have deleted a statement that the episodes were either isolated or
`intermittent as the statement is redundant.
`
`.
`
`.
`
`.
`
`l have deleted a statement that the events required no treatment other than
`the patient reasonably restrict fluid intake at bedtime (there is evidence of
`how widely this measure was used or how effective it was).
`l have added a statement that there was no firm evidence that episodes of
`urinary and fecal incontinence in patients treated with GHB were due to
`seizures
`
`Somnambu/ism/S/eepwalking
`
`.
`
`l have deleted the term “somnambulism” from the heading for this section and
`from the text. The sponsor’s reason for preferring “somnambulism" is stated
`to be as follows: the clinical term for sleepwalking is "somnambulism" and the
`common term “sleepwalking" is included in the first paragraph for clarity.
`However, the medical term “somnambulism" refers to a very specific NREM
`parasomnia and there is no evidence at all that any or most of the episodes
`
`

`

`Ranjit a. Mani, MD, HFD—120 Medical Review
`NDA 21196 (NeBZ). Xyrem® , Orphan Medical, Inc.
`
`Page 30 of 33
`2/22/02
`
`described in this section represent that entity. The more commonly used term
`“sleepwalking” has therefore been reinstated. In the clinical trials subsumed
`under this NDA the term “sleepwalking” appears to have been used loosely
`by investigators to described confused and/or wandering behavior at night; as
`adequate clinical descriptions are not provided in the vast majority of
`instances it is unclear what specific medical disorder or disorders this
`condition represents and l have attempted to make that clear in the label .
`l have deleted a statement about the frequency of somnambulism in the adult
`population: this statement refers to the incidence of the NREM parasomnia,
`somnambulism.
`
`l have inserted a statement about the actual adverse sequelae of
`sleepwalking that were seen in clinical trialsPl have also indicated that
`episodes were multiple in a number of patients.
`
`o
`
`.
`
`Sodium Intake
`
`. Changes made by the sponsor to the draft labeling accompanying the
`Approvable letter of 7/2/01 are minor and acceptable
`
`Hepatic Insufficiency
`
`No changes have been made by the sponsor to the draft label that was attached
`to the Approvable letter of 7/2/01
`
`Renal Insufficiency
`
`Changes made by the sponsor to the draft labeling accompanying the
`Approvable letter of 7/2/01 are minor and acceptable. Agency biopharmaceutics
`comments are pending.
`
`lNFORMATION FOR PATlENTS
`
`The sponsor’s changes to the draft label that accompanied the Approvable letter
`are minor and acceptable. l have substituted the word “procedure” for
`“mechanics” in regard to dose preparation.
`
`Laboratory Tests
`
`Changes made by the sponsor to the draft labeling attached to the Approvable
`letter of 7/2/01 are minor and acceptable.
`
`Drug Interactions
`
`Changes made by the sponsor to the draft labeling accompanying the
`Approvable letter of 7/2/01 are minor and acceptable. Agency biopharmaceutics
`comments are pending.
`Carcinogenicity, Mutagenicity, Impairment cf Fertility
`Changes made by the sponsor to the draft labeling accompanying the
`Approvable letter of 7/2/01 are minor and acceptable. Agency pharmacology
`comments are pending.
`
`Pregnancy
`No changes have been made by the sponsor to the draft label that was attached
`to the Approvable letter of 7/2/01. Agency pharmacology comments are pending
`
`

`

`Ranjit B. Mani, MD, HFD-120 Medical Review
`NDA 21196 (N-BZ). Xyrem® , Orphan Medical, Inc.
`
`Page 31 of 33
`2/22/02
`
`Labor and Delivery
`
`No changes have been made by the sponsor to the draft label that was attached
`to the Approvable letter of 7/2/01
`
`Nursing Mothers
`
`No changes have been made by the sponsor to the draft label that was attached
`to the Approvable letter of 7/2/01
`
`Usage in the Elderly
`
`This section uses exactly the same language that was used in the draft labeling
`that accompanied the Approvable letter of 7/2/01 but in the current version has
`been transposed from the Warnings section to the Precautions section. The
`sponsor states that since no serious adverse event profile has been documented
`in the elderly, this statement is more appropriate as a precaution. This section is
`acceptable to this reviewer
`
`Pediatric Use
`
`No changes have been made by the sponsor to the draft label that was attached
`to the Approvable letter of 7/2/01
`
`Race and Gender Effects
`
`The text of this section has been written entirely since the draft label that was
`attached to the Approvable letter of 7/2/01 was received. The text is based on
`data that I had reviewed earlier (see my main Efficacy and Safety reviews of this
`NDA), and is factually correct and acceptable.
`
`Adverse Reactions
`
`0 All adverse event percentages in the text have been placed in parentheses, in
`keeping with standard practice, and to be consistent in this document as a
`whole.
`
`.
`
`.
`
`o
`
`l have included a short statement about deaths in clinical trials (excluding the
`Scharf trial)
`l have deleted the list of adverse events that led to discontinuation and
`
`occurred at a frequency of < 1%
`l have abbreviated the description of adverse event discontinuations in
`controlled clinical trials.
`
`.
`
`In the “Other Adverse Reactions During All Clinical Trials" subsection l have
`expanded the description of the extent to which patients have been exposed
`to GHB, both in reference to all patients and in reference to those exposed to
`a dose of 9 g/day.
`. Other changes to the draft labeling submitted are acceptable
`
`Drug Abuse and Dependence
`
`o The changes proposed to this section appear acceptable to this reviewer
`. However, the formal input ofthe Controlled Substances Staff is awaited.
`
`

`

`Ranjit B. Mani, MD, HFD-120 Medical Review
`NBA 21196 (N-BZ), Xyrem® . Orphan Medical, inc.
`
`Page 32 of 33
`2/22/02
`
`Overdosage
`
`o
`
`o
`
`l have added some clinical details to the description of the first patient who
`took an overdose of GHB. The sponsor states that the patient “did not require
`medical intervention" which might even suggest that the patient was cared for
`at home by a relative; however the patient did require emergent
`hospitalization.
`In the case of the second patient who took an overdose of GHB and multiple
`other drugs, I have merely stated the names of the drugs that she took,
`deleting indications for their use which do not seem to need to be included in
`labeling.
`. Changes made by the sponsor to the draft label that accompanied the
`Approvable letter of 7/2/01 are othen/vise acceptable
`
`Dosage and Administration
`
`. Changes to this section in the current submission involve for the most part a
`reorganization of the text of the draft labeling that accompanied the
`Approvable letter without omission of any items
`. Additions to this section are minor
`
`. Changes to this section in the current submission are essentially acceptable
`
`How Supplied
`
`Changes made by the sponsor to the draft labeling accompanying the
`Approvable letter of 7/2/01 are minor and acceptable. Agency chemistry
`comments are pending
`
`Storage
`
`No changes have been made by the sponsor to the draft label that was attached
`to the Approvable letter of 7/2/01. Agency chemistry comments are pending
`
`Handling and Disposal
`
`Changes made by the sponsor to the draft labeling accompanying the
`Approvable letter of 7/2/01 are minor and acceptable. Agency chemistry
`comments are pending.
`
`Caution
`
`Changes made by the sponsor to the draft labeling accompanying the
`Approvable letter of 7/2/01 are minor and acceptable. They include deleting the
`name of the manufacturer (presumably, for security reasons). Agency chemistry
`comments are pending.
`
`Additional Comment
`
`The incidence (both numerator and denominator) and exposure data for adverse
`events included in the Warnings, Precautions, and Adverse Reactions sections
`are based on information included in the Major Amendment (dated 3/23/01) and
`earlier submissions under this application; the sponsor’s cut-off date for these
`data was 9/30/00. On the other hand, the cut—off date for data in the current
`submission is 6/30/01. The number of patients exposed in clinical trials (except
`the Scharf open—label trial) through 6/30/01 has risen from 448 (the number used
`
`

`

`Ranjit B. Mani, MD, HFDe120 Medical Review
`NDA 21196 (N-BZ). Xyrem® , Orphan Medical, lnc.
`
`Page 33 of 33
`2/22/02
`
`as a denominator in labeling) to 466. Adverse event data have not been updated
`to include those in the current submission.
`
`Ranjit B. Mani, MD.
`Medical Reviewer
`
`J. Feeney, M.D.
`
`rbm 2/22/02
`CCI
`
`HFD-120
`
`NDA 21196 (N-BZ)
`
`

`

`This is a representation of an electronic record that was signed electronically and
`this page is the manifestation of the electronic signature.
`---------------------------------------------------------------------------------------------------------------------
`
`i
`»
`
`Ranjit Mani
`3/19/02 10:31:18 AM
`MEDICAL OFFICER
`
`John Feeney
`3/30/02 03:42:10 PM
`MEDICAL OFFICER
`
`Labeling negotiations continue. My review outlines a different approach
`to the application than Dr. Mani’s.
`
`

`

`DIVISION OF NEUROPHARMACOLOGICAL DRUG PRODUCTS
`
`CLINICAL SAFETY REVIEW OF NDA
`
`Brand Name:
`
`Xyrem
`
`Generic Name:
`
`Sodium Oxybate
`
`Sponsor:
`
`Orphan Medical, Inc.
`
`Indication:
`
`Narcolepsy
`
`NDA Number:
`
`21196
`
`Original Receipt Date:
`
`10/3/00
`
`Clinical Reviewer:
`
`Ranjit B. Mani, M.D.
`
`Review Author:
`
`Ranjit B. Mani, Mb.
`
`Review Completed:
`
`6/15/01
`
`

`

`Ranjit B. Mani, MD, HFD-120 Medical Review
`NBA 21196, Xyrem , Orphan Medical. Inc.
`
`Page 2 of 89
`6/15/01
`
`SAMPLE SIZE ................................................................................................................................... 32
`7 .6
`7.7 MAIN INCLUSION CRITERIA ............................................................................................................. 32
`7.8 MAIN EXCLUSION CRITERIA ............................................................................................................ 32
`7.9
`CONCOMITANT MEDICATIONS ......................................................................................................... 32
`7.10
`SCHEDULE .................................................................................................................................. 32
`7.1 1
`EFFICACY OUTCOME MEASURES ................................................................................................ 34
`7.12
`ANALYSIS PLAN.......................................................................................................................... 35
`7.13
`PROTOCOL AMENDMENTS .......................................................................................................... 39
`7.14
`EFFICACY RESULTS .................................................................................................................... 39
`7.15
`SAFETY RESULTS ........................................................................................................................ 45
`
`7.16
`7.17
`
`SPONSOR’S CONCLUSIONS .................................‘......................................................................... 45
`REVIEWER’S COMMENTS ............................................................................................................ 45
`
`8.
`
`LAMMERS STUDY ......................................................................................................................... 46
`
`OBJECTIVES .................................................................................................................................... 46
`8.1
`DESIGN ............................................................................................................................................ 46
`8.2
`INCLUSION CRITERIA ....................................................................................................................... 47
`8.3
`EXCLUSION CRITERIA ...................................................................................................................... 47
`8.4
`CONCOM rrANT MEDICATION ........................................................................................................... 47
`8.5
`8.6 DOSAGE .......................................................................................................................................... 47
`8.7
`SCHEDULE ...................