CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`APPLICATION NUMBER:
`
`212690Orig1s000
`
`
`OTHER REVIEW(S)
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`Department of Health and Human Services
`Public Health Service
`Food and Drug Administration
`Center for Drug Evaluation and Research
`Office of Medical Policy
`
`PATIENT LABELING REVIEW
`
`July 7, 2020
`
`Vandna Kishore
`Regulatory Project Manager
`Division of Neurology I
`
`LaShawn Griffiths, MSHS-PH, BSN, RN
`Associate Director for Patient Labeling
`Division of Medical Policy Programs (DMPP)
`
`Marcia Williams, PhD
`Team Leader, Patient Labeling
`Division of Medical Policy Programs (DMPP)
`
`Lonice Carter, MS, RN, CNL
`Patient Labeling Reviewer
`Division of Medical Policy Programs (DMPP)
`Rebecca Falter, PharmD
`Regulatory Review Officer
`Office of Prescription Drug Promotion (OPDP)
`Review of Patient Labeling: Medication Guide (MG) and
`Instructions for Use (IFU)
`
`XYWAV (calcium oxybate, potassium oxybate, magnesium
`oxybate, sodium oxybate)
`
`oral solution, CIII
`
`NDA 212690
`
`Jazz Pharmaceuticals
`
`
`
`
`
`
`Reference ID: 4636772
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`
`
`Date:
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`To:
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`
`Through:
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`
`From:
`
`Subject:
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`Drug Name (established
`name):
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`Dosage Form and
`Route:
`Application
`Type/Number:
`Applicant:
`
`

`

`INTRODUCTION
`On January 21, 2020, Jazz Pharmaceuticals submitted for the Agency’s review an
`original New Drug Application (NDA) 212690 for XYWAV (calcium oxybate,
`potassium oxybate, magnesium oxybate, sodium oxybate). This NDA proposes the
`indication for the treatment of cataplexy and excessive daytime sleepiness in patients
`7 years of age and older with narcolepsy. The reference listed drug for this NDA is
`XYREM (sodium oxybate).
`This collaborative review is written by the Division of Medical Policy Programs
`(DMPP) and the Office of Prescription Drug Promotion (OPDP) in response to a
`request by the Division of Neurology I on February 4, 2020 and February 5, 2020,
`for DMPP and OPDP to review the Applicant’s proposed Medication Guide (MG),
`and Instructions for Use (IFU) for XYWAV (calcium oxybate, potassium oxybate,
`magnesium oxybate, sodium oxybate) oral solution, CIII.
`
` 1
`
`
`
` 2
`
` MATERIAL REVIEWED
`• Draft XYWAV (calcium oxybate, potassium oxybate, magnesium oxybate,
`sodium oxybate) MG and IFU received on January 21, 2020, revised by the
`Review Division throughout the review cycle, and received by DMPP and OPDP
`on June 22, 2020.
`• Draft XYWAV (calcium oxybate, potassium oxybate, magnesium oxybate,
`sodium oxybate) Prescribing Information (PI) received on January 21, 2020,
`revised by the Review Division throughout the review cycle, and received by
`DMPP and OPDP on June 22, 2020.
`• XYREM (sodium oxybate) comparator labeling dated October 26, 2018.
`
`3 REVIEW METHODS
`To enhance patient comprehension, materials should be written at a 6th to 8th grade
`reading level, and have a reading ease score of at least 60%. A reading ease score of
`60% corresponds to an 8th grade reading level. In our review of the MG and IFU the
`target reading level is at or below an 8th grade level.
`Additionally, in 2008 the American Society of Consultant Pharmacists Foundation
`(ASCP) in collaboration with the American Foundation for the Blind (AFB)
`published Guidelines for Prescription Labeling and Consumer Medication
`Information for People with Vision Loss. The ASCP and AFB recommended using
`fonts such as Verdana, Arial or APHont to make medical information more
`accessible for patients with vision loss.
`In our collaborative review of the MG and IFU we:
`simplified wording and clarified concepts where possible
`•
`•
`ensured that the MG and IFU are consistent with the Prescribing Information
`(PI)
`
`
`
`
`
`
`
`Reference ID: 4636772
`
`

`

`•
`•
`
`•
`•
`
`•
`
`removed unnecessary or redundant information
`ensured that the MG and IFU are free of promotional language or suggested
`revisions to ensure that it is free of promotional language
`ensured that the MG meets the Regulations as specified in 21 CFR 208.20
`ensured that the MG and IFU meet the criteria as specified in FDA’s Guidance
`for Useful Written Consumer Medication Information (published July 2006)
`ensured that the MG and IFU are consistent with the approved comparator
`labeling where applicable.
`
` CONCLUSIONS
`The MG and IFU are acceptable with our recommended changes.
`
` RECOMMENDATIONS
`• Please send these comments to the Applicant and copy DMPP and OPDP on the
`correspondence.
`• Our collaborative review of the MG and IFU is appended to this memorandum.
`Consult DMPP and OPDP regarding any additional revisions made to the PI to
`determine if corresponding revisions need to be made to the MG and IFU.
` Please let us know if you have any questions.
`
` 4
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` 5
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`Reference ID: 4636772
`
`18 Page(s) of Draft Labeling have been Withheld in Full as b4 (CCI/TS) immediately following this page
`
`

`

`Signature Page 1 of 1
`--------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically. Following this are manifestations of any and all
`electronic signatures for this electronic record.
`--------------------------------------------------------------------------------------------
`/s/
`------------------------------------------------------------
`
`LONICE J CARTER
`07/07/2020 07:47:45 AM
`
`REBECCA A FALTER
`07/07/2020 08:03:39 AM
`
`MARCIA B WILLIAMS
`07/07/2020 10:13:13 AM
`
`LASHAWN M GRIFFITHS
`07/07/2020 06:18:55 PM
`
`Reference ID: 4636772
`
`

`

`FOOD AND DRUG ADMINISTRATION
`Center for Drug Evaluation and Research
`Office of Prescription Drug Promotion
`****Pre-decisional Agency Information****
`
`
`
`
`Memorandum
`
`Date:
`July 07, 2020
`
`
`To:
`
`
`
`
`
`
`From:
`
`
`
`CC:
`
`Subject:
`
`Vandna Kishore, Regulatory Project Manager
`Division of Neurology-I (DN-I)
`
`Tracy Peters, PharmD, Associate Director for Labeling, (DN-I)
`
`Rebecca Falter, PharmD, Regulatory Review Officer
`Office of Prescription Drug Promotion (OPDP)
`
`Susannah O’Donnell, MPH, RAC, Team Leader, OPDP
`
`OPDP Labeling Comments for Xywav™ (calcium, magnesium, potassium,
`and sodium oxybates) oral solution, CIII
`
`
`NDA:
`
`
`
`In response to DN-I’s consult request dated February 5, 2020, OPDP has reviewed the
`proposed product labeling (PI), Medication Guide, Instructions for Use (IFU), and carton and
`container labeling for the original NDA submission for Xywav.
`
`PI and Medication Guide/IFU: OPDP’s comments on the proposed labeling are based on the
`draft PI received by electronic mail from DN-I (Vandna Kishore) on June 22, 2020, and are
`provided below.
`
`212690
`
` A
`
` combined OPDP and Division of Medical Policy Programs (DMPP) review was completed,
`and comments on the proposed Medication Guide and IFU were sent under separate cover on
`July 7, 2020.
`
`Carton and Container Labeling: OPDP has reviewed the attached proposed carton and
`container labeling submitted by the Sponsor to the electronic document room on June 19,
`2020, and we do not have any comments.
`
`Thank you for your consult. If you have any questions, please contact Rebecca Falter at (301)
`837-7107 or Rebecca.Falter@fda.hhs.gov.
`
`
`
`
`Reference ID: 4637079
`
`1
`
`23 Page(s) of Draft Labeling have been Withheld in Full as b4 (CCI/TS) immediately following this page
`
`

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`Signature Page 1 of 1
`--------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically. Following this are manifestations of any and all
`electronic signatures for this electronic record.
`--------------------------------------------------------------------------------------------
`/s/
`------------------------------------------------------------
`
`REBECCA A FALTER
`07/07/2020 01:34:52 PM
`
`Reference ID: 4637079
`
`

`

`MEMORANDUM
`REVIEW OF REVISED LABEL AND LABELING
`Division of Medication Error Prevention and Analysis (DMEPA)
`Office of Medication Error Prevention and Risk Management (OMEPRM)
`Office of Surveillance and Epidemiology (OSE)
`Center for Drug Evaluation and Research (CDER)
`
`Date of This Memorandum:
`June 24, 2020
`Requesting Office or Division:
`Division of Neurology 1 (DN 1)
`Application Type and Number: NDA 212690
`Product Name and Strength:
`Xywav (calcium, magnesium, potassium, sodium oxybates)
`oral solution, 0.5 g/mL
`Jazz Pharmaceuticals Ireland Limited
`2020-132-2
`Justine Kalonia, PharmD
`Lolita White, PharmD
`
`Applicant/Sponsor Name:
`OSE RCM #:
`DMEPA Safety Evaluator:
`DMEPA Team Leader:
`
`PURPOSE OF MEMORANDUM
`1
`The Applicant submitted the revised container label received on June 19, 2020 for Xywav. The
`Division of Neurology 1 (DN 1) requested that we review the revised container label for Xywav
`(Appendix A) to determine if it is acceptable from a medication error perspective. The revisions
`are in response to recommendations that we made during a previous label and labeling review
`and memorandum. a,b
`
` CONCLUSION
`2
`The Applicant implemented all of our recommendations and we have no additional
`recommendations at this time.
`
`a Kalonia J. Label and Labeling Review for Xywav (NDA 212690). Silver Spring (MD): FDA, CDER, OSE, DMEPA (US);
`2020 JUN 11. RCM No.: 2020-132.
`b Kalonia J. Label and Labeling Memorandum for Xywav (NDA 212690). Silver Spring (MD): FDA, CDER, OSE, DMEPA
`(US); 2020 JUN 17. RCM No.: 2020-132-1.
`
`1
`
`Reference ID: 4630350
`
`1 Page(s) of Draft Labeling have been Withheld in Full as b4 (CCI/TS) immediately following this page
`
`

`

`Signature Page 1 of 1
`--------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically. Following this are manifestations of any and all
`electronic signatures for this electronic record.
`--------------------------------------------------------------------------------------------
`/s/
`------------------------------------------------------------
`
`JUSTINE H KALONIA
`06/24/2020 08:44:29 AM
`
`LOLITA G WHITE
`06/24/2020 02:04:39 PM
`
`Reference ID: 4630350
`
`

`

`MEM OR AN D UM
`
`Department of Health and Human Services
`Food and Drug Administration
`Center for Drug Evaluation and Resear ch
`
`Date:
`
`To:
`
`Through:
`
`From:
`
`Subject:
`
`June 21 , 2020
`
`Eric Bastings, M.D., Director
`Division ofNem ology Products 1
`
`Dominic Chiapperino, Ph.D., Director
`Controlled Substance Staff
`
`Chad Reissig, Ph.D., Superviso1y Phaimacologist
`Controlled Substance Staff
`
`Gamma-hydroxybutyrate (JZP-258), NDA 212690
`XYW AV oral solution, 0.5 g/mL
`IND 49641
`Indication(s): treatment of cataplexy and excessive daytime sleepiness (EDS) in
`Patients 7 years of age and older with narcolepsy
`Sponsor: Jazz Phan naceuticals Ireland Limited
`PDUFA Goal Date: July 21, 2020
`
`Materials Reviewed:
`Abuse-related clinical data and labeling in NDA 212690
`
`Table of Contents
`I. EXECUTIVE SUMMARY .................................................................................................................. 2
`1. Background ....................................................................................................................................... 2
`2. Conclusions ....................................................................................................................................... 2
`3. Reco1nmendations ............................................................................................................................. 2
`DISCUSSION ................................................................................................................................... 3
`II.
`1. Cheinistiy .......................................................................................................................................... 4
`2. Clinical Phaimacology ...................................................................................................................... 4
`3. Clinical Studies ................................................................................................................................. 4
`4. Regulato1y Issues and Labeling ........................................................................................................ 9
`
`Reference ID 4628634
`
`

`

`XYWAV
`NDA 212690
`
`EXECUTIVE SUMMARY
`I.
`Background
`1.
`This memorandum responds to a consult request by the Division of Neurology Products 1 (DNP1) to
`evaluate the abuse potential of JZP-258 (proposed trade name: XYWAV) submitted by Jazz
`pharmaceuticals in NDA 212690. JZP-258 is an orally administered solution. The drug product is
`indicated for the treatment of cataplexy and excessive daytime sleepiness (EDS) in patients 7 years of
`age and older with narcolepsy. The recommended dose is 0.5 g/mL. According to the Sponsor, JZP-258
`contains the active moiety oxybate (4-hydroxybutanoate), a central nervous system depressant, and
`belongs to the same pharmacologic class as Xyrem (sodium oxybate). Xyrem was first reviewed by
`CSS in 2001 (DARRTS entry by Michael Klein, 5/8/2001) and approved on July 17, 2002 for the
`treatment of cataplexy associated with narcolepsy. The Sponsor states that JZP-258 and Xyrem contain
`the same concentration of active ingredients (0.5 g/mL) and the same concentration of active moiety.
`The Sponsor is developing JZP-258 to reduce the sodium content of their product while retaining the
`treatment benefits of Xyrem. Xyrem is controlled in Schedule III (C-III) of the Controlled Substances
`Act (CSA).
`
`JZP-258 is a new molecular entity. The mechanism of action of oxybate in the treatment of narcolepsy
`is unknown. It is hypothesized that the therapeutic effects of oxybate on the symptoms of narcolepsy
`(cataplexy and excessive daytime sleepiness [EDS]) are mediated through interactions with the B-
`subtype of the gamma-aminobutyric acid (GABAB) receptors on noradrenergic and dopaminergic
`neurons, and thalamocortical neurons.
`
`2.
`
`Conclusions
`
`
`
`
`
`JZP-258 contains the same active pharmaceutical ingredient (API) as Xyrem and in an
`equivalent amount
`JZP-258 may have a slightly longer time to reach maximum concentration (i.e., increased Tmax)
`and an approximately 20% lower peak concentration (decreased Cmax). Thus, the abuse
`potential of JZP-258 does not appear to be increased relative to Xyrem
` Clinical studies with JZP-258 did not appear to produce an adverse event (AE) profile
`demonstrating an increased abuse potential relative to Xyrem
`JZP-258 is labeled appropriately and nearly identical to Xyrem
`
`
`
`Recommendations
`3.
`Based on our findings, we recommend the following:
`
`1. JZP-258 does not appear to have an increased abuse potential relative to Xyrem (C-III) and
`contains the same active moiety in an equivalent amount. Accordingly, JZP-258 should be
`controlled in schedule III of the Controlled Substances Act.
`
`Sections of product labeling for JZP-258 related to abuse and dependence are similar to Xyrem labeling,
`appropriate, and appears as follows:
`
`5.2 Abuse and Misuse
`
`Page 2 of 10
`
`Reference ID: 4628634
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`

`

`XYWAV
`NDA 212690
`
`XYWAV is a Schedule III controlled substance. The active moiety of XYWAV, is oxybate also
`known as gamma-hydroxybutyrate (GHB), a Schedule I controlled substance. Abuse of illicit GHB,
`either alone or in combination with other CNS depressants, is associated with CNS adverse reactions,
`including seizure, respiratory depression, decreases in the level of consciousness, coma, and death.
`The rapid onset of sedation, coupled with the amnestic features of GHB, particularly when combined
`with alcohol, has proven to be dangerous for the voluntary and involuntary user (e.g., assault victim).
`Because illicit use and abuse of GHB have been reported, physicians should evaluate patients for a
`history of drug abuse and follow them closely, particularly for signs of misuse or abuse of GHB
`(including but not limited to increase in size or frequency of dosing, drug-seeking behavior, feigned
`cataplexy) [see Drug Abuse and Dependence (9.2)]. If abuse is suspected, treatment with XYWAV
`should be discontinued.
`XYWAV is available only through a restricted program under a REMS [see Warnings and
`Precautions (5.3)].
`
`9 DRUG ABUSE AND DEPENDENCE
`9.1 Controlled Substance
`TRADENAME is a Schedule III controlled substance under the Federal Controlled Substances Act.
`Non-medical use of TRADENAME could lead to penalties assessed under the higher Schedule I
`controls.
`
`9.2 Abuse
`The active moiety of TRADENAME, oxybate, produces dose-dependent central nervous system
`effects, including hypnotic and positive subjective reinforcing effects. The onset of effect is rapid,
`enhancing its potential for abuse or misuse.
`The rapid onset of sedation, coupled with the amnestic features of oxybate, particularly when
`combined with alcohol, has proven to be dangerous for the voluntary and involuntary user (e.g.,
`assault victim).
`Illicit GHB is abused in social settings primarily by young adults. Some of the doses estimated to be
`abused are in a similar dosage range to that used for treatment of patients with cataplexy. GHB has
`some commonalities with ethanol over a limited dose range, and some cross tolerance with ethanol
`has been reported as well. Cases of severe dependence and craving for GHB have been reported
`when the drug is taken around the clock. Patterns of abuse indicative of dependence include: 1) the
`use of increasingly large doses, 2) increased frequency of use, and 3) continued use despite adverse
`consequences.
`Because illicit use and abuse of GHB have 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 GHB (e.g., increase in size or frequency of dosing, drug-seeking behavior,
`feigned cataplexy). Dispose of TRADENAME according to state and federal regulations. It is safe to
`dispose of TRADENAME down the sanitary sewer.
`
`9.3 Dependence
`There have been case reports of withdrawal, ranging from mild to severe, following discontinuation
`of illicit use of GHB at frequent repeated doses (18 g to 250 g per day) in excess of the recommended
`dosage range. Signs and symptoms of GHB withdrawal following abrupt discontinuation included
`insomnia, restlessness, anxiety, psychosis, lethargy, nausea, tremor, sweating, muscle cramps,
`Page 3 of 10
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`Reference ID: 4628634
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`

`

`XYWAV
`NDA 212690
`
`tachycardia, headache, dizziness, rebound fatigue and sleepiness, confusion, and, particularly in the
`case of severe withdrawal, visual hallucinations, agitation, and delirium. These symptoms generally
`abated in 3 to 14 days. In cases of severe withdrawal, hospitalization may be required. The
`discontinuation effects of TRADENAME have not been systematically evaluated in controlled
`clinical trials. In the clinical trial experience with Xyrem in narcolepsy/cataplexy patients at
`recommended doses, two patients
`reported anxiety and one reported insomnia following abrupt discontinuation at the termination of the
`clinical trial; in the two patients with anxiety, the frequency of cataplexy had increased markedly at
`the same time. In the TRADENAME clinical trial in adult narcolepsy/cataplexy patients at
`recommended doses, one patient reported insomnia following abrupt discontinuation of
`TRADENAME.
`
`Tolerance
`Tolerance to TRADENAME has not been systematically studied in controlled clinical trials. There
`have been some case reports of symptoms of tolerance developing after illicit use at dosages far in
`excess of the recommended TRADENAME dosage regimen. Clinical studies of sodium oxybate in
`the treatment of alcohol withdrawal suggest a potential cross-tolerance with alcohol. The safety and
`effectiveness of TRADENAME in the treatment of alcohol withdrawal have not been established.
`
`17 PATIENT COUNSELING INFORMATION
`[relevant sections for abuse, dependence, and diversion risks]
`
`Abuse and Misuse
`Inform patients and/or caregivers that the active ingredient of XYWAV is gamma-hydroxybutyrate
`(GHB), which is associated with serious adverse reactions with illicit use and abuse [see Warnings
`and Precautions (5.2)].
`
`XYWAV/XYREM REMS Program
`XYWAV is available only through a restricted program called the XYWAV/XYREM REMS
`Program [see Warnings and Precautions (5.3)]. Inform the patient and/or caregiver of the following
`notable requirements:
`• XYWAV is dispensed only by the central pharmacy
`• XYWAV will be dispensed and shipped only to patients enrolled in the XYWAV/XYREM REMS
`Program
`
`XYWAV is available only from the central pharmacy participating in the program. Therefore,
`provide patients and/or caregivers with the telephone number and website for information on how to
`obtain the product.
`
`II. DISCUSSION
`1.
`Chemistry
`
`According to the Sponsor, JZP-258 drug substance consists of mixed oxybate salts (calcium, potassium,
`magnesium, and sodium). The molecular formula of the active moiety, oxybate, is C4H8O3. The
`Page 4 of 10
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`Reference ID: 4628634
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`XYWAV
`NDA 212690
`
`molecular weight of oxybate (as its neutral species) is 104.10 g/mol. JZP-258 does not have a CAS
`number or IUPAC name.
`
`JZP-258 does not have any chiral centers and the structure appears below:
`
`The drug product formulation is an oral solution containing the oxybate salts active ingredient at a
`concentration of 0.5 g/mL, with only sucralose and purified water as excipients.
`
`Clinical Pharmacology
`2.
`Two studies (13-010 and JZP258-101) evaluated the bioavailability/bioequivalence (BE) of JZP-258 and
`characterized the basic pharmacokinetic (PK) properties of JZP-258, including food effects (both studies)
`and dose proportionality (only in Study 13-010) relative to Xyrem. Overall, relative to Xyrem, under fasting
`conditions JZP-258 had a slightly longer time to peak concentration (i.e., longer Tmax) and lower peak
`plasma concentration (i.e., decreased Cmax), with a similar area under the curve (AUC), and similar half-
`life. The Sponsor notes that JZP-258 met FDA bioequivalence criteria for AUC, but not Cmax.
`
`Under fed conditions, exposure was decreased for both formulations while the half-life was unchanged.
`Food had a greater effect on the Cmax of Xyrem relative to JZP-258 (~40% reduction for Xyrem compared
`to ~25% for JZP-258). In addition, food increased the time to Tmax for Xyrem and not JZP-258. The
`Sponsor notes that JZP-258 met bioequivalence criteria for Xyrem under fed conditions.
`
`Based on the PK studies, the clinical pharmacology of JZP-258 is similar to Xyrem and thus
`pharmacodynamic abuse-related effects predicted to be similar to Xyrem. See the clinical pharmacology
`review for additional discussion.
`
`Clinical Studies
`3.
`The clinical development program for JZP-258 included four studies: three phase 1 bioavailability
`bioequivalence (BA/BE) studies (Studies 13-010, JZP258-101, and 15-003) and a Phase 3 study (study
`15-006). Each of these studies was assessed for abuse-related AEs and briefly summarized below:
`
`Study 13-010: “An Open-Label, Randomized Crossover Study to Evaluate the Pharmacokinetics of
`Oxybate Formulations in Healthy Subjects, Bioavailability, Bioequivalence, and Food Effect Following
`Administration.”
`
`Page 5 of 10
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`Reference ID: 4628634
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`

`

`XYWAV
`NDA 212690
`
`This study was divided into two phases. The first phase examined the bioavailability and
`bioequivalence (BA/BE) of JZP-258 compared to Xyrem under fasting and fed conditions (phase 1).
`The second study phase (phase 2) evaluated the BA/BE of two admixtures of JZP-258 and Xyrem at
`different ratios. A range of N=35-36 subjects completed phase 1 of the study and n=23-24 completed
`phase 2. Relative to Xyrem, mean oxybate concentration time profiles were similar under fasted
`conditions, although values for JZP-258 were lower for the first 1.5 hours. Overall, both JZP-258 and
`the admixtures produced slightly delayed Tmax and Cmax values relative to Xyrem.
`
`
`Abuse-related adverse events judged as “related” to study drug by the Investigator from both phases of
`the study are shown below in Table 1.
`
`Table 1: Abuse-related AEs from Study 13-010
`Part 1, food-effect study
`Fasting JZP*
`System Organ Class
`n=35 (%)
`Preferred term
`25 (71.4%)
`Somnolence
`5 (14.3%)
`Euphoric Mood
`2 (5.7%)
`Disturbance in Attention
`3 (8.6%)
`Feeling of relaxation
`1 (2.9%)
`Feeling Drunk
`2 (5.7%)
`Restlessness
`1 (2.9%)
`Confusional State
`Emotional Disorder
`0 (0.0%)
`Irritability
`1 (2.9%)
`1 (2.9%)
`Hypervigilance
`*JZP and Xyrem were administered as a 4.5g dose
`
`Fed JZP
`n=36 (%)
`27 (75%)
`2 (5.6%)
`3 (8.3%)
`2 (5.6%)
`2 (5.6%)
`1 (2.8%)
`0 (0.0%)
`0 (0.0%)
`0 (0.0%)
`0 (0.0%)
`
`Fasting
`Xyrem
`n=36 (%)
`32 (88.9%)
`4 (11.1%)
`3 (8.3%)
`3 (8.3%)
`2 (5.6%)
`1 (2.8%)
`2 (5.6%)
`1 (2.8%)
`1 (2.8%)
`0 (0.0%)
`
`Fed Xyrem
`n=36 (%)
`27 (75%)
`1 (2.8%)
`3 (8.3%)
`1 (2.8%)
`3 (8.3%)
`0 (0.0%)
`0 (0.0%)
`1 (2.8%)
`0 (0.0%)
`0 (0.0%)
`
`Overall
`subjects n=
`36 (%)
`35 (97.2%)
`8 (22.2%)
`8 (22.2%)
`9 (25%)
`7 (19.4%)
`3 (8.3%)
`3 (8.3%
`2 (5.6%)
`2 (5.6%)
`1 (2.8%)
`
`Number
`of
`Events
`134
`13
`11
`9
`9
`4
`3
`2
`2
`1
`
`Part 2 admixture study
`
`System Organ Class
`Preferred term
`
`Fasting 2.5 g
`JZP + Xyrem
`2g Subjects
`n=23 (%)
`
`Somnolence
`Feeling of Relaxation
`Euphoric mood
`Feeling Drunk
`Feeling abnormal
`Irritability
`Disturbance in Attention
`Confusional state
`Disinhibition
`Restlessness
`
`20 (87.0%)
`2 (8.7%)
`1 (4.3%)
`1 (4.3%)
`0 (0.0%)
`0 (0.0%)
`0 (0.0%)
`0 (0.0%)
`0 (0.0%)
`0 (0.0%)
`
`Fasting
`Xyrem 4g
`Subjects
`n=23 (%)
`
`Fasting 3.75
`g JZP +
`Xyrem 0.75g
`Subjects
`n=23 (%)
`18 (78.3%)
`17 (77.3%)
`1 (4.3%)
`1 (4.5%)
`1 (4.3%)
`0 (0.0%)
`0 (0.0%)
`0 (0.0%)
`0 (0.0%)
`0 (0.0%)
`1 (4.3%)
`0 (0.0%)
`1 (4.3%)
`0 (0.0%)
`0 (0.0%)
`1 (4.5%)
`0 (0.0%)
`1 (4.5%)
`0 (0.0%)
`1 (4.3%)
`Page 6 of 10
`
`Fasting JZP
`2.25 g
`Subjects
`n=23 (%)
`
`11 (47.8%)
`3 (13.0%)
`0 (0.0%)
`1 (4.3%)
`1 (4.3%)
`0 (0.0%)
`0 (0.0%)
`0 (0.0%)
`0 (0.0%)
`0 (0.0%)
`
`Overall
`subjects n=
`24(%)
`
`Number
`of
`Events
`
`24 (100.0%)
`4 (16.7%)
`2 (8.3%)
`2 (8.3%)
`1 (4.2%)
`1 (4.2%)
`1 (4.2%)
`1 (4.2%)
`1 (4.2%)
`1 (4.2%)
`
`93
`7
`2
`2
`1
`1
`1
`1
`1
`1
`
`Reference ID: 4628634
`
`

`

`XYWAV
`NDA 212690
`
`As seen in the tables above, in both parts of the study somnolence was the most commonly reported AE.
`This might be expected for a drug indicated for treatment of cataplexy and excessive daytime sleepiness,
`where the therapeutic effect is derived from the promotion of sleep. Though a formal statistical analysis
`of abuse-related AEs was not performed, JZP-258 did not appear to produce an increase in AEs relative
`to Xyrem.
`
`Study JZP258-101: “An Open-Label, Randomized, Crossover, Phase 1 Study to Evaluate the
`Pharmacokinetics, Bioavailability, and Bioequivalence Following Administration of Oxybate
`Formulations in Healthy Subjects”
`
`According to the Sponsor, the primary objective of this study was to assess the relative bioavailability
`and bioequivalence of JZP-258 oral solution versus Xyrem when taken with 60 or 240 mL water under
`fasting or fed conditions. This was an open-label, within-subjects study evaluating JZP-258 and Xyrem,
`each dosed at 500 mg/mL. Secondary outcome measures evaluated food effects and safety and
`tolerability. Forty two (n=42) subjects aged 18-45 were assessed in the completer population. To
`evaluate PK effects, blood samples were taken predose, and 10, 20, 30, 45, 60, and 75 minutes postdose,
`and at 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 7, and 8 hours postdose following each treatment.
`
`The PK analyses demonstrated that relative to Xyrem, JZP-258 had decreased exposure. This was
`demonstrated by the fact that across all conditions (e.g., fast vs fed, and 60 vs. 240 mL of water) JZP-
`258 generally produced lower PK values at equivalent doses. For example, in every condition, JZP-258
`had a reduced Cmax, AUC, and increased Tmax (i.e., longer time to Cmax). Across the conditions, both
`drugs had roughly equivalent t½ values. The Sponsor reports AEs were similar between JZP-258 and
`Xyrem and that “no clinically import differences in AEs were observed between JZP-258 and Xyrem.”
`Common AEs (incidence ≥5%) included somnolence, dizziness, nausea, headache, fatigue, paresthesia,
`vertigo, euphoric mood, feeling drunk, feeling hot, and limb discomfort.
`
`No significant adverse events (SAEs) or deaths occurred. Abuse-related AEs are tabulated and
`summarized below in table 2. Only AEs that were categorized by the Sponsor as “related” to study drug
`are shown.
`Table 2: Abuse-related AEs from study JZP 258-101*
`JZP-258 + 60mL
`Xyrem + 60 mL
`System Organ Class
`water (fasting)
`water (fasting)
`Preferred term
`n= 47 (%)
`n= 47 (%)
`Somnolence
`39 (83%)
`41 (87%)
`Euphoric Mood
`6 (12.8%)
`2 (4.3%)
`Feeling Drunk
`4 (8.5%)
`4 (8.5%)
`Disturbance in Attention
`2 (4.3%)
`3 (6.4%)
`Depression
`0 (0.0%
`0 (0.0%
`Feeling of Relaxation
`0 (0.0%
`1 (2.1%)
`Feeling Abnormal
`2 (4.3%)
`2 (4.3%)
`Confusional State
`0 (0.0%
`0 (0.0%
`Agitation
`1 (2.1%)
`1 (2.1%)
`Memory Impairment
`0 (0.0%
`0 (0.0%
`* Both JZP-258 and Xyrem were dosed as 4.5g
`
`Xyrem + 240 mL
`water (fasting) n=
`47 (%)
`37 (78.7%)
`1 (2.1%)
`4 (8.5%)
`0 (0.0%
`3 (6.4%)
`2 (4.3%)
`0 (0.0%
`1 (2.1%)
`0 (0.0%
`1 (2.1%)
`
`Overall**
`n=48 (%)
`47 (97.9%)
`11 (22.9%)
`8 (16.7%)
`5 (10.4%)
`5 (10.4%)
`4 (8.3%)
`4 (8.3%)
`2 (4.2%)
`2 (4.2%)
`1 (2.1%)
`
`JZP + 60 mL
`water (fed) n=
`46 (%)
`34 (73%)
`3 (6.5%)
`2 (4.3%)
`1 (2.2%)
`0 (0.0%
`1 (2.2%)
`0 (0.0%
`0 (0.0%
`0 (0.0%
`0 (0.0%
`
`Xyrem + 60 mL
`water (fed) n= 46
`(%)
`33 (71.7%)
`2 (4.3%)
`1 (2.2%)
`1 (2.2%)
`1 (2.2%)
`0 (0.0%
`0 (0.0%
`0 (0.0%
`0 (0.0%
`0 (0.0%
`
`JZP + 240 mL
`water (fasting)
`n= 47 (%)
`38 (80.9%)
`1 (2.1%)
`3 (6.4%)
`1 (2.1%)
`3 (6.4%)
`1 (2.1%)
`0 (0.0%
`2 (4.3%)
`0 (0.0%
`0 (0.0%
`
`Page 7 of 10
`
`Reference ID: 4628634
`
`

`

`XYWAV
`NDA 212690
`
`** AEs are shown as a percentage of subjects experiencing an AE. Subjects may have had the same AE on multiple occasions
`
`Similar to study 13-010, somnolence was the most commonly observed abuse-related AE. In the
`treatment arms receiving 60mL water (i.e., JZP vs. Xyrem after dosing with 60mL water), euphoric
`mood AEs were three times more prevalent with JZP-258 than Xyrem (2 vs. 3 incidents), however, the
`low occurrence overall (i.e., 12.% vs. 4.3%) is not amenable to clear interpretation. Overall, abuse-
`related AEs did not appear to differ between Xyrem and JZP-258 to a substantial degree.
`
`Study 15-003: “A Randomized, Double-Blind, Crossover Taste Testing Study in Healthy
`Subjects Comparing JZP-258 and Placebo”
`According to the Sponsor, the objective of this study was to compare the taste of JZP-258 to placebo for
`sameness. Sixty eight subjects (n=68) completed the study and were included in the safety evaluation. In
`the study, subjects underwent a screening period where they had to discriminate salt water vs. distilled
`water to be eligible for the main portion of the study. Eligible subjects were enrolled in a 4-sequence, 4-
`period, 2-treatment, crossover study and randomized into one of the following four treatment sequences:
`
`The Sponsor describes the study procedures as follows:
`
`On Day 1, two liquids were rated for sameness in duplicate by each subject as follows:
` Treatment A and Treatment B twice, in different replicates, or
` Treatment A and Treatment A twice, in different replicates
`Treatment pairs were tested in 2 replicates. In each sequence, Replicate 1 contained the first 2 pairs of
`test liquids. Replicate 2 contained the second 2 pairs of test liquids. Replicates 1 and 2 contained the
`same 2 pairs of test liquids; however, the order of the pairs could have been different. One hour after
`breakfast and brushing of teeth, each subject was asked to taste the first liquid of the pair and then
`remember that taste so that he/she could compare that liquid for sameness to the second liquid.
`An hour later, the subject tasted the second liquid and rated the liquid for sameness to the prior liquid of
`the pair. Subjects rated the sameness of each pair of test liquids (X, Y) by answering “Yes” or “No” to
`the following question: “Does liquid Y taste the same as liquid X?” An hour following the taste test of
`the first pair of liquids (Replicate 1, Period 1), the second pair of liquids was tested (Replicate 1,
`Period 2).
`
`One hour after lunch and the brushing of teeth, the sequence was repeated with subjects beginning
`Replicate 2 and tasting another two pairs of liquids an hour apart (periods 3 and 4). Only 30 mL of the
`sample solution was administered. The Sponsor states that subjects were told that “test samples were to
`be tasted not consumed.” The specifics of this study procedure are not clear, but they imply that only
`Page 8 of 10
`
`Reference ID: 4628634
`
`

`

`XYWAV
`NDA 212690
`
`miniscule amounts of JZP-258 were administered to subjects to avoid producing a pharmacological
`effect that might influence the