CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`APPLICATION NUMBER:
`212690Orig1s000
`PRODUCT QUALITY REVIEW(S)
`
`
`
`
`
`
`

`

`11 U.S. FOOD & DRUG
`
`ADM I NISTRATION
`
`RECOMMENDATION: Approval
`
`NOA 212690
`Review #1
`
`XYWAV (calcium, magnesium, potassium and sodium
`oxybates) oral solution
`Solution
`0.5 glmL Total Salts comprised of:
`0.234 glml calcium oxybate
`0.130 glml potassium oxybate
`0.096 glml magnesium oxybate
`0.040 glml sodium oxybate
`(Equivalent to 0 .413 glml oxybate)
`Oral
`Rx
`Jazz Pharmaceuticals Ireland Limited
`Jazz Pharmaceuticals, Inc.
`
`QUALITY TEAM
`
`Primary Assessment
`Gaetan Ladouceur
`Grace Chiou
`Joanne Wang
`Hemlata Tamta
`NIA
`
`Secondary Assessment
`Donna Christner
`Julia Pinto
`Frank Wackes
`Nandini Bhattacharya
`NIA
`
`Florence Aisida
`
`Martha Heimann
`
`NIA
`NIA
`
`NIA
`NIA
`
`Drug Product Name
`
`Dosage Form
`Strength
`
`Route of Administration
`Rx/OTC Dispensed
`Applicant
`US agent, if applicable
`
`Discipline
`Drug Substance
`Drug Product
`Manufacturing
`Microbiology
`Biopharmaceutics
`Regulatory Business
`Process Manager
`Application Technical
`Lead
`Laboratory (OTR)
`Environmental
`
`Reference ID: 464MZI
`
`

`

`SUBMISSIONS REVIEWED
`
`Submission
`SD-01, Original NOA
`SD-03, Response to IR
`SD-04, Response to IR
`SD-05, Response to IR
`SD-06, Response to IR
`
`Document Date
`1/21 /2020
`21412020
`2/11/2020
`3/31 /2020
`4/3/2020
`
`SD-10, Response to IR
`
`412412020
`
`Disciplines Affected
`
`All
`Manufacturing
`Drug Product
`Drug Product
`Drug Product
`Drug Substance, Drug Product,
`Microbiology
`
`NOA 212690
`
`Page 2
`
`61212020
`
`Reference ID: 464MZI
`
`

`

`QUALITY ASSESSMENT DATA SHEET
`
`1. RELATED/SUPPORTING DOCUMENTS
`
`Holder
`
`Item Referenced
`(b)(4
`
`A. DMFs:
`
`DMF# Type
`(b)(4)- -
`111
`
`111
`
`111
`
`111
`
`111
`
`111
`1 Adequate information in NOA
`
`Status
`
`N/A 1
`
`N/A 1
`
`N/A 1
`
`N/A 1
`
`N/A 1
`
`N/A 1
`
`Comments
`
`Date
`Assessed
`--
`--
`
`--
`
`--
`
`--
`-
`
`B. Other Documents: IND, RLD, or sister applications
`
`Document Application Number
`21196
`NOA
`
`IND
`
`49641
`
`Description
`Approved NOA held by Jazz Pharmaceuticals for
`Xyrem® (sodium oxybate) oral solution
`Development of Xyrem and the proposed mixed
`oxybate salts product
`
`2. CONSULTS
`
`Not applicable
`
`NOA 212690
`
`Page 3
`
`61212020
`
`Reference ID: 464M ZI
`
`

`

`EXECUTIVE SUMMARY
`
`I. RECOMMENDATIONS AND CONCLUSION ON APPROVABILITY
`
`The Office of Product Quality (OPQ) review team recommends that the Agency
`Approve NOA 212690 for XYWAV (calcium, magnesium, potassium, and sodium
`oxybates) oral solution . From a quality perspective, the application provides
`adequate information to ensure that the Applicant can consistently manufacture a
`product that is suitable for use by the intended patients.
`
`II. SUMMARY OF QUALITY ASSESSMENTS
`
`A. Product Overview
`
`Sodium oxybate (sodium gamma-hydroxybutyrate) was approved in under
`NOA 21196 in 2002 as Xyrem® (sodium oxybate) oral solution 0.5 g/ml. Xyrem is
`indicated for treatment of cataplexy or excessive daytime sleepiness (EDS) in
`patients with narcolepsy. The current holder NOA 21196, Jazz Pharmaceuticals, is
`seeking approval for an oxybate "mixed salts" oral solution (JZP-258) as a follow-on
`to the approved product. Due to the high doses used, the Xyrem formulation results
`in high sodium intake (maximum dose of 9 g sodium oxybate/night is equivalent to
`1640 mg sodium). The intent of the JZP-258 formulation is to reduce sodium
`content by replacing most of the sodium with other cations, i.e., calcium, potassium,
`and magnesium. By adjusting the relative amounts of each cation, the applicant
`developed a product that contains the same concentration of the active moiety,
`oxybate (0.413 g/ml ) and a total salt concentration of 0.5 g/ml. Note that although
`Xyrem and JZP-258 are both simple aqueous solutions that contain the same
`concentration of the active moiety; the products are not bioequivalent. Therefore,
`the applicant was required to perform a clinical study to demonstrate efficacy.
`
`Proposed indication(s) including
`intended patient population
`
`Duration of treatment
`
`Maximum daily dose
`
`Alternative methods of
`administration
`
`Treatment of cataplexy or excessive daytime
`sleepiness in patients 7 years of age and older
`with narcolepsy
`Chronic
`
`9 g/day
`
`None
`
`B. Quality Assessment Overview
`
`The proposed product contains an active moiety with a simple chemical structure in
`a nonsterile aqueous solution. Based on the initial risk assessment, the product was
`classified as low risk for all critical attributes except palatability and leachables,
`
`NOA 212690
`
`Page4
`
`61212020
`
`Reference ID: 464MZI
`
`

`

`which were considered moderate risk. However, labeling the product (assignment of
`established name and label potency) consistent with current USP and FDA policies,
`while minimizing potential medication errors required extensive discussions with the
`Divisions of Medication Error Prevention and Analysis (DMEPA) and Risk
`Management (DRISK), and consultation within OPQ.
`
`Drug Substance:
`
`Adequate
`
`The drug substance (calcium oxybate, potassium oxybate, magnesium oxybate, and
`sodium oxybate) is a new salt form of oxybate and is considered a new active
`ingredient. The molecular formula of the salt free form is C4H8O3 and the molecular
`weight is 104.10 Daltons. The bulk drug substance is a clear to slightly opalescent
`solution in water. The density of the solution is
` and it has a viscosity of
`
`
`
`The drug substance manufacturing process is
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` Acceptance criteria for impurities are
`adequately justified. Analytical methods are validated and deemed suitable for
`quality control.
`
`Based on the stability data provided, a
`substance stored at
`.
`
` retest period is assigned for drug
`
`Drug Product: Adequate
`
`The drug product is a clear to slightly opalescent aqueous oral solution. Each mL of
`the solution contains 0.234 g calcium oxybate, 0.130 g potassium oxybate, 0.096 g
`magnesium oxybate, and 0.040 g sodium oxybate. The total concentration of the
`active moiety is 0.413 g/mL of oxybate. Use of multiple cations in the formulation
`allows for reduction of sodium, while ensuring that no single cation exceeds the daily
`intake recommended by the USDA’s Dietary Reference Intake (RDI). The only other
`ingredient is sucralose
`, which is commonly used in foods, and present
`at a level consistent with other approved products.
`
`bottle
`The primary container for the product is a 6 oz round amber two-piece
`
`with a press-in-bottle adapter (PIBA) and a
`child resistant
`closure. The bottle is filled to deliver 180 mL solution. An oral syringe is
`used to withdraw the prescribed dose. All product contacts components are
`compatible with the formulation.
`
`The drug product specification provides for testing of all critical quality attributes for
`the dosage form.
` assay for cations
`
`NDA 212690
`
`Page 5
`
`6/2/2020
`
`
`
`Reference ID: 4618674Reference ID: 4644439
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`

`

`request.
`
` added the test at the Agency’s
`
`
`
`, analytical methods for the product are similar to those for
`the drug substance. All noncompendial procedures are described and validated.
`The applicant performed a risk assessment for elemental impurities per ICH Q3D
`and provided data from development batches to justify exclusion of testing for
`elemental impurities from the specification.
`
`Based on the stability data provided, the expiration dating period requested by the
`applicant, i.e., 60 months for product stored at controlled room temperature, is
`granted.
`
`Labeling:
`
`Adequate
`
`The original oxybate, Xyrem was approved in 2002 with label potency based on the
`sodium salt content, i.e., 0.5 g/mL (equivalent to 0.413 g/mL oxybate). Approval of
`Xyrem occurred prior to implementation of the USP Salt Policy (SP); however, an
`exception would likely be granted due to the high sodium content if the product had
`been reviewed after implementation of the SP. The mixed salt product is considered
`a new active ingredient; thus, the SP applies. This was noted and discussed with
`the applicant during development. In the initial NDA submission, the applicant
`requested an exception based on the potential for medication errors. In discussions
`between ONDP and DMEPA it was determined that application of the SP (
`
` would result in the highest risk for
`medication errors. However, granting an exception to the SP and
`
` was also unacceptable due to potential
`medication errors. As an alternative, ONDP and DMEPA proposed expressing
`potency based on total salt content and including amounts of individual salts in
`Section 11 of the PI on the side panel of the container label. E.g., for container:
`
`Principle Display Panel
`
`TRADENAME
`(calcium, magnesium, potassium, and sodium oxybates) oral solution
`*0.5 g/mL total salts
`
`Side Panel
`
`*Each mL contains 0.5 g of total salts present as 0.234 g calcium oxybate, 0.096 g
`magnesium oxybate, 0.13 g potassium oxybate and 0.04 g sodium oxybate (equivalent to
`0.413 g total oxybate).
`
`The acceptability of this approach was confirmed with the Office of Policy for
`Pharmaceutical Quality and the changes will be incorporated into final labeling.
`
`Manufacturing: Adequate
`
`The drug product manufacturing process consists of
`
`
`
`
`
`NDA 212690
`
`Page 6
`
`6/2/2020
`
`
`
`Reference ID: 4618674Reference ID: 4644439
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`

`

` Exhibit batches manufactured at
`the proposed commercial facility, Jazz Pharmaceutical Ireland Limited (JPIL)
`Athlone, were produced at commercial scale. The manufacturing process and
`controls are deemed adequate given the simple formulation.
`
`All proposed commercial manufacturing and testing facilities are currently
`acceptable. It is noted that the Agency had not previously inspected the JPIL
`Athlone facility as a drug manufacturer and physical inspection was not possible due
`to the COVID-19 pandemic. Acceptability of the facility was determined based on
`review of an inspection report from the Irish Health Products and Regulatory
`Authority (HPRA) and documents requested from the applicant under 704(a)(4).
`
`Microbiology: Adequate
`
`The drug product is a nonsterile aqueous oral solution that will be diluted with water
`prior to use. The product does not contain antimicrobial agents; however, the
`formulation has inherent antimicrobial properties. The product specification includes
`microbial enumeration testing and absence of specified microorganisms appropriate
`per USP <1111> aqueous preparations for oral use. All microbiological tests for
`batch release and stability testing are deemed suitable for quality control.
`
`Environmental: Adequate
`
`The applicant claims a categorical exclusion under 21 CFR 25.31(b). Approval of
`the NDA will increase the use of the active moiety, but the estimated concentration
`of the substance at the point of entry into the aquatic environment will be below
`1 part per billion. The claim for categorical exclusion is granted.
`
`NDA 212690
`
`Page 7
`
`6/2/2020
`
`
`
`Reference ID: 4618674Reference ID: 4644439
`
`(b) (4)
`
`

`

`C. Risk Assessment
`
`Attribute/ CQA
`
`From Initial Risk Identification
`Fact ors that can impact
`the CQA
`
`Initial Risk
`Ranking
`
`Risk Mitigation Approach
`
`Review Assessment
`Final Risk
`Evaluation
`
`Comments
`
`Assay, stability
`
`Dosing accuracy
`
`Palatability
`
`Microbial limits
`
`x Formulation
`x Container Closure
`x Process Parameters
`
`x Dosing device
`x Raw materials
`x Formulation
`x Formulation
`x Raw Materials
`x Process Parameters
`
`x Formulation
`x Raw materials
`x Process parameters
`x Scale/Equipment/Site
`
`Leach ables
`
`x Formulation
`x Container Closure
`x Raw materials
`
`L
`
`L
`
`L
`
`M
`
`(b)(4)
`
`I
`
`Adequate
`
`Adequate
`
`Adequate
`
`Adequate
`
`I
`I
`
`Adequate
`I
`
`NOA 212690
`
`Reference ID: 464MZI
`
`Page 8
`
`61212020
`
`

`

`
`
`
`D. List of Deficiencies for Complete Response
`
`Not applicable
`
`
`
`
`
`Application Technical Lead Name and Date:
`
`Martha R. Heimann, Ph.D.
`CMC Lead
`Office of New Drug Products
`Division of New Drug Products II
`
`6/2/2020
`
`
`
`NDA 212690
`
`Page 9
`
`6/2/2020
`
`
`
`Reference ID: 4618674Reference ID: 4644439
`
`

`

`Martha
`Heimann
`
`Digitally signed by Martha Heimann
`Date: 6/03/2020 12:31:29AM
`GUID: 504f845f00000ed260627d268a8cdc9d
`
`
`
`Reference ID: 4618674Reference ID: 4644439
`
`42 Page(s) has been Withheld in Full as b4 (CCI/TS) immediately following this page
`
`

`

`~ U.S. FOOD & DRUG
`
`-
`
`ADMINISTRATION
`
`CHAPTER IV: LABELING
`IQA NOA Assessment Guide Reference
`
`1.0 PRESCRIBING INFORMATION
`
`Assessment of Product Quality Related Aspects of the Prescribing
`Information: The Pl and Medication Guide assessed in this review was
`submitted on April 4, 2020 and the bottle label was submitted on January
`21 , 2020. Based on the information provided, there are edits to be made to
`the labeling portion of this submission. A majority of these edits relate to
`the USP Salt Policy.
`
`1.1 HIGHLIGHTS OF PRESCRIBING INFORMATION
`Information Provided
`in the NOA
`
`Item
`
`Product Title in Hiahliahts
`Proprietary name
`Established name(s)
`
`TRADENAME™
`(calcium r--<bH4!,
`potassium
`r--<bJ (4I l 1
`magnesium
`r--<bH4!, sodium
`r -<6H4!) oral
`solution, Cll l
`Oral solution
`Route(s) of administration
`Dosage Forms and Strengths Heading in Highlights
`Summary of the dosage
`Oral solution, 0.5
`form(s) and strength(s)
`g per ml
`in metric system.
`
`Assessor's Comments
`
`Inadequate
`(calcium,
`magnesium,
`potassium, and
`sodium oxybates)
`oral solution
`
`Adequate
`
`Inadequate
`Revise to "0.5 g/ml
`total salts" and
`include equivalency
`statement
`NA
`
`NA
`
`NA
`
`NA
`
`Assess if the tablet is
`scored. If product meets
`guidelines and criteria for a
`scored tablet, state
`"functionally scored"
`For injectable drug
`products for parental
`administration, use
`appropriate package type
`term (e.g., single-dose,
`multiple-dose, single-
`patient-use). Other
`package terms include
`OPQ-XOPQ-TEM-0001 v06
`
`Reference ID: 464M ZI
`
`Page 1
`
`Effective Date: Febrnaiy 1, 2019
`
`

`

`pharmacy bulk package
`and imaging bulk package.
`
`Assessor's Comments
`
`Item
`
`1.2 FULL PRESCRIBING INFORMATION
`1.2.1 Section 2 (DOSAGE AND ADMINISTRATION)
`Information Provided
`in the NOA
`DOSAGE AND ADMINISTRATION section
`Special instructions for
`Prepare both doses of Adequate
`product preparation (e.g.,
`TRADENAME prior to
`reconstitution and resulting bedtime. Prior to
`concentration, dilution,
`ingestion, each dose of
`compatible diluents,
`TRADENAME should
`storage conditions needed be diluted with
`approximately v.i cup
`to maintain the stability of
`the reconstituted or diluted
`(approximately 60 ml)
`of water in the
`product)
`provided pharmacy
`containers.
`
`1.2.2 Section 3 (DOSAGE FORMS AND STRENGTHS)
`
`OPQ-XOPQ-TEM-0001 v06
`
`Page 2
`
`Effective Date: Febrnaiy 1, 2019
`
`Reference ID: 464MZI
`
`

`

`Item
`
`Information
`Provided
`in the NOA
`DOSAGE FORMS AND STRENGTHS section
`Available dosage form (s)
`TRADENAME is a
`clear to slightly
`Strength(s) in metric system
`opalescent oral
`If the active ingredient is a salt,
`apply the USP Salt Policy per FDA solution at a
`concentration of 0.5
`Guidance
`g per mL 1
`A description of the identifying
`Ml~~4
`characteristics of the dosage
`forms, including shape, color,
`coating, scoring, and imprinting
`
`(b) 4
`
`Assessor's Comments
`
`Inadequate
`Revise to say "at a total
`salt concentration of 0.5 g
`per ml. .. "
`
`(b)(4
`'iequivalent
`to 0.413 g/ml of
`oxvbate.
`NA
`
`NA
`
`NA
`
`NA
`
`Assess if the tablet is scored. If
`product meets guidelines and
`criteria for a scored tablet, state
`"functionally scored"
`For injectable drug products for
`parental administration, use
`appropriate labeling term (e.g.,
`single-dose, multiple-dose, single-
`patient-use). Other package type
`terms include pharmacy bulk
`package and imaging bulk
`package.
`
`1.2.3. Section 11 DESCRIPTION
`
`OPQ-XOPQ-TEM-0001 v06
`
`Page 3
`
`Effective Date: Febrnaiy 1, 2019
`
`Reference ID: 464MZI
`
`

`

`Item
`
`Information Provided
`in the NOA
`
`Assessor's Comments
`
`Inadequate
`Revise to include
`appearance (i.e.
`"TRADENAME oral solution
`is a clear to slightly opaque
`solution that contains ... . "
`
`DESCRIPTION section
`Proprietary and established TRADENAME oral
`name(s)
`solution contains
`Dosage form (s) and route(s) oxybate, a CNS
`depressant. The
`of administration
`chemical name of
`If the active ingredient is a
`oxybate is gamma-
`salt, apply the USP Salt
`hydroxybutyrate (GHB).
`Policy and include the
`equivalency statement per TRADENAME contains a
`mixture of calcium
`FDA Guidance.
`oxybate, potassium
`oxybate, magnesium
`oxybate, and sodium
`oxybate equivalent to 0.5
`g/ml, which corresponds
`to 0.413 g/ml oxybate.
`Each ml of
`TRADENAME contains:
`0.234 g calcium oxybate,
`Ca(C4H103)2; 0. 130 g
`potassium oxybate,
`K(C4H103); 0.096 g
`magnesium oxybate,
`Mg(C4H103)2; and 0.040
`g sodium oxybate,
`Na(C4H103) in
`dissociated form in the
`solution.
`The inactive ingredients Adequate
`List names of all inactive
`are sucralose and
`ingredients. Use USP/NF
`names. Avoid Brand names. purified water.
`For parenteral injectable
`NA
`dosage forms, include the
`name and quantities of all
`inactive ingredients. For
`ingredients added to adjust
`the pH or make isotonic,
`include the name and
`statement of effect.
`If alcohol is present, must
`provide the amount of
`alcohol in terms of percent
`volume of absolute alcohol
`
`NA
`
`NA
`
`NA
`
`OPQ-XOPQ-TEM-0001v06
`
`Page 4
`
`Effective Date: February 1, 2019
`
`Reference ID: 464MZI
`
`

`

`CNS depressant
`
`NA
`
`Adequate
`
`Statement of being sterile (if NA
`applicable)
`Pharmacological/
`therapeutic
`class
`Chemical name, structural
`formula, molecular weight
`
`The chemical structure
`Inadequate
`Revise to include molecular
`is:
`weights. Note, chemical
`c:i· ..
`0
`K'
`II
`names and formulas are
`Mg ..
`-0-C--CH, --Cfh--CH,--OH
`Na' - ,_
`~ rC:i•1I provided above.
`
`'
`
`);-=l f«N.\. •• uidK~~ ., =2 fotMi • .uidCa.:-
`
`If radioactive, statement of NA
`important nuclear
`characteristics.
`Other important chemical or None provided
`physical properties (such as
`pKa or pH)
`
`NA
`
`None provided
`
`Section 11 (DESCRIPTION) Continued
`Information Provided
`in the NOA
`TRADENAME contains Adequate
`no ingredient made from
`a gluten-containing grain
`(wheat, barley, or rye).
`NA
`
`Item
`
`For oral prescription drug
`products, include gluten
`statement if applicable
`
`Remove statements that
`may be misleading or
`promotional (e.g.,
`"synthesized and developed
`by Drug Company X,"
`"structurally unique
`molecular entity"
`
`Assessor's Comments
`
`NA
`
`1.2.3 Section 16 (HOW SUPPLIED/STORAGE AND HANDLING)
`
`OPQ-XOPQ-TEM-0001v06
`
`Page 5
`
`Effective Date: February 1, 2019
`
`Reference ID: 464MZI
`
`

`

`Item
`
`Assessor's Comments
`
`Information Provided
`in the NOA
`HOW SUPPLIED/STORAGE AND HANDLING section
`Available dosage form (s)
`TRAOENAME is a clear Adequate
`StrenQth(s) in metric system
`to slightly opalescent
`Available units (e.g., bottles oral solution. Each
`prescription includes
`of 100 tablets)
`one bottle of
`Identification of dosage
`TRAOENAME with
`forms, e.g., shape, color,
`coating, scoring, imprinting, attached press in bottle
`adaptor, an oral
`NOC number
`measuring device
`(plastic syringe), and a
`Medication Guide. The
`pharmacy provides two
`empty containers with
`child-resistant caps with
`each TRAOENAME
`shipment.
`Each amber bottle
`contains TRAOENAME
`oral solution at a
`concentration of 0.5
`g/ml and has a child-
`resistant cap.
`One 180 ml bottle NOC
`68727-150-01
`--- --- --- --- --- --- --- --- --- --- --- --- --- -
`Assess if the tablet is scored. NA
`If product meets guidelines
`and criteria for a scored
`tablet, state "functionally
`scored"
`--- --- --- --- --- --- --- --- --- --- --- --- --- -
`For injectable drug products NA
`for parental administration,
`use appropriate package
`type term (e.g., single-dose,
`multiple-dose, single-patient-
`use). Other package terms
`include pharmacy bulk
`package and imaging bulk
`packaQe.
`
`NA
`
`NA
`
`OPQ-XOPQ-TEM-0001v06
`
`Page 6
`
`Effective Date: February 1, 2019
`
`Reference ID: 464MZI
`
`

`

`Item
`
`Assessor's Comments
`
`Adequate
`
`NA
`
`NA
`
`Section 16 (HOW SUPPLIED/STORAGE AND HANDLING) (Continued)
`Information Provided
`in the NOA
`Dispense in tight
`Special handling about the
`containers.
`supplied product (e.g.,
`Solutions prepared
`protect from light,
`following dilution
`refrigerate). If there is a
`should be consumed
`statement to "Dispense in
`original container," provide within 24 hours.
`reason why (e.g. to protect
`from light or moisture, to
`maintain stability, etc.)
`If the product contains a
`desiccant, ensure the size
`and shape differ from the
`dosage form and desiccant
`has a warning such as "Do
`not eat."
`Storage conditions. Where
`applicable, use USP
`storage range rather than
`storage at a single
`temperature.
`
`TRADENAME should
`be stored between
`20°-25°C (68°-77°F};
`excursions permitted
`between 15°and 30°C
`(59°and 86°F} (see
`USP Controlled Room
`Temperature).
`NA
`
`Inadequate
`Replace "-" with "to" to avoid
`confusion with minus sign
`
`NA
`
`Adequate
`
`The pharmacy
`provides two empty
`containers with child-
`resistant caps with
`each TRADENAME
`shipment.
`
`Latex: If product does not
`contain latex and
`manufacturing of product
`and container did not
`include use of natural
`rubber latex or synthetic
`derivatives of natural rubber
`latex, state: "Not made with
`natural rubber latex. Avoid
`statements such as "latex-
`free."
`Include information about
`child-resistant packaging
`
`OPQ-XOPQ-TEM-0001v06
`
`Page 7
`
`Effective Date: February 1, 2019
`
`Reference ID: 464MZI
`
`

`

`1.2.4 Other Sections of Labeling
`There may be other sections of labeling that contain product-quality related
`information. For example, there are specific required/recommended warnings
`for certain inactive ingredients [e.g., aspartame, aluminum in large and small
`volume parenterals, sulfites, FD&C Yellow Number 5 (tartrazine), and benzyl
`alcohol]. Please notify the prescription drug division if the product contains any
`of these inactive ingredients.
`
`Please include your comments about other sections of labeling if they contain
`product quality information.
`
`Item
`
`1.2.5 Manufacturina Information After Section 17 (for drua oroducts)
`Information Provided
`in the NOA
`Manufacturing Information After Section 17
`Name and location of
`Jazz Pharmaceuticals, Adequate
`business (street address,
`Inc.
`city, state and zip code) of
`Palo Alto, CA 94304
`the manufacturer, distributor,
`and/or packer
`
`Assessor's Comments
`
`2.0 PATIENT LABELING
`
`Assessment of Product Quality Related Aspects of Patient Labeling (e.g.,
`Medication Guide, Patient Information, Instructions for Use): The information
`provided for patient labeling appears acceptable.
`
`3.0 STRUCTURED PRODUCT LABELING (SPL)
`TRAD EN AMI
`(«>kiwn (b) (4)poe • .,iuru (b) (4)nugnwum (b) (4)>odium
`
`Prodt1cl ll.fonn1t1ou
`
`HUMAN PRESCRIPTION DRUG
`
`ORAL
`
`Jt.,.C11d11(Su•rnt)
`
`D£ASdlMuJt
`
`NDC:6S727·1 SO
`cm
`
`Actn-e IogrtdttaflActtn Moiety
`
`la1~M:.tNaat
`SODltlM OXYB-' TE ( I.nm: iG3301?Sl4) (J..lfl'D~O}.."\'BtitANOtC ACID . U~'1l:Ml£\Vl6iVSB2)
`Cakfel O:Q'll:Ue{UNll: 3W2-4S)'D6Zl) (4·H)'DR.OXY&;l.o\l.'\\OlC.-\CID • li':\1I:30lW36W5B2)
`POCIS$fnnt ~blfe (li}.ll: S3NKFJK}KT)(ll·HYDROXY81JfANOlC ACCO· 1..'}.''IMOJ\\'36\\1582')
`M•pt:iju.n Oxylnt~ (UNIJ G9S3HL V~ S)(.f-.·HYDROX\'BUTANOIC ACJD • UNU:3QfW'J6W'SB2)
`
`BuUolStftllph
`
`SODMJOXY8ATE
`Calcium OX}~~
`
`Pow;.ront~e
`M'$fl01UIU ~i!ue
`
`Senoa•.h
`O.Sg inlml
`O.Sg inl CIL
`05 t inlatl..
`O.Sa inllt!.L
`
`Packlg!Dg
`
`I NDC:~ST.?H !i0-01
`
`Paeba• Douripfltu•
`UOllll. 1.:3 I BOTTLE, PLASTIC: ty~o. NCt 'l COm~ll3tOO ProlJut(
`
`ll:u·bti•a St:irt Dafci
`(D)
`I I (' hoio
`
`Muktllug lulormatloo
`
`NDA212690
`
`~ Ja.rk111iafS11M1Dat•
`
`)I =~?<JlO
`
`Effective Date: February 1, 2019
`Page 8
`OPQ-XOPQ-TEM-0001v06
`2 Page(s) of Draft [ at5eling tiave 15een Wittitiela in Full as !'A (CCI/TS) immeaiately following ttiis page
`
`Reference ID: 464MZI
`
`

`

`(b)(-41
`
`Assessment of Carton and Container Labeling: Adequate
`The carton and container labeling is adequate, pending the Applicant's acceptance of
`the revisions noted above in red .
`
`ITEMS FOR ADDITIONAL ASSESSMENT
`Adequate. The Structured Product Labeling does not include excipients and the UNll
`codes. This is a minor edit and will be addressed later in labeling discussions.
`Pending the Applicant's acceptance of the revisions noted above in red and the
`Structured Product Labeling comment, the labeling information is adequate.
`
`OPQ-XOPQ-TEM-0001v06
`
`Page 11
`
`Effective Date: February 1, 2019
`
`Reference ID: 464MZI
`
`

`

`Overall Assessment and Recommendation:
`This application is recommended for approval per labeling/labels perspective once
`the following changes have been made to the label.
`
`OPQ-XOPQ-TEM-0001v06
`
`Page 12
`
`Effective Date: February 1, 2019
`
`Reference ID: 464MZI
`
`

`

`Grace
`Chiou
`
`Julia
`Pinto
`
`Digitally signed by Grace Chiou
`Date: 5/19/2020 05:27:46PM
`GUID: 5c5df155002b1863abe42e6c00c2780f
`
`Digitally signed by Julia Pinto
`Date: 5/19/2020 05:32:34PM
`GUID: 5050dbcb00001294a888a4bdc20a3a58
`
`
`
`Reference ID: 4618674Reference ID: 4644439
`
`

`

`~ U.S. FOOD & DRUG
`
`-
`
`ADMINISTRATION
`
`CHAPTER VII: MICROBIOLOGY
`
`Product Information
`
`NOA Number
`Assessment Cycle Number
`Drug Product Name I Strength
`
`Route of Administration
`Applicant Name
`
`Manufacturing Site
`
`Method of Sterilization
`
`XYWAV® is indicated for treatment of
`cataplexy or excessive daytime
`sleepiness (EDS) in patients 7 years of
`aae and older with narcolepsv.
`212690
`01
`XYWAV® (Calcium oxybate, potassium
`oxybate, magnesium oxybate, sodium
`oxvbate) Oral solution 0.5 Q/ ml
`Oral solution
`Jazz Pharmaceuticals Ireland Limited
`Fifth Floor, Waterloo Exchange, Dublin,
`Ireland D04E5W7
`Jazz Pharmaceuticals Ireland Limited
`Monksland, Athlone, Roscommon
`Ireland N37 AX84
`Not applicable (Non-sterile)
`
`Assessment Recommendation: Adequate
`
`Theme:
`
`181 N/A
`
`D Product Sterility Assurance
`
`D Media Fill Data
`
`D Validation of Product Test
`D Due to Consult
`
`D Depyrogenation Validation Data
`D Product Release and/or Stability
`Specifications
`D Validation for Product Release and/or
`Stability Test Method
`D Other (Requires Division Director
`Approval)
`
`Justification: N/A
`Assessment Summary: Bulk solution is prepared by
`
`(b)(4J
`
`Drug product is filled into 6 oz round amber two-piece
`- - - - - - - - - - - .<bH4f bottle with a
`<5><41child resistant!
`<b><4J closure with
`<b><4J press-in-bottle-adapter (PIBA).
`
`List Submissions Being Assessed (table):
`
`OPQ-XOPQ-TEM-0002v01
`
`Page 1
`
`Effective Date: February 1, 2019
`
`Reference ID: 464MZI
`
`

`

`~ U.S. FOOD & DRUG
`
`-
`
`ADMINISTRATION
`
`Document(s) Assessed
`0001
`0010
`
`Date Received
`01/21/2020
`04/24/2020
`
`Highlight Key Issues from Last Cycle and Their Resolution: None
`
`Remarks: This is an eCTD submission. IR was conveyed to the applicant on
`4/ 10/2020. Response received on 4/24/2020 was incorporated in the review.
`
`Concise Description of Outstanding Issues (List bullet points with key
`information and update as needed): None
`
`Supporting Documents: None
`
`Select Number of Approved Comparability Protocols: O
`
`S DRUG SUBSTANCE
`Assessment: Not applicable
`
`P.1 DESCRIPTION OF THE COMPOSITION OF THE DRUG PRODUCT
`
`Description of drug product- XYWAV® (Calcium oxybate, potassium oxybate,
`magnesium oxybate, sodium oxybate) 0.5 g/ ml is a non-sterile aqueous oral
`solution.
`
`Amount per g I Amount % J
`
`w/w
`
`(b)(4 )
`
`Drug product composition- XYWAV®0.5 g/ ml oral solution:
`Quality
`Pharmaceutical
`function
`standard
`Active ingredient
`In-house
`
`Component
`
`solution
`
`JZP-258 Drug substance•
`Sucralose
`Purified Waterl<bf<4J
`. .
`*Drug substance 1s an aqueous solution containing 0.5 g/ ml mixed oxybate salts
`
`(b)(4)
`
`Description of container closure system: 6 oz round amber two-piece
`(bn4 · bottle with a
`<bH4Ichild resistant/
`:::::===~<b>~<4:-I c':":l:-:-o":'"su'."".".r::e""".'w~ith::==<~bJ<4r a press-in-bottle-adapter (PISA).
`
`Assessment: {Adequate}
`The applicant provided an adequate description of the drug product
`composition and the container closure system designed to maintain product
`microbiological quality.
`
`P.2 PHARMACEUTICAL DEVELOPMENT
`
`38 Page(s) has been Withheld in Full as b4 (CCI/TS) immediately following this page
`
`OPQ-XOPQ-TEM-0002v01
`
`Page 2
`
`Effective Date: February 1, 2019
`
`Reference ID: 464MZI
`
`

`

`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/
`------------------------------------------------------------
`
`MARTHA R HEIMANN
`06/03/2020 10:17:50 AM
`
`
`
`Reference ID: 4618674Reference ID: 4644439
`
`