CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`APPLICATION NUMBER:
`
`212535Orig1s000
`
`
`
`
`MULTI-DISCIPLINE REVIEW
`Summary Review
`Office Director
`Cross Discipline Team Leader Review
`Clinical Review
`Non-Clinical Review
`Statistical Review
`Clinical Pharmacology Review
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`

`

`NDA/BLA Multi-disciplinary Review and Evaluation for NDA 212535 Nouress (cysteine
`hydrochloride)
`
`NDA/BLA Multi-Disciplinary Review and Evaluation
`Application Type NDA
`Application Number(s) 212535
`Priority or Standard Priority
`Submit Date(s) 3/15/2019
`Received Date(s) 3/15/2019
`Filing and Priority Review 5/13/2019
`Extension Letter 7/31/2019
`PDUFA Goal Date 9/15/2019 (original); 12/15/2019 (new date after extension)
`Division/Office Division of Gastroenterology and Inborn Errors Products
`(DGIEP)
`Review Completion Date 12/13/2019
`Established/Proper Name Cysteine Hydrochloride
`(Proposed) Trade Name Nouress
`Pharmacologic Class Sulfur-containing amino acid
`Applicant Avadel Legacy Pharmaceuticals LLC
`Dosage form
`Injection
`Applicant proposed Dosing Regimen 50 mg/mL
`Applicant Proposed
`Use as an additive to amino acid (AA) solutions to meet the
`Indication(s)/Population(s)
`nutritional requirements of neonates requiring total parental
`nutrition (TPN)
`Approval
`
`Recommendation on Regulatory
`Action
`Recommended
`Use as an additive to AA solutions to meet nutritional
`Indication(s)/Population(s) (if
`requirements of neonates (preterm and term infants less than
`applicable)
`one month of age) requiring total parenteral nutrition
`Recommended Dosing Regimen 50 mg/mL
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`NDA/BLA Multi-disciplinary Review and Evaluation for NDA 212535 Nouress (cysteine
`hydrochloride)
`Table of Contents
`
`Table of Tables ................................................................................................................................ 5
`Table of Figures ............................................................................................................................... 6
`Reviewers of Multi-Disciplinary Review and Evaluation ................................................................ 7
`Glossary ........................................................................................................................................... 9
`1. Executive Summary ................................................................................................................... 10
`1.1. Product Introduction ......................................................................................................... 10
`1.2. Conclusions on the Substantial Evidence of Effectiveness ................................................ 10
`1.3. Benefit-Risk Assessment .................................................................................................... 11
`1.4. Patient Experience Data .................................................................................................... 14
`2. Therapeutic Context ................................................................................................................. 14
`2.1. Analysis of Condition ......................................................................................................... 14
`2.2. Analysis of Current Treatment Options ............................................................................. 16
`3. Regulatory Background ............................................................................................................. 18
`3.1. U.S. Regulatory Actions and Marketing History ................................................................ 18
`3.2. Summary of Presubmission/Submission Regulatory Activity ............................................ 20
`4. Significant Issues from Other Review Disciplines Pertinent to Clinical Conclusions on Efficacy
`and Safety .............................................................................................................................. 21
`4.1. Office of Scientific Investigations (OSI) .............................................................................. 21
`4.2. Product Quality .................................................................................................................. 22
`4.2.1. Drug Substance ....................................................................................................... 22
`4.2.2. Summary and Recommendation ............................................................................ 23
`4.3. Clinical Microbiology .......................................................................................................... 24
`4.4. Devices and Companion Diagnostic Issues ........................................................................ 24
`4.5. Biopharmaceutics .............................................................................................................. 24
`5. Nonclinical Pharmacology/Toxicology ...................................................................................... 24
`5.1. Executive Summary ............................................................................................................ 24
`5.2. Referenced NDAs, BLAs, DMFs .......................................................................................... 24
`5.3. Pharmacology .................................................................................................................... 25
`5.4. ADME/PK ............................................................................................................................ 25
`5.5. Toxicology .......................................................................................................................... 25
`5.5.1. General Toxicology .................................................................................................. 25
`5.5.2. Genetic Toxicology .................................................................................................. 25
`5.5.3. Carcinogenicity ........................................................................................................ 25
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`NDA/BLA Multi-disciplinary Review and Evaluation for NDA 212535 Nouress (cysteine
`hydrochloride)
`5.5.4. Reproductive and Developmental Toxicology ........................................................ 25
`6. Clinical Pharmacology ............................................................................................................... 25
`6.1. Executive Summary ............................................................................................................ 25
`6.1.1. Recommendations .................................................................................................. 26
`6.2. General Dosing and Therapeutic Individualization ............................................................ 26
`6.2.1. General Dosing ........................................................................................................ 26
`6.2.2. Therapeutic Individualization ................................................................................. 26
`6.3. Summary of Clinical Pharmacology Assessment ............................................................... 26
`6.3.1. General Pharmacology and Pharmacokinetic Characteristics ................................ 26
`6.3.2. Clinical Pharmacology Questions ............................................................................ 27
`7. Sources of Clinical Data and Review Strategy ........................................................................... 27
`7.1. Table of Clinical Studies ..................................................................................................... 27
`7.2. Review Strategy ................................................................................................................. 27
`8. Statistical and Clinical and Evaluation ...................................................................................... 28
`8.1. Review of Evidence Used to Support Efficacy ................................................................... 28
`8.1.1. Listed Drug .............................................................................................................. 28
`8.1.2. Published Literature ................................................................................................ 29
`8.1.3. Assessment of Efficacy Across Trials ....................................................................... 33
`8.1.4. Assessment of Efficacy Across Trials ....................................................................... 33
`8.1.5. Integrated Assessment of Effectiveness ................................................................. 33
`8.2. Review of Safety ................................................................................................................ 34
`8.2.1. Safety Review Approach ......................................................................................... 34
`8.2.2. Review of the Safety Database ............................................................................... 34
`8.2.3. Adequacy of Applicant’s Clinical Safety Assessments ............................................ 36
`8.2.4. Safety Results .......................................................................................................... 36
`8.2.5. Analysis of Submission-Specific Safety Issues......................................................... 37
`8.2.6. Clinical Outcome Assessment Analyses Informing Safety/Tolerability .................. 38
`8.2.7. Safety Analyses by Demographic Subgroups .......................................................... 38
`8.2.8. Specific Safety Studies/Clinical Trials ...................................................................... 38
`8.2.9. Additional Safety Explorations ................................................................................ 38
`8.2.10. Safety in the Postmarket Setting .......................................................................... 39
`8.2.11. Integrated Assessment of Safety .......................................................................... 39
`8.3. Statistical Issues ................................................................................................................. 40
`8.4. Conclusions and Recommendations .................................................................................. 40
`9. Advisory Committee Meeting and Other External Consultations ............................................ 40
`10. Pediatrics ................................................................................................................................. 41
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`NDA/BLA Multi-disciplinary Review and Evaluation for NDA 212535 Nouress (cysteine
`hydrochloride)
`11. Labeling Recommendations .................................................................................................... 42
`11.1. Prescription Drug Labeling ............................................................................................... 42
`12. Risk Evaluation and Mitigation Strategies (REMS) ................................................................. 44
`13. Postmarketing Requirements and Commitment .................................................................... 44
`14. Division Director Comments ................................................................................................... 44
`15. Appendices .............................................................................................................................. 45
`15.1. References ....................................................................................................................... 45
`15.2. Financial Disclosure ......................................................................................................... 47
`15.3. Nonclinical Pharmacology/Toxicology ............................................................................. 47
`15.4. OCP Appendices (Technical documents supporting OCP recommendations) ................ 60
`15.5. Additional Clinical Outcome Assessment Analyses ......................................................... 60
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`NDA/BLA Multi-disciplinary Review and Evaluation for NDA 212535 Nouress (cysteine
`hydrochloride)
`Table of Tables
`
`Table 1. Approved Amino Acid Products ...................................................................................... 17
`Table 2. Currently Available Approved Cysteine Products ........................................................... 18
`Table 3. Recommended Daily Dosage of Nouress in Neonates (Preterm and Term Infants Less
`Than One Month of Age) .............................................................................................................. 26
`Table 4. Effect of Cysteine Supplementation on Plasma Levels of Cysteine and Taurine ............ 31
`Table 5. Effect of Cysteine Supplementation on Plasma Levels of Taurine and Cystine .............. 31
`Table 6. Effect of Cysteine Supplementation on Glutathione Levels ........................................... 32
`Table 7. Effect of Cysteine Supplementation on Nitrogen Balance ............................................. 33
`Table 8. Effect of Cysteine Supplementation on Growth ............................................................. 33
`Table 9. Summary of Discussions With the Experts...................................................................... 41
`Table 10. Acceptance Criteria for Impurities in Drug Product ...................................................... 47
`Table 11. Maximum Daily Dose of Cysteine•HCl•H2O for Term Infants Less Than 1 Month of Age
`....................................................................................................................................................... 48
`Table 12. Experimental Design for Extractables Study (522-EXR-B) ............................................. 51
`Table 13. Summary of Extractable Elements1 From the Vial and Stopper Samples ..................... 52
`Table 14. GC/MS Results From the Headspace Analysis of the Stopper (Study Report 158-EXR) 52
`Table 15. Samples Evaluated for Leachables ................................................................................ 53
`Table 16. GC/MS DI Spike Recovery and Estimated Detection Limit of Targeted Analytes ......... 54
`Table 17. Additional Samples Evaluated for Leachables .............................................................. 55
`Table 18. GC/MS HS Spike Recovery and % RSD of Spiked Matrix Blank Injections .................... 56
`Table 19. Elements1 Detected in the Packaged Drug Product ...................................................... 57
`Table 20. Summary of Elemental Impurities1 Detected in Drug Product Stored at Different
`Times, Temperatures, and/or Positions (Upright or Inverted) ..................................................... 58
`Table 21. Levels of
` From Five Lots of Drug Product ....................................................... 59
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`NDA/BLA Multi-disciplinary Review and Evaluation for NDA 212535 Nouress (cysteine
`hydrochloride)
`Table of Figures
`
` Amino Acids ................................................................................ 15
`Figure 1. Metabolism of
`Figure 2. Major Pathways of Cysteine Metabolism in Mammals ................................................. 30
`Figure 3. Marketed Unapproved (
`) and Approved (Exela Pharma) Usage Data From
`Jan. 2018-Aug. 2019 ...................................................................................................................... 35
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`(b) (4)
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`(b) (4)
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`NDA/BLA Multi-disciplinary Review and Evaluation for NDA 212535 Nouress (cysteine
`hydrochloride)
`Reviewers of Multi-Disciplinary Review and Evaluation
`
`Thao Vu, R.Ph.
`Fresnida Ramos, Ph.D.
`David Joseph, Ph.D.
`Xiaohui (Michelle) Li, Ph.D.
`
`Jie (Jack) Wang, Ph.D
`
`Yao-Yao Zhu, M.D., Ph.D
`Suna Seo, M.D.
`NA
`NA
`Joette Meyer, Pharm.D.
`Suna Seo, M.D.
`Lisa Soule, M.D.
`
`Regulatory Project Manager
`Nonclinical Reviewer
`Nonclinical Team Leader
`Office of Clinical Pharmacology
`Reviewer(s)
`Office of Clinical Pharmacology Team
`Leader(s)
`Clinical Reviewer
`Clinical Team Leader
`Statistical Reviewer
`Statistical Team Leader
`Associate Director of Labeling
`Cross-Disciplinary Team Leader
`Office Director (or designated signatory
`authority)
`
`Additional Reviewers of Application
`OPQ
`ATL:
`RBPM:
`DP:
`
`DS:
`
`Process/Facility:
`
`Biopharm:
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`Micro:
`
`Hitesh Shroff, Ph.D.
`Oumou Barry, Pharm.D.
`Hong Cai, Ph.D.
`Moo Jhong Rhee, Ph.D.
`Lawrence Perez, Ph.D.
`Donna Christner, Ph.D.
`Qin Liang, Ph.D.
`Tianhong Tim Zhou, Ph.D.
`Vincent Li, Ph.D
`Tapash Ghosh, Ph.D
`Dupeh Palmer, Ph.D.
`Marla Stevens-Riley, Ph.D.
`Julieann Dubeau, M.S.N, R.N.
`Richard Ishihara, Pharm.D.
`Meeta Patel, Pharm.D.
`Alvis Dunson, M.S.
`Aleksander Winiarski, Pharm.D., R.Ph.
`Joel Weissfeld, M.D.
`Patricia Bright, Ph.D.
`Sandhu, Sukhminder, Ph.D., M.P.H., M.S.
`Sherly Abraham, R.Ph.
`Idalia Rychlik, R.Ph.
`Jamie Klucken, Pharm.D., BCPS, BCACP
`Lisa Harinstein, Pharm.D., BCOP
`CDR Monica Muñoz, Pharm.D., Ph.D., B.C.P.S.
`
`Regulatory Policy Advisor
`
`OPDP
`OSE SRPM
`OSE SRPM Team Leader
`OSE/DEPI
`
`OSE/DMEPA
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`OSE/DPV
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`NDA/BLA Multi-disciplinary Review and Evaluation for NDA 212535 Nouress (cysteine
`hydrochloride)
`DPMH RPM
`DPMH RPM Team Leader
`DPMH/Pediatrics
`
`DPMH/Maternal
`
`Denise Johnson Lyles
`George Greeley, M.S., M.B.A.
`Carolyn Yancey, M.D.
`Hari Cheryl Sachs, M.D.
`Carrie Caresa, M.D.
`Miriam Dinatale, M.D.
`
`OPQ=Office of Pharmaceutical Quality
`OPDP=Office of Prescription Drug Promotion
`OSE=Office of Surveillance and Epidemiology
`SRPM=Safety Regulatory Project Manager
`DEPI=Division of Epidemiology
`DMEPA=Division of Medication Error Prevention and Analysis
`DPV=Division of Pharmacovigilance
`DPMH=Division of Pediatric and Maternal Health
`RPM=Regulatory Project Manager
`PBPM=Regulatory Business Project Manager
`ATL=Application Technical Lead
`DP=Drug Product
`DS=Drug Substance
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`NDA/BLA Multi-disciplinary Review and Evaluation for NDA 212535 Nouress (cysteine
`hydrochloride)
`Glossary
`
`
`AA
`ADME
`AE
`
`AET
`
`ANDA
`BLA
`
`CFR
`
`cys
`
`DGIEP
`DMF
`
`ECG
`
`FAERS
`FDA
`
`GC/MS DI
`ICH
`
`HS
`
`ICP-MS
`IND
`
`LC/DAD/MS
`LD
`
`LOQ
`
`NDA
`
`NDC
`
`NMT
`
`OPQ
`
`OSE
`
`OSI
`
`PDE
`
`PK
`
`PN
`
`PLR
`
`PREA
`
`REMS
`RRT
`
`RSD
`
`TDI
`
`TPN
`
`TTC
`
`USP
`
`WRO
`
`
`amino acid
`absorption, distribution, metabolism, excretion
`adverse event
`analytical evaluation threshold
`abbreviated new drug application
`biologics license application
`Code of Federal Regulations
`cysteine
`Division of Gastroenterology and Inborn Errors Products
`drug master file
`electrocardiogram
`FDA Adverse Event Reporting System
`Food and Drug Administration
`Gas Chromatography/Mass Spectrometry Direct Injection
`International Council on Harmonization
`Headspace
`Inductively Coupled Plasma / Mass Spectrometry
`Investigational New Drug
`Liquid Chromatography/Diode Array Detector/Mass Spectrometry
`listed drug
`limits of quantitation
`new drug application
`national drug code
`not more than
`Office of Pharmaceutical Quality
`Office of Surveillance and Epidemiology
`Office of Scientific Investigation
`permitted daily exposure
`pharmacokinetics
`parenteral nutrition
`Physician Labeling Rule
`Pediatric Research Equity Act
`risk evaluation and mitigation strategy
`relative retention time
`relative standard deviation
`total daily intake
`total parenteral nutrition
`threshold for toxicological concern
`United States Phamacopeia
`Written Response Only
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`NDA/BLA Multi-disciplinary Review and Evaluation for NDA 212535 Nouress (cysteine
`hydrochloride)
`1. Executive Summary
`
`1.1. Product Introduction
`Nouress (cysteine hydrochloride injection) is a sulfur-containing amino acid (AA) supplement
`administered through parenteral nutrition. The Applicant’s proposed indication is used as an
`additive to AA solutions to meet the nutritional requirements of neonates (preterm and term
`Infants less than one month of age) requiring total parental nutrition (TPN). The recommended
`dose for Nouress is 22 mg/gram AAs, providing 15 mg of cysteine/gram AAs. The corresponding
`volume is 0.44 mL Nouress/g AAs.
`
`During the review cycle for Nouress, on April 16, 2019, Elcys™ (cysteine hydrochloride injection)
`was approved for use to meet the nutritional requirements of newborn infants requiring TPN;
`and of adult and pediatric patients with severe liver disease who may have impaired enzymatic
`processes and require TPN. Elcys is currently the only approved cysteine product on the market.
`
`
`1.2. Conclusions on the Substantial Evidence of Effectiveness
`As a 505(b)(2) application, the efficacy of Nouress is established through reliance on the
`effectiveness of the listed drug (LD), 7.25% Cysteine Hydrochloride (NDA 019523, held by
`Hospira, Inc.). At this time, there are insufficient direct data and information to fully support
`the proposed indication of “meeting the nutritional requirements…”. Although the essential
`need for cysteine in select populations of patients who require parenteral nutrition (PN) has
`been widely accepted as reflected by clinical practice guidelines and the current market
`demand, the specific evidentiary support for the nutritional requirement of cysteine in the
`Applicant’s proposed target population, as demonstrated by subsequent clinical benefit relating
`to “how a patient feels, functions, and survives” is inadequate to support a complete
`assessment of Nouress’ ability to meet “nutritional requirements.” This is due to a lack of
`knowledge regarding the exact daily nutritional requirement for cysteine, which contributes to
`inadequate information on optimal dosing, as well as an absence of high-quality randomized
`controlled trials in the published literature to provide evidence of effectiveness for cysteine in
`promoting growth, impacting a patient’s clinical course, or providing additional clinical benefit.
`
`Despite these limitations, generally accepted scientific knowledge, (i.e., “AAs are building blocks
`of protein synthesis,” “supply of AAs promotes growth,” and “parenteral nutrition that provides
`a full profile of AAs is optimal”), together with the historical approval and subsequent safety
`and efficacy determinations of the LD for this 505(b)(2) application and the evidence available
`from current widespread clinical use of cysteine support a finding of substantial evidence of
`effectiveness for Nouress for the recommended indication as source of cysteine.
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`NDA/BLA Multi-disciplinary Review and Evaluation for NDA 212535 Nouress (cysteine hydrochloride)
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`1.3. Benefit-Risk Assessment
`Benefit-Risk Summary and Assessment
`
`The NDA for the proposed product relies upon the Agency’s findings of safety and efficacy for 7.25% Cysteine Hydrochloride, initially
`approved in 1986. Of note, although the listed drug (LD) has been withdrawn from the market, it was determined not to have been
`withdrawn due to reasons of efficacy or safety (see Section 3.1).
`
`Cysteine Hydrochloride 5% carries a comparable benefit-risk potential to 7.25% Cysteine Hydrochloride. Parenterally-administered
`cysteine products are effective sources of the conditionally essential amino acid (AA) cysteine, as evidenced by the increased plasma
`cysteine and taurine concentration following supplementation with these products. A meta-analysis of small published trials
`demonstrated that cysteine supplementation led to a positive nitrogen balance; however, no significant effect on growth in
`neonates was reported with the administration of parenteral cysteine products. In clinical practice, addition of cysteine to the total
`parenteral nutrition (TPN) causes acidification of the admixture, which improves calcium and phosphate solubility, thereby
`enhancing delivery of these important nutritional components.
`
`No new safety data were submitted in this application using the proposed drug product, and no new safety signals were identified
`upon review of the postmarket data of the previously available marketed unapproved formulations. Absence of any major
`identifiable safety signal within the published literature and the FDA Adverse Event Reporting System (FAERS) database gives
`reasonable reassurance of the overall safety of cysteine hydrochloride. As cysteine is a naturally-occurring AA that can be
`endogenously synthesized from methionine, the product is anticipated to be well-tolerated. In general, risks of Nouress appear
`consistent with the known risks of other AA solutions; however, the risk of metabolic acidosis in preterm infants may be increased
`specifically with cysteine administration. This risk is likely to be mitigated by the expected usage of this product by providers with
`expertise in managing TPN, including titration of cysteine (and other small volume parenterals) in the context of individual patients’
`requirements and tolerance.
`
`Discrepancies and variabilities in the dosing exist between the original approved dose for the LD and the current clinical practice
`guidelines; however, there are insufficient data to warrant a modification to the proposed dose recommendation of 15 mg
`cysteine/g of AA to an alternate higher dose (i.e., 20 mg, 30 mg or 40 mg/g) at this time.
`
`In summary, Nouress represents a medically necessary product. Based on the comparability of the proposed product to the LD,
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`NDA/BLA Multi-disciplinary Review and Evaluation for NDA 212535 Nouress (cysteine hydrochloride)
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`scientific understanding of protein and AA metabolism, which supports the conditional essentiality of cysteine, the benefits of the
`proposed product outweigh the risks. Cysteine hydrochloride products have been on the national drug shortage list in the past.
`Approval of an additional cysteine hydrochloride product will ensure quality and availability. Therefore, the overall benefit/risk
`assessment is favorable and the approval of Nouress for the proposed indication is recommended.
`Dimension
`Evidence and Uncertainties
`Conclusions and Reasons
`Cysteine is used in vivo as a building block in the biosynthesis of various
`There is an unmet need for an intravenous
`proteins necessary for growth and development.
`source of cysteine for TPN-dependent patients
`such as preterm and term neonates, in whom
`In addition, as a precursor for both glutathione and taurine, cysteine is
`cysteine is a conditionally essential AA due to
`thought to be necessary for formation of natural antioxidants and soluble
`immature or impaired liver function.
`biliary salts, respectively.
`
`In adults, cysteine is synthesized de novo from ingested methionine via
`cystathionase enzyme in the trans-sulfuration pathway and is considered
`non-essential. However, in preterm and term infants, the cystathionase
`activity does not reach mature levels until about 3 months of age. This
`pathway is also impaired in adults with liver insufficiency.
`Cysteine reduces the pH of TPN mixtures and increases the solubility of
`calcium and phosphate, thereby decreasing precipitation and enhancing
`availability.
`Published clinical practice guidelines by both American and European
`parenteral nutrition societies recommend routine cysteine supplementation
`for neonates.
`Commercially available AA formulations do not contain an appreciable
`amount of cysteine hydrochloride. In premixed solutions of crystalline AAs,
`cysteine is relatively unstable over time, eventually converting to insoluble
`cystine. To limit precipitation and provide usable cysteine, doses of cysteine
`hydrochloride products are commonly admixed into parenteral nutrition on
`the day of administration. There has been a reported drug shortage of L-
`cysteine from January 9, 2015 to April 16, 2019.
`There is one approved product, Elcys (NDA 210660; approved 2019).
`Plasma cysteine concentrations have been shown to increase with cysteine
`supplementation.
`
`Cysteine hydrochloride products are critical to
`public supply and patient needs.
`Approved injectable cysteine hydrochloride
`products provide assurance of product quality
`and availability.
`
`Parenterally administered cysteine products
`are effective sources of this conditionally
`essential AA, evidenced by the increased
`
`Analysis of
`Condition
`
`Current
`Treatment
`Options
`
`Benefit
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`NDA/BLA Multi-disciplinary Review and Evaluation for NDA 212535 Nouress (cysteine hydrochloride)
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`Dimension
`
`Risk and Risk
`Management
`
`Evidence and Uncertainties
`Plasma taurine concentrations have been shown to increase or normalize
`after cysteine supplementation in studies of older pediatric patients.
`The 2006 Cochrane review meta-analysis of the available data from four
`randomized controlled trials concluded that cysteine supplementation
`significantly increased nitrogen retention. Growth was not significantly
`affected by cysteine supplementation in the meta-analysis; this is likely due
`to the limitations of the trial design.
`Clinical uses of cysteine supplementation in TPN also include acidification of
`the admixture to improve calcium and phosphate solubility.
`No new safety data were submitted using the proposed drug product.
`No new safety signals were identified upon review of the postmarket data
`with comparable marketed unapproved formulations of cysteine.
`The major known safety concerns with Nouress are vein damage and
`thrombosis, increased blood urea nitrogen, acid-base imbalance (e.g.,
`metabolic acidosis), hepatobiliary disorders, hyperammonemia, and
`aluminum toxicity.
`Nouress is intended to be prescribed by physicians as a component of the
`daily TPN prescription, prepared by dedicated TPN pharmacies, and
`administered intravenously as part of an admixture solution by trained
`nursing staff.
`Typical prescribers, i.e., neonatologists, intensivists, etc., are well-versed in
`the identification and management of the toxicities associated with
`parenteral nutrition administration.
`
`Conclusions and Reasons
`plasma cysteine and taurine concentration
`following cysteine supplementation.
`The impact of the addition of cysteine to affect
`calcium and phosphate delivery to premature
`infants who require TPN is beneficial, as
`calcium and phosphate availability may be
`limited due to incompatibility with the
`components of TPN solutions.
`
`The overall safety profile of Nouress as a
`source of intravenous cysteine is acceptable.
`In general, risks of Nouress appear consistent
`with the known risks of AA solutions, albeit
`certain potentially serious risks may be
`potentiated, including metabolic acidosis.
`In clinical practice, Nouress will be used by
`providers experienced with the potential risks
`of administration in a setting where those risks
`can be adequately monitored and managed.
`A Risk Evaluation and Mitigation Strategy
`(REMS) or Food and Drug Administration
`Amendments Act of 2007 postmarketing
`requirements are not needed to ensure the
`benefits of Nouress outweigh its risks.
`
`
`Version date: September 12, 2018
`
`
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`13
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`Reference ID: 4533707Reference ID: 4534716
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`

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`NDA/BLA Multi-disciplinary Review and Evaluation for NDA 212535 Nouress (cysteine
`hydrochloride)
`
`1.4. Patient Experience Data
`Patient Experience Data Relevant to This Application (check all that apply)
`□ The patient experience data that were submitted as part of the
`Section of review where
`application include:
`discussed, if applicable
` □ Clinical outcome assessment data, such as
`
` □ Patient reported outcome (PRO)
`
`
` □ Observer reported outcome (ObsRO)
`
`
` □ Clinician reported outcome