Citrulline: Summary Report

Item Type Report

Authors Yuen, Melissa V.; Gianturco, Stephanie L.; Pavlech, Laura L.; Storm, Kathena D.; Yoon, SeJeong; Mattingly, Ashlee N.

Publication Date 2019-12

Keywords Citrulline; Compounding; Food, Drug, and Cosmetic Act, Section 503B; Food and Drug Administration; Outsourcing facility; Drug compounding; Legislation, Drug; United States Food and Drug Administration

Rights Attribution-NoDerivatives 4.0 International

Download date 28/09/2021 06:54:06

Item License http://creativecommons.org/licenses/by-nd/4.0/

Link to Item http://hdl.handle.net/10713/12090 Summary Report

Citrulline

Prepared for: Food and Drug Administration Clinical use of bulk drug substances nominated for inclusion on the 503B Bulks List Grant number: 2U01FD005946

Prepared by: University of Maryland Center of Excellence in Regulatory Science and Innovation (M-CERSI) University of Maryland School of

December 2019

This report was supported by the Food and Drug Administration (FDA) of the U.S. Department of Health and Human Services (HHS) as part of a financial assistance award (U01FD005946) totaling $2,342,364, with 100 percent funded by the FDA/HHS. The contents are those of the authors and do not necessarily represent the official views of, nor an endorsement by, the FDA/HHS or the U.S. Government.

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Table of Contents

REVIEW OF NOMINATIONS ...... 4 METHODOLOGY ...... 4 Background information...... 4 Systematic literature review ...... 5 Outreach to medical specialists and specialty organizations ...... 8 Survey ...... 8 CURRENT AND HISTORIC USE...... 10 Summary of background information ...... 10 Summary of literature review ...... 11 Summary of focus groups/interviews of medical experts and specialty organizations ...... 15 Summary of survey results...... 16 CONCLUSION ...... 18 REFERENCES...... 19 APPENDICES ...... 24 Appendix 1. Search strategies for new nominations ...... 24 Appendix 2. Survey instrument ...... 27

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Table of Tables

Table 1. Participating associations ...... 8 Table 2. Associations that declined participation...... 9 Table 3. Currently approved products – US...... 10 Table 4. Currently approved products – select non-US countries and regions ...... 10 Table 5. Types of studies ...... 11 Table 6. Number of studies by country ...... 11 Table 8. Dosage by indication – US ...... 13 Table 9. Dosage by indication – non-US countries ...... 14 Table 10. Compounded products – US ...... 15 Table 11. Compounded products – non-US countries ...... 15 Table 12. Overview of interviewees ...... 15 Table 13. Characteristics of survey respondents ...... 16 Table 14. Types of products used, prescribed, or recommended ...... 17 Table 15. Compounded use of citrulline in practice ...... 17 Table 16. Indications for which citrulline is considered a standard ...... 17 Table 17. Reasons for using compounded product instead of the FDA-approved products ...... 17 Table 18. Change in frequency of compounded citrulline usage over the past 5 years ...... 18 Table 19. Do you stock non-patient specific compounded citrulline in your practice? ...... 18 Table 20. Questions related to stocking non-patient specific compounded citrulline ...... 18

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REVIEW OF NOMINATIONS Citrulline (UNII code: 29VT07BGDA) was nominated for inclusion on the 503B Bulks List by Empower Pharmacy and Outsourcing Facilities Association (OFA). While the exact medical condition for which the compounded product is being requested may not be known, citrulline is often given for supplementation in deficiency of and nitric oxide production. Citrulline is also given as an alternative to arginine in the management of hyperammonaemia due to cycle disorders. Additionally, citrulline was nominated for use in postoperative pediatric pulmonary hypertension and disorders. The nominated formulations include 300-1000mh oral capsules, 1-5g powders and solutions, and 100-300mg/mL intravenous (IV) injections. Reasons provided for nomination to the 503B Bulks List include: • There are no FDA-approved products that contain citrulline. • The compounded drug product may be the only product to effectively treat the indication for which it is intended to treat. • It may be necessary to compound a product with greater concentration than what is commercially available, as a patient may need a prescribed dosage form or strength that is not commercially available. • There may be a need for a prescribed dosage form or strength not commercially available. • Possible patient sensitivities to manufactured product dyes, fillers, preservatives, and other excipients. • Manufacturer backorders.

METHODOLOGY Background information The national registers of 13 countries and regions were searched to establish the availability of citrulline products in the United States (US) and around the world. The World Health Organization, the European Agency (EMA), and globalEDGE were used to identify regulatory agencies in non- US countries. The medicine registers of non-US regulatory agencies were selected for inclusion if they met the following criteria: freely accessible; able to search and retrieve results in English language; and desired information (product trade name, active ingredient, strength, form, route of administration (ROA), and approval status) provided in a useable format. Based on these criteria, the medicine registers of 13 countries/regions were searched: US, Canada, European Union (EU), United Kingdom (UK), Ireland, Belgium, Latvia, Australia, New Zealand, Saudi Arabia, Abu Dhabi, Hong Kong, and Namibia. Both the EMA and the national registers of select EU countries (Ireland, UK, Belgium, and Latvia) were searched because some medicines were authorized for use in the EU and not available in a member country and vice versa. Each medicine register was searched for citrulline; name variations of citrulline were entered if the initial search retrieved no results. The following information from the search results of each register was recorded in a spreadsheet: product trade name; active ingredient(s); strength; form; ROA; status and/or schedule; approval date. Information was recorded only for products with strengths, forms and/or ROA similar to those requested in the nominations. In addition to the aforementioned medicine registers, the DrugBank database (version 5.1.4) and the Natural Medicines database were searched for availability of over-the-counter (OTC) products containing

4 citrulline. The availability of OTC products (yes/no) in the US and the ROA of these products were recorded in a spreadsheet. Individual product information was not recorded. Systematic literature review Search strategy Two databases (PubMed and Embase) were searched including any date through February 22, 2019. The search included a combination of (citrulline [TIAB]) AND (treatment [TIAB] OR therapy [TIAB] OR therapeutic* [TIAB] OR clinical [TIAB] OR arginine [TIAB] OR "nitric oxide"[TIAB] OR hyperammonaemia [TIAB] OR [TIAB] OR urea [TIAB] OR [TIAB] OR urine [TIAB] OR deficiency [TIAB] OR OTCD [TIAB]) AND humans [MeSH Terms] AND English[language] NOT autism. Peer-reviewed articles as well as grey literature were included in the search. Search results from each database were exported to Covidence®, merged, and sorted for removal of duplicate citations. Upon receipt of new nominations for substances for which a literature review had already been conducted, additional search strategies were constructed for dosage forms, ROA, and/or indications that were not captured in the original searches. A medical librarian constructed comprehensive search strategies for PubMed and Embase. These search strategies used a combination of controlled vocabulary terms and keywords to describe three concepts: citrulline; pulmonary hypertension; and therapeutic use. Results were limited to original research articles or conference abstracts in English language. All searches were conducted on July 22, 2019. Results were exported to EndNote for Windows version X9.2 (Clarivate Analytics), and duplicates were removed. The de-duplicated results were uploaded to Covidence® for screening. Study selection Articles were not excluded on the basis of study design. Articles were considered relevant based on the identification of a clinical use of citrulline or the implementation of citrulline in clinical practice. Articles were excluded if not in English, a clinical use was not identified, incorrect salt form, or if the study was not conducted in humans. Screening of all titles, abstracts, and full-text were conducted independently by two reviewers. All screening disagreements were reconciled by a third reviewer. Data extraction A standard data extraction form was used to collect study authors; article title; year published; journal title; country; indication for citrulline use; dose; strength; dosage form; ROA; frequency and duration of therapy; any combination therapy utilized; if applicable, formulation of compounded products; study design; and any discussion surrounding the use of citrulline compared to alternative . Results Please refer to Figure 1 and Figure 2.

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Figure 1. Summary of literature screening and selection (PRISMA 2009 Flow Diagram) – Initial Search

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Figure 2. Summary of literature screening and selection (PRISMA 2009 Flow Diagram) – Additional Search

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Outreach to medical specialists and specialty organizations Using the indications from the nominations and the results of the literature review, eight (8) medical specialties that would potentially use citrulline were identified: , critical care, , , naturopathy, , , and primary care. To determine if a formal interview was warranted, medical experts in gastroenterology, hepatology, and neurology were provided the list of substances pertinent to their specialty via email. The gastroenterologist and hepatologists replied that they do not utilize any of the substances listed. The neurologist failed to respond to the interview request. No additional follow-up was considered necessary for experts with these specialties. Survey General professional medical associations and specialty associations for cardiology, critical care, gastroenterology, hepatology, naturopathy, neurology, pediatrics, and primary care, identified from the nominations and literature review were contacted to facilitate distribution of an online survey. A Google™ search was conducted to identify relevant professional associations within each specialty. Associations were included if their members are predominantly practitioners, national associations, and organizations focused on practice within the US. Organizations without practicing and state or regional organizations were excluded. The association’s website was searched in order to identify the email of the executive director, regulatory director, media director, association president, board members, or other key leaders within the organization to discuss survey participation. If no contact information was available, the “contact us” tab on the association website was used. The online surveys were created using Qualtrics® software (Provo, UT). The survey link was distributed to eleven (11) associations. If an association had more than one (1) substance with indications relevant to that specialty, substances were combined into one (1) survey with no more than 14 substances per survey. Table 1 highlights the associations that agreed to distribute the survey link and Table 2 includes the associations that declined to participate. Additionally, single substance surveys were created and posted on the project website which was shared with survey participants. Participation was anonymous and voluntary. The estimated time for completion was 30 minutes with a target of 50 responses per survey. The Office of Management and Budget (OMB) approved this project.

Table 1. Participating associations

Specialty Association

Naturopathy American Association of Naturopathic Physicians (AANP)

Pediatrics American Academy of Pediatrics (AAP)

Primary Care American Association of Environmental Medicine (AAEM)

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Table 2. Associations that declined participation

Specialty Association Reasons for Declining

Declined, "this project is so unique that SCCM may not Society of Critical Care Medicine be the audience for the survey; I have impression that this Critical Care (SCCM) project is so narrow that the link between improvement in ICU care is very remote and does not justify the study”

American Gastroenterological Gastroenterology Failed to respond Association (AGA)

American Association for the Hepatology Failed to respond Study of Diseases (AASLD)

American Medical Association Failed to respond (AMA) Medicine American Osteopathic Association Failed to respond (AOA)

American Academy of Neurology Neurology Failed to respond (AAN)

American College of Physicians Failed to respond (ACP) Primary Care American Academy of Family Failed to respond Physicians (AAFP)

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CURRENT AND HISTORIC USE Summary of background information • Citrulline is not available as an FDA-approved product. • Citrulline is available in various oral dosage forms as an OTC product in the US. • There is a current United States Pharmacopeia (USP) dietary monograph for citrulline. • Citrulline is available in Abu Dhabi.

Table 3. Currently approved products – US No approved products in the US

Table 4. Currently approved products – select non-US countries and regionsa

Approved For Use Active Concentration Dosage Form ROA Ingredient Country Status Approval Dateb

Citrulline 500mg Capsule – Abu Dhabi – 01/30/2011 Abbreviations: “–“, not mentioned; ROA, route of administration aMedicine registers of national regulatory agencies were searched if they met the following criteria: freely accessible; able to search and retrieve results in English language; and desired information (product trade name, active ingredient, strength, form, ROA and approval status) provided in a useable format. Information was recorded only for products with strengths, forms and/or ROAs similar to those requested in the nominations. See Methodology for full explanation. bIf multiple approval dates and/or multiple strengths, then earliest date provided.

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Summary of literature review • Total number of studies included: 67 studies (20 descriptive, 40 experimental, and 7 observational). • Most of the studies were from the US (27). • The most common indication in the US was for various urea cycle disorders (ornithine transcarbaymlase deficiency, carbamoylphosphate synthetase deficiency, lysinurinic intolerance) followed by mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) syndrome. • From the non-US studies, the most common indication was also various urea cycle disorders (lysinuric protein intolerance, ornithine transcarbamylase deficiency, hyperornithinemia- hyperammonemia-homocitrullinuria syndrome, argininaemia, carbamoylphosphate synthetase deficiency). • There were two (2) US studies utilizing citrulline as a compounded product (5-10% solution for postoperative pulmonary hypertension. • There was one (1) non-US study utilizing citrulline as a compounded product (800 mg capsule) for erectile dysfunction.

Table 5. Types of studies

Types of Studies Number of Studies

Descriptive1-20 20

Experimental21-60 40

Observational61-67 7

Table 6. Number of studies by country

Country Number of Studies

Austria 10 1

Canada16 1

China 7,50 2

Finland42,51,52,64,65 5

France38,39 2

Germany1,59,60 3

Iran55 1

Italy5,27,30,66 4

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Japan41,44,47,48,57,63 6

Mexico22,49 2

Morocco14 1

Poland15 1

South Korea13 1

Spain43 1

Switzerland4,36 2

Turkey8 1

UK11,18,20 3

US2,3,6,9,12,17,19,21,23-26,28,29,31-34,40,45,46,53,54,56,58,62,67 27

Multiple Countries • Austria, Germany, Italy, Switzerland61 • Austria, Germany, Switzerland35,37

Total US: 27 Total non-US Countries: 40

Table 7. Number of studies by combinations No combination products were nominated

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Table 7. Dosage by indication – US

Indication Dose Concentration Dosage Form ROA Duration of Treatment

2.8-7g/day – – 12 days-7 months Urea cycle disorders (ornithine transcarbamylase deficiency3,6,12,24,25, carbamoylphosphate synthetase deficiency2, lysinurinic protein 30-286mg/kg/day – – Oral – intolerance19,26) 1mmol/kg/day – – –

500mg/kg/day – – 2 days Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like Oral episodes (MELAS) syndrome29,31-34,62 10g/m2/day – – 2-7 days

Erectile dysfunction45,46 1600mg/day – Capsule Oral 3 months

50-150mg/kg – Injection Once or twice Intravenous Postoperative pulmonary hypertension9,23,58 9mg/kg/hour – – 48 hours

3.8g/m2/day 10% Solution Oral 2.5 days

Reye syndrome17,28 80-600mg/kg/day – – Nasogastric tube –

Hereditary dibasicaminoaciduria21 3g/day – – Oral 5-8 days

Osteonecrosis40 800mg/day – – – –

Post-polio syndrome54 15g/day – – Oral 24 weeks

10-20mg/kg – Solution Bolus Sepsis53 Intravenous 4.5-9mg/kg/h – Solution 96 hours

Sickle cell disease67 0.1g/kg/day – Capsule Oral 4 weeks

Type 2 diabetes56 2000mg/day – – – 1 month Abbreviations: “–“, not mentioned; ROA, route of administration

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Table 8. Dosage by indication – non-US countries

Indication Dose Concentration Dosage Form ROA Duration of Treatment

1.1mmol/kg – Solution Intravenous Once

Urea cycle disorder43,61,63 (lysinuric protein 0.828-12g/day 0.4g/tablet Sachet, Tablet Once-2.2 years intolerance4,5,8,13,20,30,41,42,44,47,51,52,64,65, ornithine transcarbamylase deficiency1,10,14,18, hyperornithinemia- 58-431mg/kg/day – Capsules Oral 3-12 months hyperammonemia-homocitrullinuria syndrome16,66, argininaemia7, carbamoylphosphate synthetase deficiency11) 0.43-2mmol/kg/day – – 2 weeks

4g/day – – – –

Erectile dysfunction27,57,60 800mg-1.5g/day – Capsule, Tablet Oral 1-2 months

Drinking solution, Muscular dystrophy (Duchenne35,36, Becker37) 7.5-15g/day – Oral 6-26 weeks Sachets

Short bowel syndrome38,39 0.18g/kg/day – – Oral 7 days

Arterial stiffness48 5.6g/day – – – 7 days

Chronic pulmonary hypertension due to bronchopulmonary 150mg/kg/day – Powder Oral 70 days dysplasia15

Eisenmenger sydnrome55 1g/day – Powder Oral 2 weeks

Heart failure (Preserved ejection fraction49, Reduced ejection 3g/day – Powder Oral 60 days-4 months fraction22)

Male fertility59 1.2g/day – Tablet Oral 4 weeks

Prehypertension50 6g/day – – – 8 weeks

Pulmonary arterial hypertension55 1g/day – Powder Oral 2 weeks Abbreviations: “–“, not mentioned; ROA, route of administration

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Table 9. Compounded products – US

Indication Year Published Compounding Method Dosage Form Final Strength

Postoperative pulmonary hypertension23,58 2007, 2017 • With distilled water as a suspending agent Solution 5-10%

Table 10. Compounded products – non-US countries

Indication Compounding Method Dosage Form Final Strength

L-citrulline with transresveratrol mixed with crystalline cellulose and calcium stearate and encapsulated in a Erectile dysfunction57 Capsule 800mg hydroxypropyl methylcellulose capsule

Summary of focus groups/interviews of medical experts and specialty organizations No interviews were conducted. A Medical Doctor (MD) specializing in hepatology, an MD specializing in gastroenterology, and an MD specializing in neurology were provided the list of substances pertinent to their specialty via email, which included citrulline. Per the gastroenterologist’s knowledge, citrulline is not used in gastroenterology. Per the hepatologist, citrulline has no indication in liver disease. The neurologist failed to respond to the interview request.

Table 11. Overview of interviewees No interviews were conducted

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Summary of survey results Table 12. Characteristics of survey respondents [29 people responded to the survey.a]

Board Certification MD ND PharmD No Response

Anesthesiology 7 0 0 0

Clinical Pharmacology 1 0 0 0

Critical Care Medicine 3 0 0 0

Gastroenterology 1 0 0 0

Fellow of the American Board of 0 1 0 0 Naturopathic

Hospice & Palliative Medicine 1 0 0 0

Naturopathic Doctor 0 6 0 0

Naturopathic 0 5 0 0

Pediatrics 5 0 0 0

Pediatric 3 0 0 0

No Board Certification 1 2 1 0

No Response 0 0 0 9 Abbreviations: MD, ; ND, Naturopathic Doctor; PharmD, Doctor of Pharmacy. aSome respondents reported more than one terminal clinical degree or board certification.

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Table 13. Types of products used, prescribed, or recommended

Types of Products Respondents, n (N=6a)

Compounded 1

FDA-approved 3

Over-the-counter 0

Dietary 1

Unsure 0

No response 2 aOut of 29 respondents, six (6) reported using, prescribing, or recommending multiple types of citrulline products

Table 14. Compounded use of citrulline in practice No survey respondents provided this information

Table 15. Indications for which citrulline is considered a standard therapy

Standard Therapy Indication Compounded, n Non-Compounded, n No Response, n Unsure, n (N=0) (N=1) (N=4) (N=2)

Inborn error of 0 1 0 0 metabolism

Mild cognitive impairment, 0 1 0 0 memory concerns

No response 1 2 0 2

Table 16. Reasons for using compounded product instead of the FDA-approved products

Reasons

“We use fda approved powder and make it into a liquid”

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Table 17. Change in frequency of compounded citrulline usage over the past 5 years

Respondents, n (N=1)

No - use has remained consistent 1

Yes - I use it LESS often now 0

Yes - I use it MORE often now 0

Table 18. Do you stock non-patient specific compounded citrulline in your practice? No survey respondents provided this information

Table 19. Questions related to stocking non-patient specific compounded citrulline No survey respondents provided this information

CONCLUSION Citrulline (UNII code: 29VT07BGDA) was nominated for inclusion on the 503B Bulks List for postoperative pediatric pulmonary hypertension, urea cycle disorders, supplementation in deficiency of arginine and nitric oxide production, and management of hyperammonemia due to urea cycle disorders. The nominated formulations include 300-1000mg oral capsules, 1-5g powders and solutions, and 100- 300mg/mL IV injections. Citrulline is available in various oral dosage forms OTC in the US and has a USP dietary monograph. From the foreign regulatory databases searched, citrulline was available in Abu Dhabi. From the literature review, the most common indication in the US was for various urea cycle disorders followed by mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) syndrome. From the non-US studies, the most common indication was also various urea cycle disorders. There were two (2) US studies using citrulline as a compounded product (5-10% solution) for postoperative pulmonary hypertension. There was one (1) non-US study utiziling a compounded product (800 mg capsule) for erectile dysfunction. No interviews were conducted. The hepatology and gastroenterology medical experts emailed both stated that they do not use citrulline. The neurology medical expert failed to respond to interview requests. From the survey results, six (6) out of 29 respondents reported using citrulline and one (1) reported using a compounded product. No survey respondents provided information on use of compounded citrulline products and the need for office stock.

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14. Kriouile Y. Ornithine carbamyl transferase deficiency: Report of two cases. Journal of Inborn Errors of Metabolism and Screening. 2017;5((Kriouile Y.) Faculty of Medicine and Pharmacy of Rabat, University Hospital Ibn Sina, Children's Hospital In Rab, Rabat, Morocco):167. 15. Lauterbach R, Pawlik D, Lauterbach JP. L-citrulline supplementation in the treatment of pulmonary hypertension associated with bronchopulmonary dysplasia in preterm infant: A case report. SAGE Open Medical Case Reports. 2018;6((Lauterbach J.P.) Department of , Hospital “Ujastki” Neo-medic Centre, Kraków, Poland). 16. Mhanni AA, Chan A, Collison M, et al. Hyperornithinemia-hyperammonemia-homocitrullinuria syndrome (HHH) presenting with acute fulminant hepatic failure. Journal of pediatric gastroenterology and nutrition. 2008;46(3):312-315. 17. Oetgen WJ. The use of citrulline for the treatment of Reye's syndrome: case reports. Military medicine. 1977;142(2):162-164. 18. Pagedar R, Quak EKY, Pickett JA. Ornithine transcarbamylase deficiency: The importance of multidisciplinary peripartum care. International Journal of Obstetric Anesthesia. 2013;22((Pagedar R.; Quak E.K.Y.; Pickett J.A.) Anaesthesia, Addenbrooke's Hospital, Cambridge, United Kingdom):S28. 19. Patel RM, Singh N, Ramji F, Adler J, Yu Z, Wierenga K. Lysinuric protein intolerance: Not your usual case of nausea and vomiting. Journal of Investigative Medicine. 2012;60(1):320. 20. Shaw PJ, Dale G, Bates D. Familial lysinuric protein intolerance presenting as coma in two adult siblings. Journal of Neurology and . 1989;52(5):648-651. 21. Awrich AE, Stackhouse WJ, Cantrell JE, Patterson JH, Rudman D. Hyperdibasicaminoaciduria, hyperammonemia, and growth retardation: Treatment with arginine, , and citrulline. The Journal of pediatrics. 1975;87(5):731-738. 22. Balderas-Munãoz K, Castillo-Martínez L, Orea-Tejeda A, et al. Improvement of ventricular function in systolic heart failure patients with oral L-citrulline supplementation. Cardiology Journal. 2012;19(6):612-617. 23. Barr FE, Tirona RG, Taylor MB, et al. Pharmacokinetics and safety of intravenously administered citrulline in children undergoing congenital heart : Potential therapy for postoperative pulmonary hypertension. Journal of Thoracic and Cardiovascular Surgery. 2007;134(2):319-326. 24. Brusilow SW. Arginine, an indispensable amino acid for patients with inborn errors of urea synthesis. Journal of Clinical Investigation. 1984;74(6):2144-2148. 25. Brusilow SW, Finkelstien J. Restoration of nitrogen homeostasis in a man with ornithine transcarbamylase deficiency. Metabolism: Clinical and Experimental. 1993;42(10):1336-1339. 26. Carpenter TO, Levy HL, Holtrop ME. Lysinuric protein intolerance presenting as childhood osteoporosis. Clinical and skeletal response to citrulline therapy. New England Journal of Medicine. 1985;312(5):290-294. 27. Cormio L, De Siati M, Lorusso F, et al. Oral L-citrulline supplementation improves erection hardness in men with mild erectile dysfunction. . 2011;77(1):119-122. 28. DeLong GR, Glick TH. Ammonia metabolism in Reye syndrome and the effect of citrulline. Annals of neurology. 1982;11(1):53-58.

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29. Dewan R, Stack C, Cole J. Canagliflozin associated with melas pseudoexacerbation. Neurology. 2018;90(15). 30. DiRocco M, Garibotto G, Rossi GA, et al. Role of haematological, pulmonary and renal complications in the long-term prognosis of patients with lysinuric protein intolerance. European Journal of Pediatrics. 1993;152(5):437-440. 31. El-Hattab AW, Emrick LT, Chanprasert S, et al. Utility of citrulline in treating hypoargininemia in children with MELAS. Mitochondrion. 2015;24((Hsu J.W.; Jahoor F.) Children's Nutrition Research Center, Baylor College of Medicine, Houston, TX, United States):S18-S19. 32. El-Hattab AW, Emrick LT, Hsu JW, et al. Impaired nitric oxide production in children with MELAS syndrome and the effect of arginine and citrulline supplementation. Molecular Genetics and Metabolism. 2016;117(4):407-412. 33. El-Hattab AW, Emrick LT, Williamson KC, Craigen WJ, Scaglia F. The effect of citrulline and arginine supplementation on lactic acidemia in MELAS syndrome. Meta Gene. 2013;1((El-Hattab A.W.) Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, United States):8-14. 34. El-Hattab AW, Hsu JW, Emrick LT, et al. Restoration of impaired nitric oxide production in MELAS syndrome with citrulline and arginine supplementation. Molecular Genetics and Metabolism. 2012;105(4):607-614. 35. Hafner P, Bonati U, Klein A, et al. L-citrulline and metformin delay muscle degeneration in duchenne muscular dystrophy: Results from a andomised clinical trial. Journal of Neuromuscular Diseases. 2018;5((Fischer D.) Division of Neurology, Kantonsspital Bruderhlz, Bruderholz, Switzerland):S116. 36. Hafner P, Bonati U, Rubino D, et al. Treatment with l-citrulline and metformin in Duchenne muscular dystrophy: Study protocol for a single-centre, randomised, placebo-controlled trial. Trials. 2016;17(1). 37. Hanff E, Hafner P, Bollenbach A, et al. Effects of single and combined metformin and l-citrulline supplementation on l-arginine-related pathways in Becker muscular dystrophy patients: possible biochemical and clinical implications. Amino Acids. 2018;50(10):1391-1406. 38. Jirka A, Layec S, Picot D, Bernon-Ferreira S, Darmaun D. Effect of citrulline supplementation on protein metabolism in patients with short bowel syndrome: A stable isotope study. Clinical Nutrition. 2016;35((Darmaun D.) Nutrition Support Team, Dept of Gastroenterology, Chu De Nantes, Nantes, France):S131. 39. Jirka A, Layec S, Picot D, et al. Effect of oral citrulline supplementation on whole body protein metabolism in adult patients with short bowel syndrome: A pilot, randomized, double-blind, cross-over study. Clinical Nutrition. 2019((Thibault R.) INSERM, INRA, Univ Rennes, Nutrition Metabolism and Cancer, NuMeCan, Nutrition Unit, CHU Rennes, Rennes, France). 40. Khan AM, Choi J, Freiberg RA, Glueck CJ, Goldenberg N, Wang P. T786C mutation in the endothelial nitric oxide synthase gene in patients with primary osteonecrosis. Orthopedics. 2017;40(5):e898-e903. 41. Koizumi A, Matsuura N, Inoue S, et al. Evaluation of a mass screening program for lysinuric protein intolerance in the northern part of Japan. Genetic Testing. 2003;7(1):29-35.

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42. Lukkarinen M, Näntö-Salonen K, Pulkki K, Aalto M, Simell O. Oral supplementation corrects plasma lysine concentrations in lysinuric protein intolerance. Metabolism: Clinical and Experimental. 2003;52(7):935-938. 43. Martín-Hernández E, Aldámiz-Echevarría L, Castejón-Ponce E, et al. Urea cycle disorders in Spain: an observational, cross-sectional and multicentric study of 104 cases. Orphanet journal of rare diseases. 2014;9((Pérez-Cerdá C.) CEDEM. Facultad de Ciencias, Universidad Autónoma de Madrid, Madrid, Spain. [email protected]):187. 44. Mizutani N, Kato T, Maehara M. Oral administration of arginine and citrulline in the treatment of lysinuric protein intolerance. Tohoku Journal of Experimental Medicine. 1984;142(1):15-24. 45. Nguyen S, Rajfer J, Shaheen M. Safety and efficacy of daily Revactin® in men with erectile dysfunction: A 3-month pilot study. Translational and Urology. 2018;7(2):266-273. 46. Nguyen S, Shaheen M, Teklehaimanot S, Kermah D, Ferrini M, Rajfer J. Daily ingestion of the combination of ginger, muira puama, paullina cupana and l-citrulline improves erectile function. Andrology. 2018;6((Rajfer J.) UCLA, United States):91-92. 47. Noguchi AN, Kondo DK, Kikuchi WK, Takasago YT, Takahashi TT, Tsukahara HT. Lysinuric protein intolerance: Analysis of nitric oxide and re-dox marker. Journal of Inherited Metabolic Disease. 2018;41((Tsukahara H.T.) Dep Ped, Okayama Univ Hosp, Okayama, Japan):S112. 48. Ochiai M, Hayashi T, Morita M, et al. Short-term effects of L-citrulline supplementation on arterial stiffness in middle-aged men. International Journal of Cardiology. 2012;155(2):257-261. 49. Orozco-Gutiérrez JJ, Castillo-Martínez L, Orea-Tejeda A, et al. Effect of L-arginine or L- citrulline oral supplementation on blood pressure and right ventricular function in heart failure patients with preserved ejection fraction. Cardiology Journal. 2010;17(6):612-618. 50. Qiu J, Niu F, Wang X, Yang J, Zhao X. L-citrulline supplementation reduced peripheral blood pressure in chinese adults with prehypertension. Journal of Hypertension. 2012;30((Qiu J.; Niu F.; Wang X.; Yang J.; Zhao X.) First Affiliated Hospital, Soochow University, China):e150. 51. Rajantie J. Orotic aciduria in lysinuric protein intolerance: dependence on the urea cycle intermediates. Pediatric research. 1981;15(2):115-119. 52. Rajantie J, Simell O, Rapola J, Perheentupa J. Lysinuric protein intolerance: a two-year trial of dietary supplementation therapy with citrulline and lysine. The Journal of pediatrics. 1980;97(6):927-932. 53. Rice TW, Hays M, Mogan S, Wheeler AP. Intravenous citrulline in critically ill patients with sepsis. American Journal of Respiratory and Critical Care Medicine. 2017;195((Rice T.W., [email protected]; Hays M.; Mogan S.; Wheeler A.P.) Vanderbilt University, Nashville, TN, United States). 54. Schmidt S, Gocheva V, Zumbrunn T, et al. Treatment with L-citrulline in patients with post-polio syndrome: Study protocol for a single-center, randomised, placebo-controlled, double-blind trial. Trials. 2017;18(1). 55. Sharif Kashani B, Pour PT, Malekmohammad M, et al. Oral l-citrulline malate in patients with idiopathic pulmonary arterial hypertension and Eisenmenger Syndrome: A clinical trial. Journal of Cardiology. 2014;64(3):231-235.

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56. Shatanawi A, Momani MS, Aqtash R, Hamdan MH, Caldwell RB, Caldwell RW. L-citrulline supplementation reduces plasma activity in type 2 diabetes patients. Circulation. 2015;132((Caldwell R.W.) Pharmacology and Toxicology, Georgia Regents Univ, Augusta, GA, United States). 57. Shirai M, Hiramatsu I, Aoki Y, et al. Oral L-citrulline and Transresveratrol Supplementation Improves Erectile Function in Men With Phosphodiesterase 5 Inhibitors: A Randomized, Double- Blind, Placebo-Controlled Crossover Pilot Study. . 2018;6(4):291-296. 58. Smith HAB, Canter JA, Christian KG, et al. Nitric oxide precursors and congenital heart surgery: A randomized controlled trial of oral citrulline. Journal of Thoracic and Cardiovascular Surgery. 2006;132(1):58-65. 59. Stanislavov R, Rohdewald P. Sperm quality in men is improved by supplementation with a combination of L-arginine, L-citrulline, roburins and Pycnogenol®. Minerva Urologica e Nefrologica. 2014;66(4):217-223. 60. Stanislavov R, Rohdewald P. Improvement of erectile function by a combination of French maritime pine bark and roburins with aminoacids. Minerva urologica e nefrologica = The Italian journal of urology and . 2015;67(1):27-32. 61. Bachmann C. Outcome and survival of 88 patients with urea cycle disorders: A retrospective evaluation. European Journal of Pediatrics. 2003;162(6):410-416. 62. Ganetzky RD, Falk MJ. 8-year retrospective analysis of intravenous arginine therapy for acute metabolic strokes in pediatric mitochondrial disease. Molecular Genetics and Metabolism. 2018;123(3):301-308. 63. Tanaka K, Nakamura K, Matsumoto S, et al. Citrulline for urea cycle disorders in Japan. Pediatrics International. 2017;59(4):422-426. 64. Tanner LM, Näntö-Salonen K, Niinikoski H, Huoponen K, Simell O. Long-term oral lysine supplementation in lysinuric protein intolerance. Metabolism: Clinical and Experimental. 2007;56(2):185-189. 65. Tanner LM, NäntöSalonen K, Venetoklis J, et al. Nutrient intake in lysinuric protein intolerance. Journal of Inherited Metabolic Disease. 2007;30(5):716-721. 66. Vici CD, Bachmann C, Gambarara M, Colombo JP, Sabetta G. Hyperornithinemia- hyperammonemia-homocitrullinuria syndrome: Low excretion and effect of citrulline, arginine, or ornithine supplement. Pediatric Research. 1987;22(3):364-367. 67. Waugh WH, Daeschner 3rd CW, Files BA, McConnell ME, Strandjord SE. Oral citrulline as arginine precursor may be beneficial in sickle cell disease: early phase two results. Journal of the National Medical Association. 2001;93(10):363-371.

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APPENDICES Appendix 1. Search strategies for new nominations PubMed Search Strategy • Years searched: 1946 to present • Limits: English language • Date searched: July 22, 2019 • Number of results: 14

1 Search "citrulline"[MeSH] OR "citrullin*"[TIAB] OR "citrulin*"[TIAB] 4084

2 Search "hypertension, pulmonary"[MeSH] OR "pulmonary heart disease"[MeSH] OR 55438 "pulmonary hypertension"[TIAB] OR "pulmonary hypertensive"[TIAB] OR "hypertensive pulmonary"[TIAB] OR "pulmonary artery hypertension"[TIAB] OR "pulmonary arterial hypertension"[TIAB] OR "lung artery hypertension"[TIAB] OR "lung arterial hypertension"[TIAB] OR "lung hypertension"[TIAB] OR "lung hypertensive"[TIAB] OR "pulmonary fixed hypertension"[TIAB] OR "pulmonary heart disease"[TIAB] OR "pulmonary heart diseases"[TIAB] OR "pulmonary cardiac disease"[TIAB] OR "pulmonary cardiac diseases"[TIAB] OR "cor pulmonale"[TIAB]

3 Search "administration, intravenous"[MeSH] OR "administration, oral"[MeSH] OR "drug 9629278 compounding"[MeSH] OR "therapeutic use"[subheading] OR "drug therapy"[subheading] OR "administration and dosage"[subheading] OR intravenous*[TIAB] OR oral*[TIAB] OR treat*[TIAB] OR therap*[TIAB] OR compound*[TIAB]

4 Search ("animals"[MeSH] NOT "humans"[MeSH]) 4600157

5 Search (#1 AND #2 AND #3) 20

6 Search (#5 NOT #4) 15

7 Search (#6 AND English[lang]) 14

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Embase Search Strategy • Platform: Elsevier • Years Searched: 1947 to present • Limits: English language • Date Searched: July 22, 2019 • Number of Results: 90

1 'citrulline'/de 8005

2 'citrul$in*':ti,ab,tn 15074

3 #1 OR #2 17138

4 'pulmonary hypertension'/exp 95026

5 ((lung OR pulmonary) NEAR/2 hypertensi*):ti,ab 72723

6 'pulmonary heart disease*':ti,ab 760

7 'pulmonary cardiac disease*':ti,ab 9

8 'cor pulmonale':ti,ab 6552

9 #4 OR #5 OR #6 OR #7 OR #8 104813

10 'intravenous drug administration'/exp 389308

11 'oral drug administration'/de 402298

12 'drug formulation'/de 115535

13 'drug therapy':lnk 3731530

14 'drug comparison':lnk 582360

15 'drug adminstration':lnk 1667840

16 'intravenous*':ti,ab 466762

17 'intra venous*':ti,ab 1383

18 'oral*':ti,ab 904360

19 'treat*':ti,ab 7431367

20 'therap*':ti,ab 3881495

21 'compound*':ti,ab 975423

22 #10 OR #11 OR #12 OR #13 OR #14 OR #15 OR #16 OR #17 OR #18 OR #19 OR #20 12247912 OR #21

25

23 [animals]/lim NOT [humans]/lim 5867441

24 #3 AND #9 AND #22 111

25 #24 NOT #23 93

26 #25 AND [english]/lim 90

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Appendix 2. Survey instrument

Start of Block: Welcome Page The University of Maryland Center of Excellence in Regulatory Science and Innovation (M-CERSI), in collaboration with the Food and Drug Administration (FDA), is conducting research regarding the use of certain bulk drug substances nominated for use in compounding by outsourcing facilities under section 503B of the Federal Food, Drug, and Cosmetic Act. In particular, we are interested in the current and historic use of these substances in clinical practice. This survey is for citrulline. As a medical expert, we appreciate your input regarding the use of this substance in your clinical practice. This information will assist FDA in its development of a list of bulk drug substances that outsourcing facilities can use in compounding under section 503B of the Act. All responses are anonymous.

OMB Control No. 0910-0871 Expiration date: June 30, 2022

The time required to complete this information collection is estimated to average 30 minutes, including the time to review instructions, search existing data sources, gather the data needed, and complete and review the information collection. An agency may not conduct or sponsor, and a person is not required to respond to a collection of information unless it displays a currently valid OMB control number.

If you have additional questions or concerns about this research study, please email: [email protected]. If you have questions about your rights as a research subject, please contact HRPO at 410-760-5037 or [email protected]. End of Block: Welcome Page

Start of Block: Citrulline Q1. What type(s) of product(s) do you use, prescribe, or recommend for citrulline? Please check all that apply. ▢ Compounded drug product ▢ FDA-approved drug product ▢ Over the counter drug product ▢ Dietary supplement (e.g. vitamin or herbal supplement products sold in retail setting) ▢ Unsure Skip To: Q14 If What type(s) of product(s) do you use, prescribe, or recommend for citrulline? Please check all th... != Compounded drug product Skip To: Q3 If What type(s) of product(s) do you use, prescribe, or recommend for citrulline? Please check all th... = Compounded drug product Display This Question: If What type(s) of product(s) do you use, prescribe, or recommend for citrulline? Please check all th... = Compounded drug product Q2. Please list any conditions or diseases for which you use compounded citrulline in your practice. Please include the strength(s), dosing frequency(ies), dosage form(s), route(s) of administration, duration of therapy, and patient population (ex. age, gender, comorbidities, , etc).

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Strength(s) Dosing Dosage Route(s) of Duration of Patient (please frequency(ies) form(s) administration therapy population include units)

Condition 1 (please describe)

Condition 2 (please describe)

Condition 3 (please describe)

Condition 4 (please describe)

Condition 5 (please describe)

Q3. Do you use compounded citrulline as a single agent active ingredient, or as one active ingredient in a combination product? Please check all that apply. ▢ Single ▢ Combination Skip To: Q6 If Do you use compounded citrulline as a single agent active ingredient, or as one active ingredient... != Combination Display This Question: If Loop current: Do you use compounded citrulline as a single agent active ingredient, or as one active ingredient... = Combination Q4. Please list all combination products in which you use compounded citrulline.

______Q5. For which, if any, diseases or conditions do you consider compounded citrulline standard therapy?

______Q6. Does your specialty describe the use of compounded citrulline in medical practice guidelines or other resources? ______

Q7. Over the past 5 years, has the frequency in which you have used compounded citrulline changed? o Yes - I use it MORE often now (briefly describe why) ______o Yes - I use it LESS often now (briefly describe why) ______o No - use has remained consistent

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Q8. Why do you use compounded citrulline instead of any FDA-approved drug product? ______Q9. Do you stock non-patient-specific compounded citrulline in your practice location? o Yes o No Skip To: End of Block If Do you stock non-patient-specific compounded citrulline in your practice location? = No Display This Question: If Do you stock non-patient-specific compounded citrulline in your practice location? = Yes Q10. In what practice location(s) do you stock non-patient-specific compounded citrulline? Please check all that apply. ▢ Physician office ▢ Outpatient clinic ▢ Emergency room ▢ Operating room ▢ Inpatient ward ▢ Other (please describe) ______Q11. How do you obtain your stock of non-patient-specific compounded citrulline? Please check all that apply. ▢ Purchase from a compounding pharmacy ▢ Purchase from an outsourcing facility ▢ Compound the product yourself ▢ Other (please describe) ______Q12. Why do you keep a stock of non-patient-specific compounded citrulline? Please check all that apply. ▢ Convenience ▢ Emergencies ▢ Other (please describe) ______Skip To: End of Block If Why do you keep a stock of non-patient-specific compounded citrulline? Please check all that apply. = Convenience Skip To: End of Block If Why do you keep a stock of non-patient-specific compounded citrulline? Please check all that apply. = Emergencies Skip To: End of Block If Why do you keep a stock of non-patient-specific compounded citrulline? Please check all that apply. = Other (please describe) Q13. For which, if any, diseases or conditions do you consider citrulline standard therapy? ______Q14. Does your specialty describe the use of citrulline in medical practice guidelines or other resources? ______End of Block: Citrulline

Start of Block: Background Information Q15. What is your terminal clinical degree? Please check all that apply. ▢ Doctor of Medicine (MD)

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▢ Doctor of Osteopathic Medicine (DO) ▢ Doctor of Medicine in (DMD/DDS) ▢ Naturopathic Doctor (ND) ▢ Nurse Practitioner (NP) ▢ Physician Assistant (PA) ▢ Other (please describe) ______Q16. Which of the following Board certification(s) do you hold? Please check all that apply. ▢ No Board certification ▢ and ▢ Anesthesiology ▢ Cardiovascular Disease ▢ Critical Care Medicine ▢ ▢ ▢ , Diabetes and Metabolism ▢ ▢ Gastroenterology ▢ ▢ Infectious Disease ▢ ▢ Medical Toxicology ▢ Naturopathic Doctor ▢ Naturopathic Physician ▢ Nephrology ▢ Neurology ▢ and Gynecology ▢ Oncology ▢ ▢ Otolaryngology ▢ Pain Medicine ▢ Pediatrics ▢ Psychiatry ▢ ▢ ▢ Surgery (please describe) ______▢ Urology ▢ Other (please describe) ______End of Block: Background Information

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