Methylcobalamin: Summary Report

Item Type Report

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

Publication Date 2020-02

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

Rights Attribution-NoDerivatives 4.0 International

Download date 27/09/2021 02:17:34

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

Link to Item http://hdl.handle.net/10713/12216 Summary Report

Methylcobalamin

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 Pharmacy

February 2020

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.

Table of Contents

REVIEW OF NOMINATIONS ...... 4 METHODOLOGY ...... 4 Background information...... 4 Systematic literature review ...... 5 Outreach to medical specialists and specialty organizations ...... 7 Survey ...... 7 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 ...... 16 Summary of survey results...... 17 CONCLUSION ...... 20 APPENDICES ...... 21 Appendix 1. References...... 21 Appendix 2. Survey instrument ...... 28

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 ...... 12 Table 7. Number of studies by combinations ...... 13 Table 8. Dosage by indication – US ...... 13 Table 9. Dosage by indication – non-US countries ...... 14 Table 10. Compounded products – US ...... 16 Table 11. Compounded products – non-US countries ...... 16 Table 12. Overview of interviewee ...... 16 Table 13. Characteristics of survey respondents ...... 17 Table 14. Types of products used, prescribed, or recommended ...... 17 Table 15. Compounded use of methylcobalamin in practice...... 18 Table 16. Indications for which methylcobalamin is considered a standard therapy ...... 19 Table 17. Reasons for using compounded product instead of the FDA-approved products ...... 19 Table 18. Change in frequency of compounded methylcobalamin usage over the past 5 years ...... 20 Table 19. Do you stock non-patient specific compounded methylcobalamin in your practice?...... 20 Table 20. Questions related to stocking non-patient specific compounded methylcobalamin ...... 20

REVIEW OF NOMINATIONS Methylcobalamin (UNII code: BR1SN1JS2W) was nominated for inclusion on the 503B Bulks List by McGuff Compounding Pharmacy Services, Inc, The American Association of Naturopathic Physicians, Alliance for Natural Health, Integrative Medicine Consortium, American College for Advancement in Medicine, and David Smith. While the exact medical condition in which the compounded product is requested is generally unknown, methylcobalamin is generally indicated for the treatment of vitamin deficiency and associated pathologies arising therefrom, such as pernicious anemia. Methylcobalamin was also nominated for use in combination with chorionic gonadotrophin as a 1-5mg/mL injection for testicular atrophy and weight loss, refer to Table 7 for the nominated combination formulations. Additionally, methylcobalamin was nominated for treatment of vitamin B12 deficiency in patients with methylation issues, a treatment for autism spectrum disorder with methylation issues, gastrointestinal disorders, lack of intrinsic factor, fibromyalgia, chronic fatigue syndrome, neuropathic pain, multiple sclerosis, Parkinsonism, and pernicious anemia. Methylcobalamin will be compounded as a 1-10mg/mL multi-dose vial and a 20mg/mL preservative-free vial for intramuscular or subcutaneous injection. Reasons provided for nomination to the 503B Bulks List include: • There are no FDA-approved products with methylcobalamin as a single agent, or in combination with chorionic gonadotrophin in injection form • Compounded drug products are requested by prescribers to treat the individual needs of prescribers’ patients. • Methylcobalamin is a metabolically active form of vitamin B12 especially suited for neurological complaints. • Duloxetine has a significant boxed warning, side effects, and drug interaction profile. • Risperidone and aripiprazole are not FDA-approved to treat autistic syndrome disorder itself, only irritability associated with autism. • Risperidone and aripiprazole have a significant boxed warning and profile of CNS side effects in long-term use. • Thousands of patients with methylation issues, autism, chronic fatigue, fibromyalgia, multiple sclerosis, Parkinsonism, neuropathy, autoimmune, and heavy metal toxic syndrome are prescribed and use methylcobalamin daily.

METHODOLOGY Background information The national medicine registers of 13 countries and regions were searched to establish the availability of methylcobalamin products in the United States (US) and around the world. The World Health Organization, the European Medicines 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, specifically, 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 methylcobalamin; name variations of methylcobalamin 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; 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 methylcobalamin. 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 15, 2019. The search included a combination of (Methylcobalamin[TIAB] OR Mecobalamin[TIAB] OR "Methyl Vitamin B12"[TIAB] OR "Methyl Vitamin B 12"[TIAB] OR "Methyl B12"[TIAB] OR "Methyl B 12"[TIAB] OR Methycobal[TIAB] OR CH3-B12[TIAB]) AND (clinical[TIAB] OR therap*[TIAB] OR treat*[TIAB] OR deficien*[TIAB] OR methylation[TIAB] OR gastrointestinal[TIAB] OR pain[TIAB] OR neuro*[TIAB] OR neuropath*[TIAB] OR fatigue[TIAB] OR sclerosis[TIAB] OR parkinson*[TIAB] OR atrophy[TIAB] OR weight[TIAB]) AND (humans[MeSH Terms] AND English[lang]) 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. 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 methylcobalamin or the implementation of methylcobalamin 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 methylcobalamin 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 methylcobalamin compared to alternative therapies. Results Please refer to Figure 1.

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

Outreach to medical specialists and specialty organizations Using the indications from the nominations and the results of the literature review, 12 medical specialties that would potentially use methylcobalamin were identified: dermatology, endocrinology, gastroenterology, naturopathy, neurology, ophthalmology, otolaryngology, pain management, primary care, rheumatology, sleep medicine, and urology. Semi-structured interviews were conducted with subject matter experts within these specialties. Interviews lasted from 30-75 minutes and were conducted either via telephone or in-person. Criteria for selecting subject matter experts included recommendations provided by specialty professional associations, convenient geographic location, authorship within the specialty, or referral by an interviewee. Up to nine (9) interviews were conducted per substance. Four (4) experts were contacted for interviews, of which one (1) accepted. One (1) expert specializing in gastroenterology replied via email that methylcobalamin is used as a supplement in patients with vitamin B12 deficiency, but did not identify a need for a compounded product. Two (2) experts, one (1) specializing in otolaryngology and one (1) specializing in neurology failed to respond to the interview request. Interviews were recorded and transcribed via ©Rev.com. QSR International’s NVivo 12 software was utilized for qualitative data analysis. The University of Maryland, Baltimore IRB and the Food & Drug Administration RIHSC reviewed the study and found it to be exempt. Subject matter experts provided their oral informed consent to participate in interviews.

Survey General professional medical associations and specialty associations for dermatology, endocrinology, gastroenterology, naturopathy, neurology, ophthalmology, otolaryngology, pain management, primary care, rheumatology, sleep medicine, and urology, identified from the nominations, literature review, and interview, 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 physicians 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). Survey links were distributed to 21 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

American Academy of Dermatology (AAD) Dermatology American Society for Dermatologic Surgery (ASDS)

Naturopathy American Association of Naturopathic Physicians (AANP)

American Society of Cataract and Refractive Surgery (ASCRS) Ophthalmology American Society of Retina Specialist (ASRS)

Pain Medicine American Academy of Pain Medicine (AAPM)

Primary Care American Academy of Environmental Medicine (AAEM)

Rheumatology American College of Rheumatology (ACR)

Sleep Medicine American Academy of Sleep Medicine (AASM)

Table 2. Associations that declined participation

Specialty Association Reasons for Declining

American Association of Clinical Endocrinologists Declined, “endocrinologists are not Endocrinology (AACE) generally in the compounding space.”

Gastroenterology American Gastroenterological Association (AGA) Failed to respond

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

Neurology American Academy of Neurology (AAN) Failed to respond

Ophthalmology American Academy of Ophthalmology (AA) “I would take this off the list”

American Academy of Otolaryngology-Head and Failed to respond Neck Surgery (AAO-HNS)

Declined, stating that they did not think American Academy of Otolaryngic Allergy otolaryngologists were the target (AAOA) Otolaryngology market for the survey

Declined, stating they do not send out surveys unless they are requested by a American Rhinologic Society (ARS) member; unable to identify a member to request survey distribution

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

Declined, “our physicians are inundated with surveys and I’m afraid Urology American Urology Association (AUA) you won’t be able to get the information you need”

CURRENT AND HISTORIC USE Summary of background information • Methylcobalamin is not available as an FDA-approved product. • Methylcobalamin is not available as an OTC product in the US. • There is a current United States Pharmacopeia (USP) dietary supplement monograph for methylcobalamin. • Methylcobalamin is available in Abu Dhabi, Australia, and Hong Kong (see Table 4).

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 Ingredient Concentration Dosage Form ROA Country Status Approval Dateb

Mecobalamin 0.5mg/mL Injection Hong Kong Prescription 2/18/1992

10mg Powder for injection - Mecobalamine Abu Dhabi Active - 0.5mg/mL Solution for injection

Methylcobalamin 5mg/mL Injection, solution Intramuscular Australia Not scheduled 10/08/1991 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 ROA similar to those requested in the nominations. See Methodology for full explanation. bIf multiple approval dates and/or multiple strengths, then earliest date provided.

Summary of literature review • Total number of studies included: 114 studies (26 descriptive, 85 experimental, and 3 observational). • Most of the studies were from Japan (38). • The most common indications for the use of methylcobalamin in both the US and non-US studies were diabetic peripheral neuropathy and hyperhomocysteinemia. • No compounded products were identified from any studies.

Table 5. Types of studies

Types of Studies Number of Studies

Descriptive1–26 26

Experimental27–111 85

Observational112–114 3

Table 6. Number of studies by country

Country Number of Studies

Argentina 82 1

China 19,21,92,93,95–101,108,30,110–112,31,33,44,53–56 23

India 4,14,76,78,79,83,85–87,105,114,22,32,40,47,50,68,74,75 19

Indonesia43 1

Italy12 1

Japan3,5,23–28,35,36,39,45,6,46,49,51,52,58,59,62–65,7,69,73,80,81,90,102,103,107,8,15–18,20 38

Jordan109 1

Korea 48 1

Malaysia34,41,61 3

New Zealand67 1

Pakistan42 1

Saudi Arabia104 1

Singapore72 1

Spain9 1

Switzerland13 1

Taiwan2,77 2

Thailand88,89 2

The Netherlands70 1

Turkey1,57 2

UK10,60 2

US11,29,113,37,38,66,71,84,91,94,106 11

Total US: 11 Total Non-US Countries: 103

Table 7. Number of studies by combinations

Combination Formula Number of Studies

Nominated Methylcobalamin 1-5mg/ml / Chorionic gonadotrophin - Injection 0

Methylcobalamin 750mcg / Alpha lipoic acid 100mg / Pregabalin 75mg85 1

Methylcobalamin 500mcg / Benfotiamine 50mg / Pyridoxamine 50mg – Oral tablet78,79,105 3

Methylcobalamin 1000mcg / Folic acid 400mcg / Pyridoxine HCl 5mg - Tablet106 1

Methylcobalamin 1000mcg/2mL / Lidocaine 20mg/3mL96,97 2 Others found in literature Methylcobalamin / L-methylfolate / N-acetyl-cysteine71 1

Methylcobalamin 2mg / L-methylfolate 2.8mg / Pyridoxal-5’-phosphate 25mg37 1

Methylcobalamin 2mg / L-methylfolate calcium 3mg / Pyridoxal-5’-phosphate 35mg – Oral tablet38,84,91,94 4

Methylcobalamin / Pregabalin57,68 2

Table 8. Dosage by indication – US

Indication Dose Concentration Dosage Form ROA Duration of Treatment

Diabetic peripheral neuropathy37,38,66,84,91,94 2-4mg/day 2mg Tablet Oral 3 months-15 months

Hyperhomocysteinemia29,71,106,113 0.5-1mg/day – Tablet Oral 6 weeks-2 years

5,10-methenyltetrahydrofolate synthetase deficiency 11 10mg/day – – Intramuscular – Abbreviations: “–“, not mentioned; ROA, route of administration.

Table 9. Dosage by indication – non-US countries

Indication Dose Concentration Dosage Form ROA Duration of Treatment

0.5-1500mg/day 0.5-500mg Capsule, tablet Oral 14 days-1 year

0.5mg/dose – – Intramuscular 10 doses Peripheral neuropathy2,19,50,52,55,57,62– 64,68,72,73,27,81,83,85,98,99,102,104,107,112,28,30,31,33,35,43,44 1.5mg/week-25mg/day – – Intravenous 10 doses-6 months

2.5-5mg/month 2.5mg/10mL Solution Intrathecal 1 year

0.5-1.5mg/day – Capsule/Lozenge Oral 1-20 months Hyperhomocysteinemia9,13,76,77,82,92,95,108,111,22,34,39,4 7,49,51,53,60 1mg/month-1mg/day – – Intramuscular, intravenous 1 week-10 years

0.5-1.5mg/day – Tablet Oral 1-6 months Vitamin B12 0.5mg/3 months-0.5mg/day – – Intramuscular 9 days-6 months deficiency3,5,67,70,74,86,109,12,14,23,24,26,42,47,48 1.5mg/week – – Intravenous 5 weeks

0.5-6mg/day – Tablet Oral 1-14 months Sleep-wake disorders6–8,15–18,65,80,101 1.5mg/week – – Intravenous 1 month

0.5-3mg/day – Capsule, tablet Oral 3-27 months Cognitive impairment10,36,54,77,87 1.5mg/week – – Intravenous 2 months

1mg/day 1mg/2mL – Intramuscular, subcutaneous 2-4 weeks Herpetic neuralgia 96,97,100 1.5mg/day – – Oral 4 weeks

Amyotrophic lateral sclerosis45,46,59 0.5-25mg/day – – Intramuscular, intravenous 2-170 weeks

Osteoarthritis79,105 1.5mg/day – Tablet Oral 24 weeks

Rheumatoid arthritis78 1mg/day – Capsule Oral –

1mg/week – – Intravenous – Tinnitus20,56 1.5mg/day – Tablet Oral 30 days

Vitiligo32,114 1.5mg/day – Tablet Oral –

Parathesia4,88 1.5mg/day – – Oral –

Carpal tunnel syndrome69 1.5mg/day – Tablet Oral 2 years

Degenerative lumbar spinal stenosis89 1.5mg/day – – Oral 6 months

60mg/day – – Oral 6 months Multiple sclerosis25 5mg/day – – Intravenous 14 days

Glossopharyngeal neuralgia 75 0.5mg/day – – Oral –

Low back pain61 1.5mg/week – – Intramuscular 2 weeks

Migraine without aura58 0.1-0.2mL – – - –

Epilepsy110 0.5mg/day – Tablet Oral 12 months

Bell’s palsy41 1.5mg/week – – Intramuscular 2 months

0.5mg/day – – - 15 days Oculomotor nerve palsy93 1.5mg/day – Tablet Oral 4 months

0.5mg/day – – Intravenous 3 days Optic neuritis90 – – – Oral 7 days

Diabetic retinopathy40 1.5mg/day – – Oral 10 months

Glaucoma103 1.5mg/day – – Oral 4 years

Vertebrobasilar dolichectasia21 1.5mg/day – – Oral 6 months Abbreviations: “–“, not mentioned; ROA, route of administration.

Table 10. Compounded products – US No compounded products from reported studies

Table 11. Compounded products – non-US countries No compounded products from reported studies

Summary of focus groups/interviews of medical experts and specialty organizations One (1) interview was conducted.

Table 12. Overview of interviewee

Level of Current Experience with Interviewee Specialty Interview Summary Response Training Practice Setting Methylcobalamin

• If a patient has an optic neuritis from B12 deficiency, the Academic ophthalmologist would diagnose, but not administer vitamin OPH_05 MD Ophthalmology No medical institute B12. Would refer patient to the primary physician. • Stated it is an old practice, and nobody is doing it. Abbreviation: MD, Doctor of Medicine.

Summary of survey results Table 13. Characteristics of survey respondents [30 people responded to the surveya]

Board Certification DO MD ND No Response

Anesthesiology 0 1 0 0

Family Medicine 0 1 0 0

Integrative Medicine 0 1 0 0

Naturopathic Doctor 0 0 5 0

Naturopathic Physician 0 0 4 0

Neurology 0 1 0 0

Obstetrics and Gynecology 0 1 0 0

Ophthalmology 0 4 0 0

Pain Medicine 0 3 0 0

Rheumatology 1 0 0 0

No Board Certification 0 1 1 0

No Response 0 0 0 12 Abbreviations: DO, Doctor of Osteopathic Medicine; MD, Doctor of Medicine; ND, Naturopathic Doctor. aSome respondents reported more than one (1) terminal clinical degree or board certification.

Table 14. Types of products used, prescribed, or recommended

Types of Products Respondents, n (N=10a)

Compounded 5

FDA-approved 0

Over-the-counter 1

Dietary 7

Unsure 0

No Response 1 aOut of 27 respondents, ten (10) reported using, prescribing, or recommending multiple types of methylcobalamin product.

Table 15. Compounded use of methylcobalamin in practicea,b

Indication Strength Dosing Frequency Dosage Form ROA Duration of Treatment Patient Population

1-5mg Weekly to monthly Months to years Pediatric autism Autism 3 times/week 6-12 months Young children 1-1.5mg Subcutaneous Once/week 3-6 months Adults Fatigue “60 female, history 1mg/mL 1mL weekly 6 weeks malabsorption” Injectable Fatigue with low B12 Intramuscular, 1-2.5mg/mL weekly As needed – levels, macrocytic anemia subcutaneous

“Diabetes, Lyme 1.5-2mg 3 times/week 6-12 months or longer disease, MS” Neuropathy Subcutaneous Usually 1mg Weekly to monthly Months to years Anyone Vitamin B12 deficiency

“many!!” – – – – – – Abbreviations: “–“, not mentioned; ROA, route of administration. aFive (5) respondents. bQuotations are direct words from respondents.

Table 16. Indications for which methylcobalamin is considered a standard therapya

Standard Therapy Indication Compounded, n (N=5) Non-compounded, n (N=4) No Response, n (N=1)

Anemia 2 0 0

Autism 1 0 0

Back pain, muscle cramps 1 0 0

Diabetes 0 3 0

Depression 0 1 0

Fatigue 2 0 0

MTHFR defects 0 1 0

“Neurological” 0 1 0

Neuropathy 2 1 0

Vitamin B12 deficiency 1 1 0

Weight loss 1 0 0

Otherb 1 0 0

No Response 0 0 1 Abbreviation: “–“, not mentioned. aSome respondents reported more than one indication. b“many!!”

Table 17. Reasons for using compounded product instead of the FDA-approved products

Theme Reasons

• “No FDA approved non oral methylcobalamin” Availability • “Only commercial product is cyanocobalamin which contains cyanide”

• “Better” Better • “Works better than cyanocobalamin”

• “Bioavailability” • “It is already methylated. Cyanocobalamin is less bioavailable and for those with Bioavailability MTHFR SNP’s, they cannot methylate as well so methylcobalamin is more bioavailable and the methyl groups support many other methyl requiring enzymes”

Table 18. Change in frequency of compounded methylcobalamin usage over the past 5 years

Respondents, n (N=5)

No–use has remained consistent 3

Yes–I use it LESS often now 0

Yes–I use it MORE often nowa 2 aOne (1) respondent wrote “needed!!”.

Table 19. Do you stock non-patient specific compounded methylcobalamin in your practice?

Respondents, n (N=5)

No 4

Yesa 1 aRespondent reports stocking non-patient-specific compounded methylcobalamin in physician office, and purchases from a compounding pharmacy for reasons of convenience.

Table 20. Questions related to stocking non-patient specific compounded methylcobalamin No additional survey respondents provided this information

CONCLUSION Methylcobalamin (UNII code: BR1SN1JS2W) was nominated for inclusion on the 503B Bulks List for vitamin B12 deficiency in patients with methylation issues, gastrointestinal disorders, lack of intrinsic factor, fibromyalgia, chronic fatigue syndrome, neuropathic pain, multiple sclerosis, parkinsonism, pernicious anemia, testicular atrophy, and weight loss. The nominated ROA and dosage forms are intramuscular or subcutaneous injection. Methylcobalamin is approved in Abu Dhabi, Australia, and Hong Kong. From the literature review conducted, the most common indications for the use of methylcobalamin in both the US and non-US were diabetic peripheral neuropathy and hyperhomocysteinemia. No compounded products were identified from any studies. One (1) interviewee stated that using methylcobalamin for vitamin B12 deficiency is an old practice and nobody is doing it. The interviewee would not use it in office because they only give the diagnosis and then would refer the patient to the primary physician for treatment. From the survey responses, ten (10) out of 27 respondents used methylcobalamin. The most common indication respondents reported use of compounded methylcobalamin was fatigue. Bioavailability and quality were the reasons for using the compounded methylcobalamin product over an FDA-approved product. One (1) out of five (5) respondent who used compounded product reported stocking compounded methylcobalamin in their practice.

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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 methylcobalamin. 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: Methylcobalamin Q1. What type(s) of product(s) do you use, prescribe, or recommend for methylcobalamin? 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: Q13 If What type(s) of product(s) do you use, prescribe, or recommend for methylcobalamin? Please check all th... != Compounded drug product Skip To: Q2 If What type(s) of product(s) do you use, prescribe, or recommend for methylcobalamin? Please check all th... = Compounded drug product

Display This Question: If What type(s) of product(s) do you use, prescribe, or recommend for methylcobalamin? Please check all th... = Compounded drug product

Q2. Please list any conditions or diseases for which you use compounded methylcobalamin 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, allergies, etc).

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 methylcobalamin as a single agent active ingredient, or as one active ingredient in a combination product? Please check all that apply. ▢ Single ▢ Combination Skip To: Q5 If Do you use compounded methylcobalamin as a single agent active ingredient, or as one active ingredient... != Combination Display This Question: If Loop current: Do you use compounded methylcobalamin as a single agent active ingredient, or as one active ingredient... = Combination Q4. In which combination(s) do you use compounded methylcobalamin? Please check all that apply. ▢ Methylcobalamin 1-5mg/ml / Chorionic gonadotrophin ▢ Other (please describe) ______Q5. For which, if any, diseases or conditions do you consider compounded methylcobalamin standard therapy? ______Q6. Does your specialty describe the use of compounded methylcobalamin in medical practice guidelines or other resources? ______Q7. Over the past 5 years, has the frequency in which you have used compounded methylcobalamin 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

Q8. Why do you use compounded methylcobalamin instead of any FDA-approved drug product? ______Q9. Do you stock non-patient-specific compounded methylcobalamin in your practice location? o Yes o No Skip To: End of Block If Do you stock non-patient-specific compounded methylcobalamin in your practice location? = No Display This Question: If Do you stock non-patient-specific compounded methylcobalamin in your practice location? = Yes Q10. In what practice location(s) do you stock non-patient-specific compounded methylcobalamin? 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 methylcobalamin? 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 methylcobalamin? 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 methylcobalamin? Please check all that apply. = Convenience Skip To: End of Block If Why do you keep a stock of non-patient-specific compounded methylcobalamin? Please check all that apply. = Emergencies Skip To: End of Block If Why do you keep a stock of non-patient-specific compounded methylcobalamin? Please check all that apply. = Other (please describe) Q13. For which, if any, diseases or conditions do you consider methylcobalamin standard therapy? ______Q14. Does your specialty describe the use of methylcobalamin in medical practice guidelines or other resources? ______End of Block: Methylcobalamin

Start of Block: Background Information

Q15. What is your terminal clinical degree? Please check all that apply. ▢ Doctor of Medicine (MD) ▢ Doctor of Osteopathic Medicine (DO) ▢ Doctor of Medicine in Dentistry (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 ▢ Allergy and Immunology ▢ Anesthesiology ▢ Cardiovascular Disease ▢ Critical Care Medicine ▢ Dermatology ▢ Emergency Medicine ▢ Endocrinology, Diabetes and Metabolism ▢ Family Medicine ▢ Gastroenterology ▢ Hematology ▢ Infectious Disease ▢ Internal Medicine ▢ Medical Toxicology ▢ Naturopathic Doctor ▢ Naturopathic Physician ▢ Nephrology ▢ Neurology ▢ Obstetrics and Gynecology ▢ Oncology ▢ Ophthalmology ▢ Otolaryngology ▢ Pain Medicine ▢ Pediatrics ▢ Psychiatry ▢ Rheumatology ▢ Sleep Medicine ▢ Surgery (please describe) ______▢ Urology ▢ Other (please describe) ______End of Block: Background Information